Elsevier

The Lancet

Volume 352, Issue 9131, 12 September 1998, Pages 837-853
The Lancet

Articles
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

https://doi.org/10.1016/S0140-6736(98)07019-6Get rights and content

Summary

Background

Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.

Methods

3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48–60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6·1–15·0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.

Findings

Over 10 years, haemoglobin A1c (HbA1c) was 7·0% (6·2–8·2) in the intensive group compared with 7·9% (6·9–8·8) in the conventional group—an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1–21, p=0·029) for any diabetes-related endpoint; 10% lower (−11 to 27, p=0·34) for any diabetes-related death; and 6% lower (−10 to 20, p=0·44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7–40, p=0·0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin).

Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0·0001). The rates of major hypoglycaemic episodes per year were 0·7% with conventional treatment, 1·0% with chlorpropamide, 1·4% with glibenclamide, and 1·8% with insulin. Weight gain was significantly higher in the intensive group (mean 2·9 kg) than in the conventional group (p<0·001), and patients assigned insulin had a greater gain in weight (4·0 kg) than those assigned chlorpropamide (2·6 kg) or glibenclamide (1·7 kg).

Interpretation

Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.

Introduction

Started in 1977, the UK Prospective Diabetes Study (UKPDS) was designed to establish whether, in patients with type 2 diabetes, intensive blood-glucose control reduced the risk of macrovascular or microvascular complications, and whether any particular therapy was advantageous.

Most intervention studies have assessed microvascular disease: improved glucose control has delayed the development and progression of retinopathy, nephropathy, and neuropathy in patients with type 1 diabetes1, 2 and those with type 2 diabetes.3 In the UK, 9% of patients with type 2 diabetes develop microvascular disease within 9 years of diagnosis, but 20% have a macrovascular complication—and macrovascular disease accounts for 59% of deaths in these patients.4

Epidemiological studies of the general population have shown an increased risk of cardiovascular disease with concentrations of fasting glucose or haemoglobin A1c (HbA1c) just above the normal range.5, 6 The only previous large-scale randomised trial in type 2 diabetes, the University Group Diabetes Program (UGDP),7 followed 1000 patients assigned different therapies for about 5·5 years (range 3–8 years) and found no evidence that improved glucose control, by any therapy, reduced the risk of cardiovascular endpoints. That study did, however, report increased risk of cardiovascular mortality in patients allocated the sulphonylurea, tolbutamide, and this unexpected finding introduced new hypotheses.8 These hypotheses included increased myocardial damage from inhibition of ATP-K+ channel opening in the presence of myocardial ischaemia9 due to sulphonylurea binding to the cardiovascular SUR2 receptor—an event that could also increase the likelihood of ventricular arrhythmia.10 An increase in atherosclerosis with insulin treatment has also been suggested, since plasma insulin concentrations are supraphysiological.11, 12

We report the final results of our study of intensive blood-glucose control policy, with sulphonylurea or insulin therapy, compared with conventional treatment policy with diet, on the risk of microvascular and macrovascular clinical complications. We also investigated whether there was any particular benefit or risk with sulphonylurea or insulin therapy.

Section snippets

Patients

Between 1977 and 1991, general practitioners in the catchment areas of the 23 participating UKPDS hospitals were asked to refer all patients with newly diagnosed diabetes aged 25–65 years. Patients generally attended a UKPDS clinic within 2 weeks of referral. Patients who had a fasting plasma glucose (FPG) greater than 6 mmol/L on two mornings, 1–3 weeks apart, were eligible for the study. An FPG of 6 mmol/L was selected because this was just above the upper limit of normal for our reference

Background and biochemical data

4763 (93%) of 5102 patients had mean FPG of 7·0 mmol/L or more (American Diabetes Association criteria),22 and 4396 (86%) of 5102 had values greater than 7·8 mmol/L (WHO criteria).23

Baseline characteristics of the 3867 patients assigned conventional or intensive treatment are given in table 1. The baseline characteristics of the 3041 patients in the comparison of conventional treatment with each of the three intensive agents are in table 2.

The median follow-up for endpoint analyses was 10·0

Discussion

We found that an intensive blood-glucose-control policy with an 11% reduction in median HbA1c over the first 10 years decreased the frequency of some clinical complications of type 2 diabetes. The intensive treatment group had a substantial, 25% reduction in the risk of microvascular endpoints, most of which was due to fewer patients requiring photocoagulation. There was evidence, albeit inconclusive, of a 16% risk reduction (p=0·052) for myocardial infarction, which included non-fatal and

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