Metformin transporter pharmacogenomics: insights into drug disposition—where are we now?

ABSTRACT

Introduction: Metformin is recommended as first-line treatment for type 2 diabetes (T2D) by all major diabetes guidelines. With appropriate usage it is safe and effective overall, but its efficacy and tolerability show considerable variation between individuals. It is a substrate for several drug transporters and polymorphisms in these transporter genes have shown effects on metformin pharmacokinetics and pharmacodynamics.

Areas covered: This article provides a review of the current status of the influence of transporter pharmacogenomics on metformin efficacy and tolerability. The transporter variants identified to have an important influence on the absorption, distribution, and elimination of metformin, particularly those in organic cation transporter 1 (OCT1, gene SLC22A1), are reviewed.

Expert opinion: Candidate gene studies have shown that genetic variations in SLC22A1 and other drug transporters influence the pharmacokinetics, glycemic responses, and gastrointestinal intolerance to metformin, although results are somewhat discordant. Conversely, genome-wide association studies of metformin response have identified signals in the pharmacodynamic pathways rather than the transporters involved in metformin disposition. Currently, pharmacogenomic testing to predict metformin response and tolerability may not have a clinical role, but with additional data from larger studies and availability of safe and effective alternative antidiabetic agents, this is likely to change.

KEYWORDS:

• Metformin
• organic cation transporter
• pharmacogenomics
• transporter
• type 2 diabetes

Article highlights

• Metformin is currently the first-line treatment for most patients with type 2 diabetes.

• Several organic cation transporters (OCTs) and other drug transporters are involved in the absorption, distribution, and elimination of metformin.

• Candidate gene studies have shown that polymorphisms in these transporter genes can influence metformin pharmacokinetics but effects on glycemic responses were not replicated in large-scale meta-analyses.

• Some studies have found that loss-of-function variants in OCT1 (SLC22A1) can predict gastrointestinal intolerance to metformin.

• Genome-wide association studies (GWAS) of glycemic responses to metformin did not detect any variants in drug transporter genes having significant effects but variants in the pharmacodynamic pathways such as the glucose transporter GLUT2 (SLC2A2) were identified.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by grants from the Natural Science Foundation of Shanghai (18ZR1430900) and the Fundamental Research Funds for the Central Universities (22120170136).