In spite of its long history, we identified only 13 studies, including just over 2000 patients with type 2 diabetes allocated to metformin, that addressed our study question, and only four randomised-controlled cardiovascular endpoint trials simply comparing metformin with placebo among patients with type 2 diabetes. Metformin monotherapy appears safe and, while there is a suggestion of benefit, there remains uncertainty about whether it reduces risk of cardiovascular disease. According to our review it is possible that metformin reduces risk of all-cause mortality by up to 16% but it could increase risk of stroke by up to 48%. Metformin is the recommended first-line treatment worldwide for patients with type 2 diabetes. However, in contrast to some newer treatments, cardiovascular endpoint trial data for metformin are largely derived from small studies among relatively young, overweight/obese, North American and Northern European patients with poorly controlled diabetes. Metformin demonstrates cardiovascular safety as per the 2008 FDA guidance, but its use for prevention of cardiovascular disease among older individuals, those with HbA 1c less than 8% (63.9 mmol/mol), non-white ethnic groups and people living outside North America and Northern Europe is not well supported by trial evidence. Furthermore, while not specifically covered in this review, there remains concern about the observed increased risk of mortality associated with the addition of metformin to sulfonylurea treatment [14, 15].

The reports of all included trials either suggested the possibility of bias or provided insufficient information to allow risk of bias to be assessed. The one trial that appeared to exhibit low risk of bias for all but one criterion seemed to be compromised by clinically important baseline differences between study groups [22]. The majority of data for this review came from the UKPDS [21], a seminal trial concerning the effectiveness and safety of treatments for type 2 diabetes, albeit exhibiting a number of previously discussed limitations that might influence its interpretation [28]. These include the small size (only 342 patients were allocated to metformin), lack of placebo and double-blinding, ‘subgroup’ nature of the analysis with updated statistical significance thresholds, potential for between-group differences in management of other cardiovascular risk factors, unacceptably poor level of glycaemic control in the comparison group by current standards, and attrition over the near 18-year follow-up. Including data from the long-term follow-up of the UKPDS [21] introduces a number of assumptions that may lead to underestimation of effects, in particular the extent of any ‘legacy effect’ of treatment with metformin in the early part of the trial. However, a sensitivity analysis replacing the longer term follow-up with the original UKPDS trial data [12] increased the width of the 95% CIs but did not significantly change our findings.

Strengths and weaknesses

We used a sensitive search strategy and systematically searched literature databases and reference lists of previous systematic reviews. However, we only searched three databases and may have excluded trials that are not indexed on MEDLINE or EMBASE or are unpublished. We only included trials that ‘isolated’ the effects of metformin in order to distinguish between benefits of metformin and harms associated with comparator drugs. With the exception of screening of some of the full text articles, the reviewing process was undertaken by two authors independently. We undertook quality assessment but included all trials meeting our pre-specified criteria. Definitions of the different cardiovascular outcomes varied between studies, particularly for peripheral vascular disease, which included angiographic findings in Kooy et al [22] but was restricted to amputation or death because of peripheral vascular disease in Holman et al [21]. We erred on the side of sensitivity to maximise the number of events, for example, including ‘ischaemic heart disease’ endpoints in Gram et al [23] as myocardial infarctions. Reporting of adverse events was inconsistent; consequently, for trials in which cardiovascular events were not specified as study outcomes, it was not always clear from the text of articles whether or not these data were collected as part of the monitoring for adverse events. It was also not possible to obtain clarification from authors and so we may have excluded some studies in which relevant data had been collected. However, the number of missed events is likely to be small in studies in which cardiovascular disease was not the main focus and, hence, the impact on summary estimates and conclusions negligible.

Comparison with existing literature

Unsurprisingly, given the influence of the UKPDS data on this analysis and the overlap of the review question and included studies, our results are broadly similar to those of previous reviews published within the last 10 years [14, 15, 29]. In Selvin et al’s meta-analysis of trials of metformin vs any comparator, effect sizes for cardiovascular and all-cause mortality (M–H OR 0.74 [95% CI 0.62, 0.89] and M–H OR 0.81 [95% CI 0.60, 1.08], respectively) more strongly favoured metformin [29], mainly because of the inclusion of the open-label, active-comparator trial, the Comparative Outcomes Study of Metformin Intervention versus Conventional (COSMIC) Approach Study [30]. Lamanna et al’s meta-analysis, which included trials of diabetes prevention and trials with active comparators (in particular rosiglitazone), reported no overall effect of metformin on cardiovascular events (M–H OR 0.94 [95% CI 0.82, 1.07]) [15]. When analysis was restricted to comparisons of metformin with placebo or no drug treatment, metformin appeared to be beneficial (M–H OR 0.79 [95% CI 0.64, 0.98]). Our results most closely mirror those of Boussageon et al [14], who reported no effect of metformin on all-cause mortality (M–H RR 0.99 [95% CI 0.75, 1.31]) or cardiovascular mortality (M–H RR 1.05 [95% CI 0.67, 1.64]), but did not include the extended follow-up data from the UKPDS.

Implications

Metformin lowers glucose and, hence, reduces symptoms of hyperglycaemia. It has a good safety profile, even among patients with impaired renal function [31], is relatively well tolerated and may even reduce cancer incidence and mortality [32], although this was not confirmed in a meta-analysis of trials [33]. The number, size, quality, reporting and findings of randomised trials of metformin have resulted in continuing uncertainty regarding whether it reduces risk of diabetes-related complications, particularly cardiovascular disease. Furthermore, there is a lack of cardiovascular endpoint data directly relevant to a significant proportion of the patients with type 2 diabetes worldwide for whom metformin is the recommended first-line medication. This contrasts with the evidence now available for newer and more expensive glucose-lowering drugs, such as empagliflozin [34] and liraglutide [10], and of course for medications targeting different risk factors, for example statins. Nevertheless, metformin is included on the WHO model list of essential medicines, a list of ‘the most efficacious, safe and cost-effective medicines for priority conditions’ and the ‘minimum medicine needs for a basic health-care system’. It is unlikely that patients, practitioners and ethics committees are all sufficiently close to equipoise to enable a large, double-blind, placebo-controlled, cardiovascular endpoint trial of metformin among patients with diabetes. It is also doubtful that a suitable industry, charity or government funder could be identified. While such a trial might reduce uncertainty about whether metformin is more effective than placebo, it would not inform common therapeutic dilemmas, such as which of the many available glucose-lowering drugs or combination of drugs to use, in which order to use them and for which patient. Possible, at least partial, solutions include the use of electronic health records to facilitate large, long-term, pragmatic, efficient trials comparing the effect of different treatments (new and old) on cardiovascular outcomes, plus the increased use of factorial trials in which an industry-sponsored new medication can be evaluated alongside older drugs such as metformin. There has been considerable hope and hype concerning the potential for precision medicine to inform treatment decisions [35], but progress is hampered by our lack of understanding about the mechanisms of action of metformin and a focus on intermediate endpoints. Publication of cardiovascular outcome data from adverse event reporting in trials of metformin would increase the data available for meta-analysis, thereby reducing the uncertainty of effect size estimates, but the small number of additional events are unlikely to lead to definitive conclusions.