Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials

Aim: Some studies suggested that metformin could reduce cardiovascular risk to a greater extent than that determined by glucose reduction. Aim of the present meta-analysis is to assess the effects of metformin on the incidence of cardiovascular events and mortality. Methods: An extensive search of Medline, EMBASE and the Cochrane Library (any date up to 31 October 2009) was performed for all trials containing the word ‘metformin’. Randomized trials with a duration ≥52 weeks were included. A meta-regression analysis was also performed to identify factors associated with cardiovascular morbidity and mortality in metformin-treated patients. Results: A total of 35 clinical trials were selected including 7171 and 11 301 participants treated with metformin and comparator, respectively, who had 451 and 775 cardiovascular (CV) events, respectively. Overall, metformin was not associated with significant harm or benefit on cardiovascular events (MH-OR 0.94[0.82–1.07], p = 0.34). A significant benefit was observed in trials versus placebo/no therapy (MH-OR 0.79[0.64–0.98], p = 0.031), but not in active-comparator trials (MH-OR 1.03[0.72–1.77], p = 0.89). Meta-regression showed a significant correlation of the effect of metformin on cardiovascular events with trial duration and with minimum and maximum age for inclusion, meaning that the drug appeared to be more beneficial in longer trials enrolling younger patients. It is likely that metformin monotherapy is associated with improved survival (MH-OR: 0.801[0.625–1.024], p = 0.076). However, concomitant use with sulphonylureas was associated with reduced survival (MH-OR: 1.432[1.068–1.918], p = 0.016). Conclusion: Available evidence seems to exclude any overall harmful effect of metformin on cardiovascular risk, suggesting a possible benefit versus placebo/no treatment. The observed detrimental effect of the combination with sulphonylureas deserves further investigation.