A large prospective study in Great Britain reported that the use of sulfonylureas or insulin substantially reduced the risk of microvascular complications and, possibly, heart attacks in patients with type 2 diabetes. Metformin, a biguanide that decreases blood glucose concentrations by mechanisms different from those of sulfonylureas or insulin, theoretically could achieve glucose control without weight gain. The UK Prospective Diabetes Study Group examined the effect of intensive glucose control with metformin compared with that of other agents in overweight patients.

Between 1977 and 1991, 23 general practices enrolled 5,102 patients from 25 to 65 years of age who were newly diagnosed with type 2 diabetes. After three months of dietary therapy, the 4,209 eligible patients with fasting plasma glucose measurements above threshold levels were randomly assigned to continue diet therapy alone or to begin one of four drug therapies designed to achieve intensive glycemic control. Of the 1,704 patients who weighed over 120 percent of their ideal body weight, 411 were assigned to diet therapy, 342 to metformin therapy, 265 to chlorpropamide therapy, 277 to glibenclamide therapy (U.S. equivalent: glyburide) and 409 to insulin therapy.

Patients using metformin to control blood glucose were initially given 850 mg per day; the daily dosage was titrated to a maximum of 2,550 mg. The dosage was reduced if nausea or diarrhea developed. If marked hyperglycemia developed during metformin therapy, glibenclamide was added; if the hyperglycemia persisted, treatment was changed to insulin. Episodes of hypoglycemia were recorded by patients throughout the study. Patients were seen every month for the first three months of treatment, then at least every three months thereafter, depending on the clinical situation. The median duration of follow-up was 10 years. Study end points included mortality related to diabetes and multiple markers of morbidity, such as retinopathy, nephropathy, peripheral vascular disease, amputation, stroke and cardiovascular disease.

Patients who received metformin had a 32 percent lower risk of developing any of the diabetes-related end points compared with patients using diet therapy alone. The patients using metformin also experienced a 42 percent reduction in death related to diabetes and a 36 percent reduction in all causes of mortality. When compared with patients receiving the other treatments, patients taking metformin showed significant reductions in any diabetes-related end point, all-cause mortality and stroke.

During the 10-year follow-up period, similar slight gains in body weight occurred in patients treated by diet and in patients receiving metformin; however, these gains were less than the increase in body weight that occurred in patients treated with sulfonylureas or insulin. In the group taking metformin, 8.3 percent of patients reported any episodes of hypoglycemia, and 0.6 percent experienced major episodes of hypoglycemia. The corresponding figures for patients in other treatment groups were: 7.9 percent/0.7 percent for diet therapy, 15.2 percent/1.2 percent for chlorpropamide, 20.5 percent/1.0 percent for glibenclamide and 25.5 percent/2.0 percent for insulin therapy. No deaths from lactic acidosis were reported during the study period.

The authors conclude that metformin therapy provided risk reduction in key end points for overweight patients with type 2 diabetes and was associated with less weight gain and fewer episodes of hypoglycemia than treatment with insulin or sulfonylureas. They advocate metformin as first-line pharmacologic therapy for overweight patients with type 2 diabetes.