Griffin SJ, et al. – Researchers intended to systematically distinguish and pool randomised trials presenting cardiovascular outcomes in which the impact of metformin was ‘isolated’ through comparison to diet, lifestyle or placebo. In context of the findings, there remains uncertainty about whether metformin reduces risk of cardiovascular disease among patients with type 2 diabetes, for whom it is the recommended first–line drug. While this is mainly due to absence of evidence, it is unlikely that a definitive placebo–controlled cardiovascular endpoint trial among people with diabetes will be forthcoming.

Methods

• Researchers conducted an electronic literature search of MEDLINE, EMBASE and the Cochrane Library.
• They also manually screened the reference lists of previous meta-analyses of trials of metformin identified through a MEDLINE search.
• They carried out randomised controlled trials of adults with type 2 diabetes comparing any dose and preparation of oral metformin with no intervention, placebo or a lifestyle intervention and reporting mortality or a cardiovascular outcome.
• They enrolled ten articles reporting 13 trials (including a total of 2079 individuals with type 2 diabetes allocated to metformin and a similar number to comparison groups) of which only four compared metformin with placebo and collected data on cardiovascular outcomes.

Results

• The obtained data indicate that participants were mainly white, aged ≤65 years, overweight/obese and with poor glycaemic control.
• In this study, summary estimates were based on a small number of events: 416 myocardial infarctions/ischaemic heart disease events in seven studies and 111 strokes in four studies.
• In context of the findings, the UK Prospective Diabetes Study (UKPDS) contributed the majority of data to the summary estimates, with weights ranging from 52.3% for myocardial infarction to 70.5% for stroke.
• It was noted that all outcomes, with the exception of stroke, favoured metformin, with limited heterogeneity between studies, but none achieved statistical significance.
• In addition, impact sizes (Mantel–Haenszel RR) were: all-cause mortality 0.96 (95% CI 0.84, 1.09); cardiovascular death 0.97 (95% CI 0.80, 1.16); myocardial infarction 0.89 (95% CI 0.75, 1.06); stroke 1.04 (95% CI 0.73, 1.48); and peripheral vascular disease 0.81 (95% CI 0.50, 1.31).