Thirty-five trials met the inclusion criteria (7,171 participants who received metformin and 11,301 comparators). Studies that did not describe major cardiovascular events or reported no events were excluded from the analysis. Twelve trials were included in the analysis (5,455 participants who received metformin and 8,996 comparators). Randomisation was considered adequate in 19 trials. Allocation concealment was adequate in 18 trials. Blinding was adequate in 18 trials. Sixteen trials used an intention-to-treat analysis.
Overall, 451 patients who received metformin and 775 patients who received comparator treatments had cardiovascular events. Metformin did not produce any significant effect on cardiovascular events (OR 0.94, 95% CI 0.82 to 1.07). No significant heterogeneity was observed (p=0.46). Similar results were obtained for diabetic and non-diabetic populations and where metformin was used as an add-on therapy. Metformin was associated with a significant reduction in cardiovascular events when compared with placebo or no therapy (OR 0.79, 95% CI 0.64 to 0.98; eight trials), but not with active comparators.
Compared to other treatments metformin was associated with reduced cardiovascular morbidity in trials that enrolled patients aged less than 30 years (OR 0.76, 95% CI 0.61 to 0.95; four trials) or excluded patients aged more than 65 years (OR 0.78, 95% CI 0.60 to 1.00; three trials). There was no significant effect of metformin on all-cause mortality, cardiovascular mortality or incidences of myocardial infarction, stroke and heart failure. Further results were reported. There was no evidence of publication bias.