Genetic and Clinical Factors Associated With Metformin Plasma Concentrations Following an Acute Metformin Challenge

The glycemic response to metformin is highly variable, yet the genetic determinants of metformin pharmacokinetics remain poorly characterized. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), an ancestrally diverse cohort, we evaluated clinical and genetic factors associated with plasma metformin concentrations. Plasma metformin concentrations were measured in 745 participants who completed a standardized acute metformin challenge in SUGAR-MGH. Higher metformin concentrations were associated with older age (β=2.5 ng/mL per year, p = 0.02), lower eGFR (β=-3.5 ng/mL per ml/min/1.73m2, p = 4.5 × 10-4), and lower BMI (β=-7.3 ng/mL per kg/m2, p = 1.3 × 10-4). African ancestry was associated with lower metformin concentrations compared to European ancestry (β=-72.6 ng/mL, p = 0.036). A genome-wide association study (GWAS) identified four African ancestry-specific genetic variants significantly associated with higher metformin concentrations (p < 5 × 10-8) as well as several suggestive loci near genes implicated in glucose metabolism, including USP36 and DGKB. Top variants associated with metformin concentration were not associated with glycemic response endpoints following the metformin challenge, including fasting glucose at Visit 2, change in HOMA-IR, and change in fasting insulin between visits. Previously reported metformin transporter variants showed no significant associations with metformin concentration. These findings represent the first GWAS of metformin plasma concentrations and provide a novel resource for future studies of metformin pharmacogenetics.