Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis

Abstract

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Figure 1

Effects of candidate variants in transporter genes on metformin glycemic response assessed as HbA_1c reduction in patients on metformin monotherapy. Beta values obtained from individual studies are presented with 95% confidence interval (CI); arrowheads indicate the CI exceeding the limits of the graph. Overall betas are presented as black diamonds. The organic cation transporter 1 (OCT1) reduced‐function (RF) alleles denote combined genotype for R61C and M420del – number of RF alleles. MATE1, multidrug and toxin extrusion transporter 1. [Color figure can be viewed at wileyonlinelibrary.com]