Background: Considerable variability exists in response to metformin with few effective biomarkers to guide the treatment. Here we evaluated whether whole blood derived mitochondrial DNA copy number (mtDNA-CN) is a biomarker of metformin response as measured by glucose reduction or weight loss.
Methods: Using data from the trial of Metformin (n = 304) and AcaRbose (n = 300) in Chinese as the initial Hypoglycaemic treatment (MARCH), we examined the association between mtDNA-CN and two metformin response outcomes of HbA1c reduction and weight loss. The acarbose arm was used as a comparator group. Whole blood mtDNA-CN was estimated by deep whole genome sequencing with adjustments for confounders. Multiple linear regression and repeated measurement analyses were used to evaluate the association between mtDNA-CN and drug response outcomes.
Results: Here we show that glucose reduction is not significantly associated with mtDNA-CN and in either treatment arm. In the metformin arm, each increase of 1 SD in mtDNA-CN is significantly (P = 0.006) associated with a 0.43 kg more weight loss. Repeated measurement analysis shows that after 16 weeks of metformin monotherapy, patients in the top tertile of mtDNA-CN consistently lost 1.21 kg more weight than those in the bottom tertile (P < 0.001). In comparison, mtDNA-CN is not significantly associated with acarbose-induced weight loss.
Conclusions: Patients with higher mtDNA-CN are likely to lose more weight upon metformin treatment, suggesting mtDNA-CN as a potential novel biomarker for more effective weight management in type 2 diabetes.
Treatment of diabetes with the drug metformin can lead to beneficial weight loss. However, there is considerable variability in how patients respond to metformin and few markers or tests are available to guide prescribing. Here, we look at data from patients who took part in a trial comparing metformin with another diabetes drug and determine whether a particular marker—mitochondrial DNA copy number (mtDNA-CN)—is associated with weight loss with these treatments. mtDNA-CN is a proxy for the function of the mitochondria, an important organelle for the generation of metabolic energy in eukaryotic cells. Our results show that patients with diabetes with a higher mtDNA-CN lost more weight upon metformin treatment. This marker could potentially be used to guide treatment with metformin. Our findings warrant further exploration of mtDNA-CN as a marker of response to other drugs.
© 2023. The Author(s).