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Review
, 60 (9), 1620-1629

Impact of Metformin on Cardiovascular Disease: A Meta-Analysis of Randomised Trials Among People With Type 2 Diabetes

Affiliations
Review

Impact of Metformin on Cardiovascular Disease: A Meta-Analysis of Randomised Trials Among People With Type 2 Diabetes

Simon J Griffin et al. Diabetologia.

Abstract

Aims/hypothesis: Metformin is the most-prescribed oral medication to lower blood glucose worldwide. Yet previous systematic reviews have raised doubts about its effectiveness in reducing risk of cardiovascular disease, the most costly complication of type 2 diabetes. We aimed to systematically identify and pool randomised trials reporting cardiovascular outcomes in which the effect of metformin was 'isolated' through comparison to diet, lifestyle or placebo.

Methods: We performed an electronic literature search of MEDLINE, EMBASE and the Cochrane Library. We also manually screened the reference lists of previous meta-analyses of trials of metformin identified through a MEDLINE search. We included 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.

Results: We included 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. Participants were mainly white, aged ≤65 years, overweight/obese and with poor glycaemic control. 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. 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. All outcomes, with the exception of stroke, favoured metformin, with limited heterogeneity between studies, but none achieved statistical significance. Effect 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).

Conclusions/interpretation: 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. Although 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. Alternative approaches to reduce the uncertainty include the use of electronic health records in long-term pragmatic evaluations, inclusion of metformin in factorial trials, publication of cardiovascular outcome data from adverse event reporting in trials of metformin and a cardiovascular endpoint trial of metformin among people without diabetes.

Keywords: Cardiovascular disease; Meta-analysis; Metformin; Review; Systematic review.

Conflict of interest statement

Data availability

The authors declare that the data supporting the findings of this study are available within the article.

Funding

GJI is funded by a National Institute of Health Research (NIHR) Clinical Lectureship. SJG is supported by MRC Epidemiology Unit programme funding (MC_UU_12015/4). SJG is an NIHR senior investigator. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. All researchers were independent of funding bodies, which had no role in study design; data collection, analysis and interpretation of data; in the writing of the report; or decision to submit the article for publication. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Duality of interest

SJG and GJI are investigators on a recently completed feasibility study for a randomised cardiovascular endpoint trial of extended-release metformin among people without diabetes with hyperglycaemia, funded by the NIHR HTA programme (09/01/48). SJG reports receiving an honorarium and reimbursement of travel expenses from Eli Lilly associated with membership of an independent data monitoring committee for a randomised trial of a medication to lower glucose, an honorarium from Janssen for speaking at an educational meeting in 2015 and an honorarium from Astra Zeneca for speaking at an educational meeting in 2017.

Contribution statement

All authors were involved in the design of the review, GJI undertook analysis of the data, SJG drafted the manuscript, all authors reviewed the manuscript and contributed to its revision. All authors approved the version to be published.

Figures

Fig. 1
Fig. 1
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram [40]
Fig. 2
Fig. 2
Risk of bias summary. Review authors’ judgements about each risk of bias item for included studies. Risk of bias was assessed according to the methods recommended by the Cochrane Collaboration. Question mark, unclear risk of bias; negative sign, high risk of bias; positive sign, low risk of bias
Fig. 3
Fig. 3
Forest plot showing the effect of metformin on risk of all-cause mortality
Fig. 4
Fig. 4
Forest plot showing the effect of metformin on risk of cardiovascular death
Fig. 5
Fig. 5
Forest plot showing the effect of metformin on risk of myocardial infarction
Fig. 6
Fig. 6
Forest plot showing the effect of metformin on risk of stroke
Fig. 7
Fig. 7
Forest plot showing the effect of metformin on risk of peripheral vascular disease
Fig. 8
Fig. 8
Funnel plot of effect size estimates for all-cause mortality to assess risk of publication bias. Circles represent M–H RR estimates for all-cause mortality comparing metformin vs control groups

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