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.

The pharmacogenetics of metformin

“…Similarly, no associations have been found between reduced-function variants in OCT2 and metformin response [43, 47–49]. The Rotterdam group found an association of the intronic SNP rs2289669 in SLC47A1 (encoding MATE1) with metformin response, with the minor allele enhancing the reduction in HbA 1c ; though this finding is supported by similar observations by the DPP [48] and Tkáč et al [47], it was not seen in the South Danish Diabetes Study [43] nor in a large meta-analysis recently conducted by the Metformin Genetics (MetGen) Consortium [50]. In conclusion, the most solid evidence seems to support a role for coding missense variants in OCT1 with metformin response and/or intolerance.…”

Differential increments of basal glucagon‐like‐1 peptide concentration among SLC47A1 rs2289669 genotypes were associated with inter‐individual variability in glycaemic response to metformin in Chinese people with newly diagnosed Type 2 diabetes

“…might be the reasons for the discrepancy. Notably, despite the significant association between rs2289669 and HbA 1c reduction in the present study, it is still unknown whether rs2289669 can actually predict the glycaemic response to metformin, given that a large‐scale meta‐analysis performed in people of white ethnic origin found little evidence of an association between rs2289669 and the glycaemic response to metformin . A larger sample size or meta‐analysis is required for further validation in the Chinese population.…”

Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?

“…3) [33]. This finding has been replicated in one small cohort [34] but not in a large-scale meta-analysis [35]. As has been the case for many other phenotypes, candidate gene studies have failed to produce a comprehensive picture of the genetic determinants of metformin action.…”