Prof Rury R Holman FMedSci FRCP

Research Area: Health Evaluative Methodologies
Technology Exchange: Drug discovery, Epidemiology and Medical statistics
Keywords: Multinational clinical outcome trials, Translational Research Trials, Treatment of type 2 diabetes, Prevention of Type 2 diabetes, Cardiovascular risk reduction in type 2 diabetes and Mathematical modelling
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The DTU is the largest Academic Research Organisation (ARO) worldwide that specialises in performing diabetes-related mega trials. It designs, runs and analyses large-scale interventional clinical outcome trials nationally and internationally, often in collaboration with other AROs and pharmaceutical companies. The DTU also undertakes major modelling and statistical programmes to utilise fully the data available from its many studies with a particular emphasis on modelling diabetes and cardiovascular disease processes. It maintains DNA, urine and plasma biobanks and facilitates the genomic, proteomic and metabonomic evaluation of these materials. In addition, the DTU evaluates novel treatments and devices for the therapy of diabetes trials and undertakes research into potential new therapeutic agents. It is a fully registered UKCRC Clinical Trials Unit and is a founder member of the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) which forms part of the 4* rated University of Oxford Nuffield Department of Medicine.

Name Department Institution Country
Robert M Califf Duke Clinical Research Institute Duke University United States
Prof Changyu Pan Endocrinology PLA General Hospital, Beijing China
Prof Dayi Hu Heart Center Peking University’s People’s Hospital China
Prof Hertzel C Gerstein Medicine McMaster University Canada
Prof Mark McCarthy OCDEM University of Oxford United Kingdom
Prof Anna L Gloyn OCDEM University of Oxford United Kingdom
Dr Jonathan C Levy FRCP OCDEM University of Oxford United Kingdom
Prof Lionel Tarrasenko CBE Institute of Biomedical Engineering University of Oxford United Kingdom
Prof Fredrik Karpe OCDEM University of Oxford United Kingdom
Prof John Geddes Department of Psychiatry University of Oxford United Kingdom
Prof Paul Harrison (MPLS) University of Oxford United Kingdom
Prof Guy Goodwin Department of Psychiatry University of Oxford United Kingdom
Melanie Davies University of Leicester United Kingdom
Salim Yusuf McMaster University Canada
Philip Clarke School of Public Health, Sydney Australia
Preiss D, Rankin N, Welsh P, Holman RR, Kangas AJ, Soininen P, Würtz P, Ala-Korpela M, Sattar N. 2016. Effect of metformin therapy on circulating amino acids in a randomized trial: the CAMERA study: Metabolism. Diabet Med, pp. n/a-n/a. | Show Abstract | Read more

AIMS: To investigate whether metformin therapy alters amino acid concentrations, increased levels of which have been found to predict Type 2 diabetes. METHODS: In the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) study (NCT00723307), 173 individuals without Type 2 diabetes, but with coronary disease, were randomized to metformin (n=86) or placebo (n=87) for 18 months. Plasma samples, taken every 6 months, were analysed using quantitative nuclear magnetic resonance spectroscopy. Ten metabolites consisting of eight amino acids [three branched-chain (isoleucine, leucine, valine), three aromatic (tyrosine, phenylalanine, histidine) and two other amino acids (alanine, glutamine)], lactate and pyruvate were quantified and analysed using repeated-measures models. On-treatment analyses were conducted to investigate whether amino acid changes were dependent on changes in weight, fat mass or insulin resistance measured using homeostasis model assessment. RESULTS: Tyrosine decreased [-6.1 μmol/l (95% CI -8.5, -3.7); P<0.0001], while alanine [42 umol/l (95% CI 25, 59); P<0.0001] increased in the metformin-treated group compared with the placebo-treated group. Decreases in phenylalanine [-2.0 μmol/l (95% CI -3.6, -0.3); P=0.018] and increases in histidine [2.3 μmol/l (95% CI 0.1, 4.6); P=0.045] were also observed in the metformin group, although these changes were less statistically robust. No changes in these four amino acids were accounted for by changes in weight, fat mass or homeostasis model assessment of insulin resistance values. Levels of branched-chain amino acids, glutamine, pyruvate and lactate were not altered by metformin therapy. CONCLUSIONS: Metformin therapy results in a sustained and specific pattern of changes in aromatic amino acid and alanine concentrations. These changes are independent of any effects on weight and insulin sensitivity. Any causal link to metformin's unexplained cardiometabolic benefit requires further study. This article is protected by copyright. All rights reserved.

Farmer AJ, Rodgers LR, Lonergan M, Shields B, Weedon MN, Donnelly L, Holman RR, Pearson ER, Hattersley AT, MASTERMIND Consortium. 2016. Adherence to Oral Glucose-Lowering Therapies and Associations With 1-Year HbA1c: A Retrospective Cohort Analysis in a Large Primary Care Database. Diabetes Care, 39 (2), pp. 258-263. | Show Abstract | Read more

OBJECTIVE: The impact of taking oral glucose-lowering medicines intermittently, rather than as recommended, is unclear. We conducted a retrospective cohort study using community-acquired U.K. clinical data (Clinical Practice Research Database [CPRD] and GoDARTS database) to examine the prevalence of nonadherence to treatment for type 2 diabetes and investigate its potential impact on HbA1c reduction stratified by type of glucose-lowering medication. RESEARCH DESIGN AND METHODS: Data were extracted for patients treated between 2004 and 2014 who were newly prescribed metformin, sulfonylurea, thiazolidinedione, or dipeptidyl peptidase 4 inhibitors and who continued to obtain prescriptions over 1 year. Cohorts were defined by prescribed medication type, and good adherence was defined as a medication possession ratio ≥0.8. Linear regression was used to determine potential associations between adherence and 1-year baseline-adjusted HbA1c reduction. RESULTS: In CPRD and GoDARTS, 13% and 15% of patients, respectively, were nonadherent. Proportions of nonadherent patients varied by the oral glucose-lowering treatment prescribed (range 8.6% [thiazolidinedione] to 18.8% [metformin]). Nonadherent, compared with adherent, patients had a smaller HbA1c reduction (0.4% [4.4 mmol/mol] and 0.46% [5.0 mmol/mol] for CPRD and GoDARTs, respectively). Difference in HbA1c response for adherent compared with nonadherent patients varied by drug (range 0.38% [4.1 mmol/mol] to 0.75% [8.2 mmol/mol] lower in adherent group). Decreasing levels of adherence were consistently associated with a smaller reduction in HbA1c. CONCLUSIONS: Reduced medication adherence for commonly used glucose-lowering therapies among patients persisting with treatment is associated with smaller HbA1c reductions compared with those taking treatment as recommended. Differences observed in HbA1c responses to glucose-lowering treatments may be explained in part by their intermittent use.

Holman RR, Peterson ED. 2015. Sitagliptin and Cardiovascular Outcomes in Type 2 Diabetes REPLY NEW ENGLAND JOURNAL OF MEDICINE, 373 (25), pp. 2479-2479.

Holman RR, Peterson ED. 2015. Sitagliptin and Cardiovascular Outcomes in Type 2 Diabetes New England Journal of Medicine, 373 (25), pp. 2478-2479. | Read more

Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD et al. 2015. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 373 (3), pp. 232-242. | Show Abstract | Read more

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).

Bethel MA, Harrison P, Sourij H, Sun Y, Tucker L, Kennedy I, White S, Hill L, Oulhaj A, Coleman RL, Holman RR. 2016. Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily aspirin in people with Type 2 diabetes. Diabet Med, 33 (2), pp. 224-230. | Show Abstract | Read more

AIMS: Reduced aspirin efficacy has been demonstrated in people with Type 2 diabetes. Because increased platelet reactivity and/or turnover are postulated mechanisms, we examined whether higher and/or more frequent aspirin dosing might reduce platelet reactivity more effectively. METHODS: Participants with Type 2 diabetes (n = 24) but without known cardiovascular disease were randomized in a three-way crossover design to 2-week treatment periods with aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily. The primary outcome was platelet reactivity, assessed using the VerifyNow(™) ASA method. Relationships between platelet reactivity and aspirin dosing were examined using generalized linear mixed models with random subject effects. RESULTS: Platelet reactivity decreased from baseline with all doses of aspirin. Modelled platelet reactivity was more effectively reduced with aspirin 100 mg twice daily vs. 100 mg once daily, but not vs. 200 mg once daily. Aspirin 200 mg once daily did not differ from 100 mg once daily. Aspirin 100 mg twice daily was also more effective than once daily as measured by collagen/epinephrine-stimulated platelet aggregation and urinary thromboxane levels, with a similar trend measured by serum thromboxane levels. No episodes of bleeding occurred. CONCLUSIONS: In Type 2 diabetes, aspirin 100 mg twice daily reduced platelet reactivity more effectively than 100 mg once daily, and numerically more than 200 mg once daily. Clinical outcome trials evaluating primary cardiovascular disease prevention with aspirin in Type 2 diabetes may need to consider using a more frequent dosing schedule.

Levy JC, Riefflin A, Holman RR. 2015. Within-class differences of the sulfonylureas should be accounted for. Reply to Schrijnders D, Kleefstra N and Landman GWD [letter] Diabetologia, 58 (6), pp. 1376-1377. | Read more

Cholesterol Treatment Trialists' (CTT) Collaboration, Fulcher J, O'Connell R, Voysey M, Emberson J, Blackwell L, Mihaylova B, Simes J et al. 2015. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet, 385 (9976), pp. 1397-1405. | Show Abstract | Read more

BACKGROUND: Whether statin therapy is as effective in women as in men is debated, especially for primary prevention. We undertook a meta-analysis of statin trials in the Cholesterol Treatment Trialists' (CTT) Collaboration database to compare the effects of statin therapy between women and men. METHODS: We performed meta-analyses on data from 22 trials of statin therapy versus control (n=134,537) and five trials of more-intensive versus less-intensive statin therapy (n=39,612). Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1.0 mmol/L reduction in LDL cholesterol and effects in men and women compared with a Cox model that adjusted for non-sex differences. For subgroup analyses, we used 99% CIs to make allowance for the multiplicity of comparisons. FINDINGS: 46,675 (27%) of 174,149 randomly assigned participants were women. Allocation to a statin had similar absolute effects on 1 year lipid concentrations in both men and women (LDL cholesterol reduced by about 1.1 mmol/L in statin vs control trials and roughly 0.5 mmol/L for more-intensive vs less-intensive therapy). Women were generally at lower cardiovascular risk than were men in these trials. The proportional reductions per 1.0 mmol/L reduction in LDL cholesterol in major vascular events were similar overall for women (rate ratio [RR] 0.84, 99% CI 0.78-0.91) and men (RR 0.78, 99% CI 0.75-0.81, adjusted p value for heterogeneity by sex=0.33) and also for those women and men at less than 10% predicted 5 year absolute cardiovascular risk (adjusted heterogeneity p=0.11). Likewise, the proportional reductions in major coronary events, coronary revascularisation, and stroke did not differ significantly by sex. No adverse effect on rates of cancer incidence or non-cardiovascular mortality was noted for either sex. These net benefits translated into all-cause mortality reductions with statin therapy for both women (RR 0.91, 99% CI 0.84-0.99) and men (RR 0.90, 99% CI 0.86-0.95; adjusted heterogeneity p=0.43). INTERPRETATION: In men and women at an equivalent risk of cardiovascular disease, statin therapy is of similar effectiveness for the prevention of major vascular events. FUNDING: UK Medical Research Council, British Heart Foundation, Australian National Health and Medical Research Council, European Community Biomed Program.

Bethel MA, Green JB, Milton J, Tajar A, Engel SS, Califf RM, Holman RR, Armstrong PW et al. 2015. Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) Diabetes, Obesity and Metabolism, 17 (4), pp. 395-402. | Show Abstract | Read more

© 2015 John Wiley & Sons Ltd.Aims: To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. Methods: TECOS enrolled patients aged ≥50years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. Results: Patients had a mean [1 standard deviation (SD)] age of 66 (8)years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3)years, and a mean (SD) body mass index 30.2 (5.7)kg/m2. Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. Conclusion: The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.

Taylor R, Holman RR. 2015. Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin Sci (Lond), 128 (7), pp. 405-410. | Show Abstract | Read more

Type 2 diabetes (T2DM) is frequently regarded as a disease of obesity and its occurrence in individuals of normal body mass index (BMI) is often regarded as indicating a non-obesity-related subtype. However, the evidence for such a distinct, common subtype is lacking. The United Kingdom Prospective Diabetes Study (UKPDS) cohort of people diagnosed with T2DM in the 1970s and 1980s had a median BMI of only 28 kg/m2. UKPDS data form the basis of current understanding of the condition even though one in three of those studied had a BMI of less than 25 kg/m2. BMI, though, is a population measure and not a rigid personal guide. Weight loss is considered de rigueur for treating obese diabetic individuals, but it is not usually considered for those deemed to have a normal BMI. Given the new evidence that early T2DM can be reversed to normal glucose tolerance by substantial weight loss, it is important to explain why non-overweight people respond to this intervention as well as obese individuals. We hypothesize that each individual has a personal fat threshold (PFT) which, if exceeded, makes likely the development of T2DM. Subsequent weight loss to take the individual below their level of susceptibility should allow return to normal glucose control. Crucially, the hypothesized PFT is independent of BMI. It allows both understanding of development of T2DM in the non-obese and remission of diabetes after substantial weight loss in people who remain obese by definition. To illustrate this concept, we present the distribution curve of BMI at diagnosis for the UKPDS cohort, together with a diagram explaining individual behaviour within the population. The concept of PFT is of practical benefit in explaining the onset of diabetes and its logical management to the non-obese majority of people with T2DM.

Levy JC, Riefflin A, Holman RR. 2015. Within-class differences of the sulfonylureas should be accounted for. Reply to Schrijnders D, Kleefstra N and Landman GWD [letter]. Diabetologia, 58 (6), pp. 1376-1377. | Read more

Shields BM, Lonergan M, Jones A, Rodgers L, Weedon M, Donnelly LA, Holman RR, Pearson ER, Hattersley AT. 2015. Patient characteristics influence treatment response to second line glucose lowering therapy in two large UK cohorts: a MASTERMIND study DIABETIC MEDICINE, 32 pp. 2-2.

Lonergan M, Agbaje OF, Shields BM, Weeden M, Rodgers L, Donnelly LA, Hattersley AT, Holman RR, Pearson ER, Consortium MASTERMIND. 2015. Metformin, in contrast to thiazolidinediones, works best in slim, insulin sensitive patients: a MASTERMIND study DIABETIC MEDICINE, 32 pp. 1-1.

Farmer AJ, Shields BM, Lonergan M, Weedon M, Rodgers L, Donnelly LA, Holman RR, Pearson ER, Hattersley AT, Consortium MASTERMIND. 2015. Taking less oral glucose lowering treatment than prescribed is associated with a reduced improvement in 12 month HbA1c: a retrospective MASTERMIND cohort analysis stratified by type of treatment DIABETIC MEDICINE, 32 pp. 187-187.

Bethel MA, Green JB, Milton J, Tajar A, Engel SS, Califf RM, Holman RR, TECOS Executive Committee. 2015. Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabetes Obes Metab, 17 (4), pp. 395-402. | Show Abstract | Read more

AIMS: To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. METHODS: TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. RESULTS: Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. CONCLUSION: The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.

Yates T, Davies MJ, Haffner SM, Schulte PJ, Thomas L, Huffman KM, Bales CW, Preiss D et al. 2015. Physical activity as a determinant of fasting and 2-h post-challenge glucose: A prospective cohort analysis of the NAVIGATOR trial Diabetic Medicine, 32 (8), pp. 1090-1096. | Show Abstract | Read more

© 2015 Diabetes UK.Aim: To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial. Methods: Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t-2) and 1 year (t-1) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis. Results: The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R2 = 0.3473 vs. 0.3468). There was no association with fasting glucose. Conclusions: In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control. What's new?: This is the first study to investigate the prospective relationship of daily step count, as measured by a pedometer, with fasting and 2-h post-challenge glucose in an international clinical trial. Recent history of physical activity was weakly related to 2-h glucose in those with a high risk of Type 2 diabetes after taking into account the trajectory of 2-h glucose established in the preceding 3 years. A 100% increase in daily step count was associated with a 0.9% reduction in 2-h post-challenge glucose. There was no association for fasting glucose.

Preiss D, Thomas LE, Wojdyla DM, Haffner SM, Gill JM, Yates T, Davies MJ, Holman RR et al. 2015. Prospective relationships between body weight and physical activity: an observational analysis from the NAVIGATOR study. BMJ Open, 5 (8), pp. e007901. | Show Abstract | Read more

OBJECTIVES: While bidirectional relationships exist between body weight and physical activity, direction of causality remains uncertain and previous studies have been limited by self-reported activity or weight and small sample size. We investigated the prospective relationships between weight and physical activity. DESIGN: Observational analysis of data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study, a double-blinded randomised clinical trial of nateglinide and valsartan, respectively. SETTING: Multinational study of 9306 participants. PARTICIPANTS: Participants with biochemically confirmed impaired glucose tolerance had annual measurements of both weight and step count using research grade pedometers, worn for 7 days consecutively. Along with randomisation to valsartan or placebo plus nateglinide or placebo, participants took part in a lifestyle modification programme. OUTCOME MEASURES: Longitudinal regression using weight as response value and physical activity as predictor value was conducted, adjusted for baseline covariates. Analysis was then repeated with physical activity as response value and weight as predictor value. Only participants with a response value preceded by at least three annual response values were included. RESULTS: Adequate data were available for 2811 (30%) of NAVIGATOR participants. Previous weight (χ(2)=16.8; p<0.0001), but not change in weight (χ(2)=0.1; p=0.71) was inversely associated with subsequent step count, indicating lower subsequent levels of physical activity in heavier individuals. Change in step count (χ(2)=5.9; p=0.02) but not previous step count (χ(2)=0.9; p=0.34) was inversely associated with subsequent weight. However, in the context of trajectories already established for weight (χ(2) for previous weight measurements 747.3; p<0.0001) and physical activity (χ(2) for previous step count 432.6; p<0.0001), these effects were of limited clinical importance. CONCLUSIONS: While a prospective bidirectional relationship was observed between weight and physical activity, the magnitude of any effect was very small in the context of natural trajectories already established for these variables. TRIAL REGISTRATION NUMBER: NCT00097786.

Yates T, Davies MJ, Haffner SM, Schulte PJ, Thomas L, Huffman KM, Bales CW, Preiss D et al. 2015. Physical activity as a determinant of fasting and 2-h post-challenge glucose: a prospective cohort analysis of the NAVIGATOR trial. Diabet Med, 32 (8), pp. 1090-1096. | Show Abstract | Read more

AIM: To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial. METHODS: Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t-2 ) and 1 year (t-1 ) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis. RESULTS: The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R(2)  = 0.3473 vs. 0.3468). There was no association with fasting glucose. CONCLUSIONS: In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control.

Alva ML, Gray A, Mihaylova B, Leal J, Holman RR. 2015. The impact of diabetes-related complications on healthcare costs: New results from the UKPDS (UKPDS 84) Diabetic Medicine, 32 (4), pp. 459-466. | Show Abstract | Read more

© 2014 Diabetes UK.Aims: To estimate the immediate and long-term inpatient and non-inpatient costs for Type 2 diabetes-related complications. Methods: The costs of all consultations, visits, admissions and procedures associated with diabetes-related complications during UK Prospective Diabetes Study post-trial monitoring in the period 1997-2007 were estimated using hospitalization records for 2791 patients in England and resource use questionnaires that were administered to 3589 patients across the UK. Results: The estimated (95% CI) inpatient care costs (in 2012 pounds sterling) in the event year for the example of a 60-year-old man were: non-fatal ischaemic heart disease £9767 (£7038-£12 696); amputation £9546 (£6416-£13 463); non-fatal stroke £6805 (£3856-£10 278); non-fatal myocardial infarction £6379 (£4290-£8339); fatal stroke £3954 (£2012-£6428); fatal ischaemic heart disease £3766 (£746-£5512); heart failure £3191 (£1678-4903); fatal myocardial infarction £1521 (£647-£2670); and blindness in one eye £1355 (£415-£2655). In subsequent years, estimated (95% CI) costs ranged from £1792 (£1060-£2943) for amputations to £453 (£315-£691) for blindness in one eye. Costs of non-inpatient healthcare in the event year were: amputation £2699 (£1409-£4126); blindness in one eye £1790 (£878-£3056); non-fatal stroke £1019 (£770-£1499); nonfatal myocardial infarction £1963 (£794-£1157); heart failure £979 (£708-£1344); non-fatal ischaemic heart disease £864 (£718-£1014); and cataract extraction £700 (£619-£780). In each subsequent year, non-inpatient costs ranged from £1611 (£1193-£2116) for amputations to £654 (£572-£799) for ischaemic heart disease. Conclusions: Diabetic complications are associated with substantial immediate and long-term healthcare costs. Our comprehensive new estimates of these costs, derived from detailed recent UK Prospective Diabetes Study post-trial data, should aid researchers and health policy analyses.

Riefflin A, Ayyagari U, Manley SE, Holman RR, Levy JC. 2015. The effect of glibenclamide on insulin secretion at normal glucose concentrations Diabetologia, 58 (1), pp. 43-49. | Show Abstract | Read more

© 2014, Springer-Verlag Berlin Heidelberg.Aims/hypothesis: The aim of this study was to investigate the incremental and proportional effect of a sulfonylurea on insulin secretion rates at low, elevated and high blood glucose, using parallel groups with ascending or descending glucose steps to minimise potential biases of a single stepped clamp order.Methods: Following 14 days on placebo or glibenclamide (2.5 mg) tablets twice daily, separated by 14 days washout, 19 type 2 diabetic patients had ascending or descending three-step hyperinsulinaemic glucose clamps at 4, 8 and 12 mmol/l. C-peptide secretion was estimated by two-compartment C-peptide deconvolution.Results: Patients in the ascending glucose steps group (n = 10) had mean (SD) age of 60.3 (6.5) years, BMI of 29.8 (4.9) kg/m2 and fasting glucose on diet alone of 10.6 (2.9) mmol/l; while those in the descending glucose steps group (n = 9) had mean age of 58.2 (8.0) years, BMI of 30.5 (5.4) kg/m2 and fasting glucose on diet alone of 9.8 (2.2) mmol/l. The geometric means (95% CI) of C-peptide secretion rates on placebo for glucose at 4.0, 8.0 and 12.0 mmol/l were 63 (46, 86), 143 (105, 195) and 205 (149, 281) pmol/min, respectively. On glibenclamide, this increased by 140 (99, 181), 126 (85, 167) and 158 (117, 199) pmol/min, respectively (p < 0.001 vs placebo). The absolute increment was significant (p < 0.001) and independent of clamp glucose concentration (p = 0.54). The proportional increase was greater at 4 mmol/l: 2.8-fold (2.4, 3.2), compared with 1.8-fold (1.5, 2.0) and 1.7-fold (1.4, 1.9) at 8 and 12 mmol/l, respectively (p < 0.001).Conclusions/interpretation: At low-normal glucose, glibenclamide exerted a disproportionate effect on insulin secretion. This study highlights the risks of hypoglycaemia when aiming for tight glucose control on this agent.

Gray A, Holman R, Clarke P, Leal J. 2014. Performance of the UKPDS Outcomes Model for Prediction of Myocardial Infarction and Stroke in the ADDITION-Europe Trial Cohort: Does the ADDITION Validation Add Up? VALUE IN HEALTH, 17 (8), pp. 895-896. | Read more

Preiss D, Haffner SM, Thomas LE, Sun JL, Sattar N, Yates T, J Davies M, Mcmurray JJ, Holman RR, Califf RM, Kraus WE. 2014. Change in levels of physical activity after diagnosis of type 2 diabetes: An observational analysis from the NAVIGATOR study Diabetes, Obesity and Metabolism, 16 (12), pp. 1265-1268. | Show Abstract | Read more

© 2014 John Wiley & Sons Ltd.Increased physical activity is known to be beneficial in people with type 2 diabetes mellitus (T2DM), but it is not known whether individuals change their activity levels after T2DM diagnosis. The present Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, conducted in participants with impaired glucose tolerance at high cardiovascular risk, assessed ambulatory activity annually using research-grade pedometers. Oral glucose tolerance tests were performed annually and repeated to confirm T2DM diagnosis. This observational analysis used general linear models to compare step counts before and after T2DM diagnosis in the 2816 participants with the requisite data. Participants were relatively inactive at baseline, taking a median (interquartile range) of 5488 (3258-8361) steps/day, which decreased after T2DM diagnosis by a mean (s.e.) of 258 (64) steps/day (p < 0.0001); however, after adjusting for background trend for activity, step count after T2DM diagnosis was unchanged [mean (s.e.) of 103 (87) fewer steps/day; p = 0.23]. Awareness of T2DM diagnosis had no impact on the trajectory of activity established before the diagnosis.

Gray A, Holman R, Clarke P, Leal J. 2014. Performance of the UKPDS outcomes model for prediction of myocardial infarction and stroke in the ADDITION-Europe trial cohort: does the ADDITION validation add up? Value Health, 17 (8), pp. 895-896. | Read more

Alva ML, Gray A, Mihaylova B, Leal J, Holman RR. 2015. The impact of diabetes-related complications on healthcare costs: new results from the UKPDS (UKPDS 84). Diabet Med, 32 (4), pp. 459-466. | Show Abstract | Read more

AIMS: To estimate the immediate and long-term inpatient and non-inpatient costs for Type 2 diabetes-related complications. METHODS: The costs of all consultations, visits, admissions and procedures associated with diabetes-related complications during UK Prospective Diabetes Study post-trial monitoring in the period 1997-2007 were estimated using hospitalization records for 2791 patients in England and resource use questionnaires that were administered to 3589 patients across the UK. RESULTS: The estimated (95% CI) inpatient care costs (in 2012 pounds sterling) in the event year for the example of a 60-year-old man were: non-fatal ischaemic heart disease £9767 (£7038-£12 696); amputation £9546 (£6416-£13 463); non-fatal stroke £6805 (£3856-£10 278); non-fatal myocardial infarction £6379 (£4290-£8339); fatal stroke £3954 (£2012-£6428); fatal ischaemic heart disease £3766 (£746-£5512); heart failure £3191 (£1678-4903); fatal myocardial infarction £1521 (£647-£2670); and blindness in one eye £1355 (£415-£2655). In subsequent years, estimated (95% CI) costs ranged from £1792 (£1060-£2943) for amputations to £453 (£315-£691) for blindness in one eye. Costs of non-inpatient healthcare in the event year were: amputation £2699 (£1409-£4126); blindness in one eye £1790 (£878-£3056); non-fatal stroke £1019 (£770-£1499); nonfatal myocardial infarction £1963 (£794-£1157); heart failure £979 (£708-£1344); non-fatal ischaemic heart disease £864 (£718-£1014); and cataract extraction £700 (£619-£780). In each subsequent year, non-inpatient costs ranged from £1611 (£1193-£2116) for amputations to £654 (£572-£799) for ischaemic heart disease. CONCLUSIONS: Diabetic complications are associated with substantial immediate and long-term healthcare costs. Our comprehensive new estimates of these costs, derived from detailed recent UK Prospective Diabetes Study post-trial data, should aid researchers and health policy analyses.

Riefflin A, Ayyagari U, Manley SE, Holman RR, Levy JC. 2015. The effect of glibenclamide on insulin secretion at normal glucose concentrations. Diabetologia, 58 (1), pp. 43-49. | Show Abstract | Read more

AIMS/HYPOTHESIS: The aim of this study was to investigate the incremental and proportional effect of a sulfonylurea on insulin secretion rates at low, elevated and high blood glucose, using parallel groups with ascending or descending glucose steps to minimise potential biases of a single stepped clamp order. METHODS: Following 14 days on placebo or glibenclamide (2.5 mg) tablets twice daily, separated by 14 days washout, 19 type 2 diabetic patients had ascending or descending three-step hyperinsulinaemic glucose clamps at 4, 8 and 12 mmol/l. C-peptide secretion was estimated by two-compartment C-peptide deconvolution. RESULTS: Patients in the ascending glucose steps group (n = 10) had mean (SD) age of 60.3 (6.5) years, BMI of 29.8 (4.9) kg/m(2) and fasting glucose on diet alone of 10.6 (2.9) mmol/l; while those in the descending glucose steps group (n = 9) had mean age of 58.2 (8.0) years, BMI of 30.5 (5.4) kg/m(2) and fasting glucose on diet alone of 9.8 (2.2) mmol/l. The geometric means (95% CI) of C-peptide secretion rates on placebo for glucose at 4.0, 8.0 and 12.0 mmol/l were 63 (46, 86), 143 (105, 195) and 205 (149, 281) pmol/min, respectively. On glibenclamide, this increased by 140 (99, 181), 126 (85, 167) and 158 (117, 199) pmol/min, respectively (p < 0.001 vs placebo). The absolute increment was significant (p < 0.001) and independent of clamp glucose concentration (p = 0.54). The proportional increase was greater at 4 mmol/l: 2.8-fold (2.4, 3.2), compared with 1.8-fold (1.5, 2.0) and 1.7-fold (1.4, 1.9) at 8 and 12 mmol/l, respectively (p < 0.001). CONCLUSIONS/INTERPRETATION: At low-normal glucose, glibenclamide exerted a disproportionate effect on insulin secretion. This study highlights the risks of hypoglycaemia when aiming for tight glucose control on this agent.

Holman RR, Sourij H, Califf RM. 2014. Untitled reply LANCET, 384 (9948), pp. 1097-1098. | Read more

Holman RR, Sourij H, Califf RM. 2014. Cardiovascular outcome trials of glucose-lowering strategies in type 2 diabetes--Authors' reply. Lancet, 384 (9948), pp. 1097-1098. | Read more

Gray AM, Leal J, Rivero-Arias O, Reed SD, Li Y, Schulman KA, Califf RM, Holman RR. 2014. Can delaying the onset of type 2 diabetes be cost-effective? DIABETOLOGIA, 57 pp. S120-S121.

de Barros e Silva PG, Califf RM, Sun JL, McMurray JJ, Holman R, Haffner S, Thomas L, Lopes RD. 2014. Chronic obstructive pulmonary disease and cardiovascular risk: insights from the NAVIGATOR trial. Int J Cardiol, 176 (3), pp. 1126-1128. | Read more

Holman RR. 2014. Cardiovascular endocrinology: First-time heart failure increases risk of diabetes mellitus. Nat Rev Endocrinol, 10 (8), pp. 453-454. | Read more

Holman RR, Bethel MA, Chan JC, Chiasson JL, Doran Z, Ge J, Gerstein H, Huo Y et al. 2014. Rationale for and design of the Acarbose Cardiovascular Evaluation (ACE) trial. Am Heart J, 168 (1), pp. 23-9.e2. | Show Abstract | Read more

Patients with cardiovascular disease and impaired glucose tolerance are at increased risk of cardiovascular events and type 2 diabetes mellitus (T2DM). Lifestyle modification or pharmacological intervention can delay progression to T2DM, but there is no clear evidence that they reduce cardiovascular risk in this population. Acarbose, an α-glucosidase inhibitor that lowers postprandial blood glucose, has been shown to reduce T2DM risk by 25%, and possibly cardiovascular risk in impaired glucose tolerance subjects without cardiovascular disease.

Holman RR, Sourij H, Califf RM. 2014. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet, 383 (9933), pp. 2008-2017. | Show Abstract | Read more

Few trials of glucose-lowering drugs or strategies in people with type 2 diabetes have investigated cardiovascular outcomes, even though most patients die from cardiovascular causes despite the beneficial effects of lipid-reducing and blood pressure-lowering treatments. The evidence-based reduction in risk of microvascular disease with glucose lowering has resulted in guidelines worldwide recommending optimisation of glycosylated haemoglobin, but no trial results have shown unequivocal cardiovascular risk reduction with glucose lowering. However, results of the post-trial follow-up of the UK Prospective Diabetes Study, and of a meta-analysis of the four glucose-lowering outcome trials completed to date, suggest about a 15% cardiovascular relative risk reduction per 1% decrement in HbA1c. The 2008 US Food and Drug Administration industry guidance for licensing of antidiabetic drugs greatly increased the number of cardiovascular outcome trials in diabetes, but most trials opted for non-inferiority designs aiming primarily to show absence of cardiovascular toxicity in the shortest possible time. This unintended consequence of the new regulations has meant that the potential long-term benefits, and the possible risks of new therapies, are not being assessed effectively. Also, essential head-to-head trials of therapies for this complex progressive disease, to answer issues such as how best to achieve and maintain optimum glycaemia without promoting weight gain or hypoglycaemia, are not being undertaken. In this Series paper, we summarise randomised controlled cardiovascular outcome trials in type 2 diabetes, provide an overview of ongoing trials and their limitations, and speculate on how future trials could be made more efficient and effective.

Huffman KM, Sun JL, Thomas L, Bales CW, Califf RM, Yates T, Davies MJ, Holman RR et al. 2014. Impact of baseline physical activity and diet behavior on metabolic syndrome in a pharmaceutical trial: Results from NAVIGATOR Metabolism: Clinical and Experimental, 63 (4), pp. 554-561. | Show Abstract | Read more

Objective The cardiometabolic risk cluster metabolic syndrome (MS) includes ≥ 3 of elevated fasting glucose, hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-c), and increased waist circumference. Each can be affected by physical activity and diet. Our objective was to determine whether determine whether baseline physical activity and/or diet behavior impact MS in the course of a large pharmaceutical trial. Materials/Methods This was an observational study from NAVIGATOR, a double-blind, randomized (nateglinide, valsartan, both, or placebo), controlled trial between 2002 and 2004. We studied data from persons (n = 9306) with impaired glucose tolerance and cardiovascular disease (CVD) or CVD risk factors; 7118 with pedometer data were included in this analysis. Physical activity was assessed with 7-day pedometer records; diet behavior was self-reported on a 6-item survey. An MS score (MSSc) was calculated using the sum of each MS component, centered around the Adult Treatment Panel III threshold, and standardized according to sample standard deviation. Excepting HDL-c, assessed at baseline and year 3, MS components were assessed yearly. Follow-up averaged 6 years. Results For every 2000-step increase in average daily steps, there was an associated reduction in average MSSc of 0.29 (95% CI -0.33 to -0.25). For each diet behavior endorsed, there was an associated reduction in average MSSc of 0.05 (95% CI -0.08 to -0.01). Accounting for the effects of pedometer steps and diet behavior together had minimal impact on parameter estimates with no significant interaction. Relations were independent of age, sex, race, region, smoking, family history of diabetes, and use of nateglinide, valsartan, aspirin, antihypertensive, and lipid-lowering agent. Conclusions Baseline physical activity and diet behavior were associated independently with reductions in MSSc such that increased attention to these lifestyle elements provides cardiometabolic benefits. Thus, given the potential to impact outcomes, assessment of physical activity and diet should be performed in pharmacologic trials targeting cardiometabolic risk.

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Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, Welsh P, Fisher M, Packard CJ, Sattar N. 2014. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): A randomised controlled trial The Lancet Diabetes and Endocrinology, 2 (2), pp. 116-124. | Show Abstract | Read more

Background: Metformin reduces cardiovascular risk in patients with type 2 diabetes seemingly independent of lowering blood glucose concentration. We assessed the cardiovascular effects of metformin in individuals without type 2 diabetes. Methods: We did a single-centre, double-blind, placebo-controlled trial at the Glasgow Clinical Research Facility (Glasgow, UK). We enrolled patients taking statins who did not have type 2 diabetes but who did have coronary heart disease and large waist circumferences. Participants were randomly assigned (1:1) by computer to either metformin (850 mg twice daily) or matching placebo in block sizes of four. Patients, investigators, trial staff, and statisticians were masked to treatment allocation. The primary endpoint was progression of mean distal carotid intima-media thickness (cIMT) over 18 months in the modified intention-to-treat population. Secondary endpoints were changes in carotid plaque score (in six regions), measures of glycaemia (HbA1c, fasting glucose, and insulin concentrations, and Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]), and concentrations of lipids, high sensitivity C-reactive protein, and tissue plasminogen activator. The trial was registered at ClinicalTrials.gov, number NCT00723307. Findings: We screened 356 patients, of whom we enrolled 173 (86 in the metformin group, 87 in the placebo group). Average age was 63 years. At baseline, mean cIMT was 0·717 mm (SD 0·129) and mean carotid plaque score was 2·43 (SD 1·55). cIMT progression did not differ significantly between groups (slope difference 0·007 mm per year, 95% CI -0·006 to 0·020; p=0·29). Change of carotid plaque score did not differ significantly between groups (0·01 per year, 95% CI -0·23 to 0·26; p=0·92). Patients taking metformin had lower HbA1c, insulin, HOMA-IR, and tissue plasminogen activator compared with those taking placebo, but there were no significant differences for total cholesterol, HDL-cholesterol, non-HDL-cholesterol, triglycerides, high sensitivity C-reactive protein, or fasting glucose. 138 adverse events occurred in 64 patients in the metformin group versus 120 in 60 patients in the placebo group. Diarrhoea and nausea or vomiting were more common in the metformin group than in the placebo group (28 vs 5). Interpretation: Metformin had no effect on cIMT and little or no effect on several surrogate markers of cardiovascular disease in non-diabetic patients with high cardiovascular risk, taking statins. Further evidence is needed before metformin can be recommended for cardiovascular benefit in this population. Funding: Chief Scientist Office (Scotland). © 2014 Preiss et al.

Davis TME, Coleman RL, Holman RR. 2014. Ethnicity and long-term vascular outcomes in Type 2 diabetes: A prospective observational study (UKPDS 83) Diabetic Medicine, 31 (2), pp. 200-207. | Show Abstract | Read more

Aims: Evidence of ethnic differences in vascular complications of diabetes has been inconsistent. The aim of this study was to examine the relationship between ethnicity and long-term outcome in a large sample of individuals with newly diagnosed Type 2 diabetes. Methods: In a prospective observational study of 4273 UK Prospective Diabetes Study participants followed for a median of 18 years, 3543 (83%) were White Caucasian, 312 (7%) Afro-Caribbean and 418 (10%) Asian Indian. Relative risks for predefined outcomes were assessed comparing Afro-Caribbean and Asian Indian with White Caucasian using accelerated failure time models, with adjustment for cardiovascular risk factors and other potentially confounding variables. Results: During follow-up, 2468 (58%) participants had any diabetes-related end point, 1037 (24%) a myocardial infarction and 401 (9%) a stroke, and 1782 (42%) died. Asian Indian were at greater risk (relative risk, 95% confidence interval) for any diabetes-related end point (1.18, 1.07-1.29), but at lower risk of all-cause mortality (0.89, 0.80-0.97) and peripheral vascular disease (0.43, 0.23-0.82), vs. White Caucasian. Afro-Caribbean participants were at lower risk for all-cause mortality (0.84, 0.76-0.93), diabetes-related death (0.75, 0.64-0.88), myocardial infarction (0.55, 0.43-0.71) and peripheral vascular disease (0.55, 0.33-0.93) vs. White Caucasian. No ethnicity-related associations were found for stroke or microangiopathy. Conclusions: Asian Indian ethnicity is associated with the greatest burden of disease, but not with an increased risk of major vascular complications or death. Afro-Caribbean ethnicity is associated with reduced risk of all-cause and diabetes-related death, myocardial infarction and peripheral vascular disease, suggesting an ethnicity-specific protective mechanism. © 2013 Diabetes UK.

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McMurray JJV, Gerstein HC, Holman RR, Pfeffer MA. 2014. Heart failure: A cardiovascular outcome in diabetes that can no longer be ignored The Lancet Diabetes and Endocrinology, 2 (10), pp. 843-851. | Show Abstract | Read more

© 2014 Elsevier Ltd.In patients with type 1 or type 2 diabetes, glycaemic exposure assessed as HbA1c correlates strongly with risk of future microvascular and macrovascular complications. Improved glucose control substantially reduces the risk of microvascular complications and, with extended follow-up, modestly reduces the risk of atherosclerotic events. The lowering of HbA1c concentrations by newly developed glucose-lowering drugs (alone or when added to other glucose-lowering drugs) has been used, until recently, as a surrogate measure of their potential to lower cardiovascular risk. This assumption is no longer acceptable, and now demonstration of cardiovascular safety has been mandated by regulatory authorities. A major concern, however, is the universal absence in any large-scale trials of new glucose-lowering drugs of hospital admission for heart failure as a prespecified component of the primary composite cardiovascular outcomes. This omission is important because hospital admission for heart failure is a common and prognostically important cardiovascular complication of diabetes. Moreover, it is the one cardiovascular outcome for which the risk has been shown unequivocally to be increased by some glucose-lowering therapies. As such, we believe that heart failure should be systematically evaluated in cardiovascular outcome trials of all new glucose-lowering drugs.

Henry RR, Holman RR, Giugliano RP, Raal FJ, Sullivan D, Honarpour N, Nelson P, Elliott M et al. 2014. Effects of Long-term, Monthly Administration of the Pcsk9 Inhibitor Evolocumab (Amg 145) in Patients with Dysglycemia or Metabolic Syndrome JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 21 pp. S8-S8.

Holman RR. 2014. Cardiovascular endocrinology: First-time heart failure increases risk of diabetes mellitus Nature Reviews Endocrinology, 10 (8), pp. 453-454. | Read more

Preiss D, Haffner SM, Thomas LE, Sun JL, Sattar N, Yates T, J Davies M, McMurray JJ, Holman RR, Califf RM, Kraus WE. 2014. Change in levels of physical activity after diagnosis of type 2 diabetes: an observational analysis from the NAVIGATOR study. Diabetes Obes Metab, 16 (12), pp. 1265-1268. | Show Abstract | Read more

Increased physical activity is known to be beneficial in people with type 2 diabetes mellitus (T2DM), but it is not known whether individuals change their activity levels after T2DM diagnosis. The present Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, conducted in participants with impaired glucose tolerance at high cardiovascular risk, assessed ambulatory activity annually using research-grade pedometers. Oral glucose tolerance tests were performed annually and repeated to confirm T2DM diagnosis. This observational analysis used general linear models to compare step counts before and after T2DM diagnosis in the 2816 participants with the requisite data. Participants were relatively inactive at baseline, taking a median (interquartile range) of 5488 (3258-8361) steps/day, which decreased after T2DM diagnosis by a mean (s.e.) of 258 (64) steps/day (p < 0.0001); however, after adjusting for background trend for activity, step count after T2DM diagnosis was unchanged [mean (s.e.) of 103 (87) fewer steps/day; p = 0.23]. Awareness of T2DM diagnosis had no impact on the trajectory of activity established before the diagnosis.

Cited:

31

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Yates T, Haffner SM, Schulte PJ, Thomas L, Huffman KM, Bales CW, Califf RM, Holman RR et al. 2014. Association between change in daily ambulatory activity and cardiovascular events in people with impaired glucose tolerance (NAVIGATOR trial): A cohort analysis The Lancet, 383 (9922), pp. 1059-1066. | Show Abstract | Read more

Background The extent to which change in physical activity can modify the risk of cardiovascular disease in individuals at high cardiovascular risk is uncertain. We investigated whether baseline and change in objectively-assessed ambulatory activity is associated with the risk of a cardiovascular event in individuals at high cardiovascular risk with impaired glucose tolerance. Methods We assessed prospective data from the NAVIGATOR trial involving 9306 individuals with impaired glucose tolerance who were recruited in 40 countries between January, 2002, and January, 2004. Participants also either had existing cardiovascular disease (if age ≥50 years) or at least one additional cardiovascular risk factor (if age =55 years). Participants were followed-up for cardiovascular events (defi ned as cardiovascular mortality, non-fatal stroke, or myocardial infarction) for 6 years on average and had ambulatory activity assessed by pedometer at baseline and 12 months. Adjusted Cox proportional hazard models quantifi ed the association of baseline and change in ambulatory activity (from baseline to 12 months) with the risk of a subsequent cardiovascular event, after adjustment for each other and potential confounding variables. This study is registered with ClinicalTrials.gov NCT00097786. Findings During 45 211 person-years follow-up, 531 cardiovascular events occurred. Baseline ambulatory activity (hazard ratio [HR] per 2000 steps per day 0.90, 95% CI 0.84-0.96) and change in ambulatory activity (0.92, 0.86-0.99) were inversely associated with the risk of a cardiovascular event. Results for change in ambulatory activity were unaff ected when also adjusted for changes in body-mass index and other potential confounding variables at 12 months. Interpretation In individuals at high cardiovascular risk with impaired glucose tolerance, both baseline levels of daily ambulatory activity and change in ambulatory activity display a graded inverse association with the subsequent risk of a cardiovascular event. Funding Novartis Pharmaceuticals.

McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. 2014. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol, 2 (10), pp. 843-851. | Show Abstract | Read more

In patients with type 1 or type 2 diabetes, glycaemic exposure assessed as HbA1c correlates strongly with risk of future microvascular and macrovascular complications. Improved glucose control substantially reduces the risk of microvascular complications and, with extended follow-up, modestly reduces the risk of atherosclerotic events. The lowering of HbA1c concentrations by newly developed glucose-lowering drugs (alone or when added to other glucose-lowering drugs) has been used, until recently, as a surrogate measure of their potential to lower cardiovascular risk. This assumption is no longer acceptable, and now demonstration of cardiovascular safety has been mandated by regulatory authorities. A major concern, however, is the universal absence in any large-scale trials of new glucose-lowering drugs of hospital admission for heart failure as a prespecified component of the primary composite cardiovascular outcomes. This omission is important because hospital admission for heart failure is a common and prognostically important cardiovascular complication of diabetes. Moreover, it is the one cardiovascular outcome for which the risk has been shown unequivocally to be increased by some glucose-lowering therapies. As such, we believe that heart failure should be systematically evaluated in cardiovascular outcome trials of all new glucose-lowering drugs.

Huffman KM, Sun JL, Thomas L, Bales CW, Califf RM, Yates T, Davies MJ, Holman RR et al. 2014. Impact of baseline physical activity and diet behavior on metabolic syndrome in a pharmaceutical trial: results from NAVIGATOR. Metabolism, 63 (4), pp. 554-561. | Show Abstract | Read more

OBJECTIVE: The cardiometabolic risk cluster metabolic syndrome (MS) includes ≥3 of elevated fasting glucose, hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-c), and increased waist circumference. Each can be affected by physical activity and diet. Our objective was to determine whether determine whether baseline physical activity and/or diet behavior impact MS in the course of a large pharmaceutical trial. MATERIALS/METHODS: This was an observational study from NAVIGATOR, a double-blind, randomized (nateglinide, valsartan, both, or placebo), controlled trial between 2002 and 2004. We studied data from persons (n=9306) with impaired glucose tolerance and cardiovascular disease (CVD) or CVD risk factors; 7118 with pedometer data were included in this analysis. Physical activity was assessed with 7-day pedometer records; diet behavior was self-reported on a 6-item survey. An MS score (MSSc) was calculated using the sum of each MS component, centered around the Adult Treatment Panel III threshold, and standardized according to sample standard deviation. Excepting HDL-c, assessed at baseline and year 3, MS components were assessed yearly. Follow-up averaged 6 years. RESULTS: For every 2000-step increase in average daily steps, there was an associated reduction in average MSSc of 0.29 (95% CI (-)0.33 to (-)0.25). For each diet behavior endorsed, there was an associated reduction in average MSSc of 0.05 (95% CI (-)0.08 to (-)0.01). Accounting for the effects of pedometer steps and diet behavior together had minimal impact on parameter estimates with no significant interaction. Relations were independent of age, sex, race, region, smoking, family history of diabetes, and use of nateglinide, valsartan, aspirin, antihypertensive, and lipid-lowering agent. CONCLUSIONS: Baseline physical activity and diet behavior were associated independently with reductions in MSSc such that increased attention to these lifestyle elements provides cardiometabolic benefits. Thus, given the potential to impact outcomes, assessment of physical activity and diet should be performed in pharmacologic trials targeting cardiometabolic risk.

