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Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes

Blood-based epigenetic markers differentiate metformin responsiveness and tolerance in patients recently diagnosed with type 2 diabetes. How to mete out metformin Metformin is the most commonly used drug to treat type 2 diabetes (T2D), though not all patients respond to it, and still, others do not tolerate it. García-Calzón et al. analyzed genome-wide DNA methylation in the blood of drug-naïve patients who were recently diagnosed with T2D. They found that DNA methylation at specific loci associated with future metformin response or tolerance, respectively, across multiple cohorts. These epigenetic markers may have theranostic potential regarding which patients should receive metformin. Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.