Background: The UKPDS 34 showed that intensive treatment with metformin significantly reduces macrovascular end-points and mortality in individuals with newly diagnosed type 2 diabetes compared with intensive treatment with insulin or sulphonylurea derivatives, despite similar glycaemic control. How this should be explained is as yet unclear. We hypothesized that metformin may have a glucose-lowering independent effect on blood pressure and lipid profile. In order to test this hypothesis we systematically reviewed the literature and pooled the data obtained in a meta-analysis.
Methods: Included were randomized-controlled trials in patients with type 2 diabetes mellitus and metformin treatment lasting at least 6 weeks. To identify all eligible trials we conducted electronic searches using the bibliographic databases Medline and Embase, contacted the manufacturer and checked obtained publications for cross-references.
Results: Forty-one studies (3074 patients) provided data on blood pressure and/or lipid profile. When compared with control treatment, metformin associated effects on systolic and diastolic blood pressure and HDL cholesterol were small and statistically not significant [-1.09 mmHg 95% confidence interval (-3.01-0.82), P = 0.30; -0.97 (-2.15-0.21) mmHg, P = 0.11 and +0.01 (-0.02-0.03) mmol L(-1), P = 0.50, respectively]. Compared with control treatment, however, metformin decreased plasma triglycerides, total cholesterol and LDL cholesterol significantly [-0.13 (-0.21--0.04) mmol L(-1), P = 0.003; -0.26 (-0.34--0.18) mmol L(-1), P < 0.0001 and -0.22 (-0.31--0.13) mmol L(-1), P < 0.00001, respectively]. We found no indications for publication bias. Of note, glycaemic control as assessed by HbA1c was better with metformin than with control treatment [-0.74 (-0.84--0.65) percentage point; P < 0.00001]. When studies were subdivided into tertiles according to increasing difference in glycaemic control between metformin and control treatment, it appeared that in case of near similar glycaemic control metformin had no effect versus control treatment on triglycerides, whereas still there was a significant effect on total and LDL cholesterol.
Conclusions: This meta-analysis of randomized-controlled clinical trials suggests that metformin has no intrinsic effect on blood pressure, HDL cholesterol and triglycerides in patients with type 2 diabetes. This drug, however, independent of its effect on glycaemia, reduces total and LDL cholesterol significantly, but the reductions in these variables are relatively small.