EFFECT OF INTENSIVE BLOOD-GLUCOSE CONTROL WITH METFORMIN ON COMPLICATIONS IN OVERWEIGHT PATIENTS WITH TYPE-2 DIABETES (UKPDS-34)

Background In patients with type 2 diabetes, intensive blood-glucose c ontrol with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks. T his study investigated whether intensive glucose control with metformi n has any specific advantage or disadvantage. Methods Of 4075 patients recruited to UKPDS in 15 centres, 1704 overweight (>120% ideal bodywe ight) patients with newly diagnosed type 2 diabetes, mean age 53 years , had raised fasting plasma glucose (FPG; 6.1-15.0 mmol/L) without hyp erglycaemic symptoms after 3 months' initial diet. 753 were included i n a randomised controlled trial, median duration 10.7 years, of conven tional policy, primarily with diet alone (n=411) versus intensive bloo d-glucose control policy with metformin, aiming for FPG below 6 mmol/L (n=342). A secondary analysis compared the 342 patients allocated met formin with 951 overweight patients allocated intensive blood-glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). The primary outcome measures were aggregates of any diabetes -related clinical endpoint, diabetes-related death, and all-cause mort ality. In a supplementary randomised controlled trial, 537 non-overwei ght and overweight patients, mean age 59 years, who were already on ma ximum sulphonylurea therapy but had raised FPG (6.1-15.0 mmol/L), were allocated continuing sulphonylurea therapy alone (n=269) or addition of metformin (n=268). Findings Median glycated haemoglobin (HbA(1c)) w as 7.4% in the metformin group compared with 8.0% in the conventional group. Patients allocated metformin, compared with the conventional gr oup, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabet es-related endpoint, 42% for diabetes-related death (9-63, p=0.017), a nd 36% for all-cause mortality (9-55, p=0.011). Among patients allocat ed intensive blood-glucose control, metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-relate d endpoint (p=0.0034), all-cause mortality (p=0.021), and stroke (p=0. 032). Early addition of metformin in sulphonyl urea-treated patients w as associated with an increased risk of diabetes-related death (96% in creased risk [95% CI 2-275], p=0.039) compared with continued sulphony lurea alone. A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related end points (risk reduction 19% [2-33], p=0.033). Epidemiological assessmen t of the possible association of death from diabetes-related causes wi th the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a c ombination of sulphonylurea and metformin (risk reduction 5% [-33 to 3 2], p=0.78). Interpretation Since intensive glucose control with metfo rmin appears to decrease the risk of diabetes-related endpoints in ove rweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it m ay be the first-line pharmacological therapy of choice in these patien ts.