Pharmacogenetics of metformin

Metformin is the most widely prescribed antidiabetic drug in the world. Despite its beