Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
Introduction: Previously, it was noted that for people with type 2 diabetes, achieving intensive blood glucose control with insulin or sulfonylureas decreased the development of microvascular disease and perhaps also the risk of heart attack. The UK Prospective Diabetes Study (UKPDS) Group wanted to investigate if intensive blood glucose control using metformin offered any advantage or disadvantage.
Methods: 4,075 patients were recruited to participate in the UKPDS in 15 centers across the United Kingdom. 1,704 patients with recently diagnosed type 2 diabetes were overweight (>120% ideal body weight) and had an elevated fasting plasma glucose (FPG: 6.1-15.0 mmol/L) without hyperglycemic symptoms after 3 months’ initial diet. The mean age was 53 years.
753 of those patients were included in a randomized controlled trial that had a median duration of 10.7 years. The trial compared conventional treatment, mainly with diet alone (n=411), to intensive blood glucose control using metformin, targeting an FPG below 6 mmol/L (n=342). There was a secondary analysis that compared the 342 patients on metformin to 951 overweight patients on chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409) as a way to attempt intensive blood glucose control.
Aggregates of diabetes-related clinical endpoint, diabetes-related death, and all-cause mortality were the primary outcome measures.
There was a supplementary randomized controlled trial with 537 non-overweight and overweight patients. The mean age was 59 years. They were already on maximum sulfonylurea therapy but had an elevated FPG (6.1-15.0 mmol/L). They were assigned continued sulfonylurea therapy (n=269) or the addition of metformin (n=268).
Results: In the metformin group, median glycated hemoglobin (HbA1c) was 7.4%. In the group with conventional treatment, it was 8.0%. Patients using metformin, when compared to the conventional treatment group, had risk reductions of 32% (95% CI, 13-47, p=0.002) for any diabetes-related endpoint, 42% (9-63, p=0.017) for diabetes-related death, and 36% (9-55, p=0.011) for all-cause mortality.
In patients assigned intensive blood glucose control, metformin demonstrated a greater 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).
Patients using sulfonylureas who had metformin added had an increased risk of diabetes-related death (96% increased risk [95% CI, 2-275], p=0.039) when compared to the patients who continued with just sulfonylurea therapy.
In a combined analysis of the main and supplementary studies, it was shown that fewer patients assigned metformin had diabetes-related endpoints (risk reduction 19% [2-33], p=0.033). An epidemiological assessment of the possible association of death from diabetes-related causes with simultaneous treatment of diabetes in 4,416 patients did not demonstrate an increase in risk of diabetes-related death for patients using a combination of sulfonylurea and metformin (risk reduction 5% [-33 to 32], p=0.78).
Conclusions: Metformin may be a first-line pharmacological treatment of choice for patients with type 2 diabetes because intensive blood glucose control with it appears to lower the risk of diabetes-related endpoints in overweight diabetic patients. It is also associated with less weight gain and fewer hypoglycemic attacks when compared to insulin and sulfonylureas.