Abstract
The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality. This meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal) against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients) were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR)=0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR=1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17). For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I(2)=41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p=0.10 and 0.02, respectively). Although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality. Further studies are needed to clarify this situation.
Highlights
Type 2 diabetes mellitus (T2DM), is a major health problem because of its cardiovascular complications and economic costs [1]
When compared with diet alone, metformin showed a reduction of all-cause mortality in overweight patients
An increase of overall mortality (RR = 1.60; 95% CI: 1.02 to 2.52) was observed in the metformin add-on sulphonylurea group when compared with sulphonylureas alone
Summary
Type 2 diabetes mellitus (T2DM), is a major health problem because of its cardiovascular complications and economic costs [1]. The authors of recently published Cochrane systematic reviews on metformin efficacy did not include this result in their analyses [6] Their conclusion, based on the results of the overweight patient group, is that metformin reduces overall and cardiovascular mortality. Selvin et al [7] and Bennett et al [8] did not include the results of non-overweight group, even though they mentioned this subgroup They concluded that ‘‘treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular mortality (pooled OR, 0.74; 95% CI, 0.62–0.89) compared with any other oral diabetes agent or placebo’’ [7]. The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. The long-term complications of diabetes, which include an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about ten years compared to people without diabetes
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