According to Catherine Cornu, MD, of the Clinical Investigation Centre in Lyon, France, and colleagues, a meta-analysis showed that the glucose-lowering agent had no effect on all-cause or cardiovascular mortality in people with diabetes….
Indeed, the researchers reported online, the analysis could not rule out anything from a 25% decrease to a 31% increase in the risk of death for any cause, or a 33% decrease to a 64% increase in the risk of cardiovascular mortality.
The finding is surprising, Cornu and colleagues noted, because the drug has been considered to be the first-line treatment for diabetes since results of the UK Prospective Diabetes Study were published in 1998, showing a mortality benefit in overweight patients with diabetes, when combined with diet control.
On the other hand, they noted, an overlooked finding in the UK study was that in non-overweight diabetes patients, the drug, when combined with sulphonylurea, actually appeared to increase mortality.
The meta-analysis was sharply criticized on methodological grounds by the president for medicine and science of the American Diabetes Association, Vivian Fonseca, MD, of Tulane University in New Orleans who stated that, “I’m surprised this paper got published.”
Cornu and colleagues conducted a systematic review of randomized controlled trials since Jan. 1, 1950, in which metformin’s effects on all-cause or cardiovascular mortality were evaluated, either as primary outcomes, secondary outcomes, or adverse events.
In all, they found 25 studies, of which 13 had enough data on the outcomes to form the basis of a meta-analysis, with 9,560 patients given metformin and 3,550 given conventional treatment or placebo.
But Fonseca argued that they were often comparing apples to oranges, in that the 1998 UK study was over a 12-year period, while many of the other studies in the analysis lasted only six months or a year. “You cannot answer this question on studies of less than eight, nine, 10 years’ duration,” he said.
He added that trials that focus on efficacy, with mortality as a secondary outcome or part of the list of adverse events, are unlikely to give clear answers. Instead, he argued, any future research on the issue should have mortality as a primary outcome.
Indeed, Cornu and colleagues reported that only four of the studies in the meta-analysis had clinical events as primary outcomes and only one was blinded. Length of follow-up ranged from four to 128 months, with only four studies having follow-up longer than three years.
Nevertheless, Cornu and colleagues said their meta-analysis found:
- The risk ratio for all-cause mortality was 0.99 (95% CI 0.75 to 1.31).
- The risk ratio for cardiovascular mortality was 1.05 (95% CI 0.67 to 1.64).
- There was also no difference in a range of secondary outcomes, including such things as heart attacks, strokes, leg amputations, and microvascular complications.
The results of the individual trials varied more than would be expected by chance, the researchers noted, but the heterogeneity disappeared when the UK Prospective Diabetes Study was excluded, although the risk ratios for mortality did not change.
Cornu and colleagues concluded, “We cannot exclude beyond any reasonable doubt that metformin use increases or decreases the risk of all-cause mortality or cardiovascular mortality.”
But, they said, the findings should be interpreted with caution because only a few randomized controlled trials were included and relatively few patients developed cardiovascular illnesses or died.
They called for further studies to clarify the “problematic situation” and suggested that metformin may not be the best comparator in trials evaluating new drugs aimed at lowering blood sugar.
On the other hand, they argued, “compared with other antidiabetic treatments, metformin may be the one with the least disadvantages” — it does not induce hypoglycemia, weight gain, or heart failure, and it’s associated with a lower death rate among patients with atherothrombosis.
- This meta-analysis found no evidence that metformin, considered to be the first-line treatment for diabetes, has any beneficial effect on all-cause mortality, on cardiovascular mortality, or on cardiovascular morbidity among patients with type 2 diabetes.
- Note, however, that the editors and others indicated that the study is not definitive and further studies are urgently indicated.
- The meta-analysis was sharply criticized on methodological grounds by the president for medicine and science of the American Diabetes Association, Vivian Fonseca, MD, of Tulane University in New Orleans who stated that, “I’m surprised this paper got published.
Boussageon R, et al “Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials” PLoS Med 2012; 9(4): e1001204; DOI: 10.1371/journal.pmed.1001204.