ArticlesIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
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
References (47)
- et al.
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study
Diabetes Res Clin Pract
(1995) - et al.
Hyperglycaemia and coronary heart disease: the Whitehall Study
J Chronic Dis
(1979) Potassium channels in the cardiovascular system
Diabetes Res Clin Pract
(1995)Sulphonylureas in the treatment of non-insulin-dependent diabetes
Baillieres Clin Endocrinol Metab
(1988)- et al.
Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years
J Intern Med
(1991) The effect of intensive treatment of diabetes on the development and progression of long-term complications insulin-dependent diabetes mellitus
N Engl J Med
(1993)UK Prospective Diabetes Study 17: A nine-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
(1996)- et al.
High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men
Diabetes Care
(1998) Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes VII: mortality and selected nonfatal events with insulin treatment
JAMA
(1978)A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes
Diabetes
(1976)
Cardiovascular effects of sulphonylurea derivatives
Diabetologia
Insulin and atherosclerosis
Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus
Ann Intern Med
UK Prospective Diabetes Study VIII: study design, progress and performance
Diabetologia
Net weight standard for men and women
Stat Bull Metrop Insur Co
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
Lancet
Therapeutic requirements to maintain tight blood pressure control
Diabetologia
Glycaemic improvement over one year in a double-blind trial of acarbose in 1,946 NIDDM patients
Diabetologia
UK Prospective Diabetes Study XI: biochemical risk factors in type 2 diabetic patients at diagnosis compared with age-matched normal subjects
Diabet Med
Decreases in albumin/creatinine and N-acetylglucosaminidase/creatinine ratios in urine samples stored at −20°C
Clin Chem
International Classification of Procedures in Medicine
UK Prospective Diabetes Study IX: relationships of urinary albumin and N-acetylglucosaminidase to glycaemia and hypertension at diagnosis of type 2 (non-insulin-dependent) diabetes mellitus and after 3 months diet therapy
Diabetologia
Report of the expert committee on the diagnosis and classification of diabetes mellitus
Diabetes Care
Cited by (0)
Study organisation given at end of paper