Spotlight on metformin

Metformin—including its use, effects, and mechanisms—was the focus of some research published in the past month.

First, a retrospective comparative effectiveness study, published by JAMA Internal Medicine on Oct. 27, analyzed the initial choice of medication for more than 15,000 type 2 diabetes patients treated between 2009 and 2013. Metformin was prescribed to 57.8% of the patients. Patients who started with a sulfonylurea, a thiazolidinedione, or a dipeptidyl peptidase 4 inhibitor were significantly more likely to have to add a second oral agent or insulin during follow-up compared to patients taking metformin. Initial sulfonylurea therapy was associated with an increased risk of hypoglycemia and cardiovascular events compared to metformin, while the other drugs showed no significant differences on these outcomes. The results support current guidelines recommending metformin as first-line therapy, as well as existing evidence of the risks of sulfonylureas, the researchers concluded, calling for interventions to increase use of metformin. The benefits of metformin are already well known, said an accompanying editorial, but this study adds data on an outcome important to patients, who often “consider treatment intensification to be failure,” the editorialists said. They recommended reframing it as a necessary step for wellness.

Another retrospective study, published by Diabetes Care on Oct. 21, compared cancer rates in more than 20,000 German type 2 diabetes patients taking metformin or other diabetes medications. During a median follow-up of 4.8 years, 6.4% of the patients developed cancer. The difference in cancer rates was insignificant between patients taking sulfonylureas, insulin, or other diabetes medications compared to metformin monotherapy. These results support the findings of the few available randomized controlled trials (RCT) but differ from several meta-analyses of observational studies that suggested potential reduction in cancer risk with metformin therapy. The authors specifically designed this study to address time-related bias that could potentially afflict the previous observational studies. They concluded that the study did not find a reduced cancer risk in metformin users but further well-designed observational studies and RCTs should clarify this issue.

Finally, an article in the Oct. 16 New England Journal of Medicine discussed new basic research into metformin's mode of action, which had previously been uncertain. According to recent rodent research, metformin “selectively inhibits the mitochondrial isoform of glycerophosphate dehydrogenase, an enzyme that catalyzes the conversion of glycerophosphate to dihydroxyacetone phosphate” or, to put it in more patient-friendly terms, “it blocks an enzyme that makes the liver put out too much sugar into your blood,” the article concludes. The findings may be useful for gaining understanding of the gastrointestinal side effects of metformin, its effect on blood lipids, and secondary treatment failure, as well as other questions about the drug, the authors said.