Metformin is a glucose lowering drug used in the treatment of type 2 diabetes. The publication of the UK Prospective Diabetes Study in 1998 lead to the recommendation of metformin as first-line treatment for type 2 diabetes. In addition to the impressive reduction in mortality risk observed in type 2 diabetes patients treated with metformin therapy, several mice studies since the 1980s have found that metformin increases lifespan in mice and rats. These results have culminated in the recent announcement of a human trial to investigate the anti-aging effects of metformin (find out more here).
Could metformin raise mortality rates in diabetes patients?
In a new study by a Belgian research team at the University of Leuven, data from 115,896 patients using glucose lowering agents were extracted from healthcare databases to investigate the effect of these drugs on mortality. Patients treated with the different studied glucose lowering agents (metformin, insulin, sulfonylurea and combinations of these) were compared to controls matched for age, gender, heart disease risk and drug treatment for heart disease. The control population was not using glucose lowering agents. Highest 5-year mortality was found in patients treated with insulin (23.8%), followed by sulfonylurea (4.1%). Patients treated with metformin had a nonsignificant increase in 5-year mortality of 0.3%. The same trend was observed for patients with a history of heart disease. Finally, all combination therapies lead to an increase in 5-year mortality. This study confirms results from multiple previous studies, however it should be pointed out that this study also has some limitations. It is possible that patients started on metformin monotherapy are those with the mildest form of diabetes while sicker patients receive insulin, sulfonylureas or combination therapies. Another source of bias is that metformin therapy is contra-indicated for patients suffering from chronic kidney disease. So patients in this high mortality group will be found in the insulin, sulfonylurea or combination of insulin and sulfonylurea groups.
However, there was also a recent opinion piece published in the British Medical Journal (BMJ) that pointed out several methodological shortcomings in the UK Prospective Diabetes Study. The authors refer to a meta-analysis of randomized controlled studies that they published in 2012 in PLoS Medicine that found no benefit of metformin therapy in reducing mortality in type 2 diabetes. The problem with most randomized controlled trials included in this meta-analysis is that they were never intended to study mortality. Rather most trials included were short term, intended to compare the efficacy of metformin to other glucose lowering treatments. The longest term study included in their meta-analysis was the UK Prospective Diabetes Study lasting over 10 years and this one showed a reduction in mortality. The shortest studies included were two studies lasting just 4 months, a period that is highly unlikely to yield any effect on mortality. A further limitation is that both of these short studies compared the combination of metformin with sulfonylurea with sulfonylurea alone. As we saw in the new Belgian study, the beneficial effects of metformin seem to disappear when metformin is combined with sulfonylurea treatment. Another noteworthy study used in their meta-analysis is the COSMIC trial. This is the trial with the highest number of subjects studied, 7227 participants in the metformin arm. In this trial metformin reduced mortality, although with a follow-up of only 1 year this trial is also very short.
A positive effect on your microbiome
A few years ago, David Gems and colleagues showed that metformin extended the lifespan of roundworms by influencing the metabolism of bacteria that live inside the gut and also serve as the food source for the worm. In a new paper published in Nature, researchers show that metformin also influences the bacteria living in the human gut of people with type 2 diabetes. The production of health-promoting short-chain fatty acids by gut bacteria is increased in patients taking metformin. On the downside, metformin also increases the abundance of Escherichia species and this could possibly explain some of the side effects observed during metformin therapy.
Despite the fact that metformin is approaching its 60th birthday the drug continues to be a fascinating research topic.