Metformin is the most-prescribed oral medication to lower blood glucose worldwide. But research findings about its association with cardiovascular disease, the most costly complication of type 2 diabetes, remain sparse and difficult to interpret. A new meta-analysis of research on the effect of metformin on cardiovascular outcomes in diabetes patients shows that metformin monotherapy appears safe and, while there is a suggestion of benefit, there remains uncertainty about whether it reduces risk of cardiovascular disease. The review indicates that metformin may reduce risk of all-cause mortality by up to 16% but it could increase risk of stroke by up to 48%.
The review, from Professor Simon Griffin, Dr Greg Irving and Dr James Leaver at the Primary Care Unit, was published in Diabetologia within the series of articles commissioned to mark the 60th anniversary of the first clinical use of metformin in diabetes.
In spite of the long history and enormous reach of this drug, the authors found only 13 studies reporting cardiovascular outcomes in which the effect of metformin was ‘isolated’ through comparison to diet, lifestyle or placebo. The studies included just over 2000 patients with type 2 diabetes allocated to metformin. Only four randomised-controlled cardiovascular endpoint trials simply compared metformin with placebo among patients with type 2 diabetes.These small studies took place among relatively young, overweight/obese, North American and Northern European patients with poorly controlled diabetes – in contrast to some newer treatments. So, while metformin demonstrates cardiovascular safety as per the 2008 FDA guidance, its use for prevention of cardiovascular disease among older individuals, those with well controlled blood sugar levels, non-white ethnic groups and people living outside North America and Northern Europe is not well supported by trial evidence.
A definitive placebo-controlled cardiovascular endpoint trial among people with diabetes is unlikely because the drug is so ubiquitous and there is insufficient medical uncertainty about the effects of metformin to make the case for such a trial. Alternative approaches could 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.
The authors point out that several important limitations (including study bias and small sample size) should be acknowledged when interpreting these findings and that well-designed randomised studies of metformin therapy are needed to enable comparison with newer glucose-lowering drugs (e.g. empagliflozin and liraglutide), for which rigorous cardiovascular endpoint data are available.”
– Sally Marshall, from her editorial in Diabetologia, Professor of Diabetes, Newcastle University
Proponents of a medical solution to diabetes, which is essentially a societal problem, are advocating the widespread use of metformin to ‘treat’ those at risk of diabetes. Indeed, metformin is now licensed in some countries for this indication. This effectively amounts to starting glucose-lowering treatment early in order to prevent the onset of diabetes and the need for glucose-lowering treatment, the aim of which is to reduce symptoms and risk of complications.
Given that people at risk of diabetes do not have symptoms attributable to hyperglycaemia, the rationale for recommending metformin would be considerably strengthened if trial evidence was available demonstrating that the use of metformin in people at risk of diabetes reduced risk of complications, such as cardiovascular disease.”
– Professor Simon Griffin
Read the paper
Griffin SJ, Leaver JK, Irving GJ (2017) Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia doi:10.1007/s00125-017-4337-9
Find out more
Prevention Group at the Primary Care Unit