Yates T, Haffner SM, Schulte PJ, Thomas L, Huffman KM, Bales CW, Califf RM, Holman RR et al. 2014. Association between change in daily ambulatory activity and cardiovascular events in people with impaired glucose tolerance (NAVIGATOR trial): a cohort analysis. Lancet, 383 (9922), pp. 1059-1066. | Show Abstract | Read more

BACKGROUND: The extent to which change in physical activity can modify the risk of cardiovascular disease in individuals at high cardiovascular risk is uncertain. We investigated whether baseline and change in objectively-assessed ambulatory activity is associated with the risk of a cardiovascular event in individuals at high cardiovascular risk with impaired glucose tolerance. METHODS: We assessed prospective data from the NAVIGATOR trial involving 9306 individuals with impaired glucose tolerance who were recruited in 40 countries between January, 2002, and January, 2004. Participants also either had existing cardiovascular disease (if age ≥50 years) or at least one additional cardiovascular risk factor (if age ≥55 years). Participants were followed-up for cardiovascular events (defined as cardiovascular mortality, non-fatal stroke, or myocardial infarction) for 6 years on average and had ambulatory activity assessed by pedometer at baseline and 12 months. Adjusted Cox proportional hazard models quantified the association of baseline and change in ambulatory activity (from baseline to 12 months) with the risk of a subsequent cardiovascular event, after adjustment for each other and potential confounding variables. This study is registered with ClinicalTrials.govNCT00097786. FINDINGS: During 45,211 person-years follow-up, 531 cardiovascular events occurred. Baseline ambulatory activity (hazard ratio [HR] per 2000 steps per day 0·90, 95% CI 0·84-0·96) and change in ambulatory activity (0·92, 0·86-0·99) were inversely associated with the risk of a cardiovascular event. Results for change in ambulatory activity were unaffected when also adjusted for changes in body-mass index and other potential confounding variables at 12 months. INTERPRETATION: In individuals at high cardiovascular risk with impaired glucose tolerance, both baseline levels of daily ambulatory activity and change in ambulatory activity display a graded inverse association with the subsequent risk of a cardiovascular event. FUNDING: Novartis Pharmaceuticals.

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Green JB, Bethel MA, Paul SK, Ring A, Kaufman KD, Shapiro DR, Califf RM, Holman RR. 2013. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease American Heart Journal, 166 (6), | Show Abstract | Read more

Sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, lowers blood glucose when administered as monotherapy or in combination with other antihyperglycemic agents. TECOS will evaluate the effects of adding sitagliptin to usual diabetes care on cardiovascular outcomes and clinical safety. TECOS is a pragmatic, academically run, multinational, randomized, double-blind, placebo-controlled, event-driven trial recruiting approximately 14,000 patients in 38 countries who have type 2 diabetes (T2DM), are at least 50 years old, have cardiovascular disease, and have an hemoglobin A1c value between 6.5% and 8.0%. Eligible participants will be receiving stable mono- or dual therapy with metformin, sulfonylurea, or pioglitazone, or insulin alone or in combination with metformin. Randomization is 1:1 to double-blind sitagliptin or matching placebo, in addition to existing therapy in a usual care setting. Follow-up occurs at 4-month intervals in year 1 and then twice yearly until 1300 confirmed primary end points have occurred. Glycemic equipoise between randomized groups is a desired aim. The primary composite cardiovascular endpoint is time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina, with cardiovascular events adjudicated by an independent committee blinded to study therapy. TECOS is a pragmatic-design cardiovascular outcome trial assessing the cardiovascular effects of sitagliptin when added to usual T2DM management. © 2013 Mosby, Inc.

Latini R, Staszewsky L, Sun JL, Bethel MA, Disertori M, Haffner SM, Holman RR, Chang F et al. 2013. Incidence of atrial fibrillation in a population with impaired glucose tolerance: the contribution of glucose metabolism and other risk factors. A post hoc analysis of the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial. Am Heart J, 166 (5), pp. 935-40.e1. | Show Abstract | Read more

BACKGROUND: The role of dysglycemia as an additional risk factor for atrial fibrillation (AF) is controversial. Therefore, it was of interest to assess risk factors for incident AF in a large, representative population of patients with cardiovascular risk factors and impaired glucose tolerance but not overt diabetes in NAVIGATOR. METHODS: Predictors of incident AF were analyzed in 8,943 patients without AF at baseline by Cox proportional hazards regression. Study treatments (valsartan vs no valsartan and nateglinide vs no nateglinide) and the time-dependent covariate for progression to type 2 diabetes mellitus were added separately to the model. RESULTS: The median age of the 8,943 patients included in the present analysis of the NAVIGATOR trial was 63 years. Half of those patients were men, 6,922 (77.4%) had a history of hypertension, and 255 (2.9%) had heart failure. The median glycated hemoglobin was 6%. During the study, 613 of the 8,943 patients without AF at baseline presented with at least 1 episode of AF (6.9% 5-year incidence). Besides established predictors of incident AF, a 1 mmol/L increment of baseline fasting glucose, but not progression to diabetes, was found to be associated with a 33% increased risk of incident AF. Neither valsartan nor nateglinide affected AF incidence. CONCLUSIONS: In a trial population with impaired glucose tolerance, fasting plasma glucose and well-known risk factors (age, hypertension, and elevated body weight), but not progression to diabetes, predict risk of AF.

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Hayes AJ, Leal J, Gray AM, Holman RR, Clarke PM. 2013. UKPDS Outcomes Model 2: A new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year united kingdom prospective diabetes Study: UKPDS 82 Diabetologia, 56 (9), pp. 1925-1933. | Show Abstract | Read more

Aims/hypothesis: The aim of this project was to build a new version of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM1), a patient-level simulation tool for predicting lifetime health outcomes of people with type 2 diabetes mellitus. Methods: Data from 5,102 UKPDS patients from the 20 year trial and the 4,031 survivors entering the 10 year post-trial monitoring period were used to derive parametric proportional hazards models predicting absolute risk of diabetes complications and death. We re-estimated the seven original event equations and estimated new equations for diabetic ulcer and some second events. The additional data permitted inclusion of new risk factor predictors such as estimated GFR. We also developed four new equations for all-cause mortality. Internal validation of model predictions of cumulative incidence of all events and death was carried out and a contemporary patient-level dataset was used to compare 10 year predictions from the original and the new models. Results: Model equations were based on a median 17.6 years of follow-up and up to 89,760 patient-years of data, providing double the number of events, greater precision and a larger number of significant covariates. The new model, UKPDS-OM2, is internally valid over 25 years and predicts event rates for complications, which are lower than those from the existing model. Conclusions/interpretation: The new UKPDS-OM2 has significant advantages over the existing model, as it captures more outcomes, is based on longer follow-up data, and more comprehensively captures the progression of diabetes. Its use will permit detailed and reliable lifetime simulations of key health outcomes in people with type 2 diabetes mellitus. © 2013 Springer-Verlag Berlin Heidelberg.

YiHong S, Bethel MA, Holman RR, Sourij H, Harrison PF, Tucker L, Kennedy I, White S et al. 2013. ASPIRIN GIVEN TWICE DAILY REDUCED THE PLATELET REACTIVITY MORE THAN ONCE DAILY IN PEOPLE WITH TYPE 2 DIABETES WITHOUT CARDIOVASCULAR DISEASE HEART, 99 (Suppl 3), pp. E249-E250. | Read more

Preiss D, Giles TD, Thomas LE, Sun JL, Haffner SM, Holman RR, Standl E, Mazzone T et al. 2013. Predictors of stroke in patients with impaired glucose tolerance: results from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial. Stroke, 44 (9), pp. 2590-2593. | Show Abstract | Read more

BACKGROUND AND PURPOSE: Risk factors for stroke are well-established in general populations but sparsely studied in individuals with impaired glucose tolerance. METHODS: We identified predictors of stroke among participants with impaired glucose tolerance in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Cox proportional-hazard regression models were constructed using baseline variables, including the 2 medications studied, valsartan and nateglinide. RESULTS: Among 9306 participants, 237 experienced a stroke over 6.4 years. Predictors of stroke included classical risk factors such as existing cerebrovascular and coronary heart disease, higher pulse pressure, higher low-density lipoprotein cholesterol, older age, and atrial fibrillation. Other factors, including previous venous thromboembolism, higher waist circumference, lower estimated glomerular filtration rate, lower heart rate, and lower body mass index, provided additional important predictive information, yielding a C-index of 0.72. Glycemic measures were not predictive of stroke. Variables associated with stroke were similar in participants with no prior history of cerebrovascular disease at baseline. CONCLUSIONS: The most powerful predictors of stroke in patients with impaired glucose tolerance included a combination of established risk factors and novel variables, such as previous venous thromboembolism and elevated waist circumference, allowing moderately effective identification of high-risk individuals.

Bethel MA, Chacra AR, Deedwania P, Fulcher GR, Holman RR, Jenssen T, Kahn SE, Levitt NS et al. 2013. A novel risk classification paradigm for patients with impaired glucose tolerance and high cardiovascular risk American Journal of Cardiology, 112 (2), pp. 231-237. | Show Abstract | Read more

We used baseline data from the NAVIGATOR trial to (1) identify risk factors for diabetes progression in those with impaired glucose tolerance and high cardiovascular risk, (2) create models predicting 5-year incident diabetes, and (3) provide risk classification tools to guide clinical interventions. Multivariate Cox proportional hazards models estimated 5-year incident diabetes risk and simplified models examined the relative importance of measures of glycemia in assessing diabetes risk. The C-statistic was used to compare models; reclassification analyses compare the models' ability to identify risk groups defined by potential therapies (routine or intensive lifestyle advice or pharmacologic therapy). Diabetes developed in 3,254 (35%) participants over 5 years median follow-up. The full prediction model included fasting and 2-hour glucose and hemoglobin A1c (HbA1c) values but demonstrated only moderate discrimination for diabetes (C = 0.70). Simplified models with only fasting glucose (C = 0.67) or oral glucose tolerance test values (C = 0.68) had higher C statistics than models with HbA1c alone (C = 0.63). The models were unlikely to inappropriately reclassify participants to risk groups that might receive pharmacologic therapy. Our results confirm that in a population with dysglycemia and high cardiovascular risk, traditional risk factors are appropriate predictors and glucose values are better predictors than HbA1c, but discrimination is moderate at best, illustrating the challenges of predicting diabetes in a high-risk population. In conclusion, our novel risk classification paradigm based on potential treatment could be used to guide clinical practice based on cost and availability of screening tests. © 2013 Elsevier Inc. All rights reserved.

Hayes AJ, Leal J, Gray AM, Holman RR, Clarke PM. 2013. UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82. Diabetologia, 56 (9), pp. 1925-1933. | Show Abstract | Read more

AIMS/HYPOTHESIS: The aim of this project was to build a new version of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM1), a patient-level simulation tool for predicting lifetime health outcomes of people with type 2 diabetes mellitus. METHODS: Data from 5,102 UKPDS patients from the 20 year trial and the 4,031 survivors entering the 10 year post-trial monitoring period were used to derive parametric proportional hazards models predicting absolute risk of diabetes complications and death. We re-estimated the seven original event equations and estimated new equations for diabetic ulcer and some second events. The additional data permitted inclusion of new risk factor predictors such as estimated GFR. We also developed four new equations for all-cause mortality. Internal validation of model predictions of cumulative incidence of all events and death was carried out and a contemporary patient-level dataset was used to compare 10 year predictions from the original and the new models. RESULTS: Model equations were based on a median 17.6 years of follow-up and up to 89,760 patient-years of data, providing double the number of events, greater precision and a larger number of significant covariates. The new model, UKPDS-OM2, is internally valid over 25 years and predicts event rates for complications, which are lower than those from the existing model. CONCLUSIONS/INTERPRETATION: The new UKPDS-OM2 has significant advantages over the existing model, as it captures more outcomes, is based on longer follow-up data, and more comprehensively captures the progression of diabetes. Its use will permit detailed and reliable lifetime simulations of key health outcomes in people with type 2 diabetes mellitus.

Bethel MA, Chacra AR, Deedwania P, Fulcher GR, Holman RR, Jenssen T, Kahn SE, Levitt NS et al. 2013. A novel risk classification paradigm for patients with impaired glucose tolerance and high cardiovascular risk. Am J Cardiol, 112 (2), pp. 231-237. | Show Abstract | Read more

We used baseline data from the NAVIGATOR trial to (1) identify risk factors for diabetes progression in those with impaired glucose tolerance and high cardiovascular risk, (2) create models predicting 5-year incident diabetes, and (3) provide risk classification tools to guide clinical interventions. Multivariate Cox proportional hazards models estimated 5-year incident diabetes risk and simplified models examined the relative importance of measures of glycemia in assessing diabetes risk. The C-statistic was used to compare models; reclassification analyses compare the models' ability to identify risk groups defined by potential therapies (routine or intensive lifestyle advice or pharmacologic therapy). Diabetes developed in 3,254 (35%) participants over 5 years median follow-up. The full prediction model included fasting and 2-hour glucose and hemoglobin A1c (HbA1c) values but demonstrated only moderate discrimination for diabetes (C = 0.70). Simplified models with only fasting glucose (C = 0.67) or oral glucose tolerance test values (C = 0.68) had higher C statistics than models with HbA1c alone (C = 0.63). The models were unlikely to inappropriately reclassify participants to risk groups that might receive pharmacologic therapy. Our results confirm that in a population with dysglycemia and high cardiovascular risk, traditional risk factors are appropriate predictors and glucose values are better predictors than HbA1c, but discrimination is moderate at best, illustrating the challenges of predicting diabetes in a high-risk population. In conclusion, our novel risk classification paradigm based on potential treatment could be used to guide clinical practice based on cost and availability of screening tests.

Huffman K, Sun J-L, Thomas L, Bales C, Califf R, Tuomilehto J, Yates T, Davies M et al. 2013. Association of Baseline Physical Activity by Pedometer Counts and Nutritional Behavior on Metabolic Syndrome in the NAVIGATOR Study CIRCULATION, 127 (12),

Zhou K, Bennett A, Coleman R, Groves R, Holman R, McCarthy M, Palmer C, Pearson E. 2013. Metformin Pharmacogenetics and SLC2A2: Genome-Wide Association Study and 2-stage replication in GoDARTS and UKPDS DIABETIC MEDICINE, 30 pp. 52-52.

Adamson R, Sourij H, Ring A, Price HC, Holman RR. 2013. Adding value to the experience of attending a diabetes clinic appointment: provision of personalised 10 year cardiovascular disease (CVD) risk estimates DIABETIC MEDICINE, 30 pp. 194-194.

Bethel MA, Price HC, Sourij H, White S, Coleman RL, Ring A, Kennedy IE, Tucker L, Holman RR. 2013. Evaluation of a self-administered oral glucose tolerance test. Diabetes Care, 36 (6), pp. 1483-1488. | Show Abstract | Read more

OBJECTIVE: To assess the feasibility of using a disposable, self-administered, capillary blood sampling oral glucose tolerance test (OGTT) device in a community setting. RESEARCH DESIGN AND METHODS: Eighteen healthy and 12 type 2 diabetic volunteers underwent six 75-g OGTTs using a prototype device in the following three settings: unaided at home (twice); unaided but observed in clinic (twice); and performed by a nurse with simultaneous laboratory glucose assays of 0- and 120-min venous plasma samples (twice). The device displayed no results. A detachable data recorder returned to the clinic provided plasma-equivalent 0- and 120-min glucose values and key parameters, including test date, start and end times, and time taken to consume the glucose drink. RESULTS: The device was universally popular with participants and was perceived as easy to use, and the ability to test at home was well liked. Device failures meant that 0- and 120-min glucose values were obtained for only 141 (78%) of the 180 OGTTs performed, independent of setting. Device glucose measurements showed a mean bias compared with laboratory-measured values of +0.9 at 5.0 mmol/L increasing to +4.4 at 15.0 mmol/L. Paired device glucose values were equally reproducible across settings, with repeat testing showing no training effect regardless of setting order. CONCLUSIONS: Self-administered OGTTs can be performed successfully by untrained individuals in a community setting. With improved device reliability and appropriate calibration, this novel technology could be used in routine practice to screen people who might need a formal OGTT to confirm the presence of impaired glucose tolerance or diabetes.

Holman RR. 2013. Type 2 diabetes mellitus in 2012: Optimal management of T2DM remains elusive. Nat Rev Endocrinol, 9 (2), pp. 67-68. | Show Abstract | Read more

Worldwide, >366 million people with type 2 diabetes mellitus remain at excess risk of cardiovascular disease and face a lifetime of treatment escalation for this progressive disorder. Studies in 2012 have re-affirmed the safety of early insulin treatment, metformin use in renal impairment, and shown β-cell function preservation over several years.

Shen L, Shah BR, Reyes EM, Thomas L, Wojdyla D, Diem P, Leiter LA, Charbonnel B et al. 2013. Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. BMJ, 347 (dec09 7), pp. f6745. | Show Abstract | Read more

OBJECTIVE: To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes. DESIGN: Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. SETTING: NAVIGATOR trial. PARTICIPANTS: Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control. MAIN OUTCOME MEASURES: Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment. RESULTS: During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively). CONCLUSIONS: Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant. TRIAL REGISTRATION: ClinicalTrials.gov NCT00097786.

Davis TM, Coleman RL, Holman RR, UKPDS Group. 2014. Ethnicity and long-term vascular outcomes in Type 2 diabetes: a prospective observational study (UKPDS 83). Diabet Med, 31 (2), pp. 200-207. | Show Abstract | Read more

AIMS: Evidence of ethnic differences in vascular complications of diabetes has been inconsistent. The aim of this study was to examine the relationship between ethnicity and long-term outcome in a large sample of individuals with newly diagnosed Type 2 diabetes. METHODS: In a prospective observational study of 4273 UK Prospective Diabetes Study participants followed for a median of 18 years, 3543 (83%) were White Caucasian, 312 (7%) Afro-Caribbean and 418 (10%) Asian Indian. Relative risks for predefined outcomes were assessed comparing Afro-Caribbean and Asian Indian with White Caucasian using accelerated failure time models, with adjustment for cardiovascular risk factors and other potentially confounding variables. RESULTS: During follow-up, 2468 (58%) participants had any diabetes-related end point, 1037 (24%) a myocardial infarction and 401 (9%) a stroke, and 1782 (42%) died. Asian Indian were at greater risk (relative risk, 95% confidence interval) for any diabetes-related end point (1.18, 1.07-1.29), but at lower risk of all-cause mortality (0.89, 0.80-0.97) and peripheral vascular disease (0.43, 0.23-0.82), vs. White Caucasian. Afro-Caribbean participants were at lower risk for all-cause mortality (0.84, 0.76-0.93), diabetes-related death (0.75, 0.64-0.88), myocardial infarction (0.55, 0.43-0.71) and peripheral vascular disease (0.55, 0.33-0.93) vs. White Caucasian. No ethnicity-related associations were found for stroke or microangiopathy. CONCLUSIONS: Asian Indian ethnicity is associated with the greatest burden of disease, but not with an increased risk of major vascular complications or death. Afro-Caribbean ethnicity is associated with reduced risk of all-cause and diabetes-related death, myocardial infarction and peripheral vascular disease, suggesting an ethnicity-specific protective mechanism.

Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, Welsh P, Fisher M, Packard CJ, Sattar N. 2014. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol, 2 (2), pp. 116-124. | Show Abstract | Read more

BACKGROUND: Metformin reduces cardiovascular risk in patients with type 2 diabetes seemingly independent of lowering blood glucose concentration. We assessed the cardiovascular effects of metformin in individuals without type 2 diabetes. METHODS: We did a single-centre, double-blind, placebo-controlled trial at the Glasgow Clinical Research Facility (Glasgow, UK). We enrolled patients taking statins who did not have type 2 diabetes but who did have coronary heart disease and large waist circumferences. Participants were randomly assigned (1:1) by computer to either metformin (850 mg twice daily) or matching placebo in block sizes of four. Patients, investigators, trial staff, and statisticians were masked to treatment allocation. The primary endpoint was progression of mean distal carotid intima-media thickness (cIMT) over 18 months in the modified intention-to-treat population. Secondary endpoints were changes in carotid plaque score (in six regions), measures of glycaemia (HbA1c, fasting glucose, and insulin concentrations, and Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]), and concentrations of lipids, high sensitivity C-reactive protein, and tissue plasminogen activator. The trial was registered at ClinicalTrials.gov, number NCT00723307. FINDINGS: We screened 356 patients, of whom we enrolled 173 (86 in the metformin group, 87 in the placebo group). Average age was 63 years. At baseline, mean cIMT was 0·717 mm (SD 0·129) and mean carotid plaque score was 2·43 (SD 1·55). cIMT progression did not differ significantly between groups (slope difference 0·007 mm per year, 95% CI -0·006 to 0·020; p=0·29). Change of carotid plaque score did not differ significantly between groups (0·01 per year, 95% CI -0·23 to 0·26; p=0·92). Patients taking metformin had lower HbA1c, insulin, HOMA-IR, and tissue plasminogen activator compared with those taking placebo, but there were no significant differences for total cholesterol, HDL-cholesterol, non-HDL-cholesterol, triglycerides, high sensitivity C-reactive protein, or fasting glucose. 138 adverse events occurred in 64 patients in the metformin group versus 120 in 60 patients in the placebo group. Diarrhoea and nausea or vomiting were more common in the metformin group than in the placebo group (28 vs 5). INTERPRETATION: Metformin had no effect on cIMT and little or no effect on several surrogate markers of cardiovascular disease in non-diabetic patients with high cardiovascular risk, taking statins. Further evidence is needed before metformin can be recommended for cardiovascular benefit in this population. FUNDING: Chief Scientist Office (Scotland).

Green JB, Bethel MA, Paul SK, Ring A, Kaufman KD, Shapiro DR, Califf RM, Holman RR. 2013. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J, 166 (6), pp. 983-989.e7. | Show Abstract | Read more

Sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, lowers blood glucose when administered as monotherapy or in combination with other antihyperglycemic agents. TECOS will evaluate the effects of adding sitagliptin to usual diabetes care on cardiovascular outcomes and clinical safety. TECOS is a pragmatic, academically run, multinational, randomized, double-blind, placebo-controlled, event-driven trial recruiting approximately 14,000 patients in 38 countries who have type 2 diabetes (T2DM), are at least 50 years old, have cardiovascular disease, and have an hemoglobin A1c value between 6.5% and 8.0%. Eligible participants will be receiving stable mono- or dual therapy with metformin, sulfonylurea, or pioglitazone, or insulin alone or in combination with metformin. Randomization is 1:1 to double-blind sitagliptin or matching placebo, in addition to existing therapy in a usual care setting. Follow-up occurs at 4-month intervals in year 1 and then twice yearly until 1300 confirmed primary end points have occurred. Glycemic equipoise between randomized groups is a desired aim. The primary composite cardiovascular endpoint is time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina, with cardiovascular events adjudicated by an independent committee blinded to study therapy. TECOS is a pragmatic-design cardiovascular outcome trial assessing the cardiovascular effects of sitagliptin when added to usual T2DM management.

Davis TM, Coleman RL, Holman RR, UKPDS Group. 2013. Prognostic significance of silent myocardial infarction in newly diagnosed type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 79. Circulation, 127 (9), pp. 980-987. | Show Abstract | Read more

BACKGROUND: We aimed to determine the prevalence of silent myocardial infarction (SMI) in people with newly diagnosed type 2 diabetes mellitus and its relationships to future myocardial infarction (MI) and all-cause mortality. METHODS AND RESULTS: We examined data from the 5102 patients in the 30-year UK Prospective Diabetes Study (UKPDS) and used Cox proportional hazards regression to examine outcomes by SMI status. Of 1967 patients with complete baseline data, 326 (16.6%) had ECG evidence of SMI (Minnesota codes 1.1 or 1.2) at enrollment. Those with SMI were more likely to be older, female, sedentary, and nonsmokers compared with those without SMI. Their mean blood pressure was greater despite more intensive antihypertensive treatment; they were more likely to be taking aspirin and lipid-lowering therapy; and they had a greater prevalence of microangiopathy. Fully adjusted hazard ratios for those with versus those without SMI in multivariate models that included UKPDS Risk Engine variables were 1.58 (95% confidence interval, 1.22-2.05) for fatal MI and 1.31 (95% confidence interval, 1.10-1.56) for all-cause mortality. Hazard ratios for first fatal or nonfatal MI and for first nonfatal MI were nonsignificant. The net reclassification index showed no improvement when SMI was added to these models, and the integrated discrimination index showed that SMI marginally improved the prediction of fatal MI and all-cause mortality. CONCLUSIONS: About 1 in 6 UKPDS patients with newly diagnosed type 2 diabetes mellitus had evidence of SMI, which was independently associated with an increased risk of fatal MI and all-cause mortality. However, identification of SMI does not add substantively to current UKPDS Risk Engine predictive variables. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Identifier: ISRCTN number 75451837.

Holman RR. 2013. Type 2 diabetes mellitus in 2012: Optimal management of T2DM remains elusive Nature Reviews Endocrinology, 9 (2), pp. 67-68. | Read more

Leal J, Hayes AJ, Gray AM, Holman RR, Clarke PM. 2013. Temporal validation of the UKPDS outcomes model using 10-year posttrial monitoring data. Diabetes Care, 36 (6), pp. 1541-1546. | Show Abstract | Read more

OBJECTIVE: To evaluate the accuracy of the UK Prospective Diabetes Study Outcomes Model (UKPDS-OM) in predicting clinical outcomes during the UKPDS posttrial monitoring (PTM) period. RESEARCH DESIGN AND METHODS: At trial end in 1997, the 4,031 surviving UKPDS patients, of the 5,102 originally enrolled in the study, returned to their usual care providers, with no attempts made to maintain them in their randomized therapy groups. PTM risk factor data were collected for 5 years and clinical outcome data for 10 years. The UKPDS-OM was used firstly to forecast likely progression of HbA1c, systolic blood pressure, total-to-HDL cholesterol ratio, and smoking status and secondly to estimate the likely first occurrence of seven major diabetes-related complications or death from any cause. Model predictions were compared against observed PTM data for risk factor time paths and survival probabilities for major diabetes complications. RESULTS: UKPDS-OM-forecasted risk factor time paths were similar to those observed for HbA1c (up to 3 years) and total-to-HDL cholesterol ratio but underestimated for systolic blood pressure and smoking status. Predicted 10-year event probabilities were similar to those observed for blindness, ischemic heart disease, myocardial infarction, and renal failure but were higher for heart failure and death from any cause and lower for stroke and amputation. CONCLUSIONS: The UKPDS-OM has good predictive accuracy for two of four risk factor time paths and for 10-year clinical outcome probabilities with the exception of stroke, amputation, heart failure, and death from any cause. An updated version of the model incorporating PTM data is being developed.

Kraus WF, Califf RM, Tuomilehto J, Sun J-L, Thomas L, Yates T, Davies M, Holman R, McMurray JJ, Bethel A, Haffner SM. 2012. Relations between Baseline Physical Activity by Pedometer Counts and Future Cardiovascular Events in the NAVIGATOR Study CIRCULATION, 126 (21),

Shen L, Shah B, Reyes E, Thomas L, Diem P, Leiter L, Charbonnel B, Mareev V et al. 2012. Do Diuretics, Beta-Blockers, and Statins Increase the Risk of Diabetes in Patients with Impaired Glucose Tolerance? Insights from the NAVIGATOR Study CIRCULATION, 126 (21),

Stevens RJ, Ali R, Bankhead CR, Bethel MA, Cairns BJ, Camisasca RP, Crowe FL, Farmer AJ et al. 2012. Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia, 55 (10), pp. 2593-2603. | Show Abstract | Read more

AIMS/HYPOTHESIS: Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs). METHODS: RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I (2)statistics for heterogeneity were calculated by fixed effects meta-analysis. RESULTS: Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials. CONCLUSIONS/INTERPRETATION: Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.

van Leeuwen N, Nijpels G, Becker ML, Deshmukh H, Zhou K, Stricker BH, Uitterlinden AG, Hofman A et al. 2012. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia, 55 (7), pp. 1971-1977. | Show Abstract | Read more

AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.

Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C. 2012. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet, 380 (9841), pp. 581-590. | Show Abstract | Read more

BACKGROUND: Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain. METHODS: This meta-analysis included individual participant data from 22 trials of statin versus control (n=134,537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39,612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol reduction was estimated. FINDINGS: Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77-0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from lowest to highest risk: 0·62 [99% CI 0·47-0·81], 0·69 [99% CI 0·60-0·79], 0·79 [99% CI 0·74-0·85], 0·81 [99% CI 0·77-0·86], and 0·79 [99% CI 0·74-0·84]; trend p=0·04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0·57, 99% CI 0·36-0·89, p=0·0012, and 0·61, 99% CI 0·50-0·74, p<0·0001) and in coronary revascularisations (RR 0·52, 99% CI 0·35-0·75, and 0·63, 99% CI 0·51-0·79; both p<0·0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1·0 mmol/L LDL cholesterol reduction 0·76, 99% CI 0·61-0·95, p=0·0012) was also similar to that seen in higher risk categories (trend p=0·3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1·0 mmol/L LDL cholesterol reduction 0·85, 95% CI 0·77-0·95) and all-cause mortality (RR 0·91, 95% CI 0·85-0·97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1·0 mmol/L LDL cholesterol reduction 1·00, 95% CI 0·96-1·04), cancer mortality (RR 0·99, 95% CI 0·93-1·06), or other non-vascular mortality. INTERPRETATION: In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. FUNDING: British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.

Sourij H, Holman RR. 2012. Women develop diabetes at higher BMIs than men. Diabetologia, 55 (3), pp. 855-856. | Read more

Lawton J, Jenkins N, Darbyshire J, Farmer A, Holman R, Hallowell N. 2012. Understanding the outcomes of multi-centre clinical trials: A qualitative study of health professional experiences and views Social Science and Medicine, 74 (4), pp. 574-581. | Show Abstract | Read more

All trials use protocols to standardize practice within and between trial centres and to enable replication of an experiment across space and time. However, while 'centre effects' have been noted in the literature, the processes and mechanisms by which trial staff convert a protocol into practice, and create 'evidence', is a relatively understudied phenomenon. We undertook a qualitative investigation of a multi-centre, UK-based, insulin trial, where differences were found between participating centres in their attainment of the trial's primary clinical endpoint (HbA 1c), a measure of patients' average blood glucose control. In-depth interviews were conducted with 12 research nurses and nine clinicians recruited from 11 centres in 2009, and explored their views about trial participation and experiences of trial delivery from inception to closeout. Staff accounts highlighted mixed agendas and/or ambivalent views about involvement in pharmaceutically funded trials, and discursive and temporal strategies by which they attempted to separate research from clinical practice and to convert commercially funded work into better patient care. Staff in different centres also reported divergent practices by which they recruited patients into the trial and 'enacted' the protocol to enhance trial outcomes and/or to individualise and improve patient care. By exploring, and comparing, the experiences of staff who worked on the same trial but in different centres, this study highlights the importance of understanding, and exploring, the enactment of protocols in ways which situate individual practices within both local (institutional) and global contexts. © 2012 Elsevier Ltd.

Punthakee Z, Bosch J, Dagenais G, Diaz R, Holman R, Probstfield J, Ramachandran A, Riddle M et al. 2012. Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial. Diabetologia, 55 (1), pp. 36-45. | Show Abstract | Read more

AIMS/OBJECTIVE: Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality. METHODS: A large multicentre 3 × 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥ 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n = 541), rosiglitazone 4-8 mg/day (n = 399) or pioglitazone 30-45 mg/day (n = 392); 1,221 participants were randomised to placebo (n = 614) or vitamin D 1,000 IU/day (n = 607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis. RESULTS: From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups. CONCLUSIONS/INTERPRETATION: Uncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.

Lawton J, Jenkins N, Darbyshire J, Farmer A, Holman R, Hallowell N. 2012. Understanding the outcomes of multi-centre clinical trials: a qualitative study of health professional experiences and views. Soc Sci Med, 74 (4), pp. 574-581. | Show Abstract | Read more

All trials use protocols to standardize practice within and between trial centres and to enable replication of an experiment across space and time. However, while 'centre effects' have been noted in the literature, the processes and mechanisms by which trial staff convert a protocol into practice, and create 'evidence', is a relatively understudied phenomenon. We undertook a qualitative investigation of a multi-centre, UK-based, insulin trial, where differences were found between participating centres in their attainment of the trial's primary clinical endpoint (HbA(1c)), a measure of patients' average blood glucose control. In-depth interviews were conducted with 12 research nurses and nine clinicians recruited from 11 centres in 2009, and explored their views about trial participation and experiences of trial delivery from inception to closeout. Staff accounts highlighted mixed agendas and/or ambivalent views about involvement in pharmaceutically funded trials, and discursive and temporal strategies by which they attempted to separate research from clinical practice and to convert commercially funded work into better patient care. Staff in different centres also reported divergent practices by which they recruited patients into the trial and 'enacted' the protocol to enhance trial outcomes and/or to individualise and improve patient care. By exploring, and comparing, the experiences of staff who worked on the same trial but in different centres, this study highlights the importance of understanding, and exploring, the enactment of protocols in ways which situate individual practices within both local (institutional) and global contexts.

Preiss D, Thomas LE, Sun JL, Haffner SM, Holman RR, Standl E, Leiter LA, Mazzone T et al. 2012. Predictors of cardiovascular events in a contemporary population with impaired glucose tolerance: an observational analysis of the Nateglinide and Valsartan in impaired glucose tolerance outcomes research (NAVIGATOR) trial. BMJ Open, 2 (6), pp. e001925-e001925. | Show Abstract | Read more

OBJECTIVES: Risk factors for cardiovascular events are well established in general populations and those with diabetes but have been sparsely studied in impaired glucose tolerance (IGT). We sought to identify predictors of (1) a composite cardiovascular outcome (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and (2) cardiovascular death, among patients with IGT. DESIGN: We studied participants enrolled in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Predictors of cardiovascular events were identified in observational analyses. SETTING: Clinical trial participants in 40 countries. PARTICIPANTS: 9306 participants with biochemically confirmed IGT at high risk of cardiovascular events participated in NAVIGATOR. PRIMARY AND SECONDARY OUTCOME MEASURES: Cox proportional hazard regression models were constructed using variables (demographic data, medical history, clinical features, biochemical results and ECG findings) recorded at baseline to identify variables associated with and predictive of cardiovascular events. RESULTS: Over 6.4 years, 639 (6.9%) participants experienced a cardiovascular event, and 244 (2.6%) cardiovascular death. While predictors of both outcomes included established risk factors such as existing cardiovascular disease, male gender, older age, current smoking status and higher low-density lipoprotein cholesterol, other variables such as reduced estimated glomerular filtration rate, previous thromboembolic disease, atrial fibrillation, higher urinary albumin/creatinine ratio and chronic obstructive pulmonary disease were also important predictors. Glycaemic measures were not predictive of cardiovascular events. c-Statistics for predicting cardiovascular events and cardiovascular death were 0.74 and 0.82, respectively. This compares with c-statistics for cardiovascular events and cardiovascular death of 0.65 and 0.71, respectively, using the classical Framingham risk factors of age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, treatment for hypertension and smoking status. CONCLUSIONS: The most powerful independent predictors of cardiovascular events in IGT included both established risk factors and other variables excluding measures of glycaemia, allowing effective identification of high-risk individuals.

McMurray JJ, Haffner SM, Califf RM, Holman RR. 2012. Prediabetes and the risk of diabetes. Lancet, 380 (9849), pp. 1225-1226. | Read more

Mcmurray JJV, Califf RM, Bethel AM, Haffner SM, Holman RR. 2012. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers for Hypertension on Clinical End Points: A Cohort Study Journal of Clinical Hypertension, 14 (10), pp. 731-731. | Read more

Price HC, Gorst C, Ayyagari U, Levy J, Holman RR. 2012. Addition of exenatide to insulin therapy in individuals with type 2 diabetes in UK routine clinical practice Practical Diabetes, 29 (2), pp. 61-64. | Show Abstract | Read more

Our aim was to study the impact of adding twice-daily exenatide in obese patients with type 2 diabetes and poor glycaemic control who were taking insulin therapy, either alone or in combination with oral hypoglycaemic agents (OHAs), in routine clinical practice. Outcomes evaluated were glycaemic control, body weight, insulin dose, tolerability, safety and incidence of hypoglycaemia. In an open-label prospective study, twice-daily exenatide was added to existing therapy in individuals with type 2 diabetes, suboptimal glycaemic control (HbA1c >7% [53mmol/mol]) and obesity (body mass index [BMI] >30kg/m 2), who were receiving insulin therapy alone or in combination with OHA(s). Thirty-one patients (18 male) were mean (SD) age 55.7(8.6)years, weight 114.6(22.0)kg, BMI 39.1(5.6)kg/m 2, waist circumference 128(13)cm and fasting capillary glucose 11.1(3.4)mmol/L. Median (IQR) known diabetes duration was 10.0(8.0, 17.9)years, HbA1c 9.5(8.8, 10.7)% and daily insulin dose 120(74, 230)units/day. Twenty patients were also taking metformin. One-month data were available for 29 patients, three-month data for 23 patients, six-month data for 28 patients and 12-month data for 21 patients. There was a mean (SD) reduction in weight from 1.1(2.6)kg (p=0.043) at one month to 4.8(7.3)kg (p=0.007) at 12 months, with a maximal reduction at six months (5.3[5.9]kg, p<0.001). Total daily insulin dose was reduced significantly by 31.8(56.5)units (p=0.010) at one month and 49.5(85.3)units (p=0.015) at 12 months. At three months there was a significant reduction in HbA1c (1.2[1.1]%, p<0.001) which was not maintained at six or 12 months (0.5[1.8]%, p=0.139, and 0.5[1.9]%, p=0.237, respectively). The only reported adverse event at 12 months was nausea, occurring in two of 15 (13%) patients. No severe episodes of hypoglycaemia were reported throughout the study. Over one year, the addition of exenatide in individuals with type 2 diabetes on insulin therapy promoted weight loss (~4%) with a substantial reduction in insulin dose (~41%), but with a nonsustained significant improvement in glycaemic control at three months only. No serious adverse events or episodes of severe hypoglycaemia were reported. Copyright © 2012 John Wiley & Sons.

McMurray JJ, Califf RM, Bethel AM, Haffner SM, Holman RR. 2012. Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for hypertension on clinical end points: a cohort study. J Clin Hypertens (Greenwich), 14 (10), pp. 731. | Read more

van Leeuwen N, Nijpels G, Becker ML, Deshmukh H, Zhou K, Stricker BHC, Uitterlinden AG, Hofman A et al. 2012. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts Diabetologia, pp. 1-7.

Sourij H, Holman RR. 2012. Women develop diabetes at higher BMIs than men Diabetologia, pp. 1-2.

Mcmurray JJV, Laakso M, Standl E, Tognoni G, Holman RR, Giles T, Martinez F, Thomas L, Haffner SM, Califf RM. 2011. Risk factors for fatal and non-fatal cardiovascular events in 9306 subjects in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial EUROPEAN HEART JOURNAL, 32 pp. 287-287.

Farmer AJ, Oke J, Stevens R, Holman RR. 2011. Differences in insulin treatment satisfaction following randomized addition of biphasic, prandial or basal insulin to oral therapy in type 2 diabetes. Diabetes Obes Metab, 13 (12), pp. 1136-1141. | Show Abstract | Read more

AIM: No differences in patient health status as measured by the EuroQol-5 Dimension (EQ-5D) questionnaire were observed at 1 year between groups randomized to addition of biphasic, prandial or basal insulin to oral therapy in the treat-to-target in type 2 diabetes trial. We further investigated insulin treatment satisfaction between groups. METHODS: Seven hundred and eight patients with suboptimal glycated haemoglobin levels (7.0-10.0%) taking maximally tolerated doses of metformin and sulphonylurea were randomized to biphasic insulin aspart twice-daily, prandial insulin aspart three times daily or basal insulin detemir once-daily (twice if required). At 1 year self-completed Insulin Treatment Satisfaction Questionnaires (ITSQ) were administered. Lower scores indicated lower treatment satisfaction. We tested for differences between the three groups for the ITSQ total score and for each of the five ITSQ domain scores adjusting for age, gender, ethnicity and education. RESULTS: All 22 ITSQ subscales were completed by 554 (78.2%) patients. Their mean (s.d.) age was 61.5 (9.4) years, body weight 86.1 (16) kg and median (IQR) diabetes duration 9 (6-13) years. Sixty-five percent (358) were male. Median (IQR) 1-year ITSQ total score was lower in patients allocated to prandial therapy (76.5, 68.0-88.6) than in patients allocated to biphasic insulin (83.3, 74.2-90.2) or basal insulin (84.1, 73.5-93.2). With the exception of 'perceived glycaemic control', 1-year adjusted ITSQ scores were significantly different between groups for each of the ITSQ domains, with lower scores for prandial insulin compared with the basal or biphasic groups. Median (IQR) ITSQ scores were lower in patients with a gain in body mass index (BMI) > 1.23 kg/m² over 1 year (79.5, 69.7-89.4) compared to those with a lesser or no gain in BMI (84.1, 74.2-92.4) and in those with occurrence of hypoglycaemia (79.5, 69.7-88.6) compared to those with no hypoglycaemia (84.1, 73.7-93.2). CONCLUSION: Specific measurement of insulin treatment satisfaction identifies differences between regimens used to intensify treatment for type 2 diabetes. Impact of treatment on lifestyle needs to be considered as a factor in the choice of an insulin regimen.

Lawton J, Jenkins N, Darbyshire JL, Holman RR, Farmer AJ, Hallowell N. 2011. Challenges of maintaining research protocol fidelity in a clinical care setting: a qualitative study of the experiences and views of patients and staff participating in a randomized controlled trial. Trials, 12 (1), pp. 108. | Show Abstract | Read more

BACKGROUND: Trial research has predominantly focused on patient and staff understandings of trial concepts and/or motivations for taking part, rather than why treatment recommendations may or may not be followed during trial delivery. This study sought to understand why there was limited attainment of the glycaemic target (HbA(1c) ≤6.5%) among patients who participated in the Treating to Target in Type 2 Diabetes Trial (4-T). The objective was to inform interpretation of trial outcomes and provide recommendations for future trial delivery. METHODS: In-depth interviews were conducted with 45 patients and 21 health professionals recruited from 11 of 58 trial centres in the UK. Patients were broadly representative of those in the main trial in terms of treatment allocation, demographics and glycaemic control. Both physicians and research nurses were interviewed. RESULTS: Most patients were committed to taking insulin as recommended by 4-T staff. To avoid hypoglycaemia, patients occasionally altered or skipped insulin doses, normally in consultation with staff. Patients were usually unaware of the trial's glycaemic target. Positive staff feedback could lead patients to believe they had been 'successful' trial participants even when their HbA(1c) exceeded 6.5%. While some staff felt that the 4-T automated insulin dose adjustment algorithm had increased their confidence to prescribe larger insulin doses than in routine clinical practice, all described situations where they had not followed its recommendations. Staff regarded the application of a 'one size fits all' glycaemic target during the trial as contradicting routine clinical practice where they would tailor treatments to individuals. Staff also expressed concerns that 'tight' glycaemic control might impose an unacceptably high risk of hypoglycaemia, thus compromising trust and safety, especially amongst older patients. To address these concerns, staff tended to adapt the trial protocol to align it with their clinical practices and experiences. CONCLUSIONS: To understand trial findings, foster attainment of endpoints, and promote protocol fidelity, it may be necessary to look beyond individual patient characteristics and experiences. Specifically, the context of trial delivery, the impact of staff involvement, and the difficulties staff may encounter in balancing competing 'clinical' and 'research' roles and responsibilities may need to be considered and addressed.

Lachin JM, Viberti G, Zinman B, Haffner SM, Aftring RP, Paul G, Kravitz BG, Herman WH, Holman RR, Kahn SE, ADOPT Study Group. 2011. Renal function in type 2 diabetes with rosiglitazone, metformin, and glyburide monotherapy. Clin J Am Soc Nephrol, 6 (5), pp. 1032-1040. | Show Abstract | Read more

BACKGROUND AND OBJECTIVES: In ADOPT (A Diabetes Outcomes Prevention Trial), initial monotherapy with rosiglitazone provided more durable glycemic control than metformin or glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine differences in albumin excretion, renal function (estimated GFR), and BP over 5 years between treatment groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 4351 recently diagnosed, drug-naïve patients with type 2 diabetes were treated and followed for up to 5 years with rosiglitazone, metformin, or glyburide and were examined with periodic assessments of albumin/creatinine ratio (ACR), modification of diet in renal disease (MDRD)-estimated GFR, and BP. RESULTS: The ACR rose slowly with metformin. It fell with rosiglitazone and less so with glyburide over the first 2 years, and then rose slowly over time. Estimated GFR (eGFR) with all therapies rose into the high normal range over the first 3 to 4 years, more so with rosiglitazone, and then declined, more so with glyburide. Systolic BP was stable over time, values with rosiglitazone being lower, and diastolic BP declined over time, more so with rosiglitazone than with metformin or glyburide. There was no difference among groups in the incidence of emergent albuminuria (ACR ≥30 mg/g), hypertension, or impaired eGFR (<60 ml/min per 1.73 m(2)). CONCLUSIONS: Over a 5-year period, initial monotherapy with rosiglitazone retards the rise of ACR compared with metformin, preserves eGFR compared with glyburide, and lowers BP relative to both comparators.

Kahn SE, Lachin JM, Zinman B, Haffner SM, Aftring RP, Paul G, Kravitz BG, Herman WH, Viberti G, Holman RR, ADOPT Study Group. 2011. Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT. Diabetes, 60 (5), pp. 1552-1560. | Show Abstract | Read more

OBJECTIVE: ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial monotherapy with rosiglitazone provided superior durability of glycemic control compared with metformin and glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine measures of β-cell function and insulin sensitivity from an oral glucose tolerance test (OGTT) over a 4-year period among the three treatments. RESEARCH DESIGN AND METHODS: Recently diagnosed, drug-naïve patients with type 2 diabetes (4,360 total) were treated for a median of 4.0 years with rosiglitazone, metformin, or glyburide and were examined with periodic metabolic testing using an OGTT. RESULTS: Measures of β-cell function and insulin sensitivity from an OGTT showed more favorable changes over time with rosiglitazone versus metformin or glyburide. Persistent improvements were seen in those who completed 4 years of monotherapy and marked deterioration of β-cell function in those who failed to maintain adequate glucose control with initial monotherapy. CONCLUSIONS: The favorable combined changes in β-cell function and insulin sensitivity over time with rosiglitazone appear to be responsible for its superior glycemic durability over metformin and glyburide as initial monotherapy in type 2 diabetes.

Jenkins N, Hallowell N, Farmer AJ, Holman RR, Lawton J. 2011. Participants' experiences of intensifying insulin therapy during the Treating to Target in Type 2 Diabetes (4-T) trial: qualitative interview study. Diabet Med, 28 (5), pp. 543-548. | Show Abstract | Read more

AIM: To explore participants' experiences of intensifying insulin therapy during the Treating to Target in Type 2 Diabetes (4-T) trial. METHODS: In-depth interviews were conducted with 41 trial participants who had had their insulin therapy intensified during this trial. Data were analysed using an inductive, thematic approach. RESULTS: The vast majority of participants were receptive towards intensifying treatment. Whilst some were happy simply to follow health professionals' recommendations, others saw taking two types of insulin as a more effective way of controlling their diabetes. Post-intensification, participants sought to remember to take their additional injections by developing injection-related strategies and daily routines. The need to inject insulin whilst in public often arose more frequently following intensification and was a consistent source of anxiety. Those who were worried about injecting in public sought to avoid having to do so; for example, by injecting in toilets or by advancing or delaying the timing of their injections. CONCLUSIONS: IT was not increasing the number of daily injections per se which was problematic for the participants who had agreed to have their insulin therapies intensified, but the increased likelihood of having to inject insulin in public. Addressing concerns about injecting in public places may help promote adherence to intensified insulin regimens.

