Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes
Authors: Simon J Griffin
Greg J Irving
James K Leaver
Journal: Diabetologia (2017)
Discipline: CLINICAL MEDICINE
Keywords: Cardiovascular disease; Meta-analysis; Metformin; Review; Systematic review.
Affiliations: The Primary Care Unit, Institute of Public Health, School of Clinical Medicine, University of Cambridge, Box 113 Cambridge Biomedical Campus, Cambridge, CB2 0SR, UK. ., MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. ., The Primary Care Unit, Institute of Public Health, School of Clinical Medicine, University of Cambridge, Box 113 Cambridge Biomedical Campus, Cambridge, CB2 0SR, UK.

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 ‚â?5 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. 

Retracted: No

PubPeer comments:
 This is a relevant meta-analysis, which has already been cited for example in the consensus statement of the American Diabetes Association and its European counterpart (EASD): https: care.diabetesjournals.org content 41 12 2669 and actually, if incorrect, would make a cheap, effective and safe medication - Metformin look worse than it is.. In my opinion this meta-analysis does a couple of strange things. The corresponding author has never responded to my multiple e-mails. I would be very interested to find out, if there are real, relevant flaws in this meta-analysis, or if I have completely misunderstood a certain point. I was surprised to find that in Figure 3 the last study (UKPDS 1998) was included in a way that Metformin actually appears to increase the relative risk of any cause death with event numbers I could not match to the original UKPDS 34 publication 07037-8 fulltext). I have accessed the whole article at Lancet and double-checked, but already the abstract states a 36% reduction of all-cause mortality. Your review states a relative risk of 1.52 - an increased risk - which is the contrary. Moreover I am curious about both the UKPDS 34 and the Holman et al. 2008 study being included.  10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetesu201c . The data from this study already includes UKPDS 34 since itu2019s this studyu2019s 10 more years follow-up, which would mean a double-inclusion of this data. Has this maybe been somehow accounted for otherwise in the meta-analysis? Or is there an error in the footnote? Looking at year 1997 in figure 3 -u201eHu201c in the NEJM Holman et al. article data , one finds the UKPDS 34u2019s 89 deaths in control and 50 deaths in the metformin group. I have just been interested in mortality for my research, but the UKPDS 34 at a first glance appears to be on the u201ewrong sideu201c of the relative risk in all the figures. Is it possible, that errors have been made in this meta-analysis and that this fact could have an impact on the overall result of the publication? ,