I M Stratton

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study

Abstract 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 HbA1c 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 HbA1c 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 HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6.0%).

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study

Abstract 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.

UKPDS 50: RISK FACTORS FOR INCIDENCE AND PROGRESSION OF RETINOPATHY IN TYPE II DIABETES OVER 6 YEARS FROM DIAGNOSIS

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 HbA1 c) 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. [Diabetologia (2001) 44: 156–163]

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).

Aims/hypothesisThe 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.MethodsEquations 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.ResultsThe 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/interpretationsThe 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.

UKPDS 26: Sulphonylurea Failure in Non-insulin-dependent Diabetic Patients over Six Years.

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). 61 %, 39 %, and 23 %, respectively, of patients with fasting plasma glucose ≥10.0 mmol l−1, ≥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 ≥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.

UKPDS 60: Risk of Stroke in Type 2 Diabetes Estimated by the UK Prospective Diabetes Study Risk Engine

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.

Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (UKPDS 41)

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 £695 (95% confidence interval £555 to £836) per patient but reduced the cost of complications by £957 (£233 to £1681) compared with conventional management. If standard practice visit patterns were assumed rather than trial conditions, the incremental cost of intensive management was £478 (-£275 to £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 £1166 (costs and effects discounted at 6% a year) and £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.

Group sequential clinical trials with triangular continuation regions.

In this paper a new class of group sequential procedures for clinical trials is introduced, and the use of these procedures is illustrated by reference to a recently completed comparative study. In a group sequential trial the decision to stop or to continue is made at regular intervals throughout the trial, but not as frequently as after every patient response. This more practical formulation retains most of the advantages of sequential analysis, particularly the economy in sample size. Comparisons are made with group sequential designs derived from the repeated significance test.

How to deal with regression to the mean in intervention studies

A randomised trial published in 1995 compared, in adults with serum cholesterol concentrations of 5-8 mmol/L, the efficacy of three types of diet and lifestyle intervention in lowering plasma lipid levels.’ 1 After 6 months, the cholesterol concentration had fallen by around 10% in all three groups. This improvement was attributed to the interventions, but since some reduction in cholesterol would have been expected due to regression to the mean (RTM), the true efficacy of the interventions must remain unknown. So, what is regression to the mean and why does it happen? RTM is, in essence, a chance finding masquerading as a real one. Despite the name, it is not confined to regression analysis but turns up in several different situations.2 This paper is concerned with intervention studies. Such studies often target individuals who have unusually high values of a risk variable, such as cholesterol. In a group of such individuals, the mean cholesterol level will, on remeasurement, be lower than the starting mean, even without any intervention or treatment.3-6 This is the RTM effect. In a group selected on the basis of unusually low values of a variable RTM

High Prevalence of Hepatitis C Infection in Afro-Caribbean Patients with Type 2 Diabetes and Abnormal Liver Function Tests

Moderate elevations of serum transaminases are frequently found in patients with diabetes mellitus and are often attributed to fatty infiltration of the liver without further investigation. Recent studies of patients with end‐stage liver disease have suggested a possible association between Hepatitis C virus (HCV) antibody positivity and the development of diabetes (mostly Type 2). As a first step in the examination of any potential association between HCV and Type 2 diabetes in subjects without overt liver disease, we examined 200 British patients with Type 2 diabetes (100 White Caucasians, 50 Asians, and 50 Afro‐Caribbeans), recruited from the United Kingdom Prospective Study of Diabetes, half of whom had a significant elevation of alanine aminotransferase (ALT) on at least two occasions and half of whom had consistently normal ALT levels. In Afro‐Caribbean Type 2 diabetic subjects 7/25 (28%) patients with abnormal ALT and 1/25 (4%) with normal ALT were HCV antibody positive. Among White Caucasian subjects 6/50 (12%) patients with abnormal LFTs and 0/50 with normal LFTs were HCV antibody positive and in Asians the prevalence was 2/25 (8%) and 0/25, respectively. This study suggests that persistent mild to moderate elevation of serum transaminases in a patient with Type 2 diabetes should not automatically be attributed to the metabolic disturbances of diabetes. Particularly in Afro‐Caribbean subjects, HCV infection is a major diagnostic consideration. The question of whether HCV infection itself may have a diabetogenic action is worthy of further investigation.