DREAM Trial Investigators. 2011. Incidence of diabetes following ramipril or rosiglitazone withdrawal. Diabetes Care, 34 (6), pp. 1265-1269. | Show Abstract | Read more

OBJECTIVE: To examine the impact of withdrawing rosiglitazone and ramipril medication on diabetes incidence after closeout of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS: The 3,366 DREAM subjects at trial end who had not developed diabetes while taking double-blind study medication were transferred to single-blind placebo for 2 to 3 months before undergoing an oral glucose tolerance test. Glycemic status was analyzed for the trial plus washout period and for the washout period alone. RESULTS: Following median (interquartile range) 71 (63-86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo. CONCLUSIONS: In people allocated to ramipril compared with those not allocated ramipril during the trial, the postwashout normoglycemia incidence was higher. In people allocated to rosiglitazone compared with those not allocated rosiglitazone during the trial, the postwashout incidence of diabetes was significantly lower and the incidence of normoglycemia was higher. During the washout period, diabetes incidence was the same for ramipril versus placebo and for rosiglitazone versus placebo. Rosiglitazone delays disease progression during treatment but the process resumes at the placebo rate when the drug is stopped.

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Teo KK, Sleight P, Gao P, Yusuf S, Connolly S, Yusuf S, Swedberg K, Pfeffer MA et al. 2011. Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals The ARB Trialists Collaboration JOURNAL OF HYPERTENSION, 29 (4), pp. 623-635. | Read more

Price HC, Griffin SJ, Holman RR. 2011. Impact of personalized cardiovascular disease risk estimates on physical activity-a randomized controlled trial. Diabet Med, 28 (3), pp. 363-372. | Show Abstract | Read more

AIM: Informing a person of their individual risk of developing a disease in the future may be sufficient to provide the person with the impetus to adopt risk reducing behaviours. The aim of this study was to determine if a personalised 10-year cardiovascular disease (CVD) risk estimate can increase physical activity and other risk reduction behaviours in adults at high risk of CVD. METHODS: Pilot 2 × 2 factorial randomised controlled trial conducted in Oxfordshire, UK including 194 adults at increased CVD risk (10-year CVD risk ≥ 20%) recruited from four general practices. Main outcome measure at one month was physical activity measured by accelerometer. RESULTS: Median (IQR) age was 62.3 (54.9, 66.1) years, 67% were men and 19% had known diabetes. Mean (SD) total accelerometer counts per day was 297 × 10(-3) (110 × 10(-3) ) and activity of moderate or greater intensity was undertaken for 53 (22) minutes per day. In the 185 (95%) participants attending follow-up an increase in physical activity was not seen. There was a non-significant 0.5% (p = 0.56) greater increase in accelerometer counts in those receiving personalised CVD risk estimates. No significant within or between group changes were seen at one month in estimated 10-year CVD risk. A net 7% decrease in mean LDL cholesterol (p = 0.004) was seen in the intervention group despite similar increases in new prescriptions for lipid lowering therapies. CONCLUSION: In adults at increased risk of CVD provision of personalised 10-year CVD risk estimates did not appear to increase physical activity or estimated CVD risk over a one-month period.

Holman RR, Zinman B, Yusuf S, Sheridan PM, Anand SS, Bosch JJ, Conget I, Davies MJ et al. 2011. Incidence of diabetes following ramipril or rosiglitazone withdrawal Diabetes Care, 34 (6), pp. 1265-1269. | Show Abstract | Read more

OBJECTIVE - To examine the impact of withdrawing rosiglitazone and ramipril medication on diabetes incidence after closeout of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS - The 3,366 DREAM subjects at trial end who had not developed diabetes while taking double-blind study medication were transferred to single-blind placebo for 2 to 3months before undergoing an oral glucose tolerance test. Glycemic status was analyzed for the trial plus washout period and for the washout period alone. RESULTS - Following median (interquartile range) 71 (63-86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo. CONCLUSIONS - In people allocated to ramipril comparedwith those not allocated ramipril during the trial, the postwashout normoglycemia incidence was higher. In people allocated to rosiglitazone compared with those not allocated rosiglitazone during the trial, the postwashout incidence of diabetes was significantly lower and the incidence of normoglycemia was higher. During the washout period, diabetes incidence was the same for ramipril versus placebo and for rosiglitazone versus placebo. Rosiglitazone delays disease progression during treatment but the process resumes at the placebo rate when the drug is stopped. © 2011 by the American Diabetes Association.

GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, Wellcome Trust Case Control Consortium 2, Zhou K, Bellenguez C, Spencer CC, Bennett AJ, Coleman RL, Tavendale R et al. 2011. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet, 43 (2), pp. 117-120. | Show Abstract | Read more

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Jenkins N, Hallowell N, Farmer AJ, Holman RR, Lawton J. 2010. Initiating insulin as part of the Treating To Target in Type 2 Diabetes (4-T) trial: an interview study of patients' and health professionals' experiences. Diabetes Care, 33 (10), pp. 2178-2180. | Show Abstract | Read more

OBJECTIVE: To explore patients' and health professionals' experiences of initiating insulin as part of the Treating To Target in Type 2 Diabetes (4-T) randomized controlled trial. RESEARCH DESIGN AND METHODS: Interviews were conducted with 45 trial participants and 21 health professionals and thematically analyzed. RESULTS: Patients were generally psychologically insulin receptive when approached to participate in the 4-T trial. Their receptiveness arose largely from their personal experiences observing intensifying prior treatments and deteriorating blood glucose control over time, which led them to engage with and accept the idea that their diabetes was progressive. Health professionals also fostered receptiveness by drawing on their clinical experience to manage patients' anxieties about initiating insulin. CONCLUSIONS: Previous studies may have overemphasized the problem of psychological insulin resistance and overlooked factors and treatment experiences that may promote insulin receptiveness among type 2 patients.

Neil HA, Ceglarek U, Thiery J, Paul S, Farmer A, Holman RR. 2010. Impact of atorvastatin and omega-3 ethyl esters 90 on plasma plant sterol concentrations and cholesterol synthesis in type 2 diabetes: a randomised placebo controlled factorial trial. Atherosclerosis, 213 (2), pp. 512-517. | Show Abstract | Read more

OBJECTIVE: To determine the effects of statin treatment and omega-3 polyunsaturated fatty acid supplementation on plasma plant sterol concentrations and cholesterol synthesis in patients with type 2 diabetes. METHODS: Plant sterol concentrations and lanosterol (a marker of cholesterol synthesis) were measured using a high sensitivity assay to assess the effect of double-blind daily treatment for 4 months with atorvastatin 20mg or placebo and, in a 2 × 2 factorial design, omega-3 ethyl esters 90 2g or placebo. RESULTS: 658 patients were included in a per protocol analysis. The 4 treatment groups had similar mean [SD] age (63.5 years [11.7]), HbA(1c) (6.9% [1.1]) and diabetes duration (median 4 years [inter-quartile range 2, 8]). Atorvastatin treatment alone reduced low density lipoprotein (LDL) cholesterol by 1.4 mmol/l (44%, p<0.001), triglycerides by 0.3 mmol/l (20%, p<0.0001) and lanosterol by 0.36 μmol/l (72%, p<0.001). There was no significant placebo adjusted change in median [95% confidence intervals] total plant sterol concentrations (-0.77 μmol/l [inter-quartile range -2.13, 0.59]), although they were increased significantly with omega-3-acid EE90 treatment (3.23 μmol/l [1.28, 5.17]). There was a 27% smaller reduction in LDL cholesterol with atorvastatin treatment in low cholesterol synthesisers with high absorption, defined by changes at or above the median lanosterol and campesterol levels, respectively, compared with the obverse group (difference 0.42 mmol/l [0.21, 0.62]). CONCLUSION: Treatment with atorvastatin in type 2 diabetes did not change median total plasma plant sterol concentrations, but LDL cholesterol was reduced most efficaciously in high cholesterol synthesisers with low intestinal cholesterol absorption. CLINICAL TRIAL REGISTRATION INFORMATION: Current controlled trials number ISRCTN: 76737502 (http://isrctn.org).

Holman RR, Holzhauer B, McMurray JJ. 2010. Effect of Valsartan on the Incidence of Diabetes REPLY NEW ENGLAND JOURNAL OF MEDICINE, 363 (8), pp. 792-793. | Read more

Price HC, Clarke PM, Gray AM, Holman RR. 2010. Life expectancy in individuals with type 2 diabetes: implications for annuities. Med Decis Making, 30 (3), pp. 409-414. | Show Abstract | Read more

BACKGROUND: Insurance companies often offer people with diabetes ''enhanced impaired life annuity'' at preferential rates, in view of their reduced life expectancy. OBJECTIVE: To assess the appropriateness of ''enhanced impaired life annuity'' rates for individuals with type 2 diabetes. Patients. There were 4026 subjects with established type 2 diabetes (but not known cardiovascular or other life-threatening diseases) enrolled into the UK Lipids in Diabetes Study. Measurements. Estimated individual life expectancy using the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model. RESULTS: Subjects were a mean (SD) age of 60.7 (8.6) years, had a blood pressure of 141/83 (17/10) mm Hg, total cholesterol level of 4.5 (0.75) mmol/L, HDL cholesterol level of 1.2 (0.29) mmol/L, with median (interquartile range [IQR]) known diabetes duration of 6 (3-11) years, and HbA(1c) of 8.0% (7.2-9.0). Sixty-five percent were male, 91% white, 4% Afro-Caribbean, 5% Indian-Asian, and 15% current smokers. The UKPDS Outcomes Model median (IQR) estimated age at death was 76.6 (73.8-79.5) years compared with 81.6 (79.4-83.2) years, estimated using the UK Government Actuary's Department data for a general population of the same age and gender structure. The median (IQR) difference was 4.3 (2.8-6.1) years, a remaining life expectancy reduction of almost one quarter. The highest value annuity identified, which commences payments immediately for a 60-year-old man with insulin-treated type 2 diabetes investing 100,000, did not reflect this difference, offering 7.4K per year compared with 7.0K per year if not diabetic. CONCLUSIONS: The UK Government Actuary's Department data overestimate likely age at death in individuals with type 2 diabetes, and at present, ''enhanced impaired life annuity'' rates do not provide equity for people with type 2 diabetes. Using a diabetes-specific model to estimate life expectancy could provide valuable information to the annuity industry and permit more equitable annuity rates for those with type 2 diabetes.

NAVIGATOR Study Group, Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA, Belenkov Y et al. 2010. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med, 362 (16), pp. 1463-1476. | Show Abstract | Read more

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

NAVIGATOR Study Group, McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, Belenkov Y et al. 2010. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med, 362 (16), pp. 1477-1490. | Show Abstract | Read more

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Kahn R, Alperin P, Eddy D, Borch-Johnsen K, Buse J, Feigelman J, Gregg E, Holman RR et al. 2010. Age at initiation and frequency of screening to detect type 2 diabetes: a cost-effectiveness analysis. Lancet, 375 (9723), pp. 1365-1374. | Show Abstract | Read more

BACKGROUND: No clinical trials have assessed the effects or cost-effectiveness of sequential screening strategies to detect new cases of type 2 diabetes. We used a mathematical model to estimate the cost-effectiveness of several screening strategies. METHODS: We used person-specific data from a representative sample of the US population to create a simulated population of 325,000 people aged 30 years without diabetes. We used the Archimedes model to compare eight simulated screening strategies for type 2 diabetes with a no-screening control strategy. Strategies differed in terms of age at initiation and frequency of screening. Once diagnosed, diabetes treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, myocardial infarction, stroke, and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). FINDINGS: Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction (3-9 events prevented per 1000 people screened) and diabetes-related microvascular complications (3-9 events prevented per 1000 people), and increased the number of QALYs (93-194 undiscounted QALYs) added over 50 years. Most strategies prevented a significant number of simulated deaths (2-5 events per 1000 people). There was little or no effect of screening on incidence of stroke (0-1 event prevented per 1000 people). Five screening strategies had costs per QALY of about US$10,500 or less, whereas costs were much higher for screening started at 45 years of age and repeated every year ($15,509), screening started at 60 years of age and repeated every 3 years ($25,738), or a maximum screening strategy (screening started at 30 years of age and repeated every 6 months; $40,778). Several strategies differed substantially in the number of QALYs gained. Costs per QALY were sensitive to the disutility assigned to the state of having diabetes diagnosed with or without symptoms. INTERPRETATION: In the US population, screening for type 2 diabetes is cost effective when started between the ages of 30 years and 45 years, with screening repeated every 3-5 years. FUNDING: Novo Nordisk, Bayer HealthCare, [corrected] and Pfizer.

Holman RR, Darbyshire JL. 2010. Insulin Regimens in Type 2 Diabetes REPLY NEW ENGLAND JOURNAL OF MEDICINE, 362 (10), pp. 960-960.

Holman RR. 2010. Management of diabetes and cardiovascular protection ENDOCRINE JOURNAL, 57 pp. S197-S197.

Farmer AJ, Lasserson DS, Holman RR. 2010. Meta-analysis on insulin treatment for type 2 diabetes: rushed conclusions? Reply to Wägner AM, Mauricio D [letter]. Diabetologia, 53 (5), pp. 1006-1006. | Read more

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Zhou K, Bellenguez C, Spencer CCA, Bennett AJ, Coleman RL, Tavendale R, Hawley SA, Donnelly LA et al. 2011. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes NATURE GENETICS, 43 (2), pp. 117-U57. | Read more

Neil HAW, Ceglarek U, Thiery J, Paul S, Farmer A, Holman RR. 2010. Impact of atorvastatin and omega-3 ethyl esters 90 on plasma plant sterol concentrations and cholesterol synthesis in type 2 diabetes: A randomised placebo controlled factorial trial Atherosclerosis, 213 (2), pp. 512-517. | Show Abstract | Read more

Objective: To determine the effects of statin treatment and omega-3 polyunsaturated fatty acid supplementation on plasma plant sterol concentrations and cholesterol synthesis in patients with type 2 diabetes. Methods: Plant sterol concentrations and lanosterol (a marker of cholesterol synthesis) were measured using a high sensitivity assay to assess the effect of double-blind daily treatment for 4 months with atorvastatin 20. mg or placebo and, in a 2 × 2 factorial design, omega-3 ethyl esters 90 2. g or placebo. Results: 658 patients were included in a per protocol analysis. The 4 treatment groups had similar mean [SD] age (63.5 years [11.7]), HbA1c (6.9% [1.1]) and diabetes duration (median 4 years [inter-quartile range 2, 8]). Atorvastatin treatment alone reduced low density lipoprotein (LDL) cholesterol by 1.4mmol/l (44%, p<0.001), triglycerides by 0.3mmol/l (20%, p<0.0001) and lanosterol by 0.36μmol/l (72%, p<0.001). There was no significant placebo adjusted change in median [95% confidence intervals] total plant sterol concentrations (-0.77μmol/l [inter-quartile range -2.13, 0.59]), although they were increased significantly with omega-3-acid EE90 treatment (3.23μmol/l [1.28, 5.17]). There was a 27% smaller reduction in LDL cholesterol with atorvastatin treatment in low cholesterol synthesisers with high absorption, defined by changes at or above the median lanosterol and campesterol levels, respectively, compared with the obverse group (difference 0.42mmol/l [0.21, 0.62]). Conclusion: Treatment with atorvastatin in type 2 diabetes did not change median total plasma plant sterol concentrations, but LDL cholesterol was reduced most efficaciously in high cholesterol synthesisers with low intestinal cholesterol absorption. Clinical trial registration information: Current controlled trials number ISRCTN: 76737502 (http://isrctn.org). © 2010 Elsevier Ireland Ltd.

Kahn SE, Haffner SM, Viberti G, Herman WH, Lachin JM, Kravitz BG, Yu D, Paul G, Holman RR, Zinman B, Diabetes Outcome Progression Trial (ADOPT) Study Group. 2010. Rosiglitazone decreases C-reactive protein to a greater extent relative to glyburide and metformin over 4 years despite greater weight gain: observations from a Diabetes Outcome Progression Trial (ADOPT). Diabetes Care, 33 (1), pp. 177-183. | Show Abstract | Read more

OBJECTIVE: C-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown. RESEARCH DESIGN AND METHODS: In A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years. RESULTS: Baseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by -47.6% relative to glyburide and by -30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and -2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = -0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups. CONCLUSIONS: Rosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone.

Krum H, McMurray JJ, Horton E, Gerlock T, Holzhauer B, Zuurman L, Haffner SM, Bethel MA, Holman RR, Califf RM. 2010. Baseline characteristics of the Nateglinide and Valsartan Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial population: comparison with other diabetes prevention trials. Cardiovasc Ther, 28 (2), pp. 124-132. | Show Abstract | Read more

The Nateglinide and Valsartan Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is exploring two pharmacological strategies (nateglinide and valsartan, both alone and in combination) in the prevention of overt diabetes mellitus (DM) and the reduction of cardiovascular disease (CVD) in subjects at high risk for these events. In this analysis, we provide baseline characteristics of the randomized NAVIGATOR study population and contrast them with those from other trials of DM prevention. Key eligibility criteria include impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), a history of CVD (in patients aged > or =50 years), and > or =1 cardiovascular risk factor (in patients aged > or =55 years). Baseline demographic characteristics, laboratory findings, cardiovascular risk factors, CVD history, and medication use are described and compared with other trials of DM prevention. The full analysis set of subjects (N = 9306) showed a clustering of risk factors consistent with the metabolic syndrome: high rates of hypertension (77.5%), dyslipidemia (44.7%), increased waist circumference (101.0 cm), and high body mass index (BMI) (47.5% with BMI > or =30 kg/m(2)). A minority of patients had a history of CVD (24.3%); of these, 11.7% had a history of myocardial infarction and most of the remainder had evidence of coronary artery disease. Subjects also had elevated blood pressure (BP) (predominantly systolic) (139.7/82.6 mm Hg), increased serum low-density lipoproteins cholesterol levels (3.27 mmol/L), and borderline elevation of triglyceride levels (1.97 mmol/L). Demographic data, BP, and lipid profiles in NAVIGATOR were similar to those of previous DM prevention trials, which were also based largely on meeting criteria for IGT. Medication use at baseline among NAVIGATOR subjects, which frequently included aspirin, beta-blockers, calcium channel blockers, diuretics, and lipid-lowering agents, reflects enhanced CVD risk. However, little prescribing of renin-angiotensin-aldosterone system blockers was observed, likely due to protocol exclusion criteria. In conclusion, the NAVIGATOR study comprises prediabetic subjects who typically have concurrent BP and metabolic disturbances and an enhanced risk of CVD, and are thus at higher risk for cardiovascular events than subjects in previous DM prevention trials.

Holman RR, Darbyshire JL. 2010. The authors reply New England Journal of Medicine, 362 (10), pp. 960.

Holman RR, Holzhauer B, McMurray JJ. 2010. The authors reply New England Journal of Medicine, 363 (8), pp. 792-793. | Read more

Control Group, Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, Evans GW et al. 2009. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia, 52 (11), pp. 2288-2298. | Show Abstract | Read more

AIMS/HYPOTHESIS: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. METHODS: A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. RESULTS: A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). CONCLUSIONS/INTERPRETATION: Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.

Price HC, Dudley C, Barrow B, Griffin SJ, Holman RR. 2009. Perceptions of heart attack risk amongst individuals with diabetes. Prim Care Diabetes, 3 (4), pp. 239-244. | Show Abstract | Read more

AIM: Individuals with diabetes are at increased risk of cardiovascular disease (CVD). There is good evidence that this risk can be reduced by pharmacotherapies and lifestyle modification. Despite this, knowledge of CVD risk amongst individuals with diabetes remains poor. We undertook a qualitative study to investigate lay perceptions of heart attack risk amongst individuals with diabetes in order to gather information about underlying perceptions concerning risk and risk reduction strategies. METHODS: We conducted three focus groups in Oxford using an open-ended question map. Content analysis was performed to identify recurring themes, similar patterns, distinctions and supportive quotations. RESULTS: Concern about having a heart attack varied widely. A commonly held view was that a 10-year heart attack risk of 10% or greater was high and being aware of one's risk was important so that lifestyle changes or other interventions could be implemented. Participants consistently viewed physical activity as potentially harmful. Almost all participants sought healthcare and lifestyle advice from their primary healthcare providers in the first instance, preferring this to information in the lay press or government campaigns. CONCLUSION: The focus groups have allowed us to better understand lay perceptions of, and underlying assumptions about, CVD risk. These findings may be of use when discussing CVD risk and risk reduction strategies in primary care.

Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK, 4-T Study Group. 2009. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med, 361 (18), pp. 1736-1747. | Show Abstract | Read more

BACKGROUND: Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited. METHODS: In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. RESULTS: Median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens (P=0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, P=0.006) or in the basal group (43.2%, P=0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (P=0.002). [corrected] Median rates of hypoglycemia per patient per year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (P<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups. CONCLUSIONS: Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin. (Current Controlled Trials number, ISRCTN51125379.)

Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG, Paul G, Jones NP et al. 2010. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab, 95 (1), pp. 134-142. | Show Abstract | Read more

CONTEXT: An increase in bone fractures has been observed in women taking thiazolidinediones. OBJECTIVE: The objective of the study was to examine whether changes in circulating bone biomarkers provide insight into the underlying mechanisms responsible for the increase in bone fractures in female participants randomized to rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Paired stored baseline and 12-month serum samples were available from 1605 participants (689 women, 916 men) in ADOPT, a long-term clinical trial comparing the effects of rosiglitazone, glyburide, and metformin on glycemic control in patients with type 2 diabetes. RESULTS: This subset was well matched to the total ADOPT study population. In women a marker of osteoclast activity, C-terminal telopeptide (for type 1 collagen), increased by 6.1% with rosiglitazone compared with reductions of 1.3% (P = 0.03 vs. rosiglitazone) and 3.3% (P = 0.002 vs. rosiglitazone) with metformin and glyburide, respectively. In men, C-terminal telopeptide was unchanged on rosiglitazone (-1.0%) and fell on metformin (-12.7%; P < 0.001) and glyburide (-4.3%, P = NS). Markers of osteoblast activity, procollagen type 1 N-propeptide (P1NP) and bone alkaline phosphatase, were reduced for women and men in almost all treatment groups, with the greatest changes in the metformin group (P1NP in females, -14.4%; P1NP in males, -19.3%), intermediate for rosiglitazone (P1NP in females, -4.4%; P1NP in males, -14.4%), and smallest for glyburide (P1NP in males, +0.2%; bone alkaline phosphatase in females, -11.6%). CONCLUSIONS: Commonly measured bone biomarkers suggest that changes in bone resorption may be partly responsible for the increased risk of fracture in women taking thiazolidinediones.

Lasserson DS, Glasziou P, Perera R, Holman RR, Farmer AJ. 2009. Optimal insulin regimens in type 2 diabetes mellitus: systematic review and meta-analyses. Diabetologia, 52 (10), pp. 1990-2000. | Show Abstract | Read more

AIMS/HYPOTHESIS: We compared the effect of biphasic, basal or prandial insulin regimens on glucose control, clinical outcomes and adverse events in people with type 2 diabetes. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE and major American and European conference abstracts for randomised controlled trials up to October 2008. A systematic review and meta-analyses were performed. RESULTS: Twenty-two trials that randomised 4,379 patients were included. Seven trials reported both starting insulin dose and titration schedules. Hypoglycaemia definitions and glucose targets varied. Meta-analyses were performed pooling data from insulin-naive patients. Greater HbA(1c) reductions were seen with biphasic and prandial insulin, compared with basal insulin, of 0.45% (95% CI 0.19-0.70, p = 0.0006) and 0.45% (95% CI 0.16-0.73, p = 0.002), respectively, but with lesser reductions of fasting glucose of 0.93 mmol/l (95% CI 0.21-1.65, p = 0.01) and 2.20 mmol/l (95% CI 1.70-2.70, p < 0.00001), respectively. Larger insulin doses at study end were reported in biphasic and prandial arms compared with basal arms. No studies found differences in major hypoglycaemic events, but minor hypoglycaemic events for prandial and biphasic insulin were inconsistently reported as either higher than or equivalent to basal insulin. Greater weight gain was seen with prandial compared with basal insulin (1.86 kg, 95% CI 0.80-2.92, p = 0.0006). CONCLUSIONS/INTERPRETATION: Greater HbA(1c) reduction may be obtained in type 2 diabetes when insulin is initiated using biphasic or prandial insulin rather than a basal regimen, but with an unquantified risk of hypoglycaemia. Studies with longer follow-up are required to determine the clinical relevance of this finding.

Darbyshire JL, Holman RR, Price HC. 2009. Presenting the results of clinical trials to participants. Clin Med (Lond), 9 (5), pp. 415-416. | Read more

Price HC, Dudley C, Barrow B, Kennedy I, Griffin SJ, Holman RR. 2009. Use of focus groups to develop methods to communicate cardiovascular disease risk and potential for risk reduction to people with type 2 diabetes. Fam Pract, 26 (5), pp. 351-358. | Show Abstract | Read more

BACKGROUND: People need to perceive a risk in order to build an intention-to-change behaviour yet our ability to interpret information about risk is highly variable. OBJECTIVES: We aimed to use a user-centred design process to develop an animated interface for the UK Prospective Diabetes Study (UKPDS) Risk Engine to illustrate cardiovascular disease (CVD) risk and the potential to reduce this risk. In addition, we sought to use the same approach to develop a brief lifestyle advice intervention. METHODS: Three focus groups were held. Participants were provided with examples of materials used to communicate CVD risk and a leaflet containing a draft brief lifestyle advice intervention and considered their potential to increase motivation-to-change behaviours including diet, physical activity, and smoking in order to reduce CVD risk. Discussions were tape-recorded, transcribed and coded and recurring themes sought. RESULTS: Sixty-two percent of participants were male, mean age was 66 years (range = 47-76 years) and median age at leaving full-time education was 18 years (range = 15-40 years). Sixteen had type 2 diabetes and none had a prior history of CVD. Recurring themes from focus group discussions included the following: being less numerate is common, CVD risk reduction is important and a clear visual representation aids comprehension. CONCLUSION: A simple animated interface of the UKPDS Risk Engine to illustrate CVD risk and the potential for reducing this risk has been developed for use as a motivational tool, along with a brief lifestyle advice intervention. Future work will investigate whether use of this interactive version of the UKPDS Risk Engine and brief lifestyle advice is associated with increased behavioural intentions and changes in health behaviours designed to reduce CVD risk.

Paul S, Coleman RL, Price HC, Farmer AJ. 2009. Predicting 6-Year Mortality Risk in Patients With Type 2 Diabetes: Response to Wells et al. Diabetes Care, 32 (5), pp. e60-e60. | Read more

Simmons RK, Coleman RL, Price HC, Holman RR, Khaw KT, Wareham NJ, Griffin SJ. 2009. Performance of the UK Prospective Diabetes Study Risk Engine and the Framingham Risk Equations in Estimating Cardiovascular Disease in the EPIC- Norfolk Cohort. Diabetes Care, 32 (4), pp. 708-713. | Show Abstract | Read more

OBJECTIVE: The purpose of this study was to examine the performance of the UK Prospective Diabetes Study (UKPDS) Risk Engine (version 3) and the Framingham risk equations (2008) in estimating cardiovascular disease (CVD) incidence in three populations: 1) individuals with known diabetes; 2) individuals with nondiabetic hyperglycemia, defined as A1C >or=6.0%; and 3) individuals with normoglycemia defined as A1C <6.0%. RESEARCH DESIGN AND METHODS: This was a population-based prospective cohort (European Prospective Investigation of Cancer-Norfolk). Participants aged 40-79 years recruited from U.K. general practices attended a health examination (1993-1998) and were followed for CVD events/death until April 2007. CVD risk estimates were calculated for 10,137 individuals. RESULTS: Over 10.1 years, there were 69 CVD events in the diabetes group (25.4%), 160 in the hyperglycemia group (17.7%), and 732 in the normoglycemia group (8.2%). Estimated CVD 10-year risk in the diabetes group was 33 and 37% using the UKPDS and Framingham equations, respectively. In the hyperglycemia group, estimated CVD risks were 31 and 22%, respectively, and for the normoglycemia group risks were 20 and 14%, respectively. There were no significant differences in the ability of the risk equations to discriminate between individuals at different risk of CVD events in each subgroup; both equations overestimated CVD risk. The Framingham equations performed better in the hyperglycemia and normoglycemia groups as they did not overestimate risk as much as the UKPDS Risk Engine, and they classified more participants correctly. CONCLUSIONS: Both the UKPDS Risk Engine and Framingham risk equations were moderately effective at ranking individuals and are therefore suitable for resource prioritization. However, both overestimated true risk, which is important when one is using scores to communicate prognostic information to individuals.

Price HC, Coleman RL, Stevens RJ, Holman RR. 2009. Impact of using a non-diabetes-specific risk calculator on eligibility for statin therapy in type 2 diabetes. Diabetologia, 52 (3), pp. 394-397. | Show Abstract | Read more

AIMS/HYPOTHESIS: The aim of this study was to investigate the impact of using a non-diabetes-specific cardiovascular disease (CVD) risk calculator to determine eligibility for statin therapy according to current UK National Institute for Health and Clinical Excellence (NICE) guidelines for those patients with type 2 diabetes who are at an increased risk of CVD (10 year risk >or=20%). METHODS: The 10 year CVD risks were estimated using the UK Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham equation for 4,025 patients enrolled in the Lipids in Diabetes Study who had established type 2 diabetes and LDL-cholesterol <4.1 mmol/l. RESULTS: The mean (SD) age of the patients was 60.7 (8.6) years, blood pressure 141/83 (17/10) mmHg and the total cholesterol:HDL-cholesterol ratio was 3.9 (1.0). The median (interquartile range) diabetes duration was 6 (3-11) years and the HbA(1c) level was 8.0% (7.2-9.0%). The cohort comprised 65% men, 91% whites, 4% Afro-Caribbeans, 5% Asian Indians and 15% current smokers. More patients were classified as being at high risk by the UKPDS Risk Engine (65%) than by the Framingham CVD equation (63%) (p < 0.0001). The Framingham CVD equation classified fewer men and people aged <50 years old as high risk (p < 0.0001). There was no difference between the UKPDS Risk Engine and Framingham classification of women at high risk (p = 0.834). CONCLUSIONS/INTERPRETATION: These results suggest that the use of Framingham-derived rather than UKPDS Risk Engine-derived CVD risk estimates would deny about one in 25 patients statin therapy when applying current NICE guidelines. Thus, under these guidelines the choice of CVD risk calculator is important when assessing CVD risk in patients with type 2 diabetes, particularly for the identification of the relatively small proportion of younger people who require statin therapy.

Price HC, Holman RR. 2009. Primary prevention of cardiovascular events in diabetes: is there a role for aspirin? Nat Clin Pract Cardiovasc Med, 6 (3), pp. 168-169. | Show Abstract | Read more

The POPADAD (Prevention Of Progression of Arterial Disease And Diabetes) study did not show a benefit for low-dose aspirin therapy or administration of antioxidants for the primary prevention of cardiovascular disease events in individuals with diabetes and asymptomatic peripheral arterial disease. Although low-dose aspirin continues to be recommended in international guidelines, no convincing trial-based evidence exists that supports its routine use for primary prevention of cardiovascular disease in people with diabetes. This paradox is unhelpful and the guidelines should be relaxed until definitive evidence becomes available.

Hartweg J, Farmer AJ, Holman RR, Neil A. 2009. Potential impact of omega-3 treatment on cardiovascular disease in type 2 diabetes. Curr Opin Lipidol, 20 (1), pp. 30-38. | Show Abstract | Read more

PURPOSE OF REVIEW: Hypothesis-generating systematic review of the impact of marine-derived omega-3 polyunsaturated fatty acids (PUFAs) on lipid, glycemic and hematological risk factors in type 2 diabetes using pooled data from randomized controlled trials searched up to 20 September 2008. RECENT FINDINGS: Seven new trials in 2007 and 2008 were identified from 206 abstracts to give a total of 24 trials between 1966 and 2008 involving 1533 participants that could be pooled. The mean omega-3 PUFAs dose and duration of treatment in the new trials was 2.4 g/day and 24 weeks, respectively. Compared with placebo, omega-3 PUFAs supplementation decreased triglycerides by 7% (mean -0.17 mmol/l, 24 trials, 1530 participants), fibrinogen by 10% (mean -0.96 micromol/l, three trials, 159 participants), ADP platelet aggregation to ADP by 22% (mean -10.30%, two trials, 64 participants) and to collagen by 21% (mean -10.55%, two trials, 64 participants), with an LDL-cholesterol increase of 3% (mean 0.08 mmol/l, 21 trials, 1104 participants). None of the following risk factors appeared to be beneficially influenced: HDL-cholesterol, LDL particle size, glycemia, insulinemia, inflammatory biomarkers, blood pressure. However for some of these risk factors (such as inflammatory biomarkers) the number of trial patients was small Higher doses of omega-3 PUFAs (>or=2 g/day) may have greater triglyceride lowering effects. SUMMARY: This systematic review and meta-analysis confirms the triglyceride lowering effects of omega-3 PUFAs, demonstrates potential dose-response effects and shows improvements in thrombogenesis. Omega-3 PUFAs raise LDL levels without concomitant changes in lipid particle size. Changes seen in conventional risk factors are insufficient to explain the cardiovascular disease risk reductions suggested to occur with omega-3 PUFAs.

Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, Craven A, Goyder L et al. 2009. Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial. Health Technol Assess, 13 (15), pp. iii-50. | Show Abstract | Read more

OBJECTIVES: To determine whether self-monitoring of blood glucose (SMBG), either alone or with additional instruction in incorporating the results into self-care, is more effective than usual care in improving glycaemic control in non-insulin-treated diabetes. DESIGN: An open, parallel group randomised controlled trial. SETTING: 24 general practices in Oxfordshire and 24 in South Yorkshire, UK. PARTICIPANTS: Patients with non-insulin-treated type 2 diabetes, aged > or = 25 years and with glycosylated haemoglobin (HbA1c) > or = 6.2%. INTERVENTIONS: A total of 453 patients were individually randomised to one of: (1) standardised usual care with 3-monthly HbA1c (control, n = 152); (2) blood glucose self-testing with patient training focused on clinician interpretation of results in addition to usual care (less intensive self-monitoring, n = 150); (3) SMBG with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle (more intensive self-monitoring, n = 151). MAIN OUTCOME MEASURES: The primary outcome was HBA1c at 12 months, and an intention-to-treat analysis, including all patients, was undertaken. Blood pressure, lipids, episodes of hypoglycaemia and quality of life, measured with the EuroQol 5 dimensions (EQ-5D), were secondary measures. An economic analysis was also carried out, and questionnaires were used to measure well-being, beliefs about use of SMBG and self-reports of medication taking, dietary and physical activities, and health-care resource use. RESULTS: The differences in 12-month HbA1c between the three groups (adjusted for baseline HbA1c) were not statistically significant (p = 0.12). The difference in unadjusted mean change in HbA1c from baseline to 12 months between the control and less intensive self-monitoring groups was -0.14% [95% confidence interval (CI) -0.35 to 0.07] and between the control and more intensive self-monitoring groups was -0.17% (95% CI -0.37 to 0.03). There was no evidence of a significantly different impact of self-monitoring on glycaemic control when comparing subgroups of patients defined by duration of diabetes, therapy, diabetes-related complications and EQ-5D score. The economic analysis suggested that SMBG resulted in extra health-care costs and was unlikely to be cost-effective if used routinely. There appeared to be an initial negative impact of SMBG on quality of life measured on the EQ-5D, and the potential additional lifetime gains in quality-adjusted life-years, resulting from the lower levels of risk factors achieved at the end of trial follow-up, were outweighed by these initial impacts for both SMBG groups compared with control. Some patients felt that SMBG was helpful, and there was evidence that those using more intensive self-monitoring perceived diabetes as having more serious consequences. Patients using SMBG were often not clear about the relationship between their behaviour and the test results. CONCLUSIONS: While the data do not exclude the possibility of a clinically important benefit for specific subgroups of patients in initiating good glycaemic control, SMBG by non-insulin-treated patients, with or without instruction in incorporating findings into self-care, did not lead to a significant improvement in glycaemic control compared with usual care monitored by HbA1c levels. There was no convincing evidence to support a recommendation for routine self-monitoring of all patients and no evidence of improved glycaemic control in predefined subgroups of patients.

Holman RR, Matthews DR, Neil HAW. 2009. Follow-up of Intensive Glucose Control in Type 2 Diabetes Reply NEW ENGLAND JOURNAL OF MEDICINE, 360 (4), pp. 418-418.

Lund SS, Rossing P, Vaag AA. 2009. Follow-up of intensive glucose control in type 2 diabetes. N Engl J Med, 360 (4), pp. 416. | Read more

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B, American Diabetes Association, European Association for Study of Diabetes. 2009. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 32 (1), pp. 193-203. | Show Abstract | Read more

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Holman RR, Paul S, Farmer A, Tucker L, Stratton IM, Neil HA, Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes Study Group. 2009. Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes (AFORRD): a randomised controlled trial. Diabetologia, 52 (1), pp. 50-59. | Show Abstract | Read more

AIMS/HYPOTHESIS: The aim of the study was to examine the impact of statin or omega-3-acid ethyl esters 90 (omega-3 EE90; omega-3-acid ethyl esters 90 refers to a mixture of ethyl esters of n-3 fatty acids) on estimated cardiovascular disease (CVD) risk in community-based people with type 2 diabetes but without known CVD and not taking lipid-lowering therapy. METHODS: A central computer randomised 800 patients in 59 UK general practices to atorvastatin (n = 401, 20 mg/day) or placebo (n = 399) and omega-3 EE90 (n = 397, 2 g/day) or placebo (n = 403) in a concealed factorial manner. Participants with LDL-cholesterol <2.6 mmol/l, triacylglycerol <1.5 mmol/l and estimated 10-year CVD risk <20% were compared at 4 months. RESULTS: Mean (SD) age was 63.5 (11.7) years, HbA(1c) 6.9 (1.1) % and known diabetes duration (median [interquartile range]) was 4 (2-8) years. Fifty-seven per cent were men, 90% white and 74% had an estimated 10-year CVD risk >or=20%. Of 732 patients with 4-month data, more allocated atorvastatin (n = 371) compared with placebo (n = 361) achieved LDL-cholesterol <2.6 mmol/l (91% vs 24%, p < 0.001) and had estimated 10-year CVD risks <20% (38% vs 26%, p < 0.001). No differences were seen between those allocated omega-3 EE90 (n = 371) compared with placebo (n = 361) for participants achieving triacylglycerol <1.5 mmol/l (65% vs 60%, p = 0.18) or estimated 10-year CVD risks <20% (34% vs 30%, p = 0.18). There were no side effects of note. CONCLUSIONS/INTERPRETATION: Many community-based diabetic patients without known CVD remain at high CVD risk despite statin treatment and require additional risk-reduction strategies. The impact of omega-3 EE90 on CVD risk will remain uncertain until clinical endpoint trial results are available. TRIAL REGISTRATION: ISRCT no. 76737502.

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B, American Diabetes Association, European Association for the Study of Diabetes. 2009. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia, 52 (1), pp. 17-30. | Show Abstract | Read more

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Gloyn AL, van de Bunt M, Stratton IM, Lonie L, Tucker L, Ellard S, Holman RR. 2009. Prevalence of GCK mutations in individuals screened for fasting hyperglycaemia. Diabetologia, 52 (1), pp. 172-174. | Read more

Holman RR, Matthews DR, Neil HAW. 2009. Breast Reconstruction after Breast-Cancer Surgery New England Journal of Medicine, 360 (4), pp. 418-421. | Read more

Cited:

1564

Scopus

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. 2009. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy Diabetes Care, 32 (1), pp. 193-203. | Show Abstract | Read more

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience. © 2009 by the American Diabetes Association and Springer.

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. 2009. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes Clinical Diabetes, 27 (1), pp. 4-16. | Show Abstract | Read more

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience. © 2009 by the American Diabetes Association and Springer.

Cited:

57

Scopus

Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, Craven A, Goyder L et al. 2009. Blood glucose self-monitoring in type 2 diabetes: A randomised controlled trial Health Technology Assessment, 13 (15), | Show Abstract | Read more

Objectives: To determine whether self-monitoring of blood glucose (SMBG), either alone or with additional instruction in incorporating the results into self-care, is more effective than usual care in improving glycaemic control in non-insulin-treated diabetes. Design: An open, parallel group randomised controlled trial. Setting: 24 general practices in Oxfordshire and 24 in South Yorkshire, UK. Participants: Patients with non-insulin-treated type 2 diabetes, aged ≥25 years and with glycosylated haemoglobin (HbAlc) ≥6.2%. Interventions: A total of 453 patients were individually randomised to one of: (1) standardised usual care with 3-monthly HbAlc (control, n = 152); (2) blood glucose self-testing with patient training focused on clinician interpretation of results in addition to usual care (less intensive self-monitoring, n = 150); (3) SMBG with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle (more intensive self-monitoring, n = 151). Main outcome measures: The primary outcome was HBAlc at 12 months, and an intention-to-treat analysis, including all patients, was undertaken. Blood pressure, lipids, episodes of hypoglycaemia and quality of life, measured with the EuroQol 5 dimensions (EQ-5D), were secondary measures. An economic analysis was also carried out, and questionnaires were used to measure well-being, beliefs about use of SMBG and self-reports of medication taking, dietary and physical activities, and health-care resource use. Results: The differences in 12-month HbAlc between the three groups (adjusted for baseline HbAlc) were not statistically significant (p = 0.12). The difference in unadjusted mean change in HbAlc from baseline to 12 months between the control and less intensive self-monitoring groups was -0.14% [95% confidence interval (Cl) -0.35 to 0.07] and between the control and more intensive self-monitoring groups was -0.17% (95% Cl -0.37 to 0.03). There was no evidence of a significantly different impact of self-monitoring on glycaemic control when comparing subgroups of patients defined by duration of diabetes, therapy, diabetes-related complications and EQ-5D score. The economic analysis suggested that SMBG resulted in extra health-care costs and was unlikely to be cost-effective if used routinely. There appeared to be an initial negative impact of SMBG on quality of life measured on the EQ-5D, and the potential additional lifetime gains in quality-adjusted life-years, resulting from the lower levels of risk factors achieved at the end of trial follow-up, were outweighed by these initial impacts for both SMBG groups compared with control. Some patients felt that SMBG was helpful, and there was evidence that those using more intensive self-monitoring perceived diabetes as having more serious consequences. Patients using SMBG were often not clear about the relationship between their behaviour and the test results. Conclusions: While the data do not exclude the possibility of a clinically important benefit for specific subgroups of patients in initiating good glycaemic control, SBMG by non-insulin-treated patients, with or without instruction in incorporating finding into self-care, did not lead to a significant improvement in glycaemic control compared with usual care monitored by HbAlc levels. There was no convincing evidence to support a recommendation for routine self-monitoring of all patients and no evidence of improved glycaemic control in predefined subgroups of patients.

Bethel MA, Paul SK, Buse J, Deedwania P, McMurray J, Fonseca V, Kahn S, Schmitz O, Holman R. 2008. High Frequency of Unrecognized Diabetes in Cardiovascular Patients: Should All Have an Oral Glucose Tolerance Test? CIRCULATION, 118 (18), pp. S1080-S1080.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 2008. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med, 359 (15), pp. 1577-1589. | Show Abstract | Read more

BACKGROUND: During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes. METHODS: Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories. RESULTS: Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002). CONCLUSIONS: Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.)

Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. 2008. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med, 359 (15), pp. 1565-1576. | Show Abstract | Read more

BACKGROUND: Post-trial monitoring of patients in the United Kingdom Prospective Diabetes Study (UKPDS) examined whether risk reductions for microvascular and macrovascular disease, achieved with the use of improved blood-pressure control during the trial, would be sustained. METHODS: Among 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus, we randomly assigned, over a 4-year period beginning in 1987, 1148 patients with hypertension to tight or less-tight blood-pressure control regimens. The 884 patients who underwent post-trial monitoring were asked to attend annual UKPDS clinics for the first 5 years, but no attempt was made to maintain their previously assigned therapies. Annual questionnaires completed by patients and general practitioners were used to follow patients who were unable to attend the clinic in years 1 through 5, and questionnaires were used for all patients in years 6 to 10. Seven prespecified aggregate clinical end points were examined on an intention-to-treat basis, according to the previous randomization categories. RESULTS: Differences in blood pressure between the two groups during the trial disappeared within 2 years after termination of the trial. Significant relative risk reductions found during the trial for any diabetes-related end point, diabetes-related death, microvascular disease, and stroke in the group receiving tight, as compared with less tight, blood-pressure control were not sustained during the post-trial follow-up. No risk reductions were seen during or after the trial for myocardial infarction or death from any cause, but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant (P=0.02). CONCLUSIONS: The benefits of previously improved blood-pressure control were not sustained when between-group differences in blood pressure were lost. Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications, but it appears that good blood-pressure control must be continued if the benefits are to be maintained. (UKPDS 81; Current Controlled Trials number, ISRCTN75451837.)

Califf RM, Boolell M, Haffner SM, Bethel M, McMurray J, Duggal A, Holman RR, NAVIGATOR Study Group. 2008. Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial. Am Heart J, 156 (4), pp. 623-632. | Show Abstract | Read more

Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged > or = 50 years with known CVD or aged > or = 55 years with > or = 1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a "core" composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an "extended" composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT.

Bethel MA, Holman R, Haffner SM, Califf RM, Huntsman-Labed A, Hua TA, McMurray J. 2008. Determining the most appropriate components for a composite clinical trial outcome. Am Heart J, 156 (4), pp. 633-640. | Show Abstract | Read more

BACKGROUND: Because composite end points augment event rates, they are often thought to increase statistical power. This may not be true if the intervention has a lesser effect on some components of the composite. Consequently, treatment effect size may depend on the choice of composite. METHODS: To explore this issue, we performed a meta-analysis to determine the effect of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on individual cardiovascular (CV) outcomes. We then applied these treatment effects to 2 different composite CV outcomes generated using blinded data from the ongoing Nateglinide and Valsartan in Impaired Glucose Tolerance (IGT) Outcomes Research (NAVIGATOR) trial and analyzed them on a time-to-first-event basis. The composites were CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure and an "extended" composite that included hospitalization for angina and coronary revascularization. RESULTS: The odds reductions due to angiotensin-converting enzyme/angiotensin receptor blocker treatment estimated from the meta-analysis were as follows: CV death: 13%, P < .0001; nonfatal myocardial infarction: 16%, P < .00001; nonfatal stroke: 14%, P = .006; heart failure: 28%, P < .00001; hospitalization for angina: 7%, P = .02; and revascularization: 5%, P = .17. For the CV composites, the projected odds reduction was larger (17.8%, 95% CI 0.452-1.189) for the narrower composite compared with the extended CV composite (11.7%, 95% CI 0.623-1.136); that is, use of the extended composite reduced power to detect a difference between treatment groups. CONCLUSIONS: Although the use of CV composites augments event rates, it may not increase statistical power. Inclusion of events little influenced by an intervention may reduce the precision of the composite end point and mask treatment effects.

Holman RR, Watkins PJ. 2008. The UK Prospective Diabetes Study: celebrating 30 years - Introduction DIABETIC MEDICINE, 25 pp. 1-1. | Read more

Price HC, Tucker L, Griffin SJ, Holman RR. 2008. The impact of individualised cardiovascular disease (CVD) risk estimates and lifestyle advice on physical activity in individuals at high risk of CVD: a pilot 2 x 2 factorial understanding risk trial. Cardiovasc Diabetol, 7 (1), pp. 21. | Show Abstract | Read more

BACKGROUND: There is currently much interest in encouraging individuals to increase physical activity in order to reduce CVD risk. This study has been designed to determine if personalised CVD risk appreciation can increase physical activity in adults at high risk of CVD. METHODS/DESIGN: In a 2 x 2 factorial design participants are allocated at random to a personalised 10-year CVD risk estimate or numerical CVD risk factor values (systolic blood pressure, LDL cholesterol and fasting glucose) and, simultaneously, to receive a brief lifestyle advice intervention targeting physical activity, diet and smoking cessation or not. We aim to recruit 200 participants from Oxfordshire primary care practices. Eligibility criteria include adults age 40-70 years, estimated 10-year CVD risk > or =20%, ability to read and write English, no known CVD and no physical disability or other condition reducing the ability to walk. Primary outcome is physical activity measured by ActiGraph accelerometer with biochemical, anthropometrical and psychological measures as additional outcomes. Primary analysis is between group physical activity differences at one month powered to detect a difference of 30,000 total counts per day of physical activity between the groups. Additional analyses will seek to further elucidate the relationship between the provision of risk information, and intention to change behaviour and to determine the impact of both interventions on clinical and anthropometrical measures including fasting and 2 hour plasma glucose, fructosamine, serum cotinine, plasma vitamin C, body fat percentage and blood pressure. DISCUSSION: This is a pilot trial seeking to demonstrate in a real world setting, proof of principal that provision of personalised risk information can contribute to behaviour changes aimed at reducing CVD risk. This study will increase our understanding of the links between the provision of risk information and behaviour change and if successful, could be used in clinical practice with little or no modification.

Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D et al. 2008. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care, 31 (5), pp. 845-851. | Show Abstract | Read more

OBJECTIVE: The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS: In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS: Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.

2008. Effects of Ramipril and Rosiglitazone on Cardiovascular and Renal Outcomes in People With Impaired Glucose Tolerance or Impaired Fasting Glucose: Results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial Diabetes Care, 31 (5), pp. 1007-1014. | Read more

Holman RR, Farmer AJ, Davies MJ. 2008. Addition of insulin to oral therapy in type 2 diabetes - Reply NEW ENGLAND JOURNAL OF MEDICINE, 358 (11), pp. 1198-1198.

Goldberg RB, Holman R, Drucker DJ. 2008. Clinical decisions. Management of type 2 diabetes. N Engl J Med, 358 (3), pp. 293-297. | Show Abstract | Read more

This interactive Journal feature presents the case of a 55-year-old woman with type 2 diabetes, obesity, and hypertension. Three possible treatment options, any of which could be considered correct, are presented. Which option do you recommend? At www.nejm.org you can vote for one and then, if you wish, submit a comment about your clinical decision. Voting results and a broad selection of comments will be posted on the Web site. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. 2008. Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. Update regarding the thiazolidinediones. Diabetologia, 51 (1), pp. 8-11. | Read more

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. 2008. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 31 (1), pp. 173-175. | Read more

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. 2008. Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy Diabetologia, 51 (3), pp. 522-522. | Read more

Holman RR, Farmer AJ, Davies MJ. 2008. The authors reply New England Journal of Medicine, 358 (11), pp. 1198.

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Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D, Heise MA, Aftring RP, Viberti G. 2008. Rosiglitazone-associated fractures in type 2 diabetes Diabetes Care, 31 (5), pp. 845-851. | Show Abstract | Read more

OBJECTIVE - The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS - Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS - In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS-Further investigation into the risk factors and underlying pathophysi-ology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings. © 2008 by the American Diabetes Association.

Holman R. 2008. Improving outcomes for people with diabetes Diabetes and Primary Care, 10 (6), pp. 329-330.

Cull CA, Jensen CC, Retnakaran R, Holman RR. 2007. Impact of the metabolic syndrome on macrovascular and microvascular outcomes in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study 78. Circulation, 116 (19), pp. 2119-2126. | Show Abstract | Read more

BACKGROUND: The metabolic syndrome (MetS) and type 2 diabetes mellitus are both associated with increased cardiovascular disease risk. We examined retrospectively the degree to which the presence of MetS in individuals with type 2 diabetes mellitus increased their risk of diabetic complications using United Kingdom Prospective Diabetes Study data. METHODS AND RESULTS: Of 5102 United Kingdom Prospective Diabetes Study patients recruited with newly diagnosed type 2 diabetes mellitus and followed up for a median of 10.3 years, 4542 had the requisite data for these analyses. After a 3-month dietary run-in, MetS, diagnosed with National Cholesterol Education Program Adult Treatment Panel III, World Health Organization, International Diabetes Federation, or European Group for the Study of Insulin Resistance criteria, was present in 61%, 38%, 54%, and 24%, respectively. Those with MetS by these criteria had increased cardiovascular disease risks relative to those without MetS of 1.33 (95% confidence interval 1.14 to 1.54), 1.45 (95% confidence interval 1.26 to 1.66), 1.23 (95% confidence interval 1.07 to 1.42), and 1.31 (95% confidence interval 1.10 to 1.57), respectively, but similar risks for microvascular complications. The positive predictive value of MetS for cardiovascular disease events, however, was only 18%, 13%, 18%, and 39%, respectively. CONCLUSIONS: MetS, diagnosed by Adult Treatment Panel III, World Health Organization, or International Diabetes Federation criteria, identifies diabetic patients at greater risk of macrovascular but not microvascular complications. Poor discrimination by MetS with respect to cardiovascular disease outcomes means that it is of limited clinical value for cardiovascular disease risk stratification in type 2 diabetes mellitus.

Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, Levy JC, 4-T Study Group. 2007. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med, 357 (17), pp. 1716-1730. | Show Abstract | Read more

BACKGROUND: Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited. METHODS: In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. RESULTS: At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P=0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups. CONCLUSIONS: A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain. (Current Controlled Trials number, ISRCTN51125379 [controlled-trials.com].).

Desai M, Cull CA, Horton VA, Christie MR, Bonifacio E, Lampasona V, Bingley PJ, Levy JC et al. 2007. GAD autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77. Diabetologia, 50 (10), pp. 2052-2060. | Show Abstract | Read more

AIMS/HYPOTHESIS: Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes, with autoantibodies to islet proteins developing in older patients who have no immediate requirement for insulin therapy. Markers of its clinical course are uncharacterised. The aim of this study was to determine whether persistence of, or changes in, GAD65 autoantibodies (GADAs) in the LADA patients who participated in the United Kingdom Prospective Diabetes Study (UKPDS) were associated with disease progression or insulin requirement. METHODS: GADA levels and their relative epitope reactivities to N-terminal, middle and C-terminal regions of human GAD65 were determined in 242 UKPDS patients who were GADA-positive at diagnosis; samples taken after 0.5, 3 and 6 years of follow-up were tested using a radiobinding assay. Comparisons were made of GADA status with clinical details and disease progression assessed by the requirement for intensified glucose-lowering therapy. RESULTS: GADA levels fluctuated between 0.5 and 6 years but persisted in 225 of 242 patients. No association of GADA levels with disease progression or insulin requirement was observed. Antibody reactivity was directed to C-terminal and middle epitopes of GAD65 in >70% patients, and the N-terminal in <9%. There were no changes in epitope reactivity pattern over the 6 year follow-up period, nor any association between epitope reactivity and insulin requirement. CONCLUSIONS/INTERPRETATION: GADAs persist for 6 years after diagnosis of LADA, but levels and reactivity to different GAD65 epitopes are not associated with disease progression.

Hartweg J, Gunter M, Perera R, Farmer A, Cull C, Schalkwijk C, Kok A, Twaalfhoven H, Holman R, Neil A. 2007. Stability of soluble adhesion molecules, selectins, and C-reactive protein at various temperatures: implications for epidemiological and large-scale clinical studies. Clin Chem, 53 (10), pp. 1858-1860. | Show Abstract | Read more

BACKGROUND: We assessed the impact of sample storage conditions on soluble vascular cell adhesion molecules (sVCAM), soluble intracellular adhesion molecules (sICAM-1), soluble (s)E-selectin, C-reactive protein (CRP), and sP-selectin. METHODS: Markers were measured by ELISA in venous blood from 10 healthy volunteers on aliquots stored as plasma or whole blood at 4, 21, or 30 degrees C for 1-5 days and after 1-5 freeze-thaw cycles. We compared results on these samples to results for samples processed immediately and stored at -80 degrees C. Statistical models assessed time-related effects and effects of postprocessing conditions. RESULTS: Using an upper limit of 10% variation from baseline with P >0.05, we found that stability duration in plasma was 5 days for sVCAM-1 and sICAM-1 and at least 2 days for sE-selectin at 4, 21, and 30 degrees C and 5 days for CRP at 4 and 21 degrees C and 1 day at 30 degrees C. Stability duration in whole blood was 5 days for sVCAM-1 and sICAM-1 and at least 2 days for sE-selectin at 4, 21, and 30 degrees C and 5 days for CRP at 4 and 21 degrees C and 2 days at 30 degrees C. sP-selectin was not stable in plasma or whole blood. sICAM-1, sVCAM-1, CRP, and sE-selectin were stable after 5 freeze-thaw cycles. CONCLUSIONS: sVCAM-1, sICAM-1, and CRP are stable in plasma or whole blood at 4 and 21 degrees C for at least 3 days and sE-selectin for 2 days. sP-selectin is not stable and therefore requires immediate assay.

Hartweg J, Farmer AJ, Perera R, Holman RR, Neil HA. 2007. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on lipoproteins and other emerging lipid cardiovascular risk markers in patients with type 2 diabetes. Diabetologia, 50 (8), pp. 1593-1602. | Show Abstract | Read more

AIMS/HYPOTHESIS: To determine the effects of marine-derived n-3 polyunsaturated fatty acids (PUFA) on established and emerging lipid and lipoprotein cardiovascular risk markers in patients with type 2 diabetes. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of randomised controlled trials comparing dietary or non-dietary intake of n-3 PUFA with placebo in patients with type 2 diabetes by searching databases from 1966 to December 2006. Changes in the following variables were recorded triacylglycerol; total cholesterol; HDL, LDL and VLDL and their subfractions; lipid ratios; apolipoproteins; and cholesterol particle sizes. RESULTS: There were 23 trials on non-dietary supplementation, involving 1,075 subjects with a mean treatment duration of 8.9 weeks, with sufficient data to permit pooling. Compared with placebo, n-3 PUFA had a statistically significant effect on four outcomes, reducing levels of (1) triacylglycerol (18 trials, 969 subjects) by 25% (mean 0.45 mmol/l; 95% CI -0.58 to -0.32; p < 0.00001); (2) VLDL-cholesterol (7 trials, 238 subjects) by 36% (0.07 mmol/l; 95% CI -0.13 to 0.00; p = 0.04); and (3) VLDL-triacylglycerol (6 trials, 178 subjects) by 39.7% (0.44 mmol/l; 95% CI -0.83 to -0.05; p = 0.03); while slightly increasing LDL (16 trials, 565 subjects) by 5.7% (0.11 mmol/l; 95% CI 0.00 to 0.22; p = 0.05). There were no significant effects on total cholesterol, apolipoproteins, lipid subfractions or ratios. CONCLUSIONS/INTERPRETATION: In addition to recognised triacylglycerol-lowering effects, n-3 PUFA supplementation decreases VLDL-cholesterol and VLDL-triacylglycerol, but may have an adverse effect on LDL-cholesterol. Larger and longer term clinical trials are required to conclusively establish the effect of n-3 PUFA on cardiovascular risk markers and outcomes in type 2 diabetic patients.

Farmer A, Wade A, Goyder E, Yudkin P, French D, Craven A, Holman R, Kinmonth AL, Neil A. 2007. Impact of self monitoring of blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomised trial. BMJ, 335 (7611), pp. 132. | Show Abstract | Read more

OBJECTIVE: To determine whether self monitoring, alone or with instruction in incorporating the results into self care, is more effective than usual care in improving glycaemic control in non-insulin treated patients with type 2 diabetes. DESIGN: Three arm, open, parallel group randomised trial. SETTING: 48 general practices in Oxfordshire and South Yorkshire. PARTICIPANTS: 453 patients with non-insulin treated type 2 diabetes (mean age 65.7 years) for a median duration of three years and a mean haemoglobin A1c level of 7.5%. INTERVENTIONS: Standardised usual care with measurements of HbA1c every three months as the control group (n=152), blood glucose self monitoring with advice for patients to contact their doctor for interpretation of results, in addition to usual care (n=150), and blood glucose self monitoring with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle (n=151). MAIN OUTCOME MEASURE: HbA1c level measured at 12 months. RESULTS: At 12 months the differences in HbA1c level between the three groups (adjusted for baseline HbA1c level) were not statistically significant (P=0.12). The difference in unadjusted mean change in HbA1c level from baseline to 12 months between the control and less intensive self monitoring groups was -0.14% (95% confidence interval -0.35% to 0.07%) and between the control and more intensive self monitoring groups was -0.17% (-0.37% to 0.03%). CONCLUSIONS: Evidence is not convincing of an effect of self monitoring blood glucose, with or without instruction in incorporating findings into self care, in improving glycaemic control compared with usual care in reasonably well controlled non-insulin treated patients with type 2 diabetes. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47464659.

Coleman RL, Stevens RJ, Retnakaran R, Holman RR. 2007. Framingham, SCORE, and DECODE risk equations do not provide reliable cardiovascular risk estimates in type 2 diabetes. Diabetes Care, 30 (5), pp. 1292-1293. | Read more

Cull CA, Davis TME, Holman RR. 2007. Silent myocardial infarction is an independent risk factor for fatal myocardial infarction in patients with Type 2 diabetes DIABETIC MEDICINE, 24 pp. 12-12.

Price HC, Cull CA, Coleman RL, Stevens RJ, Holman RR. 2007. Framingham equations underestimate cardiovascular risk compared with the UKPDS risk engine in people with Type 2 diabetes DIABETIC MEDICINE, 24 pp. 55-55.

Coleman RL, Stevens RJ, Holman RR. 2007. Estimating cardiovascular disease risk for individuals with Type 2 diabetes: the new UKPDS Risk Engine DIABETIC MEDICINE, 24 pp. 56-56.

Hartweg J, Farmer AJ, Holman RR, Neil HA. 2007. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic factors in type 2 diabetes. Diabetologia, 50 (2), pp. 250-258. | Show Abstract | Read more

AIM/HYPOTHESIS: To determine whether marine-derived n-3 polyunsaturated fatty acids (n-3 PUFA) (also known as omega-3 fatty acids) have beneficial effects on haematological and thrombogenic risk markers in addition to dyslipidaemia, in patients with type 2 diabetes. METHODS: A systematic review and meta-analysis of randomised controlled trials comparing dietary or non-dietary intake of n-3 PUFA with placebo in type 2 diabetes was conducted by systematically searching databases from 1966 to February 2006. Changes in C-reactive protein, IL-6, TNF-alpha, platelet function, fibrinogen, factor VII, von Willebrand factor, endothelial function, heart rate and blood pressure were recorded. Inclusion of studies, data extraction and quality were assessed independently in duplicate. RESULTS: Twelve trials involving 847 subjects with a mean treatment duration of 8.5 weeks included sufficient data to permit pooling. Compared with placebo, n-3 PUFA supplementation had a significant effect on two outcomes: reducing the level of diastolic blood pressure (five trials, 248 subjects) by a mean of 1.8 mm Hg (95% CI 0.0-3.6, p = 0.05) and increasing factor VII (two trials, 116 subjects) by 24.9% (95% CI 7.2-42.6, p = 0.006). There were no significant effects on systolic blood pressure, fibrinogen or heart rate. CONCLUSIONS/INTERPRETATION: These results suggest that, in addition to the recognised effects on dyslipidaemia, n-3 PUFA decreases diastolic blood pressure, and appears to increase factor VII. Larger and more rigorously conducted clinical trials are required to establish conclusively the role of n-3 PUFA in cardiovascular risk markers and clinical outcomes in type 2 diabetes.

Desai M, Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC, Walker M, Gillespie KM et al. 2007. An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia, 50 (1), pp. 68-73. | Show Abstract | Read more

AIMS/HYPOTHESIS: Pathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis. MATERIALS AND METHODS: Patients with LADA (n = 387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects (n = 327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR. RESULTS: As in type 1 diabetes mellitus, DRB1 0301_DQB1 0201 (odds ratio [OR] = 3.08, 95% CI 2.32-4.12, p = 1.2 x 10(-16)) and DRB1 0401_DQB1 0302 (OR = 2.57, 95% CI 1.80-3.73, p = 4.5 x 10(-8)) were the main susceptibility haplotypes in LADA, and DRB1 1501_DQB1 0602 was protective (OR = 0.21, 95% CI 0.13-0.34, p = 4.2 x 10(-13)). Differential susceptibility was conferred by DR4 subtypes: DRB1 0401 was predisposing (OR = 1.79, 95% CI 1.35-2.38, p = 2.7 x 10(-5)) whereas DRB1 0403 was protective (OR = 0.37, 95% CI 0.13-0.97, p = 0.033). The highest-risk genotypes were DRB1 0301/DRB1 0401 and DQB1 0201/DQB1 0302 (OR = 5.14, 95% CI 2.68-10.69, p = 1.3 x 10(-8); and OR = 6.88, 95% CI 3.54-14.68, p = 1.2 x 10(-11), respectively). These genotypes and those containing DRB1 0401 and DQB1 0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1 1501 and DQB1 0602 associated with an older age at diagnosis. CONCLUSIONS/INTERPRETATION: Patterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes.

Holman R. 2007. Metformin as first choice in oral diabetes treatment: the UKPDS experience. Journ Annu Diabetol Hotel Dieu, pp. 13-20. | Show Abstract

Metformin has been used successfully since the 1950s as first line pharmacotherapy to treat people with type 2 diabetes. It is a biguanide that decreases blood glucose concentration by mechanisms different from those of insulin secretagogues, such as sulphonylureas, or exogenous insulin therapy. Metformin lowers, rather than increases, fasting plasma insulin concentrations and acts by enhancing insulin sensitivity, inducing greater peripheral uptake of glucose, and decreasing hepatic glucose output. By reducing hepatic glucose output it lowers blood glucose and insulin levels with minimal risk of hypoglycaemia, and when used as monotherapy can lower HbAlc by around 1.5%. It is usually well tolerated, the most common side effects being gastrointestinal. Of particular value is that the improved glucose control seen with metformin is achieved without weight gain. Concerns that it may increase the risk of lactic acidosis have largely been allayed with recent studies suggesting less than one case per 100,000 treated patients. The UK Prospective Diabetes Study (UKPDS) demonstrated a substantial beneficial effect of metformin therapy on cardiovascular disease (CVD) outcomes, with a 36% relative risk reduction in all cause mortality and a 39% relative risk reduction in myocardial infarction . The first ever joint ADA (American Diabetes Association) and EASD (European Association for the Study of Diabetes) consensus guidelines on the management of hyperglycaemia in type 2 diabetes state explicitly that metformin should be used as first-line foundation therapy, in addition to lifestyle interventions.

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Glasziou P, Alexander J, Beller E, Clarke P, Chalmers J, MacMahon S, Cooper M, Ferrannini E et al. 2007. Which health-related quality of life score? A comparison of alternative utility measures in patients with Type 2 diabetes in the ADVANCE trial Health and Quality of Life Outcomes, 5 | Show Abstract | Read more

Background: Diabetes has a high burden of illness both in life years lost and in disability through related co-morbidities. Accurate assessment of the non-mortality burden requires appropriate health-related quality of life and summary utility measures of which there are several contenders. The study aimed to measure the impact of diabetes on various health-related quality of life domains, and compare several summary utility measures. Methods: In the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) study, 978 Australian patients with Type 2 diabetes completed two health-related quality of life questionnaires at baseline: the EQ-5D and the SF-36v2, from which nine summary utility measures were calculated, and compared. The algorithms were grouped into four classes: (i) based on the EQ-5D; (ii) using fewer items than those in the SF-12 (iii) using the items in the SF-12; and (iv) using all items of the SF-36. Results: Overall health-related quality of life of the subjects was good (mean utility ranged from 0.68 (±0.08) to 0.85(±0.14) over the nine utility measures) and comparable to patients without diabetes. Summary indices were well correlated with each other (r = 0.76 to 0.99), and showed lower health-related quality of life in patients with major diabetes-related events such as stroke or myocardial infarction. Despite the smaller number of items used in the scoring of the EQ-5D, it generally performed at least as well as SF-36 based methods. However, all utility measures had some limitation such as limited range or ceiling effects. Conclusion: The summary utility measures showed good agreement, and showed good discrimination between major and minor health state changes. However, EQ-5D based measures performed as well and are generally simpler to use. © 2007 Glasziou et al; licensee BioMed Central Ltd.

Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM et al. 2006. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med, 355 (23), pp. 2427-2443. | Show Abstract | Read more

BACKGROUND: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. METHODS: We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function. RESULTS: Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons). CONCLUSIONS: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).

Calle R, McCarthy MI, Banerjee P, Zeggini E, Cull CA, Thorne KI, Wiltshire S, Terra S et al. 2006. Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76. Diabetologia, 49 (12), pp. 2892-2899. | Show Abstract | Read more

AIMS/HYPOTHESIS: Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes. METHODS: We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors. RESULTS: rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54-0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11-1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27-0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus. CONCLUSIONS/INTERPRETATION: We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.

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Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B. 2006. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy (vol 49, pg 2816, 2006) DIABETOLOGIA, 49 (11), pp. 2816-2818. | Read more

Davis TM, Cull CA, Holman RR. 2006. A clinical screening tool identifies autoimmune diabetes in adults: response to Fourlanos et al. Diabetes Care, 29 (11), pp. 2560. | Read more

Wright AD, Cull CA, Macleod KM, Holman RR, UKPDS Group. 2006. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complications, 20 (6), pp. 395-401. | Show Abstract | Read more

The UK Prospective Diabetes Study (UKPDS) showed that a more intensive glucose control policy reduced risk of diabetic complications. As hypoglycemia is a barrier to achieving glycemic targets, we examined its occurrence and contributing factors in UKPDS patients randomized to and remaining for 6 years on diet, sulfonylurea, metformin (overweight subjects only), or insulin monotherapy from diagnosis of Type 2 diabetes. Self-reported hypoglycemic episodes were categorized as (1) transient, (2) temporarily incapacitated, (3) requiring third-party assistance, and (4) requiring medical attention, recording the most severe episode each quarter. Proportions of patients reporting at least one episode per year were calculated in relation to therapy, HbA(1c), and clinical characteristics. In 5063 patients aged 25-65 years, only 2.5% per year reported substantive hypoglycemia (Grades 2-4) and 0.55% major hypoglycemia (Grade 3 or 4). Hypoglycemia was more frequent in younger (4.0% <45 years vs. 2.2% >or=45 years), female (3.0% vs. 2.2% male), normal weight (3.6% body mass index <25 kg/m(2) vs. 1.9% >or=25 kg/m(2)), less hyperglycemic (5.2% HbA(1c) <7% vs. 2.3% >or=7%), or islet autoantibody-positive patients (4.3% vs. 2.1% negative) (all P<.0001). More on basal insulin reported hypoglycemia (3.8% per year) than diet (0.1%), sulfonylurea (1.2%), or metformin (0.3%) therapy, but less than on basal and prandial insulin (5.3%) (all P<.0001). Low hypoglycemia rates seen during the first 6 years of intensive glucose lowering therapy in Type 2 diabetes are unlikely to have a major impact on attempts to achieve guideline glycemic targets when sulfonylurea, metformin, or insulin are used as monotherapy.

DREAM Trial Investigators, Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, Dagenais G, Diaz R et al. 2006. Effect of ramipril on the incidence of diabetes. N Engl J Med, 355 (15), pp. 1551-1562. | Show Abstract | Read more

BACKGROUND: Previous studies have suggested that blockade of the renin-angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension. METHODS: In a double-blind, randomized clinical trial with a 2-by-2 factorial design, we randomly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance to receive ramipril (up to 15 mg per day) or placebo (and rosiglitazone or placebo) and followed them for a median of 3 years. We studied the effects of ramipril on the development of diabetes or death, whichever came first (the primary outcome), and on secondary outcomes, including regression to normoglycemia. RESULTS: The incidence of the primary outcome did not differ significantly between the ramipril group (18.1%) and the placebo group (19.5%; hazard ratio for the ramipril group, 0.91; 95% confidence interval [CI], 0.81 to 1.03; P=0.15). Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo (hazard ratio, 1.16; 95% CI, 1.07 to 1.27; P=0.001). At the end of the study, the median fasting plasma glucose level was not significantly lower in the ramipril group (102.7 mg per deciliter [5.70 mmol per liter]) than in the placebo group (103.4 mg per deciliter [5.74 mmol per liter], P=0.07), though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group (135.1 mg per deciliter [7.50 mmol per liter] vs. 140.5 mg per deciliter [7.80 mmol per liter], P=0.01). CONCLUSIONS: Among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia. (ClinicalTrials.gov number, NCT00095654 [ClinicalTrials.gov].).

DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M et al. 2006. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet, 368 (9541), pp. 1096-1105. | Show Abstract | Read more

BACKGROUND: Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition. METHODS: 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. FINDINGS: At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01). INTERPRETATION: Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.

Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B. 2006. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 29 (8), pp. 1963-1972. | Read more

Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B, Professional Practice Committee, American Diabetes Association, European Association for the Study of Diabetes. 2006. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia, 49 (8), pp. 1711-1721. | Read more

Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. 2006. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia, 49 (8), pp. 1761-1769. | Show Abstract | Read more

AIMS/HYPOTHESIS: The relative importance of glucose and blood pressure control in type 2 diabetes remains uncertain. We assessed interactive effects of glycaemia and systolic blood pressure (SBP) exposure on the risk of diabetic complications over time. SUBJECTS, MATERIALS AND METHODS: HbA(1c) and SBP, measured annually for a median of 10.4 years in 4,320 newly diagnosed type 2 diabetic patients from the UK Prospective Diabetes Study (UKPDS), were categorised as updated mean values <6.0, 6.0-6.9, 7.0-7.9 or > or =8.0%, and <130, 130-139, 140-149 or > or =150 mmHg, respectively. Clinical outcomes were UKPDS predefined composite endpoints. RESULTS: The incidence of the "any diabetes-related endpoint" in the lowest (HbA(1c) <6.0%, SBP <130 mmHg) and highest (HbA(1c) > or =8%, SBP > or =150 mmHg) category combinations was 15 and 82 per 1,000 person-years, respectively, and 24 and 120 per 1,000 person-years in a Poisson model adjusted to white Caucasian male sex, age 50 to 54 years and diabetes duration of 7.5 to 12.5 years. Updated mean HbA(1c) and SBP effects were additive in an adjusted proportional hazards model with risk reductions of 21% per 1% HbA(1c) decrement and 11% per 10 mmHg SBP decrement. Endpoint rates obtained in the 887 patients randomised in both the glycaemia and hypertension intervention trial arms were consistent with the observational data. Those allocated to both intensive glucose and tight blood pressure control policies had fewer events than those allocated to either policy alone or to neither (p for trend 0.024). CONCLUSIONS/INTERPRETATION: Risk of complications in type 2 diabetes is associated independently and additively with hyperglycaemia and hypertension. Intensive treatment of both these risk factors is required to minimise the incidence of complications.

Kahn SE, Zinman B, Haffner SM, O'Neill MC, Kravitz BG, Yu D, Freed MI, Herman WH et al. 2006. Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes. Diabetes, 55 (8), pp. 2357-2364. | Show Abstract | Read more

The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activator-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA(1c) [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (<or=3 years), drug-naive, type 2 diabetic subjects (fasting plasma glucose <or=10 mmol/l), we examined a representative subgroup (n = 921) of the U.S. cohort in ADOPT (A Diabetes Outcome Progression Trial). The relationship between levels of CRP, fibrinogen, PAI-1 antigen and PAI-1 activity, and baseline variables including National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome phenotype were explored. All four factors increased significantly with increasing numbers of metabolic syndrome components (P = 0.0136 to P < 0.0001). BMI (P < 0.0001) and HOMA-IR (P < 0.0001) but not A1C (P = 0.65) increased with increasing numbers of metabolic syndrome components. Adjustment of CRP levels for BMI eliminated the association between CRP and the number of metabolic syndrome components, while adjusting for HOMA-IR did not (P = 0.0028). The relationships of PAI-1 antigen and PAI-1 activity with the number of metabolic syndrome components were maintained after adjusting for BMI (P = 0.0002 and P = <0.0001, respectively) or HOMA-IR (P = 0.0008 and P = <0.0001, respectively), whereas that with fibrinogen was eliminated after adjusting for BMI but not after adjusting for HOMA-IR (P = 0.013). Adjustment for A1C had no effect on any of the relationships between the inflammatory and fibrinolytic factors and the metabolic syndrome. We conclude that in recently diagnosed, drug-naive type 2 diabetic subjects, markers of inflammation and fibrinolysis are strongly related to the number of metabolic syndrome components. Further, for CRP and fibrinogen this relationship is determined by body adiposity and not by insulin sensitivity or glucose control.

Clarke PM, Simon J, Cull CA, Holman RR. 2006. Assessing the impact of visual acuity on quality of life in individuals with type 2 diabetes using the short form-36. Diabetes Care, 29 (7), pp. 1506-1511. | Show Abstract | Read more

OBJECTIVE: We sought to ascertain quality-of-life measures and utility values associated with visual acuity in type 2 diabetes. RESEARCH DESIGN AND METHODS: The Medical Outcome Study Short Form with 36 items (SF-36) was administered to 4,051 individuals with type 2 diabetes who were enrolled in the Lipids in Diabetes Study, and their best attainable vision was determined using an Early Treatment of Diabetic Retinopathy Study chart, expressed as a LogMAR score. Eight domain scores and a utility value representing an overall quality-of-life score were calculated using predefined algorithms. The associations between quality of life measured and best-eye visual acuity were assessed graphically and by regression analysis. RESULTS: All eight SF-36 domain scores were negatively associated with reduced visual acuity. The impact of lower levels of visual acuity ranged from a decline of 1.3 units for a 0.1-LogMAR increase for physical functioning and 0.6 units in mental health. Regression analysis indicated a negative association (P < 0.001) between utility and reduced visual acuity after controlling for sex, BMI, smoking status, and history of diabetes complications. Patients whose LogMAR scores equated to legally blind had, on average, 0.054 (95% CI 0.034-0.074) lower utility compared with patients with normal visual acuity. CONCLUSIONS: Reduced visual acuity is negatively associated with quality of life. The utility scores estimated here should inform studies quantifying the burden of diabetes and those evaluating potential therapies for treating or preventing diabetic eye diseases.

Stettler C, Allemann S, Jüni P, Cull CA, Holman RR, Egger M, Krähenbühl S, Diem P. 2006. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: Meta-analysis of randomized trials. Am Heart J, 152 (1), pp. 27-38. | Show Abstract | Read more

BACKGROUND: Uncertainty persists concerning the effect of improved long-term glycemic control on macrovascular disease in diabetes mellitus (DM). METHODS: We performed a systematic review and meta-analysis of randomized controlled trials comparing interventions to improve glycemic control with conventional treatment in type 1 and type 2 diabetes. Outcomes included the incidence rate ratios for any macrovascular event, cardiac events, stroke, and peripheral arterial disease, and the number needed to treat intensively during 10 years to prevent one macrovascular event. RESULTS: The analysis was based on 8 randomized comparisons including 1800 patients with type 1 DM (134 macrovascular events, 40 cardiac events, 88 peripheral vascular events, 6 cerebrovascular events, 11293 person-years of follow-up) and 6 comparisons including 4472 patients with type 2 DM (1587 macrovascular events, 1197 cardiac events, 87 peripheral vascular events, 303 cerebrovascular events, 43607 person-years). Combined incidence rate ratios for any macrovascular event were 0.38 (95% CI 0.26-0.56) in type 1 and 0.81 (0.73-0.91) in type 2 DM. In type 1 DM, effect was mainly based on reduction of cardiac and peripheral vascular events and, in type 2 DM, due to reductions in stroke and peripheral vascular events. Effects appear to be particularly important in younger patients with shorter duration of diabetes. CONCLUSIONS: Our data suggest that attempts to improve glycemic control reduce the incidence of macrovascular events both in type 1 and type 2 DM. In absolute terms, benefits are comparable, although effects on specific manifestations of macrovascular disease differ.

Desai M, Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC, Hitman GA, Walker M, Holman RR, McCarthy MI, Clark A. 2006. The variable number of tandem repeats upstream of the insulin gene is a susceptibility locus for latent autoimmune diabetes in adults. Diabetes, 55 (6), pp. 1890-1894. | Show Abstract | Read more

The etiopathological relationship between latent autoimmune diabetes in adults (LADA) and classical type 1 (insulin dependent) diabetes remains unclear. Variation at the insulin gene variable number of tandem repeats (VNTR) minisatellite influences susceptibility to type 1 diabetes, but studies in LADA have been small and inconsistent. We examined the role of insulin gene variation (using flanking variants as surrogates for VNTR subtypes) in the largest case-control study of LADA to date (400 case and 332 control subjects). Highly significant associations were identified with disease, with dominant protective effects of the T allele at -23HphI (odds ratio [OR] 0.42 [95% CI 0.31-0.58], P=2.4 x 10(-8)), A allele at +1,404Fnu4HI (0.50 [0.36-0.70], P=3.2 x 10(-5)), and C allele at +3,580MspI (0.55 [0.35-0.85], P=0.0046). As with type 1 diabetes, the -23HphI variant (a surrogate for the subdivision of VNTR into class I and III alleles) most clearly defined susceptibility in LADA. However, there was no association with age at diagnosis or requirement for insulin therapy 6 years postdiagnosis. This study establishes that variation within the insulin gene region does influence susceptibility to LADA, with the direction and magnitude of effect indistinguishable from that previously reported for type 1 diabetes. In conclusion, differences in VNTR-encoded susceptibility do not explain the differences in clinical presentation that distinguish classical type 1 diabetes and LADA.

Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, UKPDS Study Group. 2006. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes, 55 (6), pp. 1832-1839. | Show Abstract | Read more

Not all patients with type 2 diabetes develop renal dysfunction. Identifying those at risk is problematic because even microalbuminuria, often used clinically as an indicator of future renal dysfunction, does not always precede worsening renal function. We sought to identify clinical risk factors at diagnosis of type 2 diabetes associated with later development of renal dysfunction. Of 5,102 U.K. Prospective Diabetes Study (UKPDS) participants, prospective analyses were undertaken in those without albuminuria (n = 4,031) or with normal plasma creatinine (n=5,032) at diagnosis. Stepwise proportional hazards multivariate regression was used to assess association of putative baseline risk factors with subsequent development of albuminuria (microalbuminuria or macroalbuminuria) or renal impairment (Cockcroft-Gault estimated creatinine clearance <60 ml/min or doubling of plasma creatinine). Over a median of 15 years of follow-up 1,544 (38%) of 4,031 patients developed albuminuria and 1,449 (29%) of 5,032 developed renal impairment. Of 4,006 patients with the requisite data for both outcomes, 1,534 (38%) developed albuminuria and 1,132 (28%) developed renal impairment. Of the latter, 575 (51%) did not have preceding albuminuria. Development of albuminuria or renal impairment was independently associated with increased baseline systolic blood pressure, urinary albumin, plasma creatinine, and Indian-Asian ethnicity. Additional independent risk factors for albuminuria were male sex, increased waist circumference, plasma triglycerides, LDL cholesterol, HbA(1c) (A1C), increased white cell count, ever having smoked, and previous retinopathy. Additional independent risk factors for renal impairment were female sex, decreased waist circumference, age, increased insulin sensitivity, and previous sensory neuropathy. Over a median of 15 years from diagnosis of type 2 diabetes, nearly 40% of UKPDS patients developed albuminuria and nearly 30% developed renal impairment. Distinct sets of risk factors are associated with the development of these two outcomes, consistent with the concept that they are not linked inexorably in type 2 diabetes.

Thomason MJ, Biddulph JP, Cull CA, Holman RR. 2005. Reporting of diabetes on death certificates using data from the UK Prospective Diabetes Study. Diabet Med, 22 (8), pp. 1031-1036. | Show Abstract | Read more

AIMS: To study the effect of age at death, sex, ethnic group, date of death, underlying cause of death and social class on the frequency of reporting diabetes on death certificates in known cases of diabetes. METHODS: Data were extracted from certificates recording 981 deaths which occurred between 1985 and 1999 in people aged 45 years or more who participated in the UK Prospective Diabetes Study, to which 23 English, Scottish and Northern Ireland centres contributed. Diabetes (9th revision of the International Classification of Diseases; ICD-9 250) entered on parts 1A-1C or 2A-2C of the death certificate was considered as reporting diabetes. Logistic regression analyses were used to determine independent factors associated with the reporting of diabetes. RESULTS: Diabetes was reported on 42% (419/981) of all death certificates and on 46% (249/546) of those with underlying cardiovascular disease causes. Reporting of diabetes was independently associated on all death certificates with per year of age increase (OR 1.02; 95% CI 1.001-1.04, P = 0.037), underlying cause of death (non-cardiovascular causes OR 0.76; 95% CI 0.59-0.98, P = 0.035) and social class (classes I-II OR 1.00; class III OR 1.35; 95% CI 0.96-1.89, P = 0.084, classes IV-V OR 1.48; 95% CI 1.05-2.10, P = 0.027). Stratification by age, sex, and underlying cause of death also revealed significant differences in the frequency of reporting diabetes over time. CONCLUSIONS: The rate of reporting of diabetes on cardiovascular disease death certificates remains poor. This may indicate a lack of awareness of the importance of diabetes as a risk factor for cardiovascular disease.

Holman RR, Coleman RL, Shine BS, Stevens RJ. 2005. Non-HDL cholesterol is less informative than the total-to-HDL cholesterol ratio in predicting cardiovascular risk in type 2 diabetes. Diabetes Care, 28 (7), pp. 1796-1797. | Read more

Bottazzo GF, Bosi E, Cull CA, Bonifacio E, Locatelli M, Zimmet P, Mackay IR, Holman RR. 2005. IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71) (vol 48, pg 703, 2005) DIABETOLOGIA, 48 (6), pp. 1240-1240. | Read more

Cook MN, Girman CJ, Stein PP, Alexander CM, Holman RR. 2005. Glycemic control continues to deteriorate after sulfonylureas are added to metformin among patients with type 2 diabetes. Diabetes Care, 28 (5), pp. 995-1000. | Show Abstract | Read more

OBJECTIVE: To describe the course and predictors of glycemic control among patients with type 2 diabetes after sulfonylureas (SUs) are added to metformin (MF). RESEARCH DESIGN AND METHODS: Patients (n = 2,220) treated with MF monotherapy for >90 days before initiating MF plus SU combination therapy between January 1998 and March 2004 were studied in a retrospective analysis of electronic medical records from U.K. primary care practices using the General Practice Research Database. Median glycoslyated hemoglobin A(1c) (A1C) before and after SU initiation was described, and patient characteristics were evaluated as predictors of time until A1C > or =8.0% or glucose-lowering therapy was intensified (by starting insulin or adding a third oral agent). RESULTS: At 6 months post-SU initiation, median A1C resumed deteriorating at a somewhat comparable rate to that observed on MF monotherapy. Higher pre-SU A1C, younger age, female sex, shorter diabetes duration, higher serum creatinine, and being an ex-smoker predicted time until A1C > or =8.0% or glucose-lowering therapy was intensified in various analyses. Median A1C was 9.5% when therapy was intensified. A1C > or =8.0% was estimated to occur in 85% of patients 4 years after SU initiation and in 68% 4 years after initially achieving A1C <7% on MF plus SU therapy. CONCLUSIONS: In this population, glycemic control is improved following the addition of SUs to MF, but deterioration resumes as early as 6 months. The high proportion of patients remaining on MF plus SU therapy despite having A1C > or =8.0% suggests that there are significant barriers to starting insulin or adding a third agent when treatment goals are not achieved with this combination.

Clarke PM, Gray AM, Briggs A, Stevens RJ, Matthews DR, Holman RR, UKPDS 72 United Kingdom Prospective Diabetes Study. 2005. Cost-utility analyses of intensive blood glucose and tight blood pressure control in type 2 diabetes (UKPDS 72). Diabetologia, 48 (5), pp. 868-877. | Show Abstract | Read more

AIMS/HYPOTHESIS: This study estimated the economic efficiency (1) of intensive blood glucose control and tight blood pressure control in patients with type 2 diabetes who also had hypertension, and (2) of metformin therapy in type 2 diabetic patients who were overweight. METHODS: We conducted cost-utility analysis based on patient-level data from a randomised clinical controlled trial involving 4,209 patients with newly diagnosed type 2 diabetes conducted in 23 hospital-based clinics in England, Scotland and Northern Ireland as part of the UK Prospective Diabetes Study (UKPDS). Three different policies were evaluated: intensive blood glucose control with sulphonylurea/insulin; intensive blood glucose control with metformin for overweight patients; and tight blood pressure control of hypertensive patients. Incremental cost : effectiveness ratios were calculated based on the net cost of healthcare resources associated with these policies and on effectiveness in terms of quality-adjusted life years gained, estimated over a lifetime from within-trial effects using the UKPDS Outcomes Model. RESULTS: The incremental cost per quality-adjusted life years gained (in year 2004 UK prices) for intensive blood glucose control was 6,028 UK pounds, and for blood pressure control was 369 UK pounds. Metformin therapy was cost-saving and increased quality-adjusted life expectancy. CONCLUSIONS/INTERPRETATION: Each of the three policies evaluated has a lower cost per quality-adjusted life year gained than that of many other accepted uses of healthcare resources. The results provide an economic rationale for ensuring that care of patients with type 2 diabetes corresponds at least to the levels of these interventions.

Davis TM, Wright AD, Mehta ZM, Cull CA, Stratton IM, Bottazzo GF, Bosi E, Mackay IR, Holman RR. 2005. Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70). Diabetologia, 48 (4), pp. 695-702. | Show Abstract | Read more

AIMS/HYPOTHESIS: We examined the prevalence of islet autoantibodies and their relationship to glycaemic control over 10 years in patients diagnosed clinically with new-onset type 2 diabetes. METHODS: Patient clinical characteristics and autoantibody status were determined at entry to the UK Prospective Diabetes Study (UKPDS) before randomisation to different glucose control policies. Patients were followed for 10 years. RESULTS: Data available on 4,545 of the 5,102 UKPDS patients showed that 11.6% had antibodies to at least one of three antigens: islet cell cytoplasm, glutamic acid decarboxylase and islet autoantibody 2A (IA-2A). Autoantibody-positive patients were younger, more often Caucasian and leaner, with lower beta cell function and higher insulin sensitivity than autoantibody-negative patients. They also had higher HbA1c, and HDL-cholesterol levels, and lower blood pressure, total cholesterol and plasma triglyceride levels. Despite relative hyperglycaemia, autoantibody-positive patients were less likely to have the metabolic syndrome (as defined by the National Cholesterol Education Program Adult Treatment Program III), reflecting a more beneficial overall risk factor profile. Of 3,867 patients with post-dietary run-in fasting plasma glucose (FPG) values between 6.0 and 14.9 mmol/l and no hyperglycaemic symptoms, 9.4% were autoantibody-positive, compared with 25.1% of 678 patients with FPG values of 15.0 mmol/l or higher, or hyperglycaemic symptoms. In both groups, no differences were seen between those with and without autoantibodies in changes to HbA1c over time, but autoantibody-positive patients required insulin treatment earlier, irrespective of the allocated therapy (p<0.0001). CONCLUSIONS/INTERPRETATION: Autoantibody-positive patients can be treated initially with sulphonylurea, but are likely to require insulin earlier than autoantibody-negative patients.

Bottazzo GF, Bosi E, Cull CA, Bonifacio E, Locatelli M, Zimmet P, Mackay IR, Holman RR. 2005. IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71). Diabetologia, 48 (4), pp. 703-708. | Show Abstract | Read more

AIMS/HYPOTHESIS: Established autoimmune markers of type 1 diabetes, including islet cell autoantibodies (ICA) and autoantibodies to glutamic acid decarboxylase (GADA) have been used to screen people presenting with type 2 diabetes for latent autoimmune diabetes in adults. We have examined the prevalence of autoantibodies to protein tyrosine phosphatase isoforms IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA) in a cohort of adult UKPDS patients thought to have type 2 diabetes, and investigated the possible role of these autoantibodies in predicting requirement for insulin therapy. METHODS: IA-2A and IA-2betaA were measured by a validated radioimmunoassay with human recombinant autoantigens in 4,169 white Caucasian patients aged 25-65 years and newly diagnosed with type 2 diabetes. The clinical requirement for insulin therapy within 6 years was examined in 2,556 patients not randomised to insulin. RESULTS: IA-2A and IA-2betaA were present in 2.2 and 1.4%, respectively, of these patients. IA-2A were more prevalent in younger patients (p for trend <0.00001), more often associated with the HLA-DR4 allele (26.3 vs 8.0%, p<0.0001), and their presence increased the likelihood of insulin therapy requirement within 6 years from diagnosis [relative risk (95%CI) 12.2 (9.8-15.3)]. The presence of IA-2A together with GADA increased the relative risk of requiring insulin therapy from 5.4 (4.1-7.1) for GADA alone to 8.3 (3.7-18.8) and the corresponding positive predictive value from 33 to 50%. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, the presence of IA-2A is infrequent, associated with the HLA-DR4 haplotype, and highly predictive of future need for insulin therapy. The measurement of IA-2betaA does not provide additional information.

Adler AI, Levy JC, Matthews DR, Stratton IM, Hines G, Holman RR. 2005. Insulin sensitivity at diagnosis of Type 2 diabetes is not associated with subsequent cardiovascular disease (UKPDS 67). Diabet Med, 22 (3), pp. 306-311. | Show Abstract | Read more

AIMS: Insulin resistance is common in Type 2 diabetes which, in turn, is associated with a markedly increased risk of cardiovascular disease. Whether insulin sensitivity measured after diagnosis of diabetes is associated with incident cardiovascular disease was evaluated in this prospective study. METHODS: Three thousand five hundred and eighty-two subjects with newly diagnosed diabetes, recruited to the UK Prospective Diabetes Study (UKPDS), free of cardiovascular disease, and with complete information on insulin sensitivity and potential confounders, were followed prospectively to the first occurrence of (i) fatal or non-fatal myocardial infarction, MI (ii) fatal or non-fatal stroke, and (iii) coronary heart disease, CHD (fatal or non-fatal MI, sudden death or ischaemic heart disease). Insulin sensitivity was measured by Homeostatic Model Assessment (HOMA). RESULTS: Insulin sensitivity as measured by HOMA was not associated with subsequent MI, stroke, or CHD in univariate or multivariate models controlling for age, sex, ethnicity, HbA(1c), body mass index, plasma triglycerides, cholesterol and smoking. The hazard ratio associated with a doubling of insulin sensitivity with fatal or non-fatal MI in a multivariate model was 0.92 (95% confidence interval, CI, 0.80-1.05). These results were not changed by the exclusion of overweight patients randomized to metformin. DISCUSSION: Estimation of insulin sensitivity provides no additional useful information with respect to the risk of the first occurrence of cardiovascular disease in patients with newly diagnosed Type 2 diabetes. Among patients with Type 2 diabetes, insulin resistance is not a risk factor for cardiovascular disease.

Stevens RJ, Coleman RL, Holman RR. 2005. Framingham risk equations underestimate coronary heart disease risk in diabetes. Diabet Med, 22 (2), pp. 228. | Read more

Bottazzo GF, Bosi E, Cull CA, Bonifacio E, Locatelli M, Zimmet P, Mackay IR, Holman RR. 2005. Erratum: IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71) (Diabetologia (2005) 48 (703-708) DOI: http://dx.doi.org/10.1007/s00125-005-1691-9) Diabetologia, 48 (6), pp. 1240. | Read more

Cull CA, Neil HA, Holman RR. 2004. Changing aspirin use in patients with Type 2 diabetes in the UKPDS. Diabet Med, 21 (12), pp. 1368-1371. | Show Abstract | Read more

AIMS: To examine the proportion of UK Prospective Diabetes Study (UKPDS) patients with Type 2 diabetes taking aspirin regularly for the primary and secondary prevention of cardiovascular disease (CVD) before and after publication of the 1997 American Diabetes Association (ADA) Clinical Practice Recommendations and the 1998 Joint British Recommendations on the Prevention of Coronary Disease in Clinical Practice. METHODS: UKPDS annual review data from 1996/7 (n = 3190) and 2000/1 (n = 2467) were used to determine the prevalence of patients taking aspirin regularly in relation to known CVD risk factors and pre-existing CVD. RESULTS: Patients taking aspirin regularly were more often male than female (24 vs. 20%, P = 0.0033), older (66 +/- 8 vs. 62 +/- 9 years, P < 0.0001) and less often Afro-Caribbean than White Caucasian or Indian Asian (11 vs. 23 vs. 22%, respectively, P < 0.0001). Between 1996/7 and 2000/1 aspirin use in patients without pre-existing CVD increased from 17 to 31% (P < 0.0001) and for those with pre-existing CVD from 76 to 82% (P = 0.032). CONCLUSION: The majority of patients with pre-existing CVD were taking aspirin regularly. Although aspirin use in those without pre-existing CVD approximately doubled after publication of the ADA and Joint British Recommendations, less than two-thirds of these high-risk patients were being treated according to guidelines. This may relate to a lack of convincing evidence for primary CVD prevention or failure to adhere to guidelines. It may be that more trial data is needed to convince clinicians of the value of aspirin therapy in Type 2 diabetes.

Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM, UK Prospective Diabetes Study Group. 2004. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol, 122 (11), pp. 1631-1640. | Show Abstract | Read more

OBJECTIVE: To determine the relationship between tight blood pressure (BP) control and the different aspects of diabetic retinopathy in patients with type 2 diabetes mellitus (DM). SETTING: Nineteen hospital-based clinics in England, Scotland, and Northern Ireland. DESIGN: Outcome of retinopathy status assessed by 4-field retinal photography related to allocation within a randomized controlled trial comparing a tight BP control policy aiming for a BP less than 150/85 mm Hg with a less tight BP control policy aiming for a BP less than 180/105 mm Hg. SUBJECTS: One thousand one hundred forty-eight hypertensive patients with type 2 DM were studied. These patients had type 2 DM for a mean duration of 2.6 years at the inception of the Hypertension in Diabetes Study, had a mean age of 56 years; and had a mean BP of 160/94 mm Hg. Seven hundred fifty-eight patients were allocated to a tight BP control policy with angiotensin-converting enzyme inhibitor or beta-blockers as the main therapy; 390 were allocated to a less tight BP control policy. MAIN OUTCOME MEASURES: Deterioration of retinopathy (>/=2-step change on a modified Early Treatment Diabetic Retinopathy Study [ETDRS] final scale), together with end points (photocoagulation, vitreous hemorrhage, and cataract extraction) and analysis of specific lesions (microaneurysms, hard exudates, and cotton-wool spots). Visual acuity was assessed at 3-year intervals using ETDRS logarithm of the minimum angle of resolution charts. Blindness was monitored as an end point with the criterion of Snellen chart assessment at 6/60 or worse. RESULTS: By 4.5 years after randomization, there was a highly significant difference in microaneurysm count with 23.3% in the tight BP control group and 33.5% in the less tight BP control group having 5 or more microaneurysms (relative risk [RR], 0.70; P = .003). The effect continued to 7.5 years (RR, 0.66; P<.001). Hard exudates increased from a prevalence of 11.2% to 18.3% at 7.5 years after randomization with fewer lesions found in the tight BP control group (RR, 0.53; P<.001). Cotton-wool spots increased in both groups but less so in the tight BP control group which had fewer cotton-wool spots at 7.5 years (RR, 0.53; P<.001). A 2-step or more deterioration on the ETDRS scale was significantly different at 4.5 years with fewer people in the tight BP control group progressing 2 steps or more (RR, 0.75; P = .02). Patients allocated to tight BP control were less likely to undergo photocoagulation (RR, 0.65; P = .03). This difference was driven by a difference in photocoagulation due to maculopathy (RR, 0.58; P = .02). The cumulative incidence of the end point of blindness (Snellen visual acuity, >/=6/60) in 1 eye was 18/758 for the tight BP control group compared with 12/390 for less tight BP control group. These equate to absolute risks of 3.1 to 4.1 per 1000 patient-years, respectively (P = .046; RR, 0.76; 99% confidence interval, 0.29-1.99). There was no detectable difference in outcome between the 2 randomized therapies of angiotensin-converting enzyme inhibition and beta-blockade. CONCLUSIONS: High BP is detrimental to each aspect of diabetic retinopathy; a tight BP control policy reduces the risk of clinical complications from diabetic eye disease.

Clarke PM, Gray AM, Briggs A, Farmer AJ, Fenn P, Stevens RJ, Matthews DR, Stratton IM, Holman RR, UK Prospective Diabetes Study (UKDPS) Group. 2004. A model to estimate the lifetime health outcomes of patients with type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS no. 68). Diabetologia, 47 (10), pp. 1747-1759. | Show Abstract | Read more

AIMS/HYPOTHESIS: The aim of this study was to develop a simulation model for type 2 diabetes that can be used to estimate the likely occurrence of major diabetes-related complications over a lifetime, in order to calculate health economic outcomes such as quality-adjusted life expectancy. METHODS: Equations for forecasting the occurrence of seven diabetes-related complications and death were estimated using data on 3642 patients from the United Kingdom Prospective Diabetes Study (UKPDS). After examining the internal validity, the UKPDS Outcomes Model was used to simulate the mean difference in expected quality-adjusted life years between the UKPDS regimens of intensive and conventional blood glucose control. RESULTS: The model's forecasts fell within the 95% confidence interval for the occurrence of observed events during the UKPDS follow-up period. When the model was used to simulate event history over patients' lifetimes, those treated with a regimen of conventional glucose control could expect 16.35 undiscounted quality-adjusted life years, and those receiving treatment with intensive glucose control could expect 16.62 quality-adjusted life years, a difference of 0.27 (95% CI: -0.48 to 1.03). CONCLUSIONS/INTERPRETATIONS: The UKPDS Outcomes Model is able to simulate event histories that closely match observed outcomes in the UKPDS and that can be extrapolated over patients' lifetimes. Its validity in estimating outcomes in other groups of patients, however, remains to be evaluated. The model allows simulation of a range of long-term outcomes, which should assist in informing future economic evaluations of interventions in type 2 diabetes.

Mohanlal N, Holman RR. 2004. A standardized triglyceride and carlohydrate challenge - Response DIABETES CARE, 27 (8), pp. 2093-2093. | Read more

Mohanlal N, Holman RR. 2004. A standardized triglyceride and carbohydrate challenge: the oral triglyceride tolerance test. Diabetes Care, 27 (1), pp. 89-94. | Show Abstract | Read more

OBJECTIVE: A standardized method of assessing postprandial triglyceride changes is not available. We evaluated an oral triglyceride tolerance test (OTTT) designed for routine clinical and research use. RESEARCH DESIGN AND METHODS: A 200-ml strawberry-flavored test drink (50 g fat, 50 g carbohydrate) was administered twice to 30 diabetic and 20 nondiabetic subjects. Venous plasma triglyceride and glucose levels were measured when fasting and every 2 h for 8 h after the drink. Fingerprick plasma triglyceride levels were measured when fasting and at 6 and 8 h after the drink. RESULTS: The drink was consumed within 3 min and well tolerated by all subjects. The median triglyceride rise at 6 h was similar in diabetic and nondiabetic subjects (0.23 vs. 0.42 mmol/l, NS) and correlated with glucose increase at 2 h (r = 0.429, P = 0.018 and r = 0.509, P = 0.026; respectively). Diabetic subjects had higher 6-h geometric mean (1 SD range) triglyceride levels (1.82 [1.87 to 3.23] vs. 1.11 [0.66 to 1.11 mmol/l], P < 0.003) but a similar coefficient of variation (17.5 vs. 17.0%, NS) and a similar median (interquartile range) time to achieve maximal concentration (T(max)) (6.0 [4.0 to 6.0] vs. 5.0 [4.0 to 6.0] h, NS). Capillary triglyceride values were equivalent to simultaneous venous samples but consistently 10% greater. CONCLUSIONS: The OTTT permits simple evaluation of postchallenge triglyceride levels, is acceptable to subjects, and can be performed with capillary sampling. It could be used to monitor triglyceride-lowering therapies and to provide additional information concerning cardiovascular disease risk, particularly in diabetic subjects.

Stevens RJ, Coleman RL, Adler AI, Stratton IM, Matthews DR, Holman RR. 2004. Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes: UKPDS 66. Diabetes Care, 27 (1), pp. 201-207. | Show Abstract | Read more

OBJECTIVE: Patients with diabetes have a higher case fatality rate in myocardial infarction (MI) or stroke than those without diabetes: that is, MI and stroke are more often fatal if diabetes is present. We investigated whether the risk of MI or stroke being fatal in type 2 diabetes can be estimated using information available around the time diabetes is diagnosed. RESEARCH DESIGN AND METHODS: Analyses were based on 674 cases of MI (351 fatal) that occurred in 597 of 5,102 U.K. Prospective Diabetes Study (UKPDS) patients for whom covariate data were available during a median follow-up of 7 years. Multivariate logistic regression was used to examine differences in risk factors, measured within 2 years of diagnosis of diabetes, between fatal and nonfatal MI. Similar analyses were performed for 234 strokes (48 fatal) that occurred in 199 patients. RESULTS: Patients with fatal MI had higher HbA(1c) than those with nonfatal MI (odds ratio 1.17 per 1% HbA(1c), P = 0.014). Patients with fatal stroke had higher HbA(1c) than those with nonfatal stroke (odds ratio 1.37 per 1% HbA(1c), P = 0.007). Other risk factors for MI case fatality included increased age, blood pressure, and urine albumin level. CONCLUSIONS: The risk of MI or stroke being fatal in type 2 diabetes is associated with risk factors, including HbA(1c), measured many years before onset of MI or stroke. Equations have been added to the UKPDS Risk Engine to estimate likely case fatality rates in MI and stroke.

Thanopoulou AC, Karamanos BG, Roussi DP. 2004. A standardized triglyceride and carbohydrate challenge: response to Mohanlal and Holman. Diabetes Care, 27 (8), pp. 2092-2093. | Read more

Hadden DR, Cull CA, Croft DJ, Holman RR. 2003. Poor pregnancy outcome for women with Type 2 diabetes. Diabet Med, 20 (6), pp. 506-507. | Read more

Clarke P, Gray A, Legood R, Briggs A, Holman R. 2003. The impact of diabetes-related complications on healthcare costs: results from the United Kingdom Prospective Diabetes Study (UKPDS Study No. 65). Diabet Med, 20 (6), pp. 442-450. | Show Abstract | Read more

AIMS: To develop a model for estimating the immediate and long-term healthcare costs associated with seven diabetes-related complications in patients with Type 2 diabetes participating in the UK Prospective Diabetes Study (UKPDS). METHODS: The costs associated with some major complications were estimated using data on 5102 UKPDS patients (mean age 52.4 years at diagnosis). In-patient and out-patient costs were estimated using multiple regression analysis based on costs calculated from the length of admission multiplied by the average specialty cost and a survey of 3488 UKPDS patients' healthcare usage conducted in 1996-1997. RESULTS: Using the model, the estimate of the cost of first complications were as follows: amputation pound 8459 (95% confidence interval pound 5295, pound 13 200); non-fatal myocardial infarction pound 4070 ( pound 3580, pound 4722); fatal myocardial infarction pound 1152 ( pound 941, pound 1396); fatal stroke pound 3383 ( pound 1935, pound 5431); non-fatal stroke pound 2367 ( pound 1599, pound 3274); ischaemic heart disease pound 1959 ( pound 1467, pound 2541); heart failure pound 2221 ( pound 1690, pound 2896); cataract extraction pound 1553 ( pound 1320, pound 1855); and blindness in one eye pound 872 ( pound 526, pound 1299). The annual average in-patient cost of events in subsequent years ranged from pound 631 ( pound 403, pound 896) for heart failure to pound 105 ( pound 80, pound 142) for cataract extraction. Non-in-patient costs for macrovascular complications were pound 315 ( pound 247, pound 394) and for microvascular complications were pound 273 ( pound 215, pound 343) in the year of the event. In each subsequent year the costs were, respectively, pound 258 ( pound 228, pound 297) and pound 204 ( pound 181, pound 255). CONCLUSIONS: These results provide estimates of the immediate and long-term healthcare costs associated with seven diabetes-related complications.

Davis TM, Mehta Z, Mackay IR, Cull CA, Bruce DG, Fida S, Rowley MJ, Holman RR. 2003. Autoantibodies to the islet cell antigen SOX-13 are associated with duration but not type of diabetes. Diabet Med, 20 (3), pp. 198-204. | Show Abstract | Read more

AIMS: The autoantigen SOX-13 of the SRY-related high mobility group box is a low-frequency reactant in sera from patients with Type 1 diabetes. We further investigated the potential diagnostic role of anti-SOX-13, and in particular its ability to distinguish Type 1 from Type 2 diabetes, in two large, well-characterized cohorts. METHODS: SOX-13 autoantibody status was ascertained using a radioimmunoprecipitation assay in (i) a random sample of 546 participants in an Australian community-based study (the Fremantle Diabetes Study; FDS) of whom 119 had Type 1 and 427 Type 2 diabetes, and (ii) a sample of 333 subjects with Type 2 diabetes from the United Kingdom Prospective Diabetes Study (UKPDS) stratified by age, anti-glutamic acid decarboxylase (GAD) and islet cell antibody (ICA) status, and requirement for insulin therapy within 6 years of diagnosis. RESULTS: The frequencies of anti-SOX-13 in the FDS subjects were 16.0% and 14.8% for Type 1 and Type 2 patients, respectively, and levels were similar. In the UKPDS subjects, the frequency was 4.5%. In a logistic regression model involving demographic, anthropometric and metabolic variables, only diabetes duration was significantly associated with anti-SOX-13 positivity, especially for duration > 5 years (P < 0.002). When the coexistence of autoantibodies was assessed in the two study samples, there were no significant associations between anti-SOX-13 and ICA, anti-GAD or ICA512/IA-2. CONCLUSIONS: Whilst the frequency of anti-SOX-13 may be increased in some populations of diabetic patients, this reactivity does not usefully distinguish Type 1 from Type 2 diabetes. However, the association with diabetes duration suggests that anti-SOX-13 may be a non-specific marker of tissue damage associated with chronic hyperglycaemia.

Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR, UKPDS GROUP. 2003. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int, 63 (1), pp. 225-232. | Show Abstract | Read more

BACKGROUND: The progression of nephropathy from diagnosis of type 2 diabetes has not been well described from a single population. This study sought to describe the development and progression through the stages of microalbuminuria, macroalbuminuria, persistently elevated plasma creatinine or renal replacement therapy (RRT), and death. METHODS: Using observed and modeled data from 5097 subjects in the UK Prospective Diabetes Study, we measured the annual probability of transition from stage to stage (incidence), prevalence, cumulative incidence, ten-year survival, median duration per stage, and risk of death from all-causes or cardiovascular disease. RESULTS: From diagnosis of diabetes, progression to microalbuminuria occurred at 2.0% per year, from microalbuminuria to macroalbuminuria at 2.8% per year, and from macroalbuminuria to elevated plasma creatinine (>or=175 micromol/L) or renal replacement therapy at 2.3% per year. Ten years following diagnosis of diabetes, the prevalence of microalbuminuria was 24.9%, of macroalbuminuria was 5.3%, and of elevated plasma creatinine or RRT was 0.8%. Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2% (95% confidence interval, CI, 14.0 to 24.4%). There was a trend for increasing risk of cardiovascular death with increasing nephropathy (P < 0.0001), with an annual rate of 0.7% for subjects in the stage of no nephropathy, 2.0% for those with microalbuminuria, 3.5% for those with macroalbuminuria, and 12.1% with elevated plasma creatinine or RRT. Individuals with macroalbuminuria were more likely to die in any year than to develop renal failure. CONCLUSIONS: The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis. Relatively fewer patients develop macroalbuminuria, but in those who do, the death rate exceeds the rate of progression to worse nephropathy.

Karpe F, Holman R. 2002. Fire-and-forget in prevention of coronary heart disease. Lancet, 360 (9349), pp. 1984. | Read more

Stevens RJ, Stratton IM, Holman RR, UK Prospective Diabetes Study (UKPDS58). 2002. UKPDS58--modeling glucose exposure as a risk factor for photocoagulation in type 2 diabetes. J Diabetes Complications, 16 (6), pp. 371-376. | Show Abstract | Read more

In type 2 diabetes, the risk of retinopathy, and of retinal photocoagulation, rises with time after diagnosis of diabetes. In this paper, mathematical modeling shows that this ageing effect is attributable to the rise in glycemia with time since diagnosis of diabetes. Mathematical models were fitted to data from 3,648 patients from the UK Prospective Diabetes Study (UKPDS). A proportional hazards model, in which time and glycemia measured by HbA(1c) are independent risk factors for photocoagulation, was compared to a model in which time does not contribute except through a measure of cumulative glucose exposure. Since likelihood ratio tests cannot be applied to non-nested models, graphical methods were used to compare the two models. The glucose exposure model was able to fit variation in survival with time at least as well as the proportional hazards model. The proportional hazards model, however, seriously underestimates the differences in two groups of different mean HbA(1c). We conclude that duration of diabetes and HbA(1c) level better predict risk for photocoagulation when treated as two components of cumulative glucose exposure, than when treated as independent risk factors.

Molyneux A, Kerr R, International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group, Stratton I, Sandercock P, Clarke M, Shrimpton J, Holman R. 2002. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. J Stroke Cerebrovasc Dis, 11 (6), pp. 304-314. | Show Abstract | Read more

Endovascular detachable coil treatment is being increasingly used as an alternative to craniotomy and clipping for some ruptured intracranial aneurysms, although the relative benefits of these two approaches have yet to be established. We undertook a randomized, multicenter trial to compare the safety and efficacy of endovascular coiling with standard neurosurgical clipping for such aneurysms judged to be suitable for both treatments. We enrolled 2143 patients with ruptured intracranial aneurysms and randomly assigned them to neurosurgical clipping (n = 1070) or endovascular treatment by detachable platinum coils (n = 1073). Clinical outcomes were assessed at both 2 months and at 1 year with interim ascertainment of rebleeds and death. The primary outcome was the proportion of patients with a modified Rankin scale (mRs) score between 3 and 6 (dependency or death) at 1 year. Trial recruitment was stopped by the steering committee after a planned interim analysis. Analysis was per protocol. One hundred and ninety of 801 (23.7%) patients allocated endovascular treatment were dependent or dead at 1 year compared with 243 of 793 (30.6%) of those allocated neurosurgical treatment (P = .0019). The relative and absolute risk reductions in dependency or death after allocation to an endovascular versus neurosurgical treatment were 22.6% (95% CI 8.9-34.2) and 6.9% (2.5-11.3), respectively. The risk of rebleeding from the ruptured aneurysm after 1 year was two per 1276 and zero per 1081 patient-years for patients allocated endovascular and neurosurgical treatment, respectively. In patients with a ruptured intracranial aneurysm, for which endovascular coiling and neurosurgical clipping are therapeutic options, the outcome in terms of survival free of disability at 1 year is significantly better with endovascular coiling. The data available to date suggest that the long-term risks of further bleeding from the treated aneurysm are low with either therapy, although somewhat more frequent with endovascular coiling.

Molyneux A. 2002. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial The Lancet, 360 (9342), pp. 1267-1274. | Read more

Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, Holman R, International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. 2002. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet, 360 (9342), pp. 1267-1274. | Show Abstract | Read more

BACKGROUND: Endovascular detachable coil treatment is being increasingly used as an alternative to craniotomy and clipping for some ruptured intracranial aneurysms, although the relative benefits of these two approaches have yet to be established. We undertook a randomised, multicentre trial to compare the safety and efficacy of endovascular coiling with standard neurosurgical clipping for such aneurysms judged to be suitable for both treatments. METHODS: We enrolled 2143 patients with ruptured intracranial aneurysms and randomly assigned them to neurosurgical clipping (n=1070) or endovascular treatment by detachable platinum coils (n=1073). Clinical outcomes were assessed at 2 months and at 1 year with interim ascertainment of rebleeds and death. The primary outcome was the proportion of patients with a modified Rankin scale score of 3-6 (dependency or death) at 1 year. Trial recruitment was stopped by the steering committee after a planned interim analysis. Analysis was per protocol. FINDINGS: 190 of 801 (23.7%) patients allocated endovascular treatment were dependent or dead at 1 year compared with 243 of 793 (30.6%) allocated neurosurgical treatment (p=0.0019). The relative and absolute risk reductions in dependency or death after allocation to an endovascular versus neurosurgical treatment were 22.6% (95% CI 8.9-34.2) and 6.9% (2.5-11.3), respectively. The risk of rebleeding from the ruptured aneurysm after 1 year was two per 1276 and zero per 1081 patient-years for patients allocated endovascular and neurosurgical treatment, respectively. INTERPRETATION: In patients with a ruptured intracranial aneurysm, for which endovascular coiling and neurosurgical clipping are therapeutic options, the outcome in terms of survival free of disability at 1 year is significantly better with endovascular coiling. The data available to date suggest that the long-term risks of further bleeding from the treated aneurysm are low with either therapy, although somewhat more frequent with endovascular coiling.

Homocysteine Studies Collaboration. 2002. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA, 288 (16), pp. 2015-2022. | Show Abstract | Read more

CONTEXT: It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke. OBJECTIVE: To assess the relationship of homocysteine concentrations with vascular disease risk. DATA SOURCES: MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators. STUDY SELECTION: Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete. DATA EXTRACTION: Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression. DATA SYNTHESIS: Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk. CONCLUSIONS: This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.

Gray A, Clarke P, Farmer A, Holman R, United Kingdom Prospective Diabetes Study (UKPDS) Group. 2002. Implementing intensive control of blood glucose concentration and blood pressure in type 2 diabetes in England: cost analysis (UKPDS 63). BMJ, 325 (7369), pp. 860. | Show Abstract | Read more

OBJECTIVE: To estimate the incremental cost of implementing policies for intensive control of blood glucose concentration and blood pressure for all patients with type 2 diabetes in England. DESIGN: Extrapolation of resource use and cost data derived from a randomised controlled trial. SETTING: General practice, outpatient care, and inpatient care. POPULATION: Trial population with diagnosed type 2 diabetes in England extrapolated to the population of England. MAIN OUTCOME MEASURES: Total costs based on use of healthcare resources including costs of management, treatment, and hospitalisation. RESULTS: The incremental net annual cost of implementing intensive control of blood glucose and blood pressure to all people with diagnosed type 2 diabetes in England is estimated to be pound 100.5m ($156m; euro;159m), which is equivalent to less than 1% of the proposed additional annual expenditure on the NHS in 2001-5. This estimate varied in sensitivity analyses from pound 67m to pound 121m. CONCLUSIONS: Policies to improve control of blood glucose and blood pressure of people with type 2 diabetes are effective in reducing complications associated with the disease and are also cost effective. The total cost represents a small fraction of the NHS's spending plans.

Viberti G, Kahn SE, Greene DA, Herman WH, Zinman B, Holman RR, Haffner SM, Levy D et al. 2002. A diabetes outcome progression trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. Diabetes Care, 25 (10), pp. 1737-1743. | Show Abstract | Read more

OBJECTIVE: Therapies with metformin, sulfonylureas, or insulin improve glycemic control in the short term but do not prevent progressive islet beta-cell failure or long-term deterioration in glycemia. Our goal was to evaluate, in patients recently diagnosed with type 2 diabetes (<3 years), the long-term efficacy of monotherapy with rosiglitazone on glycemic control and on the progression of pathophysiological abnormalities associated with type 2 diabetes as compared with metformin or glyburide monotherapy. RESEARCH DESIGN AND METHODS: A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind, parallel-group study consisting of a screening visit, a 4-week placebo run-in, a 4-year treatment period, and an observational follow-up of approximately 3,600 drug-naïve patients with type 2 diabetes diagnosed within the previous 3 years. After run-in, patients will be randomized to rosiglitazone, glyburide, or metformin titrated to the maximum effective daily doses (8 mg rosiglitazone, 15 mg glyburide, or 2 g metformin). The primary outcome is time to monotherapy failure, defined as the time following titration to the maximal effective or tolerated dose when fasting plasma glucose exceeds 180 mg/dl (10 mmol/l). Secondary outcomes include measures of islet beta-cell function, insulin sensitivity, dyslipidemia, changes in urinary albumin excretion, plasminogen activator inhibitor-1 antigen, fibrinogen, and C-reactive protein. Safety and tolerability will also be evaluated. Patient-reported outcomes and resource utilization data will be collected and analyzed. CONCLUSIONS: ADOPT will provide data on the effect of mechanistically differing treatment options on metabolic control, beta-cell function, and markers of macrovascular disease risk in type 2 diabetes.

Colagiuri S, Cull CA, Holman RR, UKPDS Group. 2002. Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes?: U.K. prospective diabetes study 61. Diabetes Care, 25 (8), pp. 1410-1417. | Show Abstract | Read more

OBJECTIVE: Type 2 diabetes may be present for several years before diagnosis, by which time many patients have already developed diabetic complications. Earlier detection and treatment may reduce this burden, but evidence to support this approach is lacking. RESEARCH DESIGN AND METHODS: Glycemic control and clinical and surrogate outcomes were compared for 5,088 of 5,102 U.K. Diabetes Prospective Study participants according to whether they had low (<140 mg/dl [<7.8 mmol/l]), intermediate (140 to <180 mg/dl [7.8 to <10.0 mmol/l]), or high (> or =180 mg/dl [> or =10 mmol/l]) fasting plasma glucose (FPG) levels at diagnosis. Individuals who presented with and without diabetic symptoms were also compared. RESULTS: Fewer people with FPG in the lowest category had retinopathy, abnormal biothesiometer measurements, or reported erectile dysfunction. The rate of increase in FPG and HbA(1c) during the study was identical in all three groups, although absolute differences persisted. Individuals in the low FPG group had a significantly reduced risk for each predefined clinical outcome except stroke, whereas those in the intermediate group had significantly reduced risk for each outcome except stroke and myocardial infarction. The low and intermediate FPG groups had a significantly reduced risk for progression of retinopathy, reduction in vibration sensory threshold, or development of microalbuminuria. CONCLUSIONS: People presenting with type 2 diabetes with lower initial glycemia who may be earlier in the course of their disease had fewer adverse clinical outcomes despite similar glycemic progression. Since most such people are asymptomatic at diagnosis, active case detection programs would be required to identify them.

Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, Holman RR. 2002. UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine. Stroke, 33 (7), pp. 1776-1781. | Show Abstract | Read more

BACKGROUND AND PURPOSE: People with type 2 diabetes are at elevated risk of stroke compared with those without diabetes. Relative risks have been examined in earlier work, but there is no readily available method for predicting the absolute risk of stroke in a diabetic individual. We developed mathematical models to estimate the risk of a first stroke using data from 4549 newly diagnosed type 2 diabetic patients enrolled in the UK Prospective Diabetes Study. METHODS: During 30 700 person-years of follow-up, 188 first strokes (52 fatal) occurred. Model fitting was carried out by maximum likelihood estimation using the Newton-Raphson method. Diagnostic plots were used to compare survival probabilities calculated by the model with those calculated using nonparametric methods. RESULTS: Variables included in the final model were duration of diabetes, age, sex, smoking, systolic blood pressure, total cholesterol to high-density lipoprotein cholesterol ratio and presence of atrial fibrillation. Not included in the model were body mass index, hemoglobin A1c, ethnicity, and ex-smoking status. The use of the model is illustrated with a hypothetical study power calculation. CONCLUSIONS: This model forecasts the absolute risk of a first stroke in people with type 2 diabetes using variables readily available in routine clinical practice.

Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR. 2002. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care, 25 (5), pp. 894-899. | Show Abstract | Read more

OBJECTIVE: To determine the role of hyperglycemia in prospective analyses of peripheral vascular disease (PVD) in type 2 diabetes, taking into account other potential risk factors. RESEARCH DESIGN AND METHODS: Potential risk factors for the development of PVD were examined in 3,834 of 5,102 individuals enrolled in the U.K. Prospective Diabetes Study (UKPDS) without PVD at diagnosis of diabetes, followed for 6 years, and for whom relevant data were available. PVD was defined as two of the following: ankle-arm blood pressure index < 0.8, absence of both dorsalis pedis and posterior tibial pulses to palpation in one or both legs, and intermittent claudication. Logistic regression was used to estimate the association between potential risk factors measured 3-4 months after diagnosis of diabetes and incident PVD. The prevalence of PVD at 3-year intervals to 18 years was determined. RESULTS: Hyperglycemia, assessed as HbA(1c), was associated with an increased risk for incident PVD, independent of other risk factors including age, increased systolic blood pressure, reduced HDL cholesterol, smoking, prior cardiovascular disease, peripheral sensory neuropathy, and retinopathy. Each 1% increase in HbA(1c) was associated with a 28% increased risk of PVD (95% CI 12-46), and each 10-mmHg increase in systolic blood pressure with a 25% increase in risk (95% CI 10-43). CONCLUSIONS: Hyperglycemia, as well as smoking, dyslipidemia, and blood pressure are potentially modifiable risk factors for the development of PVD.

Kwong K, Hornbuckle K, Cavazonni P, Carlson C, Wu J, Breier A, Holman R. 2002. A retrospective cohort study of diabetes mellitus and antipsychotic treatment in the United Kingdom BIOLOGICAL PSYCHIATRY, 51 (8), pp. 132S-132S.

Gloyn AL, Desai M, Clark A, Levy JC, Holman RR, Frayling TM, Hattersley AT, Ashcroft SJ. 2002. Human calcium/calmodulin-dependent protein kinase II gamma gene (CAMK2G): cloning, genomic structure and detection of variants in subjects with type II diabetes. Diabetologia, 45 (4), pp. 580-583. | Show Abstract | Read more

AIMS/HYPOTHESIS: Ca(2+)/calmodulin-dependent protein kinase II, is expressed in the pancreatic beta cells and is activated by glucose and other secretagogues in a manner correlating with insulin secretion. The activation of Ca(2+)/calmodulin-dependent protein kinase II mediates some of the actions of Ca(2+) on the exocytosis of insulin. We therefore investigated the gene encoding the gamma isoform ( CAMK2G) which has been shown to be expressed in human beta cells as a candidate gene for Type II (non-insulin-dependent) diabetes mellitus. METHODS: Human CAMK2G was cloned from a total human P1 artificial chromosome library using a partial Ca(2+)/calmodulin-dependent protein kinase gamma(E) cDNA probe. Positive PAC clones were localised to chromosome 10q22 by fluorescence in situ hybridisation. To obtain structural information and the sequences of the exon-intron boundaries, the published genomic structures of the rat and mouse genes allowed the putative exon-intron boundaries of human CAMK2G to be amplified by vectorette polymerase chain reaction and sequenced. Sequence variants in each exon were identified using single stranded conformational polymorphism analysis. RESULTS: The human CAMK2G gene comprises 22 exons which range in size between 43 to 230 bp. Screening of the exons and exon-intron boundaries identified two single nucleotide polymorphisms. These did not show association with diabetes in 122 patients and 144 control subjects. CONCLUSIONS/INTERPRETATION: We have identified the genomic structure of CAMK2G to enable further study of this potential candidate gene. Variation in this gene is not strongly associated with diabetes in Caucasians in the United Kingdom. We have identified two single nucleotide polymorphisms which, with appropriately large case control studies, can be used to assess the role of CAMK2G in the susceptibility to Type II diabetes.

Hashim Y, Shepherd D, Wiltshire S, Holman RR, Levy JC, Clark A, Cull CA. 2002. Butyrylcholinesterase K variant on chromosome 3q is associated with Type II diabetes in white Caucasian subjects (vol 44, pg 2227, 2001) DIABETOLOGIA, 45 (3), pp. 459-459.

Wright A, Burden AC, Paisey RB, Cull CA, Holman RR, U.K. Prospective Diabetes Study Group. 2002. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care, 25 (2), pp. 330-336. | Show Abstract | Read more

OBJECTIVE: To evaluate the efficacy of the addition of insulin when maximal sulfonylurea therapy is inadequate in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Glycemic control, hypoglycemia, and body weight were monitored over 6 years in 826 patients with newly diagnosed type 2 diabetes in 8 of 23 U.K. Prospective Diabetes Study (UKPDS) centers that used a modified protocol. Patients were randomly allocated to a conventional glucose control policy, primarily with diet (n = 242) or an intensive policy with insulin alone (n = 245), as in the main study. However, for patients randomized to an intensive policy with sulfonylurea (n = 339), insulin was added automatically if the fasting plasma glucose remained >108 mg/dl (6.0 mmol/l) despite maximal sulfonylurea doses. RESULTS: Over 6 years, approximately 53% of patients allocated to treatment with sulfonylurea required additional insulin therapy. Median HbA(1c) in the sulfonylurea +/- insulin group was significantly lower (6.6%, interquartile range [IQR] 6.0-7.6) than in the group taking insulin alone (7.1%, IQR 6.2-8.0; P = 0.0066), and significantly more patients in the sulfonylurea +/- insulin group had an HbA(1c) <7% (47 vs. 35%, respectively; P = 0.011). Weight gain was similar in the intensive therapy groups, but major hypoglycemia occurred less frequently over all in the sulfonylurea (+/- insulin) group compared with the insulin alone group (1.6 vs. 3.2% per annum, respectively; P = 0.017). CONCLUSIONS: Early addition of insulin when maximal sulfonylurea therapy is inadequate can significantly improve glycemic control without promoting increased hypoglycemia or weight gain.

Lenzen H, Barrow BA, White S, Holman RR. 2002. A non-invasive frequent home blood glucose monitor Practical Diabetes International, 19 (4), pp. 101-103. | Show Abstract | Read more

Attaining near-normoglycaemia in patients with diabetes is essential if diabetes-related complications are to be minimised. Attempts to optimise glycaemic control are often limited by the infrequent nature of current home blood glucose monitoring systems and fear of hypoglycaemia. We evaluated the potential benefit of the GlucoWatch® Biographer, a non-invasive glucose monitoring device designed to give a frequent measure of blood glucose and provide early warning of hypoglycaemia or hyperglycaemia, in five subjects with type 1 diabetes over a three week period. Subjects found the device easy to use, obtaining 762 usable readings out of a possible 1168 (65%) although all experienced some degree of skin irritation. They felt that the device facilitated continuous blood glucose monitoring and thought that high and low glucose alarms were helpful. Subjects experienced between one and six hypoglycaemia alarms per day, usually 20 to 60 min before the appearance of clinical symptoms, and between zero and four hyperglycaemia alarms per day. The degree to which the device can improve glycaemic control remains to be evaluated. Copyright © 2002 John Wiley & Sons, Ltd.

Hashim Y, Shepherd D, Wiltshire S, Holman RR, Levy JC, Clark A, Cull CA. 2002. Erratum: Butyrylcholinesterase K variant on chromosome 3q is associated with Type II diabetes in white Caucasian subjects (Diabetologia (2001) 44 (2227-2230)) Diabetologia, 45 (3), pp. 459.

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Viberti G, Kahn SE, Greene DA, Herman WH, Zinman B, Holman RR, Haffner SM, Levy D et al. 2002. A Diabetes Outcome Progression Trial (ADOPT): An international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes Diabetes Care, 25 (10), pp. 1737-1743. | Show Abstract | Read more

OBJECTIVE - Therapies with metformin, sulfonylureas, or insulin improve glycemic control in the short term but do not prevent progressive islet β-cell failure or long-term deterioration in glycemia. Our goal was to evaluate, in patients recently diagnosed with type 2 diabetes (<3 years), the long-term efficacy of monotherapy with rosiglitazone on glycemic control and on the progression of pathophysiological abnormalities associated with type 2 diabetes as compared with metformin or glyburide monotherapy. RESEARCH DESIGN AND METHODS - A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind, parallel-group study consisting of a screening visit, a 4-week placebo run-in, a 4-year treatment period, and an observational follow-up of ∼3,600 drug-naïve patients with type 2 diabetes diagnosed within the previous 3 years. After run-in, patients will be randomized to rosiglitazone, glyburide, or metformin titrated to the maximum effective daily doses (8 mg rosiglitazone, 15 mg glyburide, or 2 g metformin). The primary outcome is time to monotherapy failure, defined as the time following titration to the maximal effective or tolerated dose when fasting plasma glucose exceeds 180 mg/dl (10 mmol/l). Secondary outcomes include measures of islet β-cell function, insulin sensitivity, dyslipidemia, changes in urinary albumin excretion, plasminogen activator inhibitor-1 antigen, fibrinogen, and C-reactive protein. Safety and tolerability will also be evaluated. Patient-reported outcomes and resource utilization data will be collected and analyzed. CONCLUSIONS - ADOPT will provide data on the effect of mechanistically differing treatment options on metabolic control, β-cell function, and markers of macrovascular disease risk in type 2 diabetes.

Clarke P, Gray A, Holman R. 2002. Estimating utility values for health states of type 2 diabetic patients using the EQ-5D (UKPDS 62). Med Decis Making, 22 (4), pp. 340-349. | Show Abstract | Read more

PURPOSE: The aim of this study was to analyze quality-of-life data from the United Kingdom Prospective Diabetes Study (UKPDS) to estimate the impact of diabetes-related complications on utility-based measures of quality of life. METHODS: The EuroQol EQ-5D instrument was administered in 1996 to 3667 UKPDS patients with type 2 diabetes. Tobit and censored least absolute deviations (CLAD) regression analysis based on data from the 3192 respondents was used to estimate the impact of major complications on (1) the visual analog scale (VAS) and (2) the EQ-5D utilities derived from population-based time trade-off values. RESULTS: Using the tobit model, the effect on tariff values was as follows: myocardial infarction = -0.055 (95% confidence interval [CI] = -0.067, -0.042), blindness in 1 eye = -0.074 (95% CI= -0.124, -0.052), ischemic heart disease = -0.090 (95% CI = -0.126, -0.054), heartfailure = -0.108 (95% CI= -0.169, -0.048), stroke = -0.164 (95% CI = -0.222, -0.105), and amputation = -0.280 (95% CI = -0.389, -0.170). The impact on the VAS scores was smaller, but the ranking was identical. Estimates of these effects, based on the nonparametric CLAD estimator, are also reported and compared. CONCLUSION: These results demonstrate the magnitude of the impact of 6 complications on utility-based measures of quality of life, which can be used to estimate the outcome of interventions that reduce these diabetes-related complications.

Karpe F, Holman R, Shepherd J. 2002. Fire-and-forget in prevention of coronary heart disease [15] (multiple letters) Lancet, 360 (9349), pp. 1984.

Stevens RJ, Kothari V, Adler AI, Stratton IM, United Kingdom Prospective Diabetes Study (UKPDS) Group. 2001. The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56). Clin Sci (Lond), 101 (6), pp. 671-679. | Show Abstract | Read more

A definitive model for predicting absolute risk of coronary heart disease (CHD) in male and female people with Type II diabetes is not yet available. This paper provides an equation for estimating the risk of new CHD events in people with Type II diabetes, based on data from 4540 U.K. Prospective Diabetes Study male and female patients. Unlike previously published risk equations, the model is diabetes-specific and incorporates glycaemia, systolic blood pressure and lipid levels as risk factors, in addition to age, sex, ethnic group, smoking status and time since diagnosis of diabetes. All variables included in the final model were statistically significant (P<0.001, except smoking for which P=0.0013) in likelihood ratio testing. This model provides the estimates of CHD risk required by current guidelines for the primary prevention of CHD in Type II diabetes.

Hashim Y, Shepherd D, Wiltshire S, Holman RR, Levy JC, Clark A, Cull CA. 2001. Butyrylcholinesterase K variant on chromosome 3 q is associated with Type II diabetes in white Caucasian subjects. Diabetologia, 44 (12), pp. 2227-2230. | Show Abstract | Read more

AIMS/HYPOTHESIS: To determine the association of three genes associated with Alzheimer's disease--butyrylcholinesterase (BcHE) on chromosome 3 q, alpha2 macroglobulin (alpha2M) on chromosome 12 p and apolipoprotein E (ApoE) on chromosome 19 q--with Type II (non-insulin-dependent) diabetes mellitus. METHODS: Frequencies of BcHE K variant, alpha2M insertion and/or deletion polymorphism, the ApoE common polymorphisms and promoter variants at ApoE-491 and -291, were examined by fluorescent RFLP in DNA from 276 United Kingdom Prospective Diabetes Study Type II diabetic subjects and 351 non-diabetic subjects from the Diabetes In Families study. Genetic data in diabetic subjects was analysed in relation to clinical characteristics and islet function as assessed by the requirement for insulin therapy 6 years after randomisation. RESULTS: The BcHE K variant allele was more common among Type II diabetic subjects (D) than non-diabetic subjects (ND) (22.8 % D vs 15.8 % ND; p = 0.00 017). Subjects homozygous for the variant were more frequent in the diabetic group (5.8 % D vs 2.6 % ND: p = 0.00 056). The K variant allele frequency was not associated with a requirement for insulin therapy (29.0 % insulin-requiring vs 21.8 % non-insulin-requiring; p = 0.121). There were no associations of alpha2M and ApoE polymorphisms or ApoE promoter variants with clinical characteristics or insulin requirement in diabetic subjects. There were differences in total cholesterol (p = 0.0005) and LDL-cholesterol (p = 0.0009) among non-diabetic subjects in relation to ApoE-491 genotypes. CONCLUSION/INTERPRETATION: The association of the BcHE gene (3q26) with Type II diabetes could be related to an identified susceptibility locus on chromosome 3q27 but appears to be independent of islet function. The absence of diabetes-specific associations with alpha2M, ApoE or ApoE promoter variants suggest that these are not important in the onset of hyperglycaemia.

Clarke R, Lewington S, Donald A, Johnston C, Refsum H, Stratton I, Jacques P, Breteler MM, Holman R. 2001. Underestimation of the importance of homocysteine as a risk factor for cardiovascular disease in epidemiological studies. J Cardiovasc Risk, 8 (6), pp. 363-369. | Show Abstract | Read more

BACKGROUND: In epidemiological studies, within-person variability in plasma total homocysteine (tHcy) measurements may dilute the association of 'usual' levels of tHcy with risk of cardiovascular disease, referred to as 'regression dilution'. The aim of this report was to estimate the magnitude of regression dilution after varying intervals of follow-up. METHODS: Regression dilution ratios (RDR) for tHcy were calculated using replicate tHcy measurements obtained after 3, 6 and 8 years from the Rotterdam, Hordaland and Framingham studies, respectively, and after 3, 6, 9 and 12 years from the United Kingdom Prospective Study of type 2 Diabetes Mellitus (UKPDS). RESULTS: The RDR for tHcy decreased with increasing interval in the three population-based studies and in the UKPDS. Moreover, the rate of decline of the RDR in the population-based studies was similar to that obtained in the UKPDS. Using linear regression analysis for the population-based studies, these results suggest an RDR of 0.83 at 2 years, 0.71 at 6 years and 0.53 at 12 years. CONCLUSIONS: These results have important implications for the interpretation of prospective studies of tHcy and cardiovascular disease. Failure to correct for increasing regression dilution using lower RDRs for longer follow-up may underestimate the relative risks of cardiovascular disease associated with tHcy by about one-fifth after 2 years and one-half after 10 years.

Holman R, Stratton I, Johnston C, Clarke R. 2001. Plasma homocysteine, type 2 diabetes and risk of coronary heart disease in the UKPDS CIRCULATION, 104 (17), pp. 3-3.

Holman RR, Matthews DR, Meade T, Grp UKPDS. 2001. Commentary: UK-PDS is well designed and clinically important BRITISH MEDICAL JOURNAL, 323 (7317), pp. 857-858.

Cull CA, Wright AD, Macleod KM, Holman RR, Grp UKPDS. 2001. Hypoglycaemia in patients with Type 2 diabetes in the UKPDS DIABETOLOGIA, 44 pp. A217-A217.

Gloyn AL, Desai M, Clark A, Holman RR, Frayling TM, Hattersley AT, Ashcroft SJH. 2001. Calcium/calmodulin dependent protein kinase II genes: Genomic structure and screening for variants in subjects with Type 2 diabetes DIABETOLOGIA, 44 pp. A88-A88.

Bosi E, Locatelli M, Cull CA, Scirpoli M, Bobifacio E, Stratton IM, Holman RR, Bottazzo GF, Grp UKPDS. 2001. Autoantibodies to JA2ic and to Phogrin increase the prediction for insulin requirement in patients with Type 2 Diabetes DIABETOLOGIA, 44 pp. A103-A103.

Mohanlal N, Holman RR. 2001. Altered postprandial responses in type 2 diabetes DIABETOLOGIA, 44 pp. A165-A165.

Horton VA, Stratton IM, Owen R, Holman RR, Levy JC, Clark A. 2001. Variation at the insulin VNTR locus but not the CTLA-4 locus is associated with age of onset and need for insulin therapy in latent autoimmune diabetes in adults (LADA) DIABETOLOGIA, 44 pp. A75-A75.

Davis TM, Cull CA, Holman RR, U.K. Prospective Diabetes Study (UKPDS) Group. 2001. Relationship between ethnicity and glycemic control, lipid profiles, and blood pressure during the first 9 years of type 2 diabetes: U.K. Prospective Diabetes Study (UKPDS 55). Diabetes Care, 24 (7), pp. 1167-1174. | Show Abstract | Read more

OBJECTIVE: To assess the relationship among self-reported ethnicity, metabolic control, and blood pressure during treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 2,999 newly diagnosed type 2 diabetic patients recruited to the U.K. Prospective Diabetes Study who were randomized to conventional or intensive glucose control policies if their fasting plasma glucose levels remained >6 mmol/l after a dietary run-in. A total of 2,484 patients (83%) were white Caucasian (WC), 265 patients (9%) were Afro-Caribbean (AC), and 250 patients (8%) were Asian of Indian origin (IA). Variables were assessed at 3, 6, and 9 years. RESULTS: During the 9-year study period, body weight increased more in WC patients (mean 5.0 kg) than in AC (3.0 kg) and IA (2.5 kg) patients (P < 0.001). After adjusting for age, sex, baseline value, treatment allocation, and change in weight, there were no consistent ethnic differences in mean change in fasting plasma glucose or HbA(1c). After adjustment for antihypertensive therapy, increase in systolic blood pressure at 9 years was greatest in AC patients (7 mmHg; P < 0.01 vs. WC patients). Mean diastolic blood pressure, total cholesterol, and LDL cholesterol decreased progressively during the 9 years in each group. In AC patients, the mean increase in HDL cholesterol (0.16 mmol/l) at 3 years, maintained to 9 years, and the mean decrease in plasma triglyceride level (0.4 mmol/l) at 9 years were greater than in WC and IA patients (P < 0.001). CONCLUSIONS: This study shows important ethnic differences in body weight, lipid profiles, and blood pressure, but not glycemic control, during 9 years after diagnosis of type 2 diabetes. AC patients maintained the most favorable lipid profiles, but hypertension developed in more AC patients than WC or IA patients. Ethnicity-specific glycemic control of type 2 diabetes seems unnecessary, but other risk factors need to be addressed independently.

Gray A, Clarke P, Raikou M, Adler A, Stevens R, Neil A, Cull C, Stratton I, Holman R, UKPDS Group. 2001. An economic evaluation of atenolol vs. captopril in patients with Type 2 diabetes (UKPDS 54). Diabet Med, 18 (6), pp. 438-444. | Show Abstract | Read more

AIMS: To compare the net cost of a tight blood pressure control policy with an angiotensin converting enzyme inhibitor (captopril) or beta blocker (atenolol) in patients with Type 2 diabetes. DESIGN: A cost-effectiveness analysis based on outcomes and resources used in a randomized controlled trial and assumptions regarding the use of these therapies in a general practice setting. SETTING: Twenty United Kingdom Prospective Diabetes Study Hospital-based clinics in England, Scotland and Northern Ireland. SUBJECTS: Hypertensive patients (n = 758) with Type 2 diabetes (mean age 56 years, mean blood pressure 159/94 mmHg), 400 of whom were allocated to the angiotensin converting enzyme inhibitor captopril and 358 to the beta blocker atenolol. MAIN OUTCOME MEASURES: Life expectancy and mean cost per patient. RESULTS: There was no statistically significant difference in life expectancy between groups. The cost per patient over the trial period was 6485 UK pounds in the captopril group, compared with 5550 UK pounds in the atenolol group, an average cost difference of 935 UK pounds (95% confidence interval 188 UK pounds, 1682 UK pounds). This 14% reduction arose partly because of lower drug prices, and also because of significantly fewer and shorter hospitalizations in the atenolol group, and despite higher antidiabetic drug costs in the atenolol group. CONCLUSIONS: Treatment of hypertensive patients with Type 2 diabetes using atenolol or captopril was equally effective. However, total costs were significantly lower in the atenolol group. Diabet. Med. 18, 438-444 (2001)

Stratton IM, Cull CA, Manley SE, Adler AI, Neil HAW, Matthews DR, Holman RR. 2001. Glycaemia and vascular effects of type 2 diabetes - Reply BRITISH MEDICAL JOURNAL, 322 (7296), pp. 1247-1247.

