INTENSIVE BLOOD-GLUCOSE CONTROL WITH SULFONYLUREAS OR INSULIN COMPARED WITH CONVENTIONAL TREATMENT AND RISK OF COMPLICATIONS IN PATIENTS WITH TYPE-2 DIABETES (UKPDS-33)

Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular compl ications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that hi gh insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylur ea 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 wit h 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 pol icy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide ) or with insulin, or conventional policy with diet. The aim in the in tensive group was FPG less than 6 mmol/L. in the conventional group, t he aim was the best achievable FPG with diet atone; drugs were added o nly if there were hyperglycaemic symptoms or FPG greater than 15 mmol/ L. Three aggregate endpoints were used to assess differences between c onventional and intensive treatment: any diabetes-related endpoint (su dden death, death from hyperglycaemia or hypoglycaemia, fatal or non-f atal myocardial infarction, angina, heart failure, stroke, renal failu re, amputation [of at least one digit], vitreous haemorrhage, retinopa thy requiring photocoagulation, blindness in one eye,or cataract extra ction); diabetes-related death (death from myocardial infarction, stro ke, peripheral vascular disease, renal disease, hyperglycaemia or hypo glycaemia, and sudden death); all-cause mortality. Single clinical end points and surrogate subclinical endpoints were also assessed. All ana lyses were by intention to treat and frequency of hypoglycaemia was al so analysed by actual therapy. Findings Over 10 years, haemoglobin A(1 c) (HbA(1c)) 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 HbA(1c) among agents in the intensive group. Compared w ith the conventional group, the risk in the intensive group was 12% lo wer (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lowe r (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-1 0 to 20, p=0.44) for all-cause mortality. Most of the risk reduction i n the any diabetes-related aggregate endpoint was due to a 25% risk re duction (7-40, p=0.0099) in microvascular endpoints, including the nee d for retinal photocoagulation. There was no difference for any of the three aggregate endpoints 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 ty pes of analysis (both p<0.0001). The rates of major hypoglycaemic epis odes per year were 0.7% with conventional treatment, 1.0% with chlorpr opamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain w as significantly higher in the intensive group (mean 2.9 kg) than in t he conventional group (p<0.001), and patients assigned insulin had a g reater 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 t he 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 in creased the risk of hypoglycaemia.