The pharmacogenetics of metformin

Abstract

Despite its widespread use as the first-line agent for the treatment of type 2 diabetes, it has become clear that metformin does not work optimally for everyone. Elucidating who are the likely metformin responders and non-responders is hampered by our limited knowledge of its precise molecular mechanism of action. One approach to achieve the related goals of stratifying patients into response subgroups and identifying the molecular targets of metformin involves the deployment of agnostic genome-wide approaches in cohorts of appropriate size to attain sufficient statistical power. While candidate gene studies have shed some light on the role of genetic variation in influencing metformin response, genome-wide association studies are beginning to provide additional insight that is unconstrained by prior knowledge. To fully realise their potential, much larger samples need to be assembled via international collaboration, preferably involving the academic community, government and the pharmaceutical industry.

Keywords: Genome-wide association studies; Metformin; Pharmacogenetics; Review; Single nucleotide polymorphisms; Type 2 diabetes.

Fig. 1

Transporters responsible for the absorption and elimination of metformin into relevant tissues. Following ingestion, metformin reaches the gut endothelium (a), where it is taken up by enterocytes via PMAT and OCT3, located on the luminal surface of the gut epithelium. OCT1 transports metformin from the enterocyte to the serosal side of the endothelium. When it reaches the liver (b), OCT1 and OCT3 aid with metformin uptake into hepatocytes. Disposal of metformin into bile is facilitated by MATE1 and taken up by epithelial cells in the kidney (c) via OCT2, while MATE1 and MATE2 are involved in excretion of unchanged metformin into the urine, as it is not metabolised in humans. Figure adapted from [56]

Fig. 2

Manhattan plot of the first GWAS for metformin response, indicating a single suggestive association signal in chromosome 11 near the ATM gene. Chromosomes are arranged linearly along the x-axis and denoted in different colours, with the negative log₁₀ (p value) for association being shown along the y-axis. Each dot represents a single nucleotide polymorphism tested in the genome-wide array for association with metformin response, defined as reaching the clinical goal of HbA_1c < 7% within 18 months of treatment initiation. Figure adapted from Zhou et al, Nature Genetics 43:117–120 [21]

Fig. 3

Meta-analysis of the largest published GWAS for metformin response (defined as on-treatment HbA_1c adjusted for baseline HbA_1c), comprising 10,557 participants of European descent. The summary result shows a genome-wide significant association at a SNP in the SLC2A2 gene, which encodes the GLUT2 glucose transporter expressed in hepatocytes. Figure adapted from Zhou et al, Nature Genetics 48: 1055–1059 [54]. ACCORD, Action to Control Cardiovascular Risk in Diabetes; DCS, Diabetes Cohort Study; PMT1/2-EU, Pharmacogenomics of Metformin Transporters project 1/2 (European descent)