Kohner EM, Stratton IM, Aldington SJ, Holman RR, Matthews DR, UK Prospective Diabetes Study (IKPDS) Group. 2001. Relationship between the severity of retinopathy and progression to photocoagulation in patients with Type 2 diabetes mellitus in the UKPDS (UKPDS 52). Diabet Med, 18 (3), pp. 178-184. | Show Abstract | Read more

AIM: to establish the degree to which the severity of retinopathy determines the risk for the need for subsequent photocoagulation in those with newly diagnosed Type 2 diabetes mellitus. METHODS: Of 5102 patients entered into the UK Prospective Diabetes Study (UKPDS), 3709 had good quality retinal photographs that could be graded at entry. They were followed until the end of the study or until lost to follow-up, or until they received photocoagulation. Retinopathy severity was categorized as no retinopathy, microaneurysms (MA) only in one eye, MA in both eyes or more severe retinopathy features. The risk of photocoagulation was assessed in relation to severity of retinopathy at baseline, 3 and 6 years. RESULTS: Of the 3709 patients assessed at entry to the UKPDS, 2316 had no retinopathy. Of these 0.2% needed photocoagulation at 3 years, 1.1% at 6 years and 2.6% at 9 years. Those with MA in one eye only (n = 708) were similar, with 0%, 1.9% and 4.7% needing photocoagulation by 3, 6 and 9 years, respectively. Amongst those who had more retinopathy features at entry (n = 509), 15.3% required photocoagulation by 3 years, and 31.9% by 9 years. When those without retinopathy at 6 years (n = 1579) were examined 3 and 6 years later (9 and 12 years after diagnosis), 0.1% and 1.8% required photocoagulation. Those with more severe retinopathy (n = 775) needed earlier treatment, 6.6% after 3 years and 13.3% after 9 years. The commonest indication for laser therapy was maculopathy, but those with more severe retinopathy were more likely to be treated for proliferative retinopathy and to need both eyes treated. CONCLUSION: Few type 2 diabetic patients without retinopathy progress to photocoagulation in the following 3-6 years, while patients with more severe retinopathy lesions need to be monitored closely.

Manley SE, Stratton IM, Cull C, Frighi V, Eeley EA, Matthews DR, Holman RR, Neil HAW. 2001. Effects of three months' diet after diagnosis of type 2 diabetes on plasma lipids and lipoproteins (UKPDS 45) (vol 17, pg 518, 2000) DIABETIC MEDICINE, 18 (3), pp. 251-251.

Clarke P, Gray A, Adler A, Stevens R, Raikou M, Cull C, Stratton I, Holman R, UKPDS Group. United Kingdom Prospective Diabetes Study. 2001. Cost-effectiveness analysis of intensive blood-glucose control with metformin in overweight patients with type II diabetes (UKPDS No. 51). Diabetologia, 44 (3), pp. 298-304. | Show Abstract | Read more

AIMS/HYPOTHESIS: To estimate the economic efficiency of intensive blood-glucose control with metformin compared with conventional therapy primarily with diet in overweight patients with Type II (non-insulin-dependent) diabetes mellitus. METHODS: Cost-effectiveness analysis based on patient level data from a randomised clinical controlled trial involving 753 overweight (> 120% ideal body weight) patients with newly diagnosed Type II diabetes conducted in 15 hospital-based clinics in England, Scotland and Northern Ireland as part of the UK Prospective Diabetes Study. Subjects were allocated at random to an intensive blood-glucose control policy with metformin (n = 342) or a conventional policy primarily with diet (n = 411). The analysis was based on the cost of health care resources associated with metformin and conventional therapy and the estimated effectiveness in terms of life expectancy gained from within-trial effects. RESULTS: Intensive blood-glucose control with metformin produced a net saving of 258 Pounds per patient (1997 United Kingdom prices) over the trial period (median duration of 10.7 years) due to lower complication costs, and increased life expectancy by 0.4 years (costs and benefits discounted at 6%). CONCLUSIONS/INTERPRETATION: As metformin is both cost-saving in the United Kingdom and extends life expectancy when used as first line pharmacological therapy in overweight Type II diabetic patients, its use should be attractive to clinicians and health care managers alike.

Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman RR, Manley SE, Matthews DR. 2001. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia, 44 (2), pp. 156-163. | Show Abstract | Read more

AIMS/HYPOTHESIS: To determine risk factors related to the incidence and progression of diabetic retinopathy over 6 years from diagnosis of Type II (non-insulin-dependent) diabetes mellitus. METHODS: This report describes 1919 patients from within the United Kingdom Prospective Diabetes Study (UKPDS), with retinal photographs taken at diagnosis and 6 years later and with complete data available. Photographs were centrally graded for lesions of diabetic retinopathy using the modified Early Treatment of Diabetic Retinopathy Study Final scale. Risk factors were assessed after 3 months diet from the time of diagnosis of diabetes. Patients were seen every 3 months in a hospital setting. Biochemical measurements were done by a central laboratory. End points of vitreous haemorrhage and photocagulation were confirmed by independent adjudication of systematically collected clinical data. The main outcome measures were incidence and progression of retinopathy defined as a two-step Early Treatment of Diabetic Retinopathy Study (ETDRS) final scale change. RESULTS: Of the 1919 patients, 1216 (63 %) had no retinopathy at diagnosis. By 6 years, 22 % of these had developed retinopathy, that is microaneurysms in both eyes or worse. In the 703 (37 %) patients with retinopathy at diagnosis, 29 % progressed by two scale steps or more. Development of retinopathy (incidence) was strongly associated with baseline glycaemia, glycaemic exposure over 6 years, higher blood pressure and with not smoking. In those who already had retinopathy, progression was associated with older age, male sex, hyperglycaemia (as evidenced by a higher HbA1c) and with not smoking. CONCLUSION/INTERPRETATION: The findings re-emphasise the need for good glycaemic control and assiduous treatment of hypertension if diabetic retinopathy is to be minimised.

Manley SE, Stratton IM, Cull C, Frighi V, Eeley EA, Matthews DR, Holman RR, Neil HAW. 2001. Dietary advice? Authors' response and erratum for 'Effects of three months' diet after diagnosis of type 2 diabetes on plasma lipids and lipoproteins (UKPDS 45)' Diabetic Medicine, 18 (3), pp. 251-251. | Read more

Stevens R, Adler A, Gray A, Briggs A, Holman R. 2000. Life-expectancy projection by modelling and computer simulation (UKPDS 46). Diabetes Res Clin Pract, 50 Suppl 3 (SUPPL. 3), pp. S5-13. | Show Abstract | Read more

A method is described for estimating the life-expectancy of cohorts of type 2 diabetic patients, based on computer simulation from a parametric model. The method can be used where non-parametric methods, such as the Kaplan-Meier estimate, fail due to lack of the data. The simulation algorithm combines observed and modelled information to estimate the life-expectancy implications of event rates observed within a study. The use of bootstrap methods to estimate confidence intervals is discussed. The methods are illustrated with results that have been previously published, without derivation, in a health economic analysis of tight blood pressure (BP) control in the UK Prospective Diabetes Study (UKPDS), and the application to other health economic analyses of UKPDS data is discussed.

Holman R, Lindbaek M, McCormack J, Greenhalgh T. 2000. Seeing what you want to see in randomised controlled trials [3] (multiple letters) British Medical Journal, 321 (7268), pp. 1078-1080.

Holman R. 2000. Seeing what you want to see in randomised controlled trials. Authors' choice of study was ill informed. BMJ, 321 (7268), pp. 1078-1079. | Read more

Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. 2000. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ, 321 (7258), pp. 412-419. | Show Abstract | Read more

OBJECTIVE: To determine the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study. SETTING: 23 hospital based clinics in England, Scotland, and Northern Ireland. PARTICIPANTS: 4801 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders. RESULTS: The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, P<0.0001). No threshold of risk was observed for any end point. CONCLUSIONS: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.

Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. 2000. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ, 321 (7258), pp. 405-412. | Show Abstract | Read more

OBJECTIVE: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study. SETTING: 23 hospital based clinics in England, Scotland, and Northern Ireland. PARTICIPANTS: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA(1c) adjusted for possible confounders at diagnosis of diabetes. RESULTS: The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA(1c) was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001), 21% for deaths related to diabetes (15% to 27%, P<0.0001), 14% for myocardial infarction (8% to 21%, P<0.0001), and 37% for microvascular complications (33% to 41%, P<0.0001). No threshold of risk was observed for any end point. CONCLUSIONS: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA(1c) is likely to reduce the risk of complications, with the lowest risk being in those with HbA(1c) values in the normal range (<6.0%).

Herlihy OM, Morris RJ, Karunakaran S, Holman RR, Grp FHS. 2000. Sulphonylurea therapy over six years does not delay progression to diabetes DIABETOLOGIA, 43 pp. A73-A73.

Citroen HA, Tunbridge FKE, Holman RR, Grp EDITS. 2000. Possible prevention of type 2 diabetes with acarbose or metformin over three years DIABETOLOGIA, 43 pp. A73-A73.

Cull CA, Wright AD, Holman RR, Grp UKPDS. 2000. Efficacy over six years of sulphonylurea plus insulin therapy in type 2 diabetic patients in the UKPDS DIABETOLOGIA, 43 pp. A40-A40.

Horton VA, Groves CJ, Naylor M, Owen R, Wiltshire S, Stratton IM, Green F, Holman RR. 2000. ApoE epsilon 2 and butyrylcholinesterase K variant are associated with coronary heart disease in type 2 diabetes DIABETOLOGIA, 43 pp. A86-A86.

Hashim Y, Shepherd D, Wiltshire S, Clarke A, Holman RR. 2000. Butyrylcholinesterase K variant is associated with type 2 diabetes in UK Caucasians DIABETOLOGIA, 43 pp. A51-A51.

Manley SE, Holman RR. 2000. Standardised HBA(1c) measurements are essential for the management of glycaemia as a risk factor in diabetes DIABETOLOGIA, 43 pp. A232-A232.

Adler AI, Stevens RJ, Holman RR, Grp UKPDS. 2000. Risk factors for incident albuminuria and renal dysfunction in the UKPDS DIABETOLOGIA, 43 pp. A25-A25.

Dyson PA, Mehta Z, Hammersley M, Holman RR, Grp FHS. 2000. Reinforced healthy living advice over six years does not delay progression to diabetes DIABETOLOGIA, 43 pp. A114-A114.

Peacey SR, Robinson R, Bedford C, Harris ND, Macdonald IA, Holman RR, Heller SR. 2000. Does the choice of treatment for type 2 diabetes affect the physiological response to hypoglycemia? Diabetes Care, 23 (7), pp. 1022-1023. | Read more

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Manley SE, Stratton IM, Cull CA, Frighi V, Eeley EA, Matthews DR, Holman RR, Turner RC, Neil HAW, Grp UKPDS. 2000. Effects of three months' diet after diagnosis of Type 2 diabetes on plasma lipids and lipoproteins (UKPDS 45) DIABETIC MEDICINE, 17 (7), pp. 518-523. | Show Abstract | Read more

Aims: To assess the effect of diet on fasting plasma lipids and lipoproteins in patients with newly diagnosed Type 2 diabetes. Methods: A total of 2906 patients each underwent 3 months' diet therapy before allocation to therapy in a randomized controlled clinical trial. Lipids and lipoproteins were measured at diagnosis and after 3 months' diet. Results: The mean body weight at diagnosis was 83 kg. Weight decreased after diet by a mean of 4.5 kg; body mass index (BMI) decreased by 1.51 kg/m2; plasma glucose fell by 3 mmol/l from 11 mmol/l; and HbA(1c) by 2% from 9%. Triglyceride concentrations were reduced in men by -0.41 (95% confidence interval (CI) -0.47 to -0.35) mmol/l from a geometric mean 1.8 (1 SD interval 1.0-3.0) mmol/l, and in women by -0.23 (-0.28 to -0.18) mmol/l from a similar level. Cholesterol decreased in men by -0.28 (-0.33 to -0.24) mmol/l from 5.5 (1.1) mmol/l, and in women by -0.09 (-0.14 to -0.04) mmol/l from 5.8 (1.2) mmol/l with corresponding changes in LDL cholesterol. HDL cholesterol increased in men by 0.02 (0.01 to 0.04) mmol/l and in women by 0.01 (0 to 0.02) mmol/l. Triglyceride concentration in the top tertile was reduced by 37% in men (> 2.1 mmol/l) and by 23% in women (> 2.2 mmol/l) with regression to mean accounting for 13% and 6%, respectively. Similarly cholesterol in the top tertile was reduced by 12% in men (> 5.8 mmol/l) and 7% in women (> 6.2 mmol/l) with 6% of the decrease in both men and women accounted for by regression to the mean. Conclusions: Initial dietary therapy in patients with newly diagnosed Type 2 diabetes substantially reduced plasma triglyceride, marginally improved total cholesterol and subfractions, and resulted in a potentially less atherogenic profile, although this did not eliminate the excess cardiovascular risk in patients with Type 2 diabetes.

Manley SE, Stratton IM, Cull CA, Frighi V, Eeley EA, Matthews DR, Holman RR, Turner RC, Neil HA, United Kingdom Prospective Diabets Study Group. 2000. Effects of three months' diet after diagnosis of Type 2 diabetes on plasma lipids and lipoproteins (UKPDS 45). UK Prospective Diabetes Study Group. Diabet Med, 17 (7), pp. 518-523. | Show Abstract

AIMS: To assess the effect of diet on fasting plasma lipids and lipoproteins in patients with newly diagnosed Type 2 diabetes. METHODS: A total of 2,906 patients each underwent 3 months' diet therapy before allocation to therapy in a randomized controlled clinical trial. Lipids and lipoproteins were measured at diagnosis and after 3 months' diet. RESULTS: The mean body weight at diagnosis was 83 kg. Weight decreased after diet by a mean of 4.5 kg; body mass index (BMI) decreased by 1.51 kg/m2; plasma glucose fell by 3 mmol/l from 11 mmol/l; and HbA1c by 2% from 9%. Triglyceride concentrations were reduced in men by -0.41 (95% confidence interval (CI) -0.47 to - 0.35) mmol/l from a geometric mean 1.8 (1 SD interval 1.0-3.0) mmol/l, and in women by -0.23 (-0.28 to -0.18) mmol/l from a similar level. Cholesterol decreased in men by -0.28 (-0.33 to -0.24) mmol/l from 5.5 (1.1) mmol/l, and in women by -0.09 (-0.14 to -0.04) mmol/l from 5.8 (1.2) mmol/l with corresponding changes in LDL cholesterol. HDL cholesterol increased in men by 0.02 (0.01 to 0.04) mmol/l and in women by 0.01 (0 to 0.02) mmol/l. Triglyceride concentration in the top tertile was reduced by 37% in men (> 2.1 mmol/l) and by 23% in women (> 2.2 mmol/l) with regression to mean accounting for 13% and 6%, respectively. Similarly cholesterol in the top tertile was reduced by 12% in men (> 5.8 mmol/l) and 7% in women (> 6.2 mmol/l) with 6% of the decrease in both men and women accounted for by regression to the mean. CONCLUSIONS: Initial dietary therapy in patients with newly diagnosed Type 2 diabetes substantially reduced plasma triglyceride, marginally improved total cholesterol and subfractions, and resulted in a potentially less atherogenic profile, although this did not eliminate the excess cardiovascular risk in patients with Type 2 diabetes.

Gray A, Raikou M, McGuire A, Fenn P, Stevens R, Cull C, Stratton I, Adler A, Holman R, Turner R. 2000. Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (UKPDS 41). United Kingdom Prospective Diabetes Study Group. BMJ, 320 (7246), pp. 1373-1378. | Show Abstract

OBJECTIVE: To estimate the cost effectiveness of conventional versus intensive blood glucose control in patients with type 2 diabetes. DESIGN: Incremental cost effectiveness analysis alongside randomised controlled trial. SETTING: 23 UK hospital clinic based study centres. PARTICIPANTS: 3867 patients with newly diagnosed type 2 diabetes (mean age 53 years). INTERVENTIONS: Conventional (primarily diet) glucose control policy versus intensive control policy with a sulphonylurea or insulin. MAIN OUTCOME MEASURES: Incremental cost per event-free year gained within the trial period. RESULTS: Intensive glucose control increased trial treatment costs by pound 695 (95% confidence interval pound 555 to pound 836) per patient but reduced the cost of complications by pound 957 (pound 233 to pound 1681) compared with conventional management. If standard practice visit patterns were assumed rather than trial conditions, the incremental cost of intensive management was pound 478 (-pound 275 to pound 1232) per patient. The within trial event-free time gained in the intensive group was 0.60 (0.12 to 1.10) years and the lifetime gain 1.14 (0.69 to 1.61) years. The incremental cost per event-free year gained was pound 1166 (costs and effects discounted at 6% a year) and pound 563 (costs discounted at 6% a year and effects not discounted). CONCLUSIONS: Intensive blood glucose control in patients with type 2 diabetes significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications.

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Gray A, Raikou M, McGuire A, Fenn P, Stevens R, Cull C, Stratton I, Adler A, Holman R, Turner R, Diabet UKP. 2000. Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (UKPDS 41) BRITISH MEDICAL JOURNAL, 320 (7246), pp. 1373-1378. | Show Abstract | Read more

Objective. To estimate the cost effectiveness of conventional versus intensive blood glucose control in patients with type 2 diabetes. Design. Incremental cost effectiveness analysis alongside randomised controlled trial. Setting. 23 UK hospital clinic based study centres. Participants. 3867 patients with newly diagnosed type 2 diabetes (mean age 53 years). Interventions. Conventional (primarily diet) glucose control policy versus intensive control policy with a sulphonylurea or insulin. Main outcome measures. Incremental cost per event-free year gained within the trial period. Results. Intensive glucose control increased trial treatment costs by u695 (95% confidence interval u555 to u836) per patient but reduced the cost of complications by u957 (u233 to u1681) compared with conventional management. If standard practice visit patterns were assumed rather than trial conditions, the incremental cost of intensive management was u478 (-u275 to u1232) per patient. The within trial event-free time gained in the intensive group was 0.60 (0.12 to 1.10) years and the lifetime gain 1.14 (0.69 to 1.61) years. The incremental cost per event-free year gained was u1166 (costs and effects discounted at 6% a year) and u563 (costs discounted at 6% a year and effects not discounted). Conclusions. Intensive blood glucose control in patients with type 2 diabetes significantly increased treatment costs but substantailly reduced the cost of complications and increased the time free of complications.

Turner R, Holman R, Butterfield J. 1999. UKPDS: what was the question? UK Prospective Diabetes Study. Lancet, 354 (9178), pp. 600. | Read more

Mehta ZM, Manley S, Zimmett P, Bottazzo GF, Cull CA, Holman RR, Turner RC, Grp UKPDS. 1999. Glucose control in UKPDS type 2 diabetic patients with and without autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase. DIABETOLOGIA, 42 pp. A81-A81.

Cull C, Neil HAW, Frighi V, Manley SE, Holman RR, Turner RC, Grp UKPDS. 1999. Plasma lipids and hypoglycaemic therapies over 6 years in Type 2 diabetic patients in the UKPDS DIABETOLOGIA, 42 pp. A18-A18.

Stratton IM, Adler IA, Matthews DR, Holman RR, Turner RC. 1999. Incidence rates of endpoints in type 2 diabetic patients by level of systolic blood pressure and duration of diabetes DIABETOLOGIA, 42 pp. A263-A263.

Stevens RJ, Adler AI, Yudkin JS, Manley SE, Cull CA, Holman RR, Turner RC. 1999. Ethnic differences in diabetic nephropathy - The UKPDS DIABETOLOGIA, 42 pp. A277-A277.

1999. Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37). U.K. Prospective Diabetes Study Group Diabetes Care, 22 (7), pp. 1125-1136. | Read more

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Turner RC, Cull CA, Frighi V, Holman RR, Grp UKPDS. 1999. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus - Progressive requirement for multiple therapies (UKPDS 49) JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 281 (21), pp. 2005-2012. | Show Abstract | Read more

Context Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A(1c) (HbA(1c)) below 7% is unknown. Objective To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. Design Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. Setting Outpatient diabetes clinics in 15 UK hospitals. Patients A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA(1c) levels of 9.1% (7.5%10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. Interventions After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. Main Outcome Measures Fasting plasma glucose and HbA(1c) levels, and the proportion of patients who achieved target levels below 7% HbA(1c) or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. Results The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA(1c) levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA(1c) levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. Conclusions Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA(1c) below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.

Turner RC, Cull CA, Frighi V, Holman RR. 1999. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA, 281 (21), pp. 2005-2012. | Show Abstract

CONTEXT: Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. OBJECTIVE: To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. DESIGN: Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. SETTING: Outpatient diabetes clinics in 15 UK hospitals. PATIENTS: A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. INTERVENTIONS: After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. MAIN OUTCOME MEASURES: Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. RESULTS: The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. CONCLUSIONS: Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.

Holman RR, Cull CA, Turner RC. 1999. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44) Diabetes Care, 22 (6), pp. 960-964. | Show Abstract | Read more

OBJECTIVE: To determine the degree to which alpha-glucosidase inhibitors, with their unique mode of action primarily reducing postprandial hyperglycemia, offer an additional therapeutic approach in the long-term treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 1,946 patients (63% men) who were previously enrolled in the U.K. Prospective Diabetes Study (UKPDS). The patients were randomized to acarbose (n = 973), titrating to a maximum dose of 100 mg three times per day, or to matching placebo (n = 973). Mean +/- SD age was 59 +/- 9 years, body weight 84 +/- 17 kg, diabetes duration 7.6 +/- 2.9 years, median (interquartile range) HbA1c 7.9% (6.7-9.5), and fasting plasma glucose (FPG) 8.7 mmol/l (6.8-11.1). Fourteen percent of patients were treated with diet alone, 52% with monotherapy, and 34% with combined therapy. Patients were monitored in UKPDS clinics every 4 months for 3 years. The main outcome measures were HbA1c, FPG, body weight, compliance with study medication, incidence of side effects, and frequency of major clinical events. RESULTS: At 3 years, a lower proportion of patients were taking acarbose compared with placebo (39 vs. 58%, P < 0.0001), the main reasons for noncompliance being flatulence (30 vs. 12%, P < 0.0001) and diarrhea (16 vs. 8%, P < 0.05). Analysis by intention to treat showed that patients allocated to acarbose, compared with placebo, had 0.2% significantly lower median HbA1c at 3 years (P < 0.001). In patients remaining on their allocated therapy, the HbA1c difference at 3 years (309 acarbose, 470 placebo) was 0.5% lower median HbA1c (8.1 vs. 8.6%, P < 0.0001). Acarbose appeared to be equally efficacious when given in addition to diet alone; in addition to monotherapy with a sulfonylurea, metformin, or insulin; or in combination with more complex treatment regimens. No significant differences were seen in FPG, body weight, incidence of hypoglycemia, or frequency of major clinical events. CONCLUSIONS: Acarbose significantly improved glycemic control over 3 years in patients with established type 2 diabetes, irrespective of concomitant therapy for diabetes. Careful titration of acarbose is needed in view of the increased noncompliance rate seen secondary to the known side effects.

Davis TM, Millns H, Stratton IM, Holman RR, Turner RC. 1999. Risk factors for stroke in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 29. Arch Intern Med, 159 (10), pp. 1097-1103. | Show Abstract | Read more

OBJECTIVE: To investigate modifiable and nonmodifiable risk factors for stroke in type 2 diabetes mellitus. PATIENTS AND METHODS: A total of 3776 patients aged 25 to 65 years newly diagnosed as having type 2 diabetes mellitus without known cardiovascular or other serious disease were studied for a median of 7.9 years. An initial stepwise evaluation of risk factors was done in 2704 patients with all risk factors measured, with the final Cox model analysis being of 3776 patients who had complete data on the selected variables. RESULTS: Of 3776 patients, 99 (2.6%) had a stroke. Significant risk factors for stroke in a multivariate model were age (estimated hazard ratio [95% confidence interval], 4.78 [2.56-8.92] for > or =60 vs <50 years), male sex (1.63 [1.08-2.47)] vs female), hypertension (2.47 [1.64-3.74)] vs normotension), and in 3728 patients who had electrocardiography at study entry, atrial fibrillation (8.05 [3.52-18.44] vs sinus rhythm). Obesity, lack of exercise, smoking, poor glycemic control, hyperinsulinemia, dyslipidemia, and microalbuminuria were not significantly associated with stroke in the model. CONCLUSION: In patients with type 2 diabetes, aggressive antihypertensive therapy and routine anticoagulation therapy for atrial fibrillation may reduce the risk of stroke.

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Horton V, Stratton I, Bottazzo GF, Shattock M, Mackay I, Zimmet P, Manley S, Holman R, Turner R, Grp UKPDS. 1999. Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43) DIABETOLOGIA, 42 (5), pp. 608-616. | Read more

Horton V, Stratton I, Bottazzo GF, Shattock M, Mackay I, Zimmet P, Manley S, Holman R, Turner R. 1999. Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). UK Prospective Diabetes Study (UKPDS) Group. Diabetologia, 42 (5), pp. 608-616. | Show Abstract

AIMS/HYPOTHESIS: Juvenile-onset, insulin-dependent diabetes is associated with islet cell antibodies and with specific "high-risk" HLA-DRB1 and HLA-DQB1 genotypes. Patients with Type II (non-insulin-dependent) diabetes mellitus can have islet-related antibodies, but the genotypic associations at different ages of onset have not been evaluated. Our aim was to determine (i) the prevalence of DRB1 and DQB1 genotypes in patients at diagnosis of Type II diabetes at different ages from 25 to 65 years compared with the general population, and (ii) whether the presence of islet cell antibodies (ICA) or glutamic acid decarboxylase antibodies (GADA) or both by age is associated with different DRB1 and DQB1 genotypes. METHODS: The antibodies to islet cells and those to glutamic acid decarboxylase were measured in 1712 white Caucasian diabetic subjects at diagnosis of diabetes and they were genotyped for HLA DRB1*03 and DRB1*04 and the high-risk DRB1*04-DQB1* 0302 haplotype. To assess over-representation of high-risk alleles for Type I (insulin-dependent) diabetes mellitus, the prevalence of high-risk alleles in diabetic patients was expressed relative to the prevalence of low-risk alleles, non-DR3/non-DR4, that provided a reference denominator in both the diabetic patients and in 200 non-diabetic control subjects. The prevalence of ICA or GADA or both in patients with different HLA genotypes was assessed in those diagnosed in four age groups, 25-34 years, 35-44 years, 45-54 years and 55-65 years. RESULTS: In Type II diabetic patients presenting at ages 25-34, 35-44 and 45-54 years, there was an increased prevalence of DR3/DR4 compared with the general population with approximately 6.5-fold, 2.9-fold, 2.1-fold over-representation, respectively (p < 0.0001, < 0.01, < 0.05) but this was not found in those aged 55-65 years old. In the group aged 25-34 years, 32 % of patients with ICA or GADA or both had DRB1*03/DRB1*04-DQB1*0302 compared with 10% in those aged 55-65 years and expected 3% prevalence. Conversely, only 14% of those aged 25-34 years with antibodies had non-DR3/non-DR4, compared with 35 % in those aged 55-65 years. There was thus pronounced age heterogeneity in DRB1 and DQB1 predisposition to Type II diabetes. The antibodies displaced DRB1 or DQB1 genotypes in the multivariate model for requiring insulin therapy by 6 years of follow-up. CONCLUSION/HYPOTHESIS: The age of presentation of Type I diabetes in adulthood was in part dependent on the DRB1/DQB1 genotype. Islet cell antibodies and glutamic acid decarboxylase antibodies were strongly associated with DRB1*03/DRB1*04-DQB1*0302 in early adulthood but showed little relation with specific HLA genotypes after the age of 55 years.

Turner R, Holman R. 1999. Important findings should not be published in two journals - Reply BRITISH MEDICAL JOURNAL, 318 (7184), pp. 667-668.

Turner RC, Holman RR. 1999. Metformin and risk of cardiovascular disease. Cardiology, 91 (3), pp. 203-204. | Read more

Holman RR, Dinneen SF. 1999. Acarbose was effective in maintaining glycemic control in type 2 diabetes mellitus but was associated with adverse effects Evidence-Based Medicine, 4 (6), pp. 189.

Turner RC, Holman R, Stratton I. 1998. The UK Prospective Diabetes Study - Reply LANCET, 352 (9144), pp. 1934-1934. | Read more

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Stearne MR, Palmer SL, Hammersley MS, Franklin SL, Spivey RS, Levy JC, Tidy CR, Bell NJ et al. 1998. Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes: UKPDS 40 BRITISH MEDICAL JOURNAL, 317 (7160), pp. 720-726. | Read more

Stearne MR, Palmer SL, Hammersley MS, Franklin SL, Spivey RS, Levy JC, Tidy CR, Bell NJ et al. 1998. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ, 317 (7160), pp. 703-713. | Show Abstract | Read more

OBJECTIVE: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. DESIGN: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg. SETTING: 20 hospital based clinics in England, Scotland, and Northern Ireland. SUBJECTS: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years. MAIN OUTCOME MEASURES: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography. RESULTS: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P=0.0046), 32% in deaths related to diabetes (6% to 51%) (P=0.019), 44% in strokes (11% to 65%) (P=0.013), and 37% in microvascular end points (11% to 56%) (P=0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P=0.0004) and a 47% reduced risk (7% to 70%) (P=0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures. CONCLUSION: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity.

Stearne MR, Palmer SL, Hammersley MS, Franklin SL, Spivey RS, Levy JC, Tidy CR, Bell NJ et al. 1998. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ, 317 (7160), pp. 713-720. | Show Abstract | Read more

OBJECTIVE: To determine whether tight control of blood pressure with either a beta blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes. DESIGN: Randomised controlled trial comparing an angiotensin converting enzyme inhibitor (captopril) with a beta blocker (atenolol) in patients with type 2 diabetes aiming at a blood pressure of <150/<85 mm Hg. SETTING: 20 hospital based clinics in England, Scotland, and Northern Ireland. SUBJECTS: 1148 hypertensive patients with type 2 diabetes (mean age 56 years, mean blood pressure 160/94 mm Hg). Of the 758 patients allocated to tight control of blood pressure, 400 were allocated to captopril and 358 to atenolol. 390 patients were allocated to less tight control of blood pressure. MAIN OUTCOME MEASURES: Predefined clinical end points, fatal and non-fatal, related to diabetes, death related to diabetes, and all cause mortality. Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography. RESULTS: Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively, with a similar proportion of patients (27% and 31%) requiring three or more antihypertensive treatments. More patients in the captopril group than the atenolol group took the allocated treatment: at their last clinic visit, 78% of those allocated captopril and 65% of those allocated atenolol were taking the drug (P<0.0001). Captopril and atenolol were equally effective in reducing the risk of macrovascular end points. Similar proportions of patients in the two groups showed deterioration in retinopathy by two grades after nine years (31% in the captopril group and 37% in the atenolol group) and developed clinical grade albuminuria >=300 mg/l (5% and 9%). The proportion of patients with hypoglycaemic attacks was not different between groups, but mean weight gain in the atenolol group was greater (3.4 kg v 1.6 kg). CONCLUSION: Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications. This study provided no evidence that either drug has any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used.

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Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, Frighi V, Manley SE, Neil A et al. 1998. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) LANCET, 352 (9131), pp. 837-853. | Read more

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Turner RC, Holman RR, Stratton IM, Cull CA, Matthews DR, Manley SE, Frighi V, Wright D et al. 1998. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) LANCET, 352 (9131), pp. 854-865. | Read more

Karunakaran S, Aldington S, North B, Ryder R, Holman RR, Grp EDITS. 1998. Retinopathy in subjects with increased fasting plasma glucose levels DIABETOLOGIA, 41 pp. A283-A283.

Horton VA, Stratton IM, Owen RJ, Bennett ST, Todd JA, Holman RR, Turner RC. 1998. Insulin VNTR and HLA DRB1/DQB1 LOCI affect age of presentation of autoimmune diabetes in adults DIABETOLOGIA, 41 pp. A105-A105.

Groves CJ, Horton VA, Ritchie A, Owen RJ, Stratton IR, Green FR, Holman RR, Turner RC. 1998. Paraoxonase polymorphism MET-LEU 54 is associated with fatal myocardial infarction in type 2 diabetic patients DIABETOLOGIA, 41 pp. A115-A115.

Rachman J, Payne MJ, Levy JC, Barrow BA, Holman RR, Turner RC. 1998. Changes in amylin and amylin-like peptide concentrations and beta-cell function in response to sulfonylurea or insulin therapy in NIDDM. Diabetes Care, 21 (5), pp. 810-816. | Show Abstract | Read more

OBJECTIVE: Amylin, a secretory peptide of beta-cells, is the constituent peptide of islet amyloid, which is characteristic of NIDDM, and changes in amylin secretion in response to therapies may influence the rate of production of islet amyloid. The primary objective of this study was to determine whether therapy with sulfonylurea or basal insulin in NIDDM would alter amylin secretion in a way that might affect the formation of islet amyloid. RESEARCH DESIGN AND METHODS: In a randomized crossover design, eight subjects with NIDDM underwent three 8-week periods of therapy with diet alone, sulfonylurea, or exogenous basal insulin, with evaluation of amylin, amylin-like peptide (ALP), and glucose and C-peptide concentrations, both during fasting and after a standard breakfast. Changes in beta-cell function (% beta) were assessed, in the basal state by homeostasis model assessment (HOMA) and in the stimulated state by hyperglycemic clamps. Seven nondiabetic control subjects each underwent a meal profile and hyperglycemic clamp. RESULTS: Both sulfonylurea and insulin therapy reduced basal glucose concentrations compared with diet alone, but neither reduced the increased postprandial glucose increments. Both sulfonylurea and insulin therapy increased basal % beta, assessed by HOMA, but only sulfonylurea increased the second-phase C-peptide responses to the hyperglycemic clamp. Sulfonylurea increased time-averaged mean postprandial amylin and ALP concentrations compared with diet alone (geometric mean [1-SD range] for amylin, 4.9 [2.0-11.8] vs. 3.0 [1.4-6.2] pmol/l, P = 0.003; for ALP, 16.4 [8.5-31.7] vs. 10.1 [4.9-20.8] pmol/l, P = 0.001). Insulin therapy reduced basal ALP concentrations compared with diet alone (2.9 [1.5-5.6] vs. 6.0 [2.6-13.6] pmol/l, P = 0.03), but had no effect on postprandial concentrations of amylin (3.0 [1.3-6.5] pmol/l) or ALP (10.0 [5.5-18.1] pmol/l). CONCLUSIONS: By increasing postprandial concentrations of the constituent peptides of islet amyloid, sulfonylurea therapy might increase the rate of deposition of islet amyloid and thereby accelerate the decline of % beta in NIDDM, compared with diet therapy alone.

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Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. 1998. UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years DIABETIC MEDICINE, 15 (4), pp. 297-303. | Show Abstract | Read more

Patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) on sulphonylurea therapy convert to insulin progressively as the sulphonylureas 'fail'. The rate of failure and the features of those who fail have been poorly described. To assess secondary failure rates of sulphonylureas, we report on the responses in 1305 patients with newly diagnosed Type 2 DM randomly allocated to therapy with either chlorpropamide or glibenclamide in the UK Prospective Diabetes Study (UKPDS). These patients were initially treated by diet for 3 months and had a fasting plasma glucose >6 mmol l-1; mean age 53 (SD 9) years; BMI 26.8 (SD 5.0) kg m-2; and median fasting plasma glucose 9.1 (7.6-12.5 quartiles) mmol l-1. If their fasting plasma glucose subsequently rose above 15.0 mmol l-1, or they developed hyperglycaemic symptoms, additional hypoglycaemic therapy was given: metformin, ultratard insulin, and soluble insulin as required. By 6 years, 44 % had required additional therapy. Of those randomized to glibenclamide, 48 % required additional therapy by 6 years, compared with 40 % of those allocated to chlorpropamide (p < 0.01). Sixty-one per cent, 39 %, and 23 %, respectively, of patients with fasting plasma glucose ≤10.0 mmol-1, ≤7.8 mmol-1 to <10.0 mmol-1 and <7.8 mmol-1 at randomization required additional therapy (p < 0.001). In the initial 3 years, non-obese subjects (BMI <30 kg m-2) were more likely to require additional therapy than obese patients (BMI ≤30 kgm-2) (43 % vs 53 % at 6 years; p < 0.001). Modelled beta-cell function showed that those with lower function were more likely to fail (p < 0.0001). Thus sulphonylureas fail as a therapeutic agent at rates which are dependent both on the phenotype at presentation and perhaps on the agent used initially. Higher failure rates were found in those with higher glucose concentrations, those who were younger, those with lower beta-cell reserve and those randomized to glibenclamide compared with chlorpropamide.

Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. 1998. UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med, 15 (4), pp. 297-303. | Show Abstract | Read more

Patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) on sulphonylurea therapy convert to insulin progressively as the sulphonylureas 'fail'. The rate of failure and the features of those who fail have been poorly described. To assess secondary failure rates of sulphonylureas, we report on the responses in 1305 patients with newly diagnosed Type 2 DM randomly allocated to therapy with either chlorpropamide or glibenclamide in the UK Prospective Diabetes Study (UKPDS). These patients were initially treated by diet for 3 months and had a fasting plasma glucose > 6 mmol l(-1); mean age 53 (SD 9) years; BMI 26.8 (SD 5.0) kg m(-2); and median fasting plasma glucose 9.1 (7.6-12.5 quartiles) mmol l(-1). If their fasting plasma glucose subsequently rose above 15.0 mmol l(-1), or they developed hyperglycaemic symptoms, additional hypoglycaemic therapy was given: metformin, ultratard insulin, and soluble insulin as required. By 6 years, 44% had required additional therapy. Of those randomized to glibenclamide, 48% required additional therapy by 6 years, compared with 40% of those allocated to chlorpropamide (p < 0.01). Sixty-one per cent, 39%, and 23%, respectively, of patients with fasting plasma glucose > or = 10.0 mmol l(-1), > or = 7.8 mmol l(-1) to < 10.0 mmol l(-1) and < 7.8 mmol l(-1) at randomization required additional therapy (p < 0.001). In the initial 3 years, non-obese subjects (BMI < 30 kg m(-2)) were more likely to require additional therapy than obese patients (BMI > or = 30 kg m(-2)) (43% vs 53% at 6 years; p < 0.001). Modelled beta-cell function showed that those with lower function were more likely to fail (p < 0.0001). Thus sulphonylureas fail as a therapeutic agent at rates which are dependent both on the phenotype at presentation and perhaps on the agent used initially. Higher failure rates were found in those with higher glucose concentrations, those who were younger, those with lower beta-cell reserve and those randomized to glibenclamide compared with chlorpropamide.

Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. 1998. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23) BMJ, 316 (7134), pp. 823-828. | Show Abstract | Read more

OBJECTIVE: To evaluate baseline risk factors for coronary artery disease in patients with type 2 diabetes mellitus. DESIGN: A stepwise selection procedure, adjusting for age and sex, was used in 2693 subjects with complete data to determine which risk factors for coronary artery disease should be included in a Cox proportional hazards model. SUBJECTS: 3055 white patients (mean age 52) with recently diagnosed type 2 diabetes mellitus and without evidence of disease related to atheroma. Median duration of follow up was 7.9 years. 335 patients developed coronary artery disease within 10 years. OUTCOME MEASURES: Angina with confirmatory abnormal electrocardiogram; non-fatal and fatal myocardial infarction. RESULTS: Coronary artery disease was significantly associated with increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, and increased triglyceride concentration, haemoglobin A1c, systolic blood pressure, fasting plasma glucose concentration, and a history of smoking. The estimated hazard ratios for the upper third relative to the lower third were 2.26 (95% confidence interval 1.70 to 3.00) for low density lipoprotein cholesterol, 0.55 (0.41 to 0.73) for high density lipoprotein cholesterol, 1.52 (1.15 to 2.01) for haemoglobin A1c, and 1.82 (1.34 to 2.47) for systolic blood pressure. The estimated hazard ratio for smokers was 1.41 (1.06 to 1.88). CONCLUSION: A quintet of potentially modifiable risk factors for coronary artery disease exists in patients with type 2 diabetes mellitus. These risk factors are increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, raised blood pressure, hyperglycaemia, and smoking.

Kohner EM, Aldington SJ, Stratton IM, Manley SE, Holman RR, Matthews DR, Turner RC. 1998. United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors. Arch Ophthalmol, 116 (3), pp. 297-303. | Show Abstract | Read more

OBJECTIVES: To report on the prevalence of retinopathy in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM) and to evaluate the relationship of retinopathy to clinical and biochemical variables. DESIGN: A multicenter, randomized, controlled clinical study of therapy in patients with NIDDM. SETTING AND PATIENTS: Patients were part of the United Kingdom Prospective Diabetes Study, a 23-center study of 2964 white patients who had both eyes photographed and assessed. OUTCOME MEASURES: The presence and severity of diabetic retinopathy were evaluated by sex, and the relationship of retinopathy to medical and biochemical parameters was assessed. RESULTS: Retinopathy, defined as microaneurysms or worse lesions in at least 1 eye, was present in 39% of men and 35% of women. Marked retinopathy with cotton wool spots or intraretinal microvascular abnormalities was present in 8% of men and 4% of women. The severity of retinopathy was related in both sexes to higher fasting plasma glucose levels, higher systolic and diastolic blood pressure, lower serum insulin levels, and reduced beta-cell function. In addition, in men, increased alcohol consumption was related to increased severity of retinopathy, while leaner women had more severe eye lesions. Visual acuity was normal in most patients, but in men there was a trend for those with more severe retinal lesions to have worse visual acuity. CONCLUSIONS: Diabetic retinopathy is common in patients with newly diagnosed NIDDM. Careful ophthalmic assessment at diagnosis is important.

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Wright A, Cull C, Holman R, Turner R, Murchison L, Wright AD, Oakley N, Kohner E et al. 1998. United kingdom prospective diabetes study 24: A 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy ANNALS OF INTERNAL MEDICINE, 128 (3), pp. 165-175. | Read more

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Wright AD, Cull CA, Holman RR, Turner RC. 1998. UKPDS 28: A randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes DIABETES CARE, 21 (1), pp. 87-92. | Read more

Adler AI, Neil HAW, Stratton IM, Holman RR, Turner RC. 1998. Ethnicity and cardiovascular disease. The incidence of myocardial infarction in white, South Asian, and Afro-Caribbean patients with type 2 diabetes (U.K. Prospective Diabetes Study 32). Diabetes Care, 21 (8), pp. 1271-1277. | Show Abstract | Read more

OBJECTIVE: To estimate the incidence of myocardial infarction (MI) by ethnicity in subjects with diabetes and to examine the effect of ethnicity, adjusting for differences in cardiovascular risk factors. RESEARCH DESIGN AND METHODS: For a prospective study, 4,974 patients with newly diagnosed type 2 diabetes, aged 25-65 years, were recruited from 23 clinics around the U.K. between 1977 and 1991. Of these subjects, 82% were white, 10% were South Asians, and 8% were Afro-Caribbeans. Fatal and first nonfatal MIs were defined by criteria based on the World Health Organization's Multinational Study of Vascular Disease. Age-standardized incidence rates were calculated. Cox regression was used to assess the independent effect of ethnicity controlling for risk factors for MI measured at study entry. RESULTS: Of the subjects, 295 had a fatal MI and 558 had a fatal or a first nonfatal MI. The age-standardized rate per 1,000 person years for fatal or nonfatal MI for whites was 14.6 (95% CI, 13.3-15.9), for Afro-Caribbeans 4.3 (2.5-7.0), and for South Asians 15.4 (10.6-21.4). The hazard ratio associated with Afro-Caribbean ethnicity for MI relative to whites was 0.3 (0.2-0.6) after adjusting for age, sex, year of study entry, systolic blood pressure, smoking, social class, total cholesterol, and HDL cholesterol, whereas the hazard ratio for South Asians was 1.2 (0.9-1.7). CONCLUSIONS: This study found that after adjusting for conventional cardiovascular risk factors, U.K. Afro-Caribbean subjects with diabetes had a lower risk for MI than whites, whereas South Asians did not have a risk different from that of whites.

1997. U.K. Prospective Diabetes Study 27: Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex Diabetes Care, 20 (11), pp. 1683-1687. | Read more

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Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R. 1997. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes LANCET, 350 (9087), pp. 1288-1293. | Read more

Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R. 1997. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet, 350 (9087), pp. 1288-1293. | Show Abstract

BACKGROUND: Autoantibodies to islet-cell cytoplasm (ICA) and glutamic acid decarboxylase (GADA) can occur in apparently typical, non-insulin dependent diabetes mellitus (type 2). We investigated whether the presence of either or both antibodies characterises a subtype of diabetes and provides better prediction of requirement for insulin therapy by 6 years' follow-up than clinical variables. METHODS: We measured ICA and GADA at diagnosis of diabetes in a representative population of 3672 white patients with type 2 diabetes, aged between 25 and 65 years. The phenotype was assessed by age of onset, body-mass index, percentage haemoglobin A1c (HbA1c), and islet beta-cell function. We investigated the need for insulin therapy among 1538 patients not assigned insulin and followed up for 6 years from diagnosis. FINDINGS: The proportion of patients with ICA and GADA decreased with increasing age at diagnosis (from 33 [21%] of 157 patients aged 25-34 [corrected] to 66 [4%] of 1769 aged 55-65 for ICA; from 53 [34%] to 122 [7%] for GADA). Among patients younger than 35 at diagnosis, those with ICA or GADA had lower body-mass index than those without (mean 24.9 [SD 6.0] vs 31.7 [7.3] kg/m2; p < 0.0001 and had higher percentage of HbA1c (9.7 vs 8.7%, p < 0.05). 94% of patients with ICA and 84% of those with GADA required insulin therapy by 6 years, compared with 14% of those without the antibodies (p < 0.0001). Among patients older than 55 at diagnosis, the difference between those with and without antibodies in body-mass index was smaller (27.2 [5.4] vs 28.6 [4.8] kg/m2, p < 0.001); 44% of those with ICA, 34% of those with GADA, and 5% with neither antibody required insulin therapy by 6 years (p < 0.0001). Among patients older than 45 years, body-mass index and HbA1c provided little predictive information for insulin requirement, whereas the positive predictive values of GADA (> or = 60 U/L) alone, or both GADA (> or = 20 U/L) and ICA (> 5 U/L), for insulin therapy were 52% and 68%. INTERPRETATION: Among young adults with type 2 diabetes, the phenotype of those with ICA or GADA antibodies was similar to that of classic juvenile-onset insulin-dependent diabetes, and either phenotype or antibodies predicted insulin requirement. In older adults, the phenotype was closer to that of patients without antibodies and only the presence of antibodies predicted an increased likelihood of insulin requirement.

Cull CA, Manley SE, Stratton IM, Neil HA, Ross IS, Holman RR, Turner RC, Matthews DR. 1997. Approach to maintaining comparability of biochemical data during long-term clinical trials. Clin Chem, 43 (10), pp. 1913-1918. | Show Abstract

Our objective was to design a structured approach to maintaining comparability of biochemical data during a long clinical trial. Maintaining the comparability of clinical and biochemical data obtained in long-term studies is essential, even though analytical methods in the laboratory may be changed, conventions on specimen handling and storage revised, calibration procedures updated, quality-control systems replaced, and secular changes may occur. The United Kingdom Prospective Diabetes Study (UKPDS), a large randomized control trial investigating therapy for type 2 diabetes, was the setting for the study. Data were collected from 5102 subjects randomized since 1977. Our techniques included quality control, external quality assurance, direct comparison of laboratory methods when updating assays and statistical techniques for the detection of unsuspected changes in assay bias, laboratory comparisons of new with old assay methodologies, the realigning of data to current methods, the use of a suitable reference population for long-term monitoring, and rules to aid decision-making about clinical vs statistical significance. Procedures by which comparability of data is assured should be specified for all long-term trials and, where possible, comparison with reference methods should be detailed to allow results from different laboratories to be compared.

