Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials

Catherine Cornu and colleagues performed a meta-analysis of randomised controlled trials of metformin efficacy on cardiovascular morbidity or mortality in patients with type 2 diabetes and showed that although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. Background: The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality. Methods and Findings: This meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal) against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients) were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR) = 0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR = 1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR = 0.90 (95% CI: 0.74 to 1.09); all strokes, RR = 0.76 (95% CI: 0.51 to 1.14); heart failure, RR = 1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR = 0.90 (95% CI: 0.46 to 1.78); leg amputations, RR = 1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR = 0.83 (95% CI: 0.59 to 1.17). For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I2 = 41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p = 0.10 and 0.02, respectively). Conclusions: Although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality. Further studies are needed to clarify this situation. : Please see later in the article for the Editors' Summary Background: Worldwide, more than 350 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone produced by the pancreas. In people with type 2 diabetes (the most common form of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing excess sugar from the blood become less responsive to insulin. Type 2 diabetes can be controlled with diet and exercise and with antidiabetic pills, each of which works in a different way to maintain a healthy blood sugar level. Metformin, for example, stops the liver making glucose and increases the body's response to insulin, whereas sulfonylureas help the pancreas make more insulin. The long-term complications of diabetes, which include an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about ten years compared to people without diabetes. Why Was This Study Done?: In 1998, a large randomized clinical trial called the UK Prospective Diabetes Study (UKPDS 34) reported that metformin in combination with dietary control reduced all-cause mortality in overweight patients with type 2 diabetes when compared to dietary control alone. Specifically, the risk of death from any cause among patients taking metformin was about a third lower than the risk of death among patients not taking metformin—a risk ratio (RR) of 0.64. This reduction in risk was significant (that is, it was unlikely to have occurred by chance) because its 95% confidence interval (95% CI; there is a 95% chance that the “true” RR lies within this interval) of 0.45–0.91 did not overlap 1.0. Given this finding, metformin is now recommended as the first-line treatment for type 2 diabetes. However, UKPDS 34 also reported an increase in death in non-overweight patients who took metformin plus sulfonylurea compared to those who took sulfonylurea alone (RR: 1.60; 95% CI: 1.02–2.52), a result considered non-significant by the UKPDS 34 researchers and largely ignored ever since. So do the benefits of metformin outweigh its risks? In this meta-analysis, the researchers re-evaluate the risk-to-benefit balance of metformin in the treatment of patients with type 2 diabetes. A meta-analysis is a statistical method that combines the results of several studies. What Did the Researchers Do and Find?: The researchers identified 13 randomized controlled trials that evaluated the effect of metformin on cardiovascular morbidity (illness) and mortality in patients with type 2 diabetes. More than 13,000 patients participated in these studies, three-quarters of whom received metformin and a quarter of whom received other treatments or a placebo. Compared to other treatments, metformin treatment had no effect on the risk of all-cause mortality (RR: 0.99; 95% CI: 0.75–1.31) or cardiovascular mortality (RR: 1.05; 95% CI: 0.67–1.64), the primary end points of this study. However, the results of the individual trials varied more than would be expected by chance (“heterogeneity”). Exclusion of the UKPDS 34 trial from the meta-analysis had no effect on the estimated risk ratio for all-cause mortality or cardiovascular deaths, but the heterogeneity disappeared. Finally, metformin treatment had no significant effect on the risk of cardiovascular conditions such as heart attacks, strokes, and heart failure; there was no heterogeneity among the trials for these secondary end points. What Do These Findings Mean?: These findings show no evidence that metformin has any beneficial effect on all-cause mortality, on cardiovascular mortality, or on cardiovascular morbidity among patients with type 2 diabetes. These findings must be cautiously interpreted because only a few randomized controlled trials were included in this study, and only a few patients died or developed any cardiovascular illnesses. Importantly, however, from these findings, it is impossible to exclude beyond reasonable doubt the possibility that metformin causes up to a 25% reduction or a 31% increase in all-cause mortality. Similarly, these findings cannot exclude the possibility that metformin causes up to a 33% reduction or a 64% increase in cardiovascular mortality. Given that a large number of patients take metformin for many years as a first-line treatment for diabetes, further studies are urgently needed to clarify this situation. Additional Information: Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001204.