Different Responses to Metformin? It's in the Genes, Study Finds

Metformin has been the foundation of type 2 diabetes (T2D) care for decades, but not everyone has a good response. A new study in the journal Nature Genetics explains why: some patients have genetic variants that cause the body to respond extremely well to the drug.

The study presents the first results from the Metformin Genetics Consortium, known as MetGen, a venture jointly led by Kathleen M. Giacomini, PhD, of the University of California at San Francisco, and Ewan Pearson, PhD, of the University of Dundee in Scotland. As the authors note, despite metformin’s widespread use—more than 100 million people take it—its mechanism of action remained unclear.

Treating everyone with diabetes the same way overlooks the fact that patients respond very differently to therapies. There are more T2D therapies than ever, and MetGen is a step toward a precision medicine approach to diabetes care, one that would steer drugs to patients who would respond the best.

MetGen reported a 3-stage genome wide association study that involved 13,123 patients of diverse ethnic backgrounds. Researchers found that a variant of the gene SLC2A2, which encodes the glucose transporter gene GLUT2, was correlated with a strong response to metformin.

GLUT2 regulates how glucose moves among the liver, the blood, and the kidneys. Patients with the variant had less of this glucose transporter gene, hampering the liver’s ability to process blood glucose. Metformin reversed this effect.

What’s more, researchers found that the variant was also linked to higher body weight, which might explain the observation that metformin works best on overweight patients. For some patients, the effect is profound: they respond as if they were taking a double dose of metformin.

In recent years, presenters at the American Diabetes Association Scientific Sessions have called for a more individualized approach to diabetes care, and some question the wisdom of trying older, cheaper drugs until they fail before tackling diabetes with newer, more powerful therapies. Diabetes, some say, should be treated more like cancer: give powerful treatment early on when they will have the greatest effect.

At the 2014 ADA meeting in San Francisco, for example, Ravi Retnakaran, MD, an endocrinologist from the University of Toronto and Mount Sinai Hospital of Toronto, discussed the effects of giving T2D patients short courses of insulin for 4-8 weeks, before beta cell function is so damaged it cannot be restored.

Pearson said more work is needed before clinicians can change the way they use metformin, but the study is an important step. “This finding suggests some patients should be treated with higher doses than others to get the same effect. This really does move us a step closer to truly targeted therapy in the treatment of diabetes.”

Reference

Zhou K, Yee SW, Seiser EL, et al. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin [published online August 9, 2016]. Nature Genetics. 2016; doi: 10.1038/ng.3632.