Davis TM, Stratton IM, Fox CJ, Holman RR, Turner RC. 1997. U.K. Prospective Diabetes Study 22. Effect of age at diagnosis on diabetic tissue damage during the first 6 years of NIDDM. Diabetes Care, 20 (9), pp. 1435-1441. | Show Abstract | Read more

OBJECTIVE: To assess the effect of age at diagnosis on the initial prevalence and subsequent risk of the progression of diabetic tissue damage in patients with NIDDM. RESEARCH DESIGN AND METHODS: The prevalence of Q-wave myocardial infarction, absent dorsalis pedis pulses, retinopathy, absent ankle jerks, hypertension, and microalbuminuria were determined at baseline and at 3 and 6 years of follow-up in five consecutive 6-year age-cohorts of 3,027 newly diagnosed white patients aged between 36 and 65 years recruited to the U.K. Prospective Diabetes Study. The effect of age at diagnosis on the initial prevalence and the risk of progression of these complications and associated conditions was analyzed using logistic regression and proportional odds methods, respectively. RESULTS: Q-wave myocardial infarction and hypertension were more prevalent in older patients at presentation, but age at diagnosis did not have a significant effect on the increased risk of either after 6 years of NIDDM. Absent dorsalis pedis pulses and ankle jerks were also more prevalent in the older age-groups at presentation, but age at diagnosis was a significant predictor of the increasing prevalence of both during follow-up. The baseline prevalence of retinopathy and microalbuminuria was not related to age. The subsequent risk of retinopathy, but not microalbuminuria, increased significantly with age at diagnosis. CONCLUSIONS: Age at diagnosis has a variable impact on different types of diabetic tissue damage and may thus be an important variable in epidemiological and intervention studies in NIDDM. Regular ophthalmologic surveillance and examination of the feet increase in importance with increasing age since the diagnosis of NIDDM.

Stratton IM, Matthews DR, Kohner EM, Aldington S, Holman RR, Turner RC. 1997. Evaluating risk of progression to photocoagulation by retinal photography or direct ophthalmoscopy. DIABETOLOGIA, 40 pp. 60-60.

Dyson PA, Morris RJ, Holman RR, Turner RC. 1997. Reinforced healthy living advice fails to prevent diabetes in subjects with increased glucose levels DIABETOLOGIA, 40 pp. 2624-2624.

Cull CA, Holman RR, Turner RC. 1997. Treatment of NIDDM - Progressive requirement for polypharmacy to attain glycaemic goals DIABETOLOGIA, 40 pp. 1366-1366.

Millns H, Stratton IM, Holman RR, Turner RC. 1997. Risk factors for stroke in non-insulin dependent diabetic subjects. DIABETOLOGIA, 40 pp. 114-114.

Davis TME, Cull CA, Holman RR, Turner RC. 1997. Effects of ethnicity on metabolic control during the first six years of NIDDM DIABETOLOGIA, 40 pp. 2526-2526.

Grant PJ, Karunakaran S, Holman RR. 1997. Suppression of fibrinolysis and increased factor VII concentrations with dysglycaemia. DIABETOLOGIA, 40 pp. 68-68.

Dyson PA, Morris RJ, Holman RR, Gregory R, Tooke JE, Turner RC. 1997. Conventional reinforced healthy living advice over three years does not delay transition to diabetes in subjects with raised fasting glucose levels. DIABETES, 46 pp. 639-639.

Dyson PA, Morris RJ, Holman RR. 1997. Dietary intake screening by means of a food-frequency questionnaire AMERICAN JOURNAL OF CLINICAL NUTRITION, 65 (4), pp. 1299-1299.

Widjaja A, Stratton IM, Horn R, Holman RR, Turner R, Brabant G. 1997. UKPDS 20: plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects. J Clin Endocrinol Metab, 82 (2), pp. 654-657. | Show Abstract | Read more

We measured plasma leptin and insulin concentrations across a spectrum of obesity in 829 white Caucasian, 154 Afro-Caribbean, and 204 Asian type 2 diabetic subjects. Although the leptin concentrations covered a large range, there were no subgroups of diabetic subjects with very high or low leptin levels that would suggest mutations in the leptin gene or leptin receptor gene comparable to the obese diabetic ob/ob and db/db mice models respectively. In all three ethnic groups, leptin concentrations correlated with body mass index (BMI) in a similar manner to nondiabetic patients and were higher in females than males after adjustment for BMI, with no difference between ethnic groups. In a multivariate regression analysis, plasma leptin was associated with gender and BMI, (both P < 1 x 10(-17)) and with fasting plasma insulin concentrations (P = 5 x 10(-9)). Subjects treated with insulin had both raised insulin and leptin concentrations. When matched for different therapies, gender, and BMI, diabetic subjects with high leptin levels also had high insulin levels (P < 0.0009). High leptin concentrations may in part be influenced by hyperinsulinemia or impaired insulin sensitivity.

Saker PJ, Hattersley AT, Barrow B, Hammersley MS, McLellan JA, Lo YM, Olds RJ, Gillmer MD, Holman RR, Turner RC. 1996. High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population. Diabetologia, 39 (11), pp. 1325-1328. | Show Abstract | Read more

A high proportion of the female patients who are members of maturity onset diabetes of the young (MODY) pedigrees, and whose diabetes mellitus is due to a glucokinase mutation, originally presented with gestational diabetes. To establish whether glucokinase mutations could be a common cause of gestational diabetes, we studied 50 subjects who presented with gestational diabetes and on follow-up had hyperglycaemia (5.5-10.0 mmol/l). Screening for glucokinase mutations using single-stranded conformational polymorphism (SSCP) analysis detected a missense mutation at position 299 (Gly299-->Arg) in three subjects. As two pedigrees in the Oxford area had the same glucokinase mutation, we suspected the role of a founder-effect, and carried out pedigree extension, haplotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area. One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects with the mutation were found to have the Z + 4/2 (GCK1/ GCK2) haplotype, suggesting that the observed high prevalence of the Gly299-->Arg glucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs.

Holman RR, Smale AD, Pemberton E, Riefflin A, Nealon JL. 1996. Randomized controlled pilot trial of a hand-held patient-oriented, insulin regimen optimizer. Med Inform (Lond), 21 (4), pp. 317-326. | Show Abstract

A robust, hand-held, patient-oriented insulin regimen optimizer (POIRO) has been developed. Relevant information is entered by selecting appropriate items from choices displayed on a touch-sensitive screen rather than a conventional keyboard. All data items are recorded, together with their time and date of entry, and may be recalled at any time with glucose values displayed graphically to provide an overview of glycaemic control. When requested, an integral, hybrid, statistical and rule-based expert system program uses all available data to suggest an optimum insulin dose within physician determined, pre-set limits. POIRO has been formally evaluated in a randomized crossover pilot trial, comparing two 3 week periods with and without decision support, in six patients with type 1 diabetes. Mean (SE) pre-prandial blood glucose levels were significantly lower during the period when decision support was available (7.5 (0.4) versus 8.9 (0.4) mmol/l, p = 0.015) with no increase in the frequency or severity of hypoglycaemia. The device, which was well received by the patients, may offer a relatively inexpensive method of providing expert diabetic advice at a distance. The persistence of improved glycaemic control, even after decision support was switched off, suggests the device could be used intermittently by patients and may have educational value.

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Turner RC, Holman RR. 1996. The UK Prospective Diabetes Study ANNALS OF MEDICINE, 28 (5), pp. 439-444. | Show Abstract | Read more

The Diabetes Control and Complications Study has shown that improved blood glucose control would delay the progress of microvascular complications of diabetes. However, in patients with non-insulin-dependent diabetes mellitus, the major morbidity and mortality arises from premature cardiovascular disease. It is uncertain whether therapy aimed to improve diabetes control will prevent cardiovascular complications, and whether the available therapies, sulphonylurea, biguanides or insulin, may even have long-term deleterious side-effects. The UK prospective Diabetes Study started in 1997 and is evaluating whether long-term therapy to improve control would be advantageous in clinical practice. The study has demonstrated that it is difficult to maintain improved glucose control because of the progressive β-cell dysfunction. The study is also evaluating whether improved control of hypertension would be advantageous. The progress of the study is summarized. The results are expected to be published in 1998.

Turner RC, Holman RR. 1996. The UK Prospective Diabetes Study. UK Prospective Diabetes Study Group. Ann Med, 28 (5), pp. 439-444. | Show Abstract

The Diabetes Control and Complications Study has shown that improved blood glucose control would delay the progress of microvascular complications of diabetes. However, in patients with non-insulin-dependent diabetes mellitus, the major morbidity and mortality arises from premature cardiovascular disease. It is uncertain whether therapy aimed to improve diabetes control will prevent cardiovascular complications, and whether the available therapies, sulphonylurea, biguanides or insulin, may even have long-term deleterious side-effects. The UK Prospective Diabetes Study started in 1977 and is evaluating whether long-term therapy to improve glucose control would be advantageous in clinical practice. The study has demonstrated that it is difficult to maintain improved glucose control because of the progressive beta-cell dysfunction. The study is also evaluating whether improved control of hypertension would be advantageous. The progress of the study is summarized. The results are expected to be published in 1998.

Widjaja A, Stratton IM, Horn R, Holman RR, Turner RC, Brabant G. 1996. UKPDS: Plasma leptin, obesity and plasma insulin in type 2 diabetic subjects DIABETOLOGIA, 39 pp. 547-547.

Stratton IM, Kohner EM, Matthews DR, Holman RR, Aldington S, Turner RC. 1996. Risk factors predicting progression of diabetic retinopathy over six years in 1579 NIDDM patients DIABETOLOGIA, 39 pp. 91-91.

Karunakaran S, Morris RJ, Turner RC, Holman RR. 1996. Microvascular and macrovascular disease in subjects with increased but not diabetic fasting glucose levels DIABETOLOGIA, 39 pp. 920-920.

Holman RR, Cull CA, Turner RC. 1996. Glycaemic improvement over one year in a double-blind trial of acarbose in 1,946 NIDDM patients DIABETOLOGIA, 39 pp. 156-156.

Rachman J, Payne MJ, Levy JC, Barrow BA, Manley SE, Holman RR, Turner RC. 1996. Post-prandial amylin concentrations are increased by sulphonylurea, but unchanged by basal insulin, in NIDDM DIABETOLOGIA, 39 pp. 565-565.

Turner RC, Millns H, Stratton IM, Neil HAW, Holman RR. 1996. Risk factors for coronary heart disease in non-insulin dependent diabetic subjects DIABETOLOGIA, 39 pp. 1047-1047.

Aldington SJ, Stratton IM, Holman RR, Matthews DR, Turner RC, Kohner EM. 1996. Nine-year status of diabetic retinopathy and photocoagulation in the UK prospective diabetes study. DIABETOLOGIA, 39 pp. 90-90.

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Eeley EA, Stratton IM, Hadden DR, Turner RC, Holman RR. 1996. UKPDS 18: Estimated dietary intake in type 2 diabetic patients randomly allocated to diet, sulphonylurea or insulin therapy DIABETIC MEDICINE, 13 (7), pp. 656-662. | Read more

Eeley EA, Stratton IM, Hadden DR, Turner RC, Holman RR. 1996. UKPDS 18: estimated dietary intake in type 2 diabetic patients randomly allocated to diet, sulphonylurea or insulin therapy. UK Prospective Diabetes Study Group. Diabet Med, 13 (7), pp. 656-662. | Show Abstract | Read more

Self-reported dietary intake was estimated from 3-day prospective food diaries completed by Type 2 diabetic patients in the UK Prospective Diabetes Study. All patients had received individual dietary advice and had been randomly allocated to diet, sulphonylurea or insulin therapy 3 months after diagnosis. A total of 132 patients (120 white Caucasian, 12 Asian) stratified for gender, obesity and allocated therapy with mean age 55 years (SD 8), body mass index 28 kg m-2 (SD 4), and with a diabetes duration of 3 to 6 years were selected at random from 5 of 23 clinical centres. Patients reported a similar proportion of their energy intake as carbohydrate (43%) to the general population and had not increased to the recommended 50-55%. Their protein intake (21%) was higher than the advised 10-15%. Estimated energy intake from fat (37%) was close to that recommended for diabetic patients (30-35%) and was lower than that reported for the UK population (40%). The estimated polyunsaturated/saturated fat intake ratio (0.48) was higher than that reported for the UK population (0.35) compared with the recommended 1.0. Mean fibre intake at 22 g day-1 was less than the recommended 30 g day-1. The 8 male Asian patients took a higher proportion of their dietary intake as fat (46% vs 37%) and lower as protein (14% vs 21%) than the male white Caucasian patients. No significant differences were seen in estimated nutrient constituents between patients allocated to diet, sulphonylurea or insulin therapy as part of the UK Prospective Diabetes Study and followed for mean 4.2 years (SD1.6). This suggests that dietary factors will not confound UK Prospective Diabetes Study treatment related analyses.

Turner RC, Cull CA, Holman RR. 1996. UK prospective diabetes study DIABETES CARE, 19 (2), pp. 182-183. | Read more

Holman R. 1996. Expert Workshop on Impaired Glucose Tolerance Held in London, UK - 29 March 1995 - Introduction DIABETIC MEDICINE, 13 (3), pp. S5-S5.

Turner R, Cull C, Holman R. 1996. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med, 124 (1 Pt 2), pp. 136-145. | Show Abstract | Read more

PURPOSE: To report the progress (after 9-year follow-up) of a study designed to determine whether improved glucose control in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM) is effective in reducing the incidence of clinical complications. DATA SOURCE: A multicenter, randomized, controlled trial of different therapies for NIDDM. After initial diet therapy, 4209 asymptomatic patients who remained hyperglycemic (fasting plasma glucose levels, 6.0 to 15.0 mmol/L) were assigned to either a conventional therapy policy, primarily with diet alone, or to an intensive therapy policy, aiming for fasting plasma glucose levels of less than 6.0 mmol/L, with assignment to primary therapy with sulfonylurea or insulin (which increased insulin supply) or metformin (which enhanced insulin sensitivity). RESULTS: All three modes of pharmacologic therapy in the intensively treated group-sulfonylurea, insulin, and metformin-had similar efficacy in reducing the fasting plasma glucose and glycated hemoglobin levels. Over 9 years, patients assigned to intensive therapy with sulfonylurea or insulin had lower fasting plasma glucose levels (median, 7.3 and 9.0 mmol/L, respectively) than patients assigned to conventional therapy. Regardless of the assigned therapy, however, the fasting plasma glucose and hemoglobin A1c levels increased, and maintaining near-normal glycemia was, in general, not feasible. Even insulin therapy did not achieve the therapeutic goal of near-normal glycemia because of the difficulty in treating marked hyperglycemia and the risk for hypoglycemic episodes. Nine years after the diagnosis of diabetes, 29% of the patients had had a diabetes-related clinical end point, 20% had had a macrovascular complication, and 9% had had a microvascular complication. CONCLUSIONS: A report will be published in 1998 after a median duration from randomization of 11 years (range, 6 to 20 years) with an 81% power at a 1% level of significance of detecting whether the obtained improvement in glucose control causes a 15% decrease or increase in the incidence of major complications and whether any specific therapy is advantageous or disadvantageous.

Holman RR, Smale AD, Pemberton E, Riefflin A, Nealon JL. 1996. Randomized controlled pilot trial of a hand-held patient-oriented, insulin regimen optimizer Medical Informatics, 21 (4), pp. 317-326. | Show Abstract | Read more

A robust, hand-held, patient-oriented insulin regimen optimizer (POIRO) has been developed. Relevant information is entered by selecting appropriate items from choices displayed on a touch-sensitive screen rather than a conventional keyboard. All data items are recorded, together with their time and date of entry, and may be recalled at any time with glucose values displayed graphically to provide an overview of glycaemic control. When requested, an integral, hybrid, statistical and rule-based expert system program uses all available data to suggest an optimum insulin dose within physician determined, pre-set limits. POIRO has been formally evaluated in a randomized crossover pilot trial, comparing two 3 week periods with and without decision support, in six patients with type 1 diabetes. Mean (SE) pre-prandial blood glucose levels were significantly lower during the period when decision support was available (7·5 (0·4) versus 8·9 (0·4) mmol/1, p = 0·015) with no increase in the frequency or severity of hypoglycaemia. The device, which was well received by the patients, may offer a relatively inexpensive method of providing expert diabetic advice at a distance. The persistence of improved glycaemic control, even after decision support was switched off, suggests the device could be used intermittently by patients and may have educational value. © 1996 Informa UK Ltd All rights reserved.

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TURNER R, CULL C, STRATTON I, MANLEY S, KOHNER E, MATTHEWS D, NEIL H, LEVY J, HOLMAN R. 1995. UK PROSPECTIVE DIABETES STUDY 16 - OVERVIEW OF 6 YEARS THERAPY OF TYPE-II DIABETES - A PROGRESSIVE DISEASE DIABETES, 44 (11), pp. 1249-1258. | Read more

DYSON P, HAMMERSLEY M, MORRIS R, HOLMAN R, TURNER R. 1995. THE EFFECT OF INTENSIVE HEALTHY LIVING ADVICE IN SUBJECTS WITH PERSISTENT FASTING HYPERGLYCEMIA DIABETOLOGIA, 38 pp. A178-A178.

Keavney BD, Dudley CR, Stratton IM, Holman RR, Matthews DR, Ratcliffe PJ, Turner RC. 1995. UK prospective diabetes study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM. Diabetologia, 38 (8), pp. 948-952. | Show Abstract | Read more

The deletion allele of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene has been suggested to be an independent risk factor for myocardial infarction, particularly in subjects judged to be "low-risk" by the criteria of lipid status and body mass index. In a prospective, matched case-control study, we have investigated the role of this polymorphism as a risk factor for myocardial infarction in 173 newly-diagnosed British Caucasian non-insulin-dependent diabetic subjects taken from the United Kingdom Prospective Diabetes Study who subsequently developed myocardial infarction and 297 control subjects from the same study population matched for known cardiovascular risk factors including age at diagnosis of diabetes, gender, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and smoking habit. A trend towards increased risk conferred by homozygosity for the deletion allele was observed in cases (odds ratio 1.63, p = 0.09). When the population was stratified according to the matched risk factors, the deletion allele was associated with myocardial infarction in those with low plasma low-density lipoprotein cholesterol (odds ratio 3.67, p = 0.002), or low triglyceride (odds ratio 3.14, p = 0.005). The strongest association of the deletion allele with myocardial infarction was observed in subjects with both low low-density lipoprotein cholesterol and low triglyceride levels (odds ratio 9.0, p < 0.001). These results show that the deletion allele is a risk factor for myocardial infarction in non-insulin-dependent diabetic patients who have a favourable lipid profile.

CULL C, HOLMAN R, TURNER R. 1995. UKPDS - 6-YEAR TRIAL OF SULFONYLUREA, INSULIN AND METFORMIN THERAPY IN TYPE-2 DIABETIC-PATIENTS WITH DIET FAILURE DIABETOLOGIA, 38 pp. A24-A24.

KARUNAKARAN S, HAMMERSLEY M, MORRIS R, HOLMAN R. 1995. RANDOMIZED CONTROLLED TRIAL OF SULFONYLUREA THERAPY IN 227 SUBJECTS WITH PERSISTENT FASTING HYPERGLYCEMIA DIABETES, 44 pp. A160-A160.

HOLMAN R, CULL C, TURNER R, FOX C. 1995. UNITED-KINGDOM PROSPECTIVE DIABETES STUDY - COMPLIANCE WITH DIET WILL AFFECT RESULTS - REPLY BRITISH MEDICAL JOURNAL, 310 (6985), pp. 1006-1006.

MEYER L, MANLEY S, FRIGHI V, BURDEN F, NEIL H, HOLMAN R, TURNER R. 1994. UK Prospective Diabetes Study. XII: Differences between Asian, Afro-Caribbean and white Caucasian type 2 diabetic patients at diagnosis of diabetes. UK Prospective Diabetes Study Group. Diabet Med, 11 (7), pp. 670-677. | Show Abstract | Read more

Clinical and biochemical variables and prevalence of complications at diagnosis of diabetes were assessed in 5098 Type 2 diabetic patients in the UK Prospective Diabetes Study of whom 82% were white Caucasian, 10% Asian of Indian origin, and 8% Afro-Caribbean. The Asian patients were (p < 0.001) younger (mean age 52.3, 47.0, 51.0 years), less obese (BMI 29.3, 26.7, 27.9 kg m-2), had a greater waist-hip ratio, lower blood pressure (systolic 145, 139, 144, diastolic 87, 86, 89 mmHg) and prevalence of hypertension. They were more often sedentary (19, 39, 15%), more often abstained from alcohol (21, 55, 25%) and had a greater prevalence of first degree relatives with known diabetes (36, 44, 34%). The Afro-Caribbean patients had (p < 0.001) higher fasting plasma glucose (11.9, 11.3, 12.5 mmol l-1), more severely impaired beta-cell function (45, 35, 28% normal) and less impaired insulin sensitivity (23, 19, 27% normal) by homeostasis model assessment, lower triglyceride (1.8, 1.8, 1.3 mmol l-1), and higher HDL-cholesterol (1.05, 1.03, 1.17 mmol l-1). Prevalence of a history of myocardial infarction, stroke or intermittent claudication at diagnosis was similar. The prevalence of ischaemic ECG (Minnesota code), microalbuminuria (urine albumin > 50 mg l-1), retinopathy ('191' grading of retinal photographs), and neuropathy (abnormal vibration perception threshold or absent leg reflexes) was also similar. At diagnosis of Type 2 diabetes there were no differences in prevalence of complications between white Caucasian, Asian, and Afro-Caribbean patients although differences were found in other clinical and biochemical variables.

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MANLEY S, MEYER L, NEIL H, ROSS I, TURNER R, HOLMAN R. 1994. UK PROSPECTIVE DIABETES STUDY (UKPDS) .11. BIOCHEMICAL RISK-FACTORS IN TYPE-2 DIABETIC-PATIENTS AT DIAGNOSIS COMPARED WITH AGE-MATCHED NORMAL SUBJECTS DIABETIC MEDICINE, 11 (6), pp. 534-544. | Read more

Turner R, Holman R, Stratton I, Manley S, Frighi V. 1994. Hypertension in Diabetes Study. III. Prospective study of therapy of hypertension in type 2 diabetic patients: efficacy of ACE inhibition and beta-blockade. Diabet Med, 11 (8), pp. 773-782. | Show Abstract | Read more

The Hypertension in Diabetes Study (HDS) is an ongoing, multicentre, prospective randomized intervention trial of therapy of hypertension (> or = 160 and/or > or = 90 mmHg) in Type 2 diabetic patients. It compares tight blood pressure control (aim: < 150/85 mmHg) versus less tight control (aim: < 180/105 mmHg) and, within the tight control group, an ACE inhibitor, captopril, versus a beta blocker, atenolol. We report the efficacy, side-effects of treatment, biochemical responses and incidence of hypoglycaemia in 755 patients (mean age 57 years, blood pressure 150/94 mmHg) followed for 2 years. At 2 years, blood pressure was 143/84 in the tight control and 156/90 mmHg in the less tight control group (p < 0.0001). Blood pressure reduction, adherence to therapy, incidence of side-effects and of hypoglycaemia were similar on captopril and on atenolol. Patients on atenolol had a greater increase in body weight (+2.3 vs +0.7 kg, p < 0.01) and a non-significant trend to a greater increase in triglyceride than patients on captopril. A large blood pressure difference between the tight control and less tight control groups was obtained, with captopril and atenolol having similar hypotensive effects. The study has the potential to determine whether strict blood pressure control reduces the incidence of diabetic complications and whether ACE inhibitor or beta-blocker therapy is clinically advantageous.

Nealon JL, Jackson-Smale AD, Holman RR. 1994. Optimized diabetes therapy knowledge-based systems: Safety critical issues IEE Colloquium (Digest), (109), | Show Abstract

Computers offer a solution to the problem of calculating the correct insulin dose, both for the physician at a clinic consultation and on a daily basis for patients. In order to be acceptable to its users the computer system must be reliable and able to adapt to the individual requirements of each patient. Two knowledge-based systems have been developed, a patient and a physician system, to accomplish these tasks.

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CULL C, MANLEY S, FRIGHI V, HOLMAN R, TURNER R. 1993. UK PROSPECTIVE DIABETES STUDY (UKPDS) .10. URINARY ALBUMIN EXCRETION OVER 3 YEARS IN DIET-TREATED TYPE-2, (NON-INSULIN-DEPENDENT) DIABETIC-PATIENTS, AND ASSOCIATION WITH HYPERTENSION, HYPERGLYCEMIA AND HYPERTRIGLYCERIDEMIA DIABETOLOGIA, 36 (10), pp. 1021-1029.

Cook JT, Page RC, O'Rahilly S, Levy J, Holman R, Barrow B, Hattersley AT, Shaw AG, Wainscoat JS, Turner RC. 1993. Availability of type II diabetic families for detection of diabetes susceptibility genes. Diabetes, 42 (10), pp. 1536-1543. | Show Abstract | Read more

Type II diabetes is a familial disorder, as evidenced by the increased prevalence in monozygotic cotwins and first-degree relatives of affected subjects; however, its genetic etiology is largely unknown. Well-characterized pedigrees are an essential resource for the study of susceptibility genes for type II diabetes. This study describes a 5-yr search for type II diabetic families in Oxfordshire, U.K. We interviewed 950 type II diabetic subjects concerning the availability of first-degree relatives; 127 Caucasian families ascertained through a proband with type II diabetes were studied, and 589 first-degree relatives were characterized. Three large pedigrees with maturity-onset diabetes of the young, and 8 multiplex multigenerational type II diabetic pedigrees were identified. We identified 12 sib-pairs in which both siblings had type II diabetes; however, only 7 sib-pairs had both parents alive, and 2 of these had both parents affected. If one also considers one sib having diabetes and one sib having glucose intolerance as being an affected sib-pair, we identified 30 sib-pairs of which 7 had both parents affected and probably had bilineal inheritance. We identified 76 complete nuclear families with both parents and offspring available for study, but only 6 were of optimal structure for linkage analysis. In conclusion, multiplex pedigrees and type II diabetic sib-pairs with living parents are uncommon, and their ascertainment requires a substantial investment of resources. Large-scale collaborative multicenter initiatives would be needed to collect a large resource of family material for the study of susceptibility genes for type II diabetes.

1993. UK prospective diabetes study (UKPDS) Diabetologia, 36 (9), pp. 835-842. | Read more

STRATTON I, KOHNER E, ALDINGTON S, HOLMAN R, MATTHEWS D, TURNER R. 1993. PROGRESSION OF DIABETIC-RETINOPATHY IN TYPE-2 DIABETIC-PATIENTS IN THE UK PROSPECTIVE DIABETES STUDY DIABETOLOGIA, 36 pp. A40-A40.

HAMMERSLEY M, MCLELLAN J, MEYER L, MANLEY S, CHRISTOPHER P, TURNER R, HOLMAN R. 1993. FASTING HYPERGLYCEMIA STUDY - TARGETED SCREENING BY 2 FASTING PLASMA-GLUCOSE MEASUREMENTS DIABETOLOGIA, 36 pp. A176-A176.

TURNER R, MEYER L, NEIL H, ROSS I, MATTHEWS D, MANLEY S, HOLMAN R. 1993. BIOCHEMICAL RISK-FACTORS FOR CARDIOVASCULAR-DISEASE IN NEWLY-DIAGNOSED TYPE-II DIABETIC-PATIENTS AND AGE-MATCHED SUBJECTS DIABETOLOGIA, 36 pp. A205-A205.

HOLMAN R, STEEMSON J, CARTER R, LEVY J. 1993. TIMING OF NASAL INSULIN DELIVERY IN TYPE-I DIABETES DIABETOLOGIA, 36 pp. A161-A161.

STRATTON I, HOLMAN R, MATTHEWS D, TURNER R. 1993. STUDY DESIGN OF THE UK PROSPECTIVE DIABETES STUDY AND PROGRESS OF EYE DATA INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 34 (4), pp. 1181-1181.

TURNER R, HOLMAN R, MATTHEWS D, BASSETT P, COSTER R, STRATTON I, CULL C, PETO R et al. 1993. Hypertension in Diabetes Study (HDS): II. Increased risk of cardiovascular complications in hypertensive type 2 diabetic patients. J Hypertens, 11 (3), pp. 319-325. | Show Abstract | Read more

OBJECTIVE: To determine the degree to which hypertension is a risk factor for macrovascular and microvascular complications in type 2 diabetes. DESIGN: Observational prospective study. SUBJECTS: Newly diagnosed Type 2 diabetic patients recruited into the UK Prospective Diabetes Study (n = 3648; mean age 52 years), 40% of whom were hypertensive (blood pressure > or = 160 mmHg systolic and/or > or = 90 mmHg diastolic or already being treated for hypertension). MEASUREMENTS: The incidence of fatal and non-fatal major diabetes- and hypertension-related clinical events was determined over a median of 4.6 years' follow-up. The 3-year change in prevalence of subclinical indices of macrovascular and microvascular disease was assessed, including ECG abnormalities (Minnesota coding), left ventricular hypertrophy (ECG and chest x-ray), microalbuminuria (albumin/creatinine ratio) and moderately severe retinopathy (grading of retinal photographs). RESULTS: The hypertensive patients had (1) a greater incidence than normotensive patients of death from diabetes-related, mainly cardiovascular events (age-adjusted odds ratio 1.82) and (2) a greater incidence of diabetes-related death and major morbidity combined, including myocardial infarctions, angina, strokes and amputation (age-adjusted odds ratio 1.56). These associations were still present after allowance for other risk factors present at the time diabetes was diagnosed. The change in the prevalence of microvascular disease over 3 years was similar in both hypertensive and normotensive subjects. CONCLUSIONS: Hypertension is a major risk factor for cardiovascular morbidity and mortality in type 2 diabetes. Comparison with other studies suggests that patients with both hypertension and diabetes have approximately four times the cardiovascular risk of non-diabetic non-hypertensive subjects. Antihypertensive therapy may provide greater benefit in this high-risk group than in the general population.

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TURNER R, HOLMAN R, MATTHEWS D, BASSETT P, COSTER R, STRATTON I, CULL C, PETO R et al. 1993. HYPERTENSION IN DIABETES STUDY (HDS) .1. PREVALENCE OF HYPERTENSION IN NEWLY PRESENTING TYPE-2 DIABETIC-PATIENTS AND THE ASSOCIATION WITH RISK-FACTORS FOR CARDIOVASCULAR AND DIABETIC COMPLICATIONS JOURNAL OF HYPERTENSION, 11 (3), pp. 309-317. | Read more

Levy JC, Cull CA, Stratton IM, Holman RR, Turner RC. 1993. [The UKPDS study on glycemic control and arterial hypertension in type II diabetes: objectives, structure and preliminary results]. Journ Annu Diabetol Hotel Dieu, pp. 123-137.

Levy JC, Cull CA, Stratton IM, Holman RR, Turner RC. 1993. The UKPDS study on glycemic control and arterial hypertension in type II diabetes: objectives, structure and preliminary results Journees annuelles de diabetologie de l"Hotel-Dieu, pp. 123-137.

EELEY E, STRATTON I, JAMES R, HOLMAN R. 1992. DIETARY EVALUATION IN TYPE-II DIABETIC SUBJECTS RANDOMLY ALLOCATED TO INSULIN, SULFONYLUREA OR DIET THERAPY DIABETOLOGIA, 35 pp. A165-A165.

HOLMAN R, STEEMSON J. 1992. NASAL INSULIN OUTPATIENT STUDY IN TYPE-I DIABETES DIABETOLOGIA, 35 pp. A14-A14.

STRATTON I, HOLMAN R. 1992. MULTICENTER TRIAL OF MIGLITOL IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES DIABETOLOGIA, 35 pp. A15-A15.

Holman RR, Steemson J, Turner RC. 1991. Post-prandial glycaemic reduction by an alpha-glucosidase inhibitor in type 2 diabetic patients with therapeutically attained basal normoglycaemia. Diabetes Res, 18 (4), pp. 149-153. | Show Abstract

Post-prandial glucose excursions remain elevated in most patients with diabetes even when normal fasting plasma glucose levels have been achieved. In 39 patients with type 2 diabetes who had attained basal normoglycaemia by therapy with diet alone, a sulphonylurea, a basal insulin supplement or basal plus prandial insulin the mean glycosylated haemoglobin (HbA1) values were at the upper end (mean +/- 1SD, 8.1 +/- 1.1%) of the normal range (5.0-8.2%). Miglitol, an alpha-glucosidase inhibitor, given in a dose of 50 mg three times a day was studied in a double blind randomized crossover study. In diet and sulphonylurea treated patients, a mean 25% reduction of the post-prandial plasma glucose excursions was obtained whereas in ultralente treated patients miglitol appeared to reduce basal plasma glucose levels (p < 0.006). Side effects were limited to minor gastrointestinal disturbances, usually ameliorating after the first week of therapy. Alpha-glucosidase inhibition to prevent post-prandial glycaemia may have a role in patients in whom sulphonylurea or diet therapy has been used to obtain normal basal glucose concentrations.

TURNER R, HOLMAN R, MATTHEWS D, OAKES S, BASSETT P, STRATTON I, CULL C, MANLEY S, FRIGHI V. 1991. UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia, 34 (12), pp. 877-890. | Show Abstract | Read more

The UK Prospective Diabetes Study (UKPDS) is a multi-centre, prospective, randomised, intervention trial of 5100 newly-diagnosed patients with Type 2 (non-insulin-dependent) diabetes mellitus which aims to determine whether improved blood glucose control will prevent complications and reduce the associated morbidity and mortality. Newly presenting Type 2 diabetic patients aged 25-65 years inclusive, median age 53 years, median body mass index 28 kg/m2 and median fasting plasma glucose 11.3 mmol/l, were recruited and treated initially by diet. Ninety five percent remained hyperglycaemic (fasting plasma glucose greater than 6 mmol/l) and were randomly allocated to different therapies. In the main randomisation, those who were asymptomatic and had fasting plasma glucose under 15 mmol/l were allocated either to diet policy, or to active policy with either insulin or sulphonylurea aiming to reduce the fasting plasma glucose to under 6 mmol/l. Over 3 years, the median fasting plasma glucose in those allocated to diet policy was 8.9 mmol/l compared with 7.0 mmol/l in those allocated to active policy. The Hypertension in Diabetes Study has been included in a factorial design to assess whether improved blood pressure control will be advantageous. Patients with blood pressure greater than or equal to 160/90 mm Hg were randomly allocated to tight control aiming for less than 150/85 mm Hg with either an angiotensin-converting enzyme inhibitor or a Beta-blocker or to less tight control aiming for less than 200/105 mm Hg. The endpoints of the studies are major clinical events which affect the life and well-being of patients, such as heart attacks, angina, strokes, amputations, blindness and renal failure. To date, 728 patients have had at least one clinical endpoint. Surrogate endpoints include indices of macrovascular and microvascular disease detected by ECG with Minnesota Coding, retinal colour photography and microalbuminuria. The studies also aim to evaluate potential risk factors for the development of diabetic complications such as smoking, obesity, central adiposity, plasma LDL- and HDL-cholesterol, triglyceride, insulin, urate and other biochemical variables. The studies are planned to terminate in 1994, with a median follow-up of 9 years (range 3-16 years) for the glucose study and 5 years (range 2-6 years) for the hypertension study.

Clark A, Yon SM, de Koning EJ, Holman RR. 1991. Autoantibodies to islet amyloid polypeptide in diabetes. Diabet Med, 8 (7), pp. 668-673. | Show Abstract | Read more

Islet amyloid polypeptide (IAPP) is the constituent peptide of amyloid in pancreatic islets of Type 2 diabetic patients and in insulinomas. Amyloid formation in Type 2 diabetes is associated with islet cell destruction which may promote formation of autoantibodies to IAPP. An ELISA method has been developed to detect IAPP autoantibodies and used to assay serum from 80 non-diabetic subjects, 49 Type 1 and 228 Type 2 diabetic patients, and 10 patients with insulinomas. Microtitre plates coated with IAPP 1-37 were used to detect antibody binding followed by an alkaline phosphatase conjugated anti-human IgG. ELISA binding decreased with sample dilution and with pre-incubation of the samples with IAPP. The optical density of the substrate reaction was compared with results from a standard serum from a non-diabetic subject (OD ratio). Elevated OD ratios were detected in some subjects from each patient group but the Type 2 diabetic group had significantly higher titres than the non-diabetic subjects (p less than 0.001). The OD ratio was elevated (greater than mean + 2SD non-diabetic group) in 15% of Type 2 and 18% of Type 1 diabetic patients and in 20% with insulinomas. IAPP antibody levels did not correlate with age or gender of subjects, or duration of diabetes. IAPP autoantibodies could be an additional marker for B-cell damage in diabetes.

Dunnett JM, Steemson J, Sear JW, Turner RC, Holman RR. 1990. Rapid restoration of normoglycaemia using intravenous insulin boluses. Diabetes Res, 15 (4), pp. 151-155. | Show Abstract

The reduction of elevated fasting plasma glucose levels to near normal by repeated intravenous bolus insulin doses, given according to a simple algorithm, has been studied in 17 Type I and 23 Type II, healthy diabetic patients. Using a formula based on the patient's plasma glucose, height and bodyweight with insulin boluses given every 30 min if the plasma glucose remained above 6 mmol/1, plasma glucose levels were reduced to less than 7.5 mmol/1 in 28 (70%) patients by 60 min at which time the mean (+/- 1 SD) plasma glucose level in the Type I diabetic patients had reduced from 18.2 +/- 4.9 to 8.9 +/- 3.5 mmol/1 and in the Type II diabetic patients from 12.3 +/- 3.1 to 5.9 +/- 1.4 mmol/1. None of the patients had symptomatic hypoglycaemia although in one Type I patient the plasma glucose level fell to 2.2 mmol/1. The rate of fall of glucose in the less insulin sensitive patients was not increased by giving more insulin. The regimen allows a reproducible and prompt glycaemic reduction in fasting diabetic patients.

1990. UK prospective diabetes study 7: Response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients Metabolism, 39 (9), pp. 905-912. | Read more

Turner RC, Holman RR. 1990. Insulin use in NIDDM. Rationale based on pathophysiology of disease. Diabetes Care, 13 (9), pp. 1011-1020. | Show Abstract | Read more

Because basal hyperglycemia is a major feature in non-insulin-dependent diabetes mellitus, diabetes control can be monitored by the fasting blood glucose concentration. A hierarchical sequence of therapies is proposed in which the major aim is to maintain near-normal fasting blood glucose concentrations, in the expectation that this will help prevent development of long-term complications. When diet and tablet therapy are no longer effective in keeping the fasting blood glucose level less than 6 mM, a basal insulin supplement from a long-acting insulin such as ultralente can be added. When monitored by fasting blood glucose concentration, there is little risk of hypoglycemia, and the patient can continue a normal life-style without restrictions concerning exercise or the size of individual meals. A basal insulin supplement does not induce marked weight gain. The dose of insulin required can be predicted from the level of the fasting blood glucose and the degree of obesity, which provides an index of the accompanying insulin resistance. Based on current evidence, insulin therapy is equally appropriate in patients with insulin deficiency and insulin resistance, because the benefit from maintaining near-normal glucose concentrations probably outweighs a putative risk of hyperinsulinemia. In more severely affected patients, additional regular insulin to cover meals is needed. Lowering fasting blood glucose to normal with a basal insulin supplement reduces endogenous insulin production, and this may be advantageous if accompanying production of islet amyloid polypeptide and islet amyloid formation are also reduced.

Holman RR. 1990. UK prospective diabetes study Current status of prevention and treatment of diabetic complications: proceedings of the Third International Symposium on treatment of Diabetes Mellitus. ICS821, pp. 154-158. | Show Abstract

The study would not be possible without the enthusiastic support of all the personnel involved and the willingness of NHS patients in the UK to participate. There is an excellent chance that the study will determine the degree to which improved blood glucose control will prevent the progress of microvascular disease and, similarly, the influence of tight blood pressure control in those patients who are found to be hypertensive. In the glucose control study (diet policy vs. active therapy), 326 diabetes-related deaths are expected by 1994 with 1000 patients having died or suffered a major diabetic complication. If active therapy reduces the complications by 15%, the study has a 65% power of achiving a three standard deviation difference (= P < 0.01 in view of multiple comparisons) and an 84% power at P < 0.05.

HOLMAN R, TURNER R. 1989. METFORMIN IN THE MANAGEMENT OF TYPE-2 DIABETES - REPLY DIABETIC MEDICINE, 6 (2), pp. 180-180.

Clark A, Wells CA, Buley ID, Cruickshank JK, Vanhegan RI, Matthews DR, Cooper GJ, Holman RR, Turner RC. 1988. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res, 9 (4), pp. 151-159. | Show Abstract

Morphometric analysis of the endocrine and exocrine pancreas was done on immunoperoxidase stained post-mortem tissue from 15 Type 2 diabetic and 10 age-matched control subjects. Thirteen of the 15 Type 2 diabetic patients had islet amyloid deposits (mean, 6.5% islet area) in the corpus (body, tail and anterior part of the head) but not in the caput (the "pancreatic polypeptide rich" part of the head) whereas none was seen in control subjects. In the corpus in diabetic subjects, the pancreatic area density of B-cells was decreased by 24% (p = 0.005) and A-cells increased by 58% (p less than 0.001) compared with control subjects. The mean A/B-cell ratio increased in the corpus from 0.27 in control subjects to 0.57 in Type 2 diabetic patients. Positive immunoreactivity for the amyloid constituent peptide, Diabetes Associated Peptide, was demonstrated in islet amyloid of diabetic subjects and in B-cells of control and diabetic subjects. The increase in A-cells may contribute to the hyperglucagonaemia and hyperglycaemia of Type 2 diabetes. The impaired insulin secretion in Type 2 diabetes may be due to a decrease in B-cells and to disruption of the islet structure by amyloid. Exocrine fat was similar in the control and diabetic subjects with both groups having more in the corpus than the caput. Diabetic subjects had increased exocrine fibrosis in the corpus region (p less than 0.001), but not in the caput. Exocrine fibrosis may be secondary to disordered islet cell function.

Holman R. 1988. Finger-prick blood samples: full blood counts in general practice. Practitioner, 232 (1454 ( Pt 2)), pp. 988-991.

Holman RR, Turner RC. 1988. Optimizing blood glucose control in type 2 diabetes: an approach based on fasting blood glucose measurements. Diabet Med, 5 (6), pp. 582-588. | Show Abstract | Read more

A structured approach to the management of Type 2 diabetes, aiming to reduce fasting blood glucose levels to near-normal, can provide effective blood glucose control with minimal risk of hypoglycaemia and in a manner acceptable to most patients. When the fasting blood glucose value is maintained in the region 4-6 mmol l-1, protein glycosylation and plasma triglyceride values usually become near-normal and this may help to prevent the development of long-term diabetic complications. We propose a simple management strategy, based on 3-monthly fasting blood glucose determination, which uses not more than two therapeutic agents at any one time. If diet and maximal oral therapy fail to keep fasting blood glucose levels below 6 mmol l-1 then the addition of a basal insulin supplement, e.g. from a once daily injection of ultralente insulin, can restore near-normal fasting blood glucose levels without the need for full insulin replacement therapy. In older patients, where long-term prevention of diabetic complications is not such an immediate priority, less strict blood glucose control may be reasonable, aiming to keep the fasting blood glucose values below 10 mmol l-1 in order to prevent symptoms secondary to glycosuria. Patients can be seen at a monthly general practice morning diabetic mini-clinic or with the aid of a nurse visiting elderly patients at home.

Dunnet JM, Holman RR, Turner RC, Sear JW. 1988. Diabetes mellitus and anaesthesia. A survey of the peri-operative management of the patient with diabetes mellitus. Anaesthesia, 43 (7), pp. 538-542. | Show Abstract | Read more

A variety of methods are currently available for the management of the diabetic patient in the peri-operative period. A questionnaire about current clinical practice was sent to all anaesthetists in the Oxford region. The majority reported that minor surgery in both insulin treated and noninsulin treated diabetic patients warranted no intervention other than avoidance of meals and medication before surgery, and that, for major surgery, a glucose-insulin-potassium infusion should be used. Fifty one out of 71 respondents in the junior staff grades preferred this latter approach for intermediate surgical procedures in insulin treated patients compared with 27 out of 69 of the consultant staff. Most anaesthetists aimed for blood glucose levels of 7-13 mmol/litre in the peri-operative period. The literature is also reviewed.

Holman RR. 1988. Insulin for the non-insulin dependent? Br Med J (Clin Res Ed), 296 (6634), pp. 1469-1470. | Read more

Turner RC, Mann JI, Holman RR, Howard-Williams JR, Oakes S, Nugent Z, Moore J, Aldington S et al. 1988. UK Prospective Diabetes Study. V. Characteristics of newly presenting type 2 diabetic patients: estimated insulin sensitivity and islet 4-cell function. Multi-centre study. Diabet Med, 5 (5), pp. 444-448. | Show Abstract | Read more

In 713 newly diagnosed Caucasian diabetic patients aged 25-65 inclusive, insulin sensitivity and islet B-cell function were estimated from fasting plasma glucose and insulin concentrations by Homeostasis Model Assessment. Insulin sensitivity was reduced in obese subjects. It was also slightly lower in male than in female diabetic patients, in those who were sedentary and in those with high fasting plasma glucose concentrations. The estimated B-cell function was particularly impaired in patients with a high fasting plasma glucose and in those with normal rather than excess body weight. Whilst diabetes can present in normal weight patients with marked deficiency of B-cell function, presenting patients often have only a moderate impairment of B-cell function with markedly impaired insulin sensitivity secondary to obesity, physical inactivity, or being male.

Turner RC, Mann JI, Holman RR, Howard-Williams JR, Oakes S, Nugent Z, Moore J, Aldington S et al. 1988. UK Prospective Diabetes Study. IV. Characteristics of newly presenting type 2 diabetic patients: male preponderance and obesity at different ages. Multi-center Study. Diabet Med, 5 (2), pp. 154-159. | Show Abstract | Read more

The characteristics of newly presenting Type 2 diabetes mellitus have been examined in 1857 newly diagnosed diabetic patients aged 25-65 years inclusive. The males were less obese than the females (121% vs 141% IBW, respectively), but a male-dominated sex ratio of 1.54 was found. Taking into account the prevalence of obesity in the general population, males had a 2.5-fold relative risk of presenting with diabetes, although with increasing obesity the male preponderance was lost. Presentation increased with age up to the age of 55 years. Patients presenting at all ages had similar glycaemia and were similarly obese. Those presenting at a younger age were usually particularly obese in relation to the general population. Obese patients were less physically active than normal weight patients. Type 2 diabetes had a seasonal variation of presentation with a peak in January to April.

Holman RR, Steemson J, Turner RC. 1987. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabet Med, 4 (5), pp. 457-462. | Show Abstract | Read more

Many diabetic patients continue to have hyperglycaemia on maximal sulphonylurea therapy. Five different therapeutic options, with the prime aim of achieving normal fasting plasma glucose concentrations, have been compared in 15 asymptomatic, sulphonylurea-treated type 2 diabetic patients in a randomized crossover study of 8-week periods. In 24 h metabolic profiles the overnight mean (+/- 1SD) basal plasma glucose level on sulphonylurea therapy was 8.9 +/- 4.2 mmol/l. This was slightly improved with added metformin therapy (7.3 +/- 4.3 mmol/l, p = 0.013), but reduced to normal by added ultralente insulin (5.2 +/- 3.2 mmol/l, p less than 0.001), ultralente insulin alone (5.1 +/- 1.6 mmol/l, p = 0.005) or by ultralente and soluble insulin (4.7 +/- 1.4 mmol/l, p = 0.003). The mean glycosylated haemoglobin concentration was reduced significantly only by the treatments which included insulin. None of the patients had severe or incapacitating hypoglycaemia and only when on additional soluble insulin did patients show a significant gain in weight. Combining sulphonylurea therapy with ultralente insulin did not significantly improve overall glucose control over treatment with ultralente alone, although the insulin dose required to restore fasting normoglycaemia was significantly lower (median (interquartile range), 25 (12-41) versus 40 (27-80) U/day, p = 0.001). In type 2 diabetic patients who continue to have fasting hyperglycaemia on maximal sulphonylurea therapy, fasting normoglycaemia can be achieved easily, without minimal changes in diet or lifestyle, by means of a basal insulin supplement.

