Effect of intensive blood-glucose control with metformin oncomplications in overweight patients with type 2 diabetes (UKPDS34).
UK Prospective Diabetes Study (UKPDS) Group.
Lancet. 1998 Sep 12; 352(9131): 854-65.
BACKGROUND: In patients with type 2 diabetes, intensive blood-glucose control with insulin or sulphonylurea therapy decreasesprogression of microvascular disease and may also reduce the riskof heart attacks. This study investigated whether intensive glucosecontrol with metformin has any specific advantage or disadvantage.
METHODS: Of 4075 patients recruited to UKPDS in 15 centres, 1704
overweight (>120% ideal bodyweight) patients with newlydiagnosed type 2 diabetes, mean age 53 years, had raised fastingplasma glucose (FPG; 6.1-15.0 mmol/L) without hyperglycaemicsymptoms after 3 months' initial diet. 753 were included in arandomised controlled trial, median duration 10.7 years, of
conventional policy, primarily with diet alone (n=411) versusintensive blood-glucose control policy with metformin, aiming forFPG below 6 mmol/L (n=342). A secondary analysis compared the342 patients allocated metformin with 951 overweight patientsallocated intensive blood-glucose control with chlorpropamide
(n=265), glibenclamide (n=277), or insulin (n=409). The primaryoutcome measures were aggregates of any diabetes-related clinicalendpoint, diabetes-related death, and all-cause mortality. In asupplementary randomised controlled trial, 537 non-overweightand overweight patients, mean age 59 years, who were already on
maximum sulphonylurea therapy but had raised FPG (6.1-15.0mmol/L) were allocated continuing sulphonylurea therapy alone(n=269) or addition of metformin (n=268). FINDINGS: Medianglycated haemoglobin (HbA1c) was 7.4% in the metformin groupcompared with 8.0% in the conventional group. Patients allocated
metformin, compared with the conventional group, had riskreductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017),and 36% for all-cause mortality (9-55, p=0.011). Among patientsallocated intensive blood-glucose control, metformin showed agreater effect than chlorpropamide, glibenclamide, or insulin for
any diabetes-related endpoint (p=0.0034), all-cause mortality(p=0.021), and stroke (p=0.032). Early addition of metformin in
sulphonylurea-treated patients was associated with an increasedrisk of diabetes-related death (96% increased risk [95% CI 2-275],p=0.039) compared with continued sulphonylurea alone. A
combined analysis of the main and supplementary studies showedfewer metformin-allocated patients having diabetes-relatedendpoints (risk reduction 19% [2-33], p=0.033). Epidemiologicalassessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416
patients did not show an increased risk in diabetes-related death inpatients treated with a combination of sulphonylurea andmetformin (risk reduction 5% [-33 to 32], p=0.78).
INTERPRETATION: Since intensive glucose control with metforminappears to decrease the risk of diabetes-related endpoints inoverweight diabetic patients, and is associated with less weight gain
and fewer hypoglycaemic attacks than are insulin andsulphonylureas, it may be the first-line pharmacological therapy ofchoice in these patients.
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