ORAHILLY S, HOLMAN R, TURNER R. 1987. MATURITY-ONSET DIABETES IN YOUNG BLACK-AMERICANS NEW ENGLAND JOURNAL OF MEDICINE, 317 (6), pp. 381-382.

HOLMAN R, STEEMSON J, TURNER R. 1987. TWICE-DAILY SUBCUTANEOUS HUMAN PROINSULIN PROVIDES A SATISFACTORY BASAL INSULIN SUPPLEMENT IN TYPE-2 (NON-INSULIN-DEPENDENT) DIABETIC-PATIENTS DIABETOLOGIA, 30 (7), pp. A532-A532.

Altman DG. 1987. Evaluation of a new blood glucose meter. Lancet, 1 (8543), pp. 1205-1206. | Read more

O'Rahilly S, Spivey RS, Holman RR, Nugent Z, Clark A, Turner RC. 1987. Type II diabetes of early onset: a distinct clinical and genetic syndrome? Br Med J (Clin Res Ed), 294 (6577), pp. 923-928. | Show Abstract | Read more

The inheritance of non-insulin-dependent (type II) diabetes was studied by a continuous infusion of glucose test in all available first degree relatives of 48 diabetic probands of various ages and with differing severity of disease. In an initial study of 38 type II diabetic subjects and their first degree relatives six islet cell antibody negative patients with early onset disease (aged 25-40 at diagnosis) were found to have a particularly high familial prevalence of diabetes or glucose intolerance. Nine of 10 parents available for study either had type II diabetes or were glucose intolerant. A high prevalence of diabetes or glucose intolerance was also found in their siblings (11/16;69%). In a second study of the families of a further 10 young diabetic probands (presenting age 25-40) whose islet cell antibody state was unknown a similar high prevalence of diabetes or glucose intolerance was found among parents of the five islet cell antibody negative probands (8/9; 89%) but not among parents of the five islet cell antibody positive probands (3/8;38%). Islet cell antibody negative diabetics with early onset type II disease may have inherited a diabetogenic gene or genes from both parents. They commonly need insulin to maintain adequate glycaemic control and may develop severe diabetic complications. Early onset type II diabetes may represent a syndrome in which characteristic pedigrees, clinical severity, and absence of islet autoimmunity make it distinct from either type I diabetes, maturity onset diabetes of the young, or late onset type II diabetes.

Matthews DR, Holman RR, Bown E, Steemson J, Watson A, Hughes S, Scott D. 1987. Pen-sized digital 30-second blood glucose meter. Lancet, 1 (8536), pp. 778-779. | Read more

Holman RR, Steemson J, Darling P, Turner RC. 1987. No glycemic benefit from guar administration in NIDDM. Diabetes Care, 10 (1), pp. 68-71. | Show Abstract | Read more

A randomized crossover study of 5-g guar minitablets against placebo, given three times per day with main meals for 8 wk, was done in 29 non-insulin-dependent diabetes mellitus (NIDDM) patients who had near-normal fasting plasma glucose concentrations on treatment with diet alone, additional sulfonylurea, or ultralente insulin. Guar did not reduce the excessive postprandial glycemic excursion, glycosylated hemoglobin values, basal plasma glucose concentrations, basal or incremental plasma C-peptide values, or body weight. There were few side effects with either guar or placebo therapy. Mean low-density lipoprotein cholesterol levels were significantly reduced (P less than .001) by guar administration (116 +/- 23 vs. 104 +/- 19 mg/dl). Guar additives did not improve the excessive postprandial glycemia found in NIDDM patients in whom near-normal fasting plasma glucose levels had been obtained.

Turner RC, Rudenski AS, Holman RR, Matthews DR, O'Rahilly SP. 1987. Quantitative modelling of endocrine diseases as exemplified by diabetes. Clin Endocrinol (Oxf), 26 (1), pp. 107-116. | Show Abstract | Read more

The feedback loops between glucose and insulin have as fundamental a role in diabetes as do the regulatory feedback loops affected in other endocrine disorders. In contrast to other endocrine diseases, diabetes mellitus is rarely investigated by measuring the key hormone, insulin. This is because both the stimulatory and inhibitory control points of the feedback lop areo effected, rendering interpretation of plasma glucose and insulin levels difficult. The application of a mathematical model of glucose-insulin interaction can provide a frame of reference which allows the feedback loop can be assessed from fasting plasma insulin and glucose concentrations alone and this analysis has been termed 'homeostasis model assessment' (HOMA). Similar analysis has been suggested for thyroid and parathyroid disease. Minimal stressing of the feedback loop by a continuous infusion of glucose re-sets the homeostatic control at higher glucose and insulin concentrations allowing more precise measurement, and this 'continuous infusion of glucose with model assessment (CIGMA)' has been used to show that the initial detectable lesion in familial Type II diabetes is deficient β-cell function rather than impaired insulin sensitivity. When hormone assays do not provide an immediately clearcut diagnosis in other endocrine disorders, similar mathematical modelling might help to detect and quantify mild and/or interacting deficits at different control points.

Holman RR, Jelfs R, Causier PM, Moore JC, Turner RC. 1987. Glycosylated haemoglobin measurement on blood samples taken by patients: an additional aid to assessing diabetic control. Diabet Med, 4 (1), pp. 71-73. | Show Abstract | Read more

200 patients attending a diabetic outpatient clinic were each asked to post to the hospital, prior to their three-monthly routine clinic visit, a finger-prick capillary blood sample for glycosylated haemoglobin assay (HbA1). Patients took their own blood into UNISTEP bottles, which automatically measure a 53 microliters aliquot and mix it with 150 microliters of diluent suitable for transport to the laboratory. During 1 year 883 (84%) of 1046 bottles sent out were returned of which 776 (87%) were suitable for analysis. The availability of the result at the time of the patients' clinic visit aided assessment of diabetic control and was associated with a mean reduction of the HbA1 by 0.8% (p less than 0.001) over a twelve-month period. This simple system facilitates remote monitoring of HbA1 levels, is suitable for both hospital and general practice use and may allow a reduction in the number of patient visits.

Howard-Williams JR, Peckar CO, Holman RR, Turner RC, Bron AJ. 1986. Quantifying early diabetic retinopathy. Diabetologia, 29 (11), pp. 761-766. | Show Abstract | Read more

A precise and accurate method of numerically quantifying diabetic retinopathy, on standardised retinal colour photographs, has been developed which allows small changes and trends to be monitored. Colour slides are projected onto a screen and features noted on an acetate sheet which provides a permanent record. Sector analysis showed microaneurysms and haemorrhages to occur most often at the temporal-to-macula area, exudates at the macula and cotton wool spots on the nasal side of the retina. Seventy percent of microaneurysms appeared in the previous year, irrespective of the severity of the retinopathy. In proportion to their usual relative prevalences, after normalisation of distribution, the various features can be combined to provide a single value, the Retinopathy Index. This provides an overall assessment of retinopathy which is suitable for comparing the progress of mild retinopathy in prospective studies.

ORAHILLY S, SPIVEY R, HOLMAN R, DAVIES G, NUGENT Z, CLARK A, TURNER R. 1986. TYPE-2 (NON-INSULIN-DEPENDENT) DIABETES OF EARLY ONSET - A DISTINCT CLINICAL AND GENETIC SYNDROME DIABETOLOGIA, 29 (8), pp. A577-A577.

Turner RC, Holman RR, Matthews DR, O'Rahilly SP, Rudenski AS, Braund WJ. 1986. Diabetes nomenclature: classification or grading of severity? Diabet Med, 3 (3), pp. 216-220. | Read more

Moore JC, Bown E, Outlaw MC, Jelfs R, Holman RR, Turner RC. 1986. Glycosylated haemoglobin: comparison of five different methods, including measurement on capillary blood samples. Ann Clin Biochem, 23 ( Pt 1) (1), pp. 85-91. | Show Abstract | Read more

Glycosylated haemoglobin was measured in venous blood samples and in blood collected in 'Unistep' bottles by isoelectric focusing (IEF), as the reference method, and by electroendosmosis (EEO), the thiobarbituric acid method (TBA), ion-exchange chromatography (IEC) and affinity chromatography (AC). Isoelectric focusing, electroendosmosis and thiobarbituric acid gave similar results. Affinity chromatography gave lower results than isoelectric focusing for normal values but similar results for diabetics. Ion-exchange chromatography gave 24% lower results than isoelectric focusing across the range. Using Unistep collected blood samples and comparing multiple samples from the same patient, electroendosmosis gave the best results (coefficient of variation 4%) and thiobarbituric acid gave slightly less good precision that other methods. Re-use of affinity chromatography columns gave less good precision. Collection of blood samples into a Unistep bottle gave similar results to venous sample results. Storage of venous capillary blood samples in Unistep bottles over 1 week at 21 degrees C gave similar results to immediate assay. Electroendosmosis of blood samples in Unistep bottles gave stable results over 2 weeks. Home collection by a patient of a capillary blood sample into a Unistep bottle allows glycosylated haemoglobin results to be available when seen in the clinic.

1985. United Kingdom Prospective Diabetes Study. III. Prevalence of hypertension and hypotensive therapy in patients with newly diagnosed diabetes. A multicenter study. Hypertension, 7 (6_Pt_2), pp. II8-II8. | Read more

1985. U.K. Prospective Diabetes Study: II. Reduction in HbA1c with Basal Insulin Supplement, Sulfonylurea, or Biguanide Therapy in Maturity-onset Diabetes Diabetes, 34 (8), pp. 793-798. | Read more

TURNER R, HOLMAN R. 1985. Intermediate acting insulin for type 2 diabetes. Lancet, 1 (8429), pp. 640-641. | Read more

Rees SG, Holman RR, Turner RC. 1985. The Christmas feast. Br Med J (Clin Res Ed), 291 (6511), pp. 1764-1765. | Show Abstract | Read more

Twenty two normal subjects and 13 maturity onset diabetic patients completed an observational study with repeated weighing and fasting blood tests from one month before to one month after Christmas. Over the Christmas period in all subjects an increase in weight was observed (mean 0.8 (SD 0.1) kg, p less than 0.001), which was maintained through January. This may signify an average additional 6000 kcal ingested. By three to six days after Christmas a slight but significant increase in fasting plasma triglyceride (p less than 0.03) and cholesterol (p less than 0.02) concentrations occurred, with a subsequent rise in glycosylated haemoglobin concentration (p less than 0.001). This study is not likely to affect any future Christmas.

Holman RR, Rees SG, Moore JC, Bown EG, Turner RC. 1985. Patient-orientated metered capillary blood collection. Ann Clin Biochem, 22 ( Pt 2) (MAR), pp. 141-143. | Show Abstract | Read more

A small collector bottle, with a precision-moulded top, allows capillary blood from a finger-prick to be automatically metered into a diluent for subsequent laboratory analysis. This device, which has been successfully used by patients to obtain full blood counts, glycosylated haemoglobin values and blood glucose measurements, may have wide application.

Matthews DR, Connolly AA, Holman RR, Turner RC. 1985. Physiology of insulin secretion: problems of quantity and timing. Neth J Med, 28 Suppl 1 (SUPPL. 1), pp. 20-24. | Show Abstract

If normal physiology could be restored to diabetic subjects, their susceptibility to complications should decline. There are considerable problems in trying to achieve this, for each individual needs the correct quantity of insulin, and the time patterns of normal insulin secretion are complex and difficult to mimic. The pancreas secretes insulin in response to both metabolic and neural cues, and a study of normal physiology is helpful in outlining the principles of insulin therapy.

Holman RR, Turner RC. 1985. A practical guide to basal and prandial insulin therapy. Diabet Med, 2 (1), pp. 45-53. | Show Abstract | Read more

Separating basal and meal-related insulin requirements allows a systematic approach to subcutaneous insulin therapy. Simple guidelines for both the doctor and patient can cater for the spectrum of severity of diabetes. A non-insulin-dependent diabetic who, despite dieting, continues to have moderate fasting hyperglycaemia (6-10 mmol/l) may need only a basal insulin supplement, whereas a totally insulin-dependent diabetic usually needs similar amounts of basal and meal-related insulin. The likely insulin requirements of individual diabetics can be predicted, including the increased amounts required by obese patients. The algorithms have been developed using ultralente to provide the basal insulin requirement, but the principles and doses probably apply to other similarly long-acting insulins or an insulin pump. The insulin doses can be easily altered for varying lifestyles, including night work, religious fasts or long distance aeroplane travel, and for temporary disturbances such as operations or intercurrent infections.

TURNER R, STEEMSON J, BURNETT M, HOLMAN R. 1984. LACK OF BENEFIT FROM ACUTE ELEVATION OF PLASMA GLIBENCLAMIDE LEVELS BEFORE MEALS DIABETOLOGIA, 27 (2), pp. A340-A340.

Clark A, Holman RR, Matthews DR, Hockaday TD, Turner RC. 1984. Non-uniform distribution of islet amyloid in the pancreas of 'maturity-onset' diabetic patients. Diabetologia, 27 (5), pp. 527-528. | Show Abstract | Read more

Quantitative morphometry of the pancreases of five 'maturity-onset' diabetic subjects has demonstrated more amyloid in islets of the head, body and tail (where it was found in a mean 29% of the islets occupying a mean 11% islet area) than in islets of the 'pancreatic-polypeptide-rich' lobule of the head (where amyloid was found in a mean of 3% of the islets occupying a mean of 0.7% islet area, both p less than 0.005). The non-uniform amyloid distribution may relate to the hormone content of the islet; the head and tail contained significantly more A, B and D-cells than the pancreatic-polypeptide-rich lobule in both non-diabetic subjects (n = 8) and diabetic patients (n = 5; p less than 0.005). This result is compatible with the previous suggestion that amyloid may be derived from insulin or its precursors.

HOLMAN R, STEEMSON J, DARLING P, TURNER R. 1984. LACK OF BENEFIT FROM GUAR ADMINISTRATION IN WELL CONTROLLED NON-INSULIN-DEPENDENT DIABETIC-PATIENTS DIABETOLOGIA, 27 (2), pp. A289-A289.

Holman RR, Steemson J, Darling P, Reeves WG, Turner RC. 1984. Human ultralente insulin. Br Med J (Clin Res Ed), 288 (6418), pp. 665-668. | Show Abstract

The greater solubility of human insulin and its possible faster action have led to doubts about whether a sufficiently long acting formulation could be produced to provide a basal supply for diabetics. In a double blind crossover study in 18 diabetics human ultralente insulin was as effective as beef ultralente insulin in controlling basal plasma glucose concentrations (median 5.7 mmol/l (103 mg/100 ml) with human and 6.3 mmol/l (114 mg/100 ml) with beef ultralente insulin respectively). There was no significant difference between human and bovine insulin in the rise in plasma glucose concentration from 0400 to 0700 after an injection the previous morning and no difference between patients receiving an adequate or insufficient dose of human ultralente insulin. Bovine insulin antibody binding was reduced with human insulin (p less than 0.002), which suggests that human insulin is less antigenic than beef insulin. Once daily human ultralente insulin provides a suitable formulation for the basal insulin requirement of diabetics.

Turner RC, Mann JI, Iceton G, Oakes S, Smith A, Moore J, Hockaday TDR, Holman RR et al. 1983. UK prospective study of therapies of maturity-onset diabetes Diabetologia, 24 (6), | Read more

READ D, HOLMAN R, FEEST T. 1983. VIBRATION SENSORY THRESHOLD - A SIMPLE GUIDE TO ADEQUACY OF DIALYSIS KIDNEY INTERNATIONAL, 23 (3), pp. 560-560.

Holman RR, Dornan TL, Mayon-White V, Howard-Williams J, Orde-Peckar C, Jenkins L, Steemson J, Rolfe R et al. 1983. Prevention of deterioration of renal and sensory-nerve function by more intensive management of insulin-dependent diabetic patients. A two-year randomised prospective study. Lancet, 1 (8318), pp. 204-208. | Show Abstract | Read more

74 insulin-dependent diabetic patients with background retinopathy were randomised to continue with usual diabetic care (group U) or to a more intensive programme (group A) using ultralente insulin as basal cover and soluble insulin at mealtimes. Group A attended the clinic more frequently, received closer dietary supervision, and were taught home blood glucose monitoring. Group A had a significantly lower mean glycosylated haemoglobin level during the study, although the mean level also fell in group U towards the end of year 2. Renal and sensory-nerve function were significantly better preserved in group A than in group U. Significant improvements were also seen in low-density-lipoprotein-cholesterol and whole-blood low-shear viscosity. The rate of progression of retinopathy was similar in both groups. It appears that a modest improvement in diabetic control, obtainable in most clinics, has been associated with a reduction in the progression of diabetic tissue damage.

HOLMAN R, STEEMSON J, DARLING P, TURNER R. 1983. HUMAN ULTRALENTE INSULIN DIABETOLOGIA, 25 (2), pp. 165-165.

HOLMAN R, DORNAN T, MAYONWHITE V, STEEMSON J, PECKAR C, HOWARDWILLIAMS J, KNIGHT A, HOCKADAY T, BRON A, TURNER R. 1982. 2-YEAR PROSPECTIVE-STUDY OF IMPROVED DIABETIC CONTROL IN INSULIN-DEPENDENT DIABETIC-PATIENTS WITH BACKGROUND RETINOPATHY DIABETOLOGIA, 23 (2), pp. 175-175.

Turner RC, Mathews DR, Holman RR, Peto J. 1982. Relative contributions of insulin deficiency and insulin resistance in maturity-onset diabetes. Lancet, 1 (8272), pp. 596-598. | Show Abstract | Read more

The effects of raised insulin resistance and decreased beta-cell function on basal plasma glucose and insulin concentrations have been estimated by means of a mathematical model which uses the available data on control of glucose and insulin flux. The model shows that near-normal basal plasma insulin levels could be maintained by means of basal hyperglycaemia when beta-cell function is deficient. The hyperglycaemia does not become pronounced until more than 80% of beta-cell function has been lost. However, when only 5-10% of beta-cell remains, plasma insulin levels fall in spite of hyperglycaemic stimulation. Conversely, raised insulin resistance in the absence of decreased beta-cell function induces only a small rise in basal plasma glucose concentrations, which stimulates a compensatory increase in basal plasma insulin concentrations from a normal beta-cell capacity. However, if the beta-cell dysfunction is sufficient to induce a basal plasma glucose concentration of 5-6 mmol/l, a slight rise in insulin resistance causes pronounced basal hyperglycaemia.

HOLMAN R, DORNAN T, MAYONWHITE V, TING A, HOWARDWILLIAMS J, PECKAR C, JENKINS L, STEEMSON J et al. 1982. 2-YEAR RANDOMIZED PROSPECTIVE-STUDY OF IMPROVED DIABETIC CONTROL IN TYPE-1 (INSULIN-DEPENDENT) DIABETIC-PATIENTS WITH RETINOPATHY - PREVENTION OF DETERIORATION OF NERVE AND RENAL-FUNCTION WITH RETINOPATHY CHANGES RELATED TO HLA-DR4 DIABETOLOGIA, 23 (5), pp. 469-469.

Evans RJ, Lane J, Holman RR, Turner RC. 1982. Induced basal normoglycemia and altered platelet aggregation in non-insulin-dependent diabetes. Diabetes Care, 5 (4), pp. 433-437. | Show Abstract | Read more

Non-insulin-dependent diabetic subjects had abnormally raised in vitro platelet aggregation rates to collagen or ristocetin when thought to be "well-controlled" on diet alone but shown to have raised basal plasma glucose levels. Basal normoglycemia, induced with either ultralente insulin or chlorpropamide, was associated with a significant reduction of the enhanced platelet aggregation rates to normal. Some sulfonylurea drugs have been reported to have specific anti-platelet aggregatory properties, but the degree of plasma glucose control is probably more relevant.

Davis TM, Holman RR, Eaton PM, Turner RC. 1982. A regular meal and insulin infusion regimen: its use in the treatment of acute-onset ketotic diabetes and in stabilization of poorly controlled established diabetic subjects. Diabetes Care, 5 (5), pp. 492-496. | Show Abstract | Read more

A simple regimen, consisting of a constant intravenous insulin infusion at either a basal, nocturnal rate or at a daytime rate matched by seven small, isocaloric meals taken every 2 h, has been applied to two clinical situations requiring optimal blood glucose control. In eight poorly controlled established diabetic subjects, quantitative estimates of daily insulin requirements were possible, with consequent improved control upon reinstitution of twice-daily subcutaneous insulin. In five acute-onset, ketotic diabetic subjects first treated by intravenous saline and low-dose intramuscular insulin, the regimen was used to achieve and maintain basal and postprandial normoglycemia. Ketonuria was abolished quickly in these patients, and falling insulin requirements and large doses of insulin were handled easily. In both clinical situations, subsequent subcutaneous insulin doses required little adjustment. The regimen is cheap, convenient to use, and widely applicable.

Holman RR, Turner RC. 1981. The basal plasma glucose: a simple relevant index of maturity-onset diabetes. Clin Endocrinol (Oxf), 14 (3), pp. 279-286. | Show Abstract | Read more

The 'basal' plasma glucose, defined as the stable overnight concentration, has been assessed as an index of diabetes control by comparison with plasma glucose measurements during 24-h profiles in diet-treated maturity-onset diabetic patients and normal subjects. The basal plasma glucose correlated with the total (r=0.98) and incremental (r=0.86) glucose areas, as well as the 24-h M value (r=0.90). In mild diabetes the basal value was more abnormal than the incremental glucose area after meals, since 3 h after meals 'reactive hypoglycaemia' lowered the plasma glucose to less than the basal value. Thus diabetics with a raised basal glucose up to 8 mmol/l can have a normal 3-h post-prandial value. A raised basal plasma glucose provides similar diagnostic information to conventional oral glucose tolerance tests and provides an apposite measure of diabetes control. Diabetics who come up to a clinic, or who exercise whilst fasting, have fasting plasma glucose and insulin concentrations slightly higher than their overnight 'basal' levels, whereas there is little change in normal subjects. This higher 'stressed fasting' plasma glucose needs to be taken into account when assessing fasting plasma glucose values.

HOCKADAY T, HOLMAN R, HILLSON R, PIM B, SMITH B. 1981. COMPARISON OF VIBRATION SENSE (BY BIOTHESIOMETER) AND FASTING GLUCOSE VALUES DURING 1ST 3 YEARS OF DIABETES DIABETOLOGIA, 20 (6), pp. 670-670.

Holman RR, Turner RC. 1981. Insulin infusion pump. Lancet, 2 (8236), pp. 41. | Read more

HOLMAN R, HILLSON R, HOCKADAY T. 1981. CORRELATES OF DETERIORATING VIBRATION SENSITIVITY 3 YEARS FROM DIAGNOSIS OF MATURITY-ONSET DIABETES DIABETOLOGIA, 21 (3), pp. 283-283.

DAVIS T, HOLMAN R, TURNER R. 1981. PRIMARY HYPERTRIGLYCERIDEMIA AND INSULIN THERAPY DIABETOLOGIA, 20 (6), pp. 667-668.

Shaw DB, Holman RR, Gowers JI. 1980. Survival in sinoatrial disorder (sick-sinus syndrome). Br Med J, 280 (6208), pp. 139-141. | Show Abstract | Read more

A total of 381 patients with established (156) or potential (225) sinoatrial dysfunction were included in a 10-year prospective survey to determine the course of the disease and the benefits of pacing. With the exclusion of nine patients who were lost to follow-up, 61 were fitted with pacemakers. The overall survival of patients with established and potential dysfunction was similar and apparently indistinguishable from that of the normal population. Pacemaker implantation had little discernible effect on mortality though it reduced some incapacitating symptoms. These findings suggest that sinoatrial dysfunction is a relatively benign condition. Hence pacing should probably not be adopted as a routing measure but be reserved for patients with troublesome symptoms.

HOWEDAVIES S, MUIR A, HOLMAN R, TURNER R. 1980. FASTING BLOOD-GLUCOSE CONCENTRATIONS AND TREATMENT OF MATURITY-ONSET DIABETES BRITISH MEDICAL JOURNAL, 280 (6223), pp. 1147-1147.

SHAW D, BOLWELL A, GOWERS J, HOLMAN R. 1979. PROGNOSIS IN SINUATRIAL DISORDER (SICK SINUS SYNDROME) BRITISH HEART JOURNAL, 42 (2), pp. 233-234.

Phillips M, Simpson RW, Holman RR, Turner RC. 1979. A simple and rational twice daily insulin regime. Distinction between basal and meal insulin requirements. Q J Med, 48 (191), pp. 493-506. | Show Abstract

A new insulin regime is described, in which the primary aim is to attain normal basal plasma glucose concentrations by means of a constant insulin delivery rate from the long-acting Ultratard insulin. Additional twice daily Actrapid insulin is given to cover meals, and we have investigated this regime in 29 insulin dependent diabetics, with control assessed by admission for 24 hour profiles. Patients with low insulin requirements only need a basal insulin supplement with Ultratard insulin. With increasing insulin requirements the dose of short-acting insulin increases more than the basal insulin supplement. Thus fixed combinations of short- and long-acting insulins cannot produce good control in all patients. Twenty-one patients were deemed 'well controlled' in that they had no symptomatic hypoglycaemia, an overnight plasma glucose concentration of <5.5 mmol/l and a mean late post-prandial glucose concentration of <6.5 mmol/l. Their average 'mean excess glycaemic exposure' (mean incremental plasma glucose above 5 mmol) was 0.7 mmol/l (normal range 0-0.5 mmol/l), which is considerably less than that found in many maturity-onset diabetics. The distinction between basal and meal insulin requirements simplifies rules of insulin therapy.

Holman RR, Turner RC. 1979. Maintenance of basal plasma glucose and insulin concentrations in maturity-onset diabetes. Diabetes, 28 (3), pp. 227-230. | Show Abstract | Read more

Normal and mildly diabetic subjects each have their own "set" of basal plasma glucose and insulin concentrations. Diabetic patients have raised basal plasma glucose, with low-normal basal plasma C-peptide concentrations. Restoring normal glucose levels in mild diabetes by an insulin infusion further reduces the C-peptide concentration, but both the plasma glucose and the C-peptide return to their "set" level when the insulin is withdrawn. These results accord with the action of beta cells and liver in a negative feedback loop that maintains basal plasma glucose and insulin concentrations.

Turner RC, Holman RR, Matthews D, Hockaday TD, Peto J. 1979. Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations. Metabolism, 28 (11), pp. 1086-1096. | Show Abstract | Read more

The liver and beta cells function in a negative feedback loop, which appears to have a predominant role in regulating both the basal plasma glucose and insulin concentrations. The degree of basal hyperglycemia in diabetes probably provides a bioassay of both the effect of a reduction in insulin secretory capacity and the degree of insulin resistance. A mathematic model of the interaction of insulin deficiency and insulin resistance has been constructed, based on the known response characteristics of the beta cells to glucose, and of plasma glucose and insulin control of hepatic and peripherpal glucose flux. The degree to which beta cell deficiency increases basal plasma glucose reflects the hyperbolic shape of the normal insulin secretory response to different glucose concentrations. The height of basal plasma insulin is a function of the degree of insulin resistance. From the basal plasma insulin and glucose concentrations, the model provides an estimate of the degree to which both beta cell deficiency and insulin resistance contribute to diabetes. The predictions arising from the model are in accord with experimental data in man and in animals. In normal-weight diabetics who do not have increased insulin resistance, the model predicts that more than 85% of beta cell function has to be lost for the basal plasma glucose to rise to 6 mmol/liter, but a further 5%--10% loss increases the basal plasma glucose to over 10 mmol/liter. In a third of a consecutive series of 65 newly presenting, uncomplicated diabetics, both normal weight and obese, the analysis from the model suggested that insulin resistance, rather than beta cell deficit, was the predominant feature.

Holman RR, Turner RC. 1978. Basal normoglycemia attained with chlorpropamide in mild diabetes. Metabolism, 27 (5), pp. 539-547. | Show Abstract | Read more

Sixteen adult-onset diabetics, who were thought by current criteria to be well controlled on diet alone, had substantially elevated overnight, basal plasma glucose concentrations. Chlorpropamide had a sufficiently prolonged stimulatory effect on the beta cells such that normal basal plasma glucose levels were obtained in 13 patients. Both basal plasma C-peptide levels and the C-peptide response to meals became normal, with improved postprandial glycemia. Diurnal plasma triglyceride levels were reduced. Plasma growth hormone levels were normal both before and after therapy. When diet alone is insufficient to maintain basal normoglycemia in mild diabetes, chlorporpamide is as effective as basal insulin supplements in producing normal basal plasma glucose levels.

Turner RC, Holman RR. 1978. Automatic lancet for capillary blood sampling. Lancet, 2 (8092 Pt 1), pp. 712. | Read more

TURNER R, PHILLIPS M, SIMPSON R, HOLMAN R. 1978. SIMPLE AND RATIONAL TWICE-DAILY INSULIN REGIME DIABETOLOGIA, 15 (3), pp. 277-277.

HOWEDAVIES S, HOLMAN R, TURNER R. 1978. CONTROL OF MATURITY-ONSET DIABETES BY HOME OR CLINIC MONITORING OF FASTING PLASMA GLUCOSE DIABETOLOGIA, 15 (3), pp. 241-241.

Mann JI, Hughson WG, Holman RR, Honour AJ, Thorogood M, Smith A, Baum JD. 1978. Serum lipids in treated diabetic children and their families. Clin Endocrinol (Oxf), 8 (1), pp. 27-33. | Show Abstract | Read more

Fasting lipid concentrations have been measured in fifty treated juvenile diabetics, their siblings and parents to determine which types of hyperlipoproteinaemia co-exist with juvenile diabetes and whether the abnormalities relate to diabetic control, or represent familial disorders. Lipid concentrations amongst the parents did not differ from adult control. Triglyceride concentrations were significantly higher in those diabetic children with fasting blood glucose concentrations greater than 10 mmol/l than those with concentrations less than 10 mmol/l. The latter group had similar triglyceride levels to non-diabetic siblings. Cholesterol concentrations were not related to fasting blood glucose and were similar in diabetic and sibling controls. Hyperlipoproteinaemia (types IIa, IIb and IV) was present in ten of the diabetic patients. Six of the nine diabetic patients with raised cholesterol had at least one parent with cholesterol in the highest quintile for the control population, whereas only six of the forty-one with lower levels had parents in this category. A similar trend for cholesterol was apparent amongst the non-diabetic siblings. However, no association was apparent between the triglyceride levels of diabetics (or their siblings) and parents. Thus although hyperlipidaemia associated with juvenile diabetes appears to be largely due to inadequate control, raised cholesterol concentrations frequently occur.

Turner RC, Holman RR. 1978. betacell function during insulin or chlorpropamide treatment of maturity-onset diabetes mellitus. Diabetes, 27 Suppl 1 (Supplement_1), pp. 241-246. | Show Abstract | Read more

Maturity-onset diabetic patients usually have raised overnight-fasting plasma glucose levels associated with "normal" basal plasma insulin levels. The basal hyperglycemia is proportional to the degree of insulin deficiency. Basal insulin or C-peptide levels become subnormal if normal fasting plasma glucose levels are attained with insulin. Basal hyperglycemia is probably a compensatory response to maintain near-normal basal insulin levels. A logical therapy of maturity-onset diabetes is to produce basal normoglycemia by means of a constant basal insulin supplement, which can be provided by ultralente insulin. The reduced insulin response of diabetics to intravenous glucose is slightly increased when basal normoglycemia is established, suggesting that the high plasma glucose levels compromise beta cell function. The insulin response to meals in a mild diabetic is not affected by mild hyperglycemia but can be depleted if gross hyperglycemia occurs. Maintenance of normoglycemia then allows beta cell "recovery". In mild diabetics (c. less than 9 mmol per liter basal plasma glucose), chlorpropamide sufficiently stimulates beta cell secretion so that basal normoglycemia can be produced. The C-peptide response to meals is improved, whereas comparable reduction of the plasma glucose with insulin does not alter the meal response. Thus basal normoglycemia can be produced by "resting" beta cells with a basal insulin supplement or by stimulating them with sulfonylurea therapy.

Howe-Davies S, Holman RR, Phillips M, Turner RC. 1978. Home blood sampling for plasma glucose assay in control of diabetes. Br Med J, 2 (6137), pp. 596-598. | Show Abstract | Read more

Estimation of plasma glucose in home blood samples is needed to improve diabetic control. Sufficiently precise measurements on capillary blood were obtained by (a) storing Reflotest glucose-oxidase strips in a desiccant container before reading and (b) collecting blood samples into a simple vacuum bottle containing potassium fluoride (assay of sodium content indicating volume of plasma collected). The precision of the methods (+/- 1 SD) was +/-0.35 mmol/1 (+/-6.3 mg/100 ml). Clinical reliability was assessed by measuring the basal plasma glucose concentration at home on different mornings in patients with maturity-onset diabetes, the day-to-day variation (+/- 1 SD) being +/-0.73 and +/-0.92 mmol/1 (+/-13.2 and +/-16.6 mg/100 ml) respectively. The mean basal plasma glucose concentration in all 84 patients with maturity-onset diabetes from three general practices was 8 mmol/1 (144 mg/100 ml), 44 of the values exceeding 6 mmol/1 (108 mg/100 ml). Improving control by monitoring the basal plasma glucose concentration in maturity-onset diabetes might help to prevent diabetic complications.

HOLMAN R, TURNER R. 1977. CLINICAL VALUE OF BASAL PLASMA GLUCOSE DIABETOLOGIA, 13 (4), pp. 402-402.

TURNER R, HOLMAN R. 1977. ATTEMPTED BETA-CELL SALVAGE BY A REGULAR MEAL INSULIN INFUSION REGIME IN NEW SEVERE KETOTIC DIABETICS CLINICAL SCIENCE AND MOLECULAR MEDICINE, 52 (2), pp. P24-P24.

HOLMAN R, TURNER R. 1977. CLINICAL VALUE OF BASAL PLASMA GLUCOSE CLINICAL SCIENCE AND MOLECULAR MEDICINE, 53 (3), pp. P10-P10.

Holman RR, Turner RC. 1977. Diabetes: The quest for basal normoglycaemia. Lancet, 1 (8009), pp. 469-474. | Show Abstract | Read more

Diabetes is an endocrine deficiency disease, a logical treatment of which is hormone replacement therapy. Many patients who are thought to be controlled by diet alone continue to have high plasma-glucose levels. As the rise in the basal plasma glucose concentration is the predominant glucose abnormality of diabetes, treatment should be aimed primarily at producing basal normoglycaemia. 18 mild, maturity onset diabetics have been treated with a basal insulin supplement provided by single daily injections of insulin zinc suspension (crystalline) 'Ultralente'. Overnight basal normoglycaemia has been obtained with markedly reduced plasma-glucose levels during the day. Plama-triglyceride levels have become normal in most patients. The required insulin dose need not be determined empirically, but can be calculated from the basal plasma-glucose level and the degree of obesity. There is minimum risk of hypoglycaemia, and rigid dietary restriction is unnecessary. As mild diabetics are prone to complications, treatment with basal insulin supplements may be beneficial when diet alone fails to produce basal normoglycaemia.

HOLMAN R, HARRIS E, HARDING P, TURNER R. 1977. COMPARISON OF TREATMENT OF MILD DIABETES WITH A BASAL INSULIN SUPPLEMENT OR SULFONYLUREA CLINICAL SCIENCE AND MOLECULAR MEDICINE, 52 (2), pp. P24-P24.

TURNER R, HOLMAN R, HARRIS E. 1977. BETA-CELL RECOVERY WITH A REGULAR MEAL-INSULIN INFUSION REGIME IN NEW, SEVERE, KETOTIC DIABETICS DIABETOLOGIA, 13 (4), pp. 437-437.

TURNER R, HOLMAN R, HARDING P. 1977. TREATMENT OF TYPE-4 HYPERTRIGLYCERIDEMIA WITH INSULIN CLINICAL SCIENCE AND MOLECULAR MEDICINE, 53 (3), pp. P3-P3.

Turner RC, McCarthy ST, Holman RR, Harris E. 1976. Beta-cell function improved by supplementing basal insulin secretion in mild diabetes. Br Med J, 1 (6020), pp. 1252-1254. | Show Abstract | Read more

Insulin supplements, predominantly as a constant basal fish insulin infusion, were given to patients with mild diabetes to reduce the overnight fasting glucose level to normal. The basal plasma human insulin levels were reduced to subnormal levels by the infusion, and the insulin response to intravenous glucose was enhanced. The beta-cell in diabetes seems to be in a vicious circle in which an impaired insulin response to glucose produces hyperglycaemia, which stresses beta-cell function, making it more inefficient. A constant basal insulin supplement to induce basal normoglycaemia may benefit beta-cell function in diabetes.

TURNER R, HOLMAN R, HOCKADAY T. 1976. BETA CELL DEFICIENCY IN MATURITY ONSET DIABETES CLINICAL SCIENCE AND MOLECULAR MEDICINE, 51 (3), pp. P18-P18.

HOLMAN R, TURNER R. 1976. NEW APPROACH TO TREATMENT OF MILD DIABETES CLINICAL SCIENCE AND MOLECULAR MEDICINE, 51 (3), pp. P18-P18.

HOLMAN R, TURNER R. 1976. NEW APPROACH TO TREATMENT OF MILD DIABETES DIABETOLOGIA, 12 (4), pp. 398-399.

Turner RC, Holman RR. 1976. Pathophysiology of diabetes. Lancet, 2 (7990), pp. 856. | Read more

Turner RC, Holman RR. 1976. Insulin rather than glucose homoeostasis in the pathophysiology of diabetes. Lancet, 1 (7972), pp. 1272-1274. | Show Abstract | Read more

Hepatic glucose efflux is very sensitive to changes in plasma-insulin and it is postulated that this provides an important feedback control of insulin secretion. In diabetes this hepatic "insulin sensor" increases the basal plasma-glucose until the impaired beta cells are sufficiently stimulated to secrete normal basal insulin concentrations. Glucose regulation thus becomes of secondary importance to the maintenance of basal insulin secretion, which is teleologically needed for the "anabolic" requirements of cell growth. This hypothesis provides an explanation for the "normal" basal plasma-insulin concentrations found in diabetes in spite of impaired beta-cell function. This maintenance of basal insulin secretion accounts for the discrepancy between the marked hyperglycaemia and minimal ketosis of maturity onset diabetic patients.

Holman RR, Kanwar S. 1975. Early life of the 'battered child'. Arch Dis Child, 50 (1), pp. 78-80. | Show Abstract | Read more

The obstetric histories and early lives of 28 subsequently abused children are reviewed. The youngest child, more often male, was shown to be most 'at risk' especially of the mother was pregnant. Reduced antenatal care, separation of mother and child during the neonatal peroid, illness, poor features. It is felt that these and other difficulties may be regarded as 'environmental pressures' leading to child abuse by susceptible indivisuals, early recognition of such situations could lead to preventive and supportive measures.

GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, Wellcome Trust Case Control Consortium 2, Zhou K, Bellenguez C, Spencer CC, Bennett AJ, Coleman RL, Tavendale R et al. 2011. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet, 43 (2), pp. 117-120. | Show Abstract | Read more

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

NAVIGATOR Study Group, Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA, Belenkov Y et al. 2010. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med, 362 (16), pp. 1463-1476. | Show Abstract | Read more

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

NAVIGATOR Study Group, McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, Belenkov Y et al. 2010. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med, 362 (16), pp. 1477-1490. | Show Abstract | Read more

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Neil HAW, Ceglarek U, Thiery J, Paul S, Farmer A, Holman RR. 2010. Impact of atorvastatin and omega-3 ethyl esters 90 on plasma plant sterol concentrations and cholesterol synthesis in type 2 diabetes: A randomised placebo controlled factorial trial Atherosclerosis, 213 (2), pp. 512-517. | Show Abstract | Read more

Objective: To determine the effects of statin treatment and omega-3 polyunsaturated fatty acid supplementation on plasma plant sterol concentrations and cholesterol synthesis in patients with type 2 diabetes. Methods: Plant sterol concentrations and lanosterol (a marker of cholesterol synthesis) were measured using a high sensitivity assay to assess the effect of double-blind daily treatment for 4 months with atorvastatin 20. mg or placebo and, in a 2 × 2 factorial design, omega-3 ethyl esters 90 2. g or placebo. Results: 658 patients were included in a per protocol analysis. The 4 treatment groups had similar mean [SD] age (63.5 years [11.7]), HbA1c (6.9% [1.1]) and diabetes duration (median 4 years [inter-quartile range 2, 8]). Atorvastatin treatment alone reduced low density lipoprotein (LDL) cholesterol by 1.4mmol/l (44%, p<0.001), triglycerides by 0.3mmol/l (20%, p<0.0001) and lanosterol by 0.36μmol/l (72%, p<0.001). There was no significant placebo adjusted change in median [95% confidence intervals] total plant sterol concentrations (-0.77μmol/l [inter-quartile range -2.13, 0.59]), although they were increased significantly with omega-3-acid EE90 treatment (3.23μmol/l [1.28, 5.17]). There was a 27% smaller reduction in LDL cholesterol with atorvastatin treatment in low cholesterol synthesisers with high absorption, defined by changes at or above the median lanosterol and campesterol levels, respectively, compared with the obverse group (difference 0.42mmol/l [0.21, 0.62]). Conclusion: Treatment with atorvastatin in type 2 diabetes did not change median total plasma plant sterol concentrations, but LDL cholesterol was reduced most efficaciously in high cholesterol synthesisers with low intestinal cholesterol absorption. Clinical trial registration information: Current controlled trials number ISRCTN: 76737502 (http://isrctn.org). © 2010 Elsevier Ireland Ltd.

Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK, 4-T Study Group. 2009. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med, 361 (18), pp. 1736-1747. | Show Abstract | Read more

BACKGROUND: Evidence supporting the addition of specific insulin regimens to oral therapy in patients with type 2 diabetes mellitus is limited. METHODS: In this 3-year open-label, multicenter trial, we evaluated 708 patients who had suboptimal glycated hemoglobin levels while taking metformin and sulfonylurea therapy. Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of the study or subsequently if glycated hemoglobin levels were more than 6.5%. Outcome measures were glycated hemoglobin levels, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. RESULTS: Median glycated hemoglobin levels were similar for patients receiving biphasic (7.1%), prandial (6.8%), and basal (6.9%) insulin-based regimens (P=0.28). However, fewer patients had a level of 6.5% or less in the biphasic group (31.9%) than in the prandial group (44.7%, P=0.006) or in the basal group (43.2%, P=0.03), with 67.7%, 73.6%, and 81.6%, respectively, taking a second type of insulin (P=0.002). [corrected] Median rates of hypoglycemia per patient per year were lowest in the basal group (1.7), higher in the biphasic group (3.0), and highest in the prandial group (5.7) (P<0.001 for the overall comparison). The mean weight gain was higher in the prandial group than in either the biphasic group or the basal group. Other adverse event rates were similar in the three groups. CONCLUSIONS: Patients who added a basal or prandial insulin-based regimen to oral therapy had better glycated hemoglobin control than patients who added a biphasic insulin-based regimen. Fewer hypoglycemic episodes and less weight gain occurred in patients adding basal insulin. (Current Controlled Trials number, ISRCTN51125379.)

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 2008. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med, 359 (15), pp. 1577-1589. | Show Abstract | Read more

BACKGROUND: During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes. METHODS: Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories. RESULTS: Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002). CONCLUSIONS: Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.)

Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. 2008. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med, 359 (15), pp. 1565-1576. | Show Abstract | Read more

BACKGROUND: Post-trial monitoring of patients in the United Kingdom Prospective Diabetes Study (UKPDS) examined whether risk reductions for microvascular and macrovascular disease, achieved with the use of improved blood-pressure control during the trial, would be sustained. METHODS: Among 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus, we randomly assigned, over a 4-year period beginning in 1987, 1148 patients with hypertension to tight or less-tight blood-pressure control regimens. The 884 patients who underwent post-trial monitoring were asked to attend annual UKPDS clinics for the first 5 years, but no attempt was made to maintain their previously assigned therapies. Annual questionnaires completed by patients and general practitioners were used to follow patients who were unable to attend the clinic in years 1 through 5, and questionnaires were used for all patients in years 6 to 10. Seven prespecified aggregate clinical end points were examined on an intention-to-treat basis, according to the previous randomization categories. RESULTS: Differences in blood pressure between the two groups during the trial disappeared within 2 years after termination of the trial. Significant relative risk reductions found during the trial for any diabetes-related end point, diabetes-related death, microvascular disease, and stroke in the group receiving tight, as compared with less tight, blood-pressure control were not sustained during the post-trial follow-up. No risk reductions were seen during or after the trial for myocardial infarction or death from any cause, but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant (P=0.02). CONCLUSIONS: The benefits of previously improved blood-pressure control were not sustained when between-group differences in blood pressure were lost. Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications, but it appears that good blood-pressure control must be continued if the benefits are to be maintained. (UKPDS 81; Current Controlled Trials number, ISRCTN75451837.)

Goldberg RB, Holman R, Drucker DJ. 2008. Clinical decisions. Management of type 2 diabetes. N Engl J Med, 358 (3), pp. 293-297. | Show Abstract | Read more

This interactive Journal feature presents the case of a 55-year-old woman with type 2 diabetes, obesity, and hypertension. Three possible treatment options, any of which could be considered correct, are presented. Which option do you recommend? At www.nejm.org you can vote for one and then, if you wish, submit a comment about your clinical decision. Voting results and a broad selection of comments will be posted on the Web site. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, Levy JC, 4-T Study Group. 2007. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med, 357 (17), pp. 1716-1730. | Show Abstract | Read more

BACKGROUND: Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited. METHODS: In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. RESULTS: At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P=0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups. CONCLUSIONS: A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain. (Current Controlled Trials number, ISRCTN51125379 [controlled-trials.com].).

Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM et al. 2006. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med, 355 (23), pp. 2427-2443. | Show Abstract | Read more

BACKGROUND: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. METHODS: We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function. RESULTS: Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons). CONCLUSIONS: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).

DREAM Trial Investigators, Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, Dagenais G, Diaz R et al. 2006. Effect of ramipril on the incidence of diabetes. N Engl J Med, 355 (15), pp. 1551-1562. | Show Abstract | Read more

BACKGROUND: Previous studies have suggested that blockade of the renin-angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension. METHODS: In a double-blind, randomized clinical trial with a 2-by-2 factorial design, we randomly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance to receive ramipril (up to 15 mg per day) or placebo (and rosiglitazone or placebo) and followed them for a median of 3 years. We studied the effects of ramipril on the development of diabetes or death, whichever came first (the primary outcome), and on secondary outcomes, including regression to normoglycemia. RESULTS: The incidence of the primary outcome did not differ significantly between the ramipril group (18.1%) and the placebo group (19.5%; hazard ratio for the ramipril group, 0.91; 95% confidence interval [CI], 0.81 to 1.03; P=0.15). Participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo (hazard ratio, 1.16; 95% CI, 1.07 to 1.27; P=0.001). At the end of the study, the median fasting plasma glucose level was not significantly lower in the ramipril group (102.7 mg per deciliter [5.70 mmol per liter]) than in the placebo group (103.4 mg per deciliter [5.74 mmol per liter], P=0.07), though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group (135.1 mg per deciliter [7.50 mmol per liter] vs. 140.5 mg per deciliter [7.80 mmol per liter], P=0.01). CONCLUSIONS: Among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia. (ClinicalTrials.gov number, NCT00095654 [ClinicalTrials.gov].).

DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M et al. 2006. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet, 368 (9541), pp. 1096-1105. | Show Abstract | Read more

BACKGROUND: Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition. METHODS: 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. FINDINGS: At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01). INTERPRETATION: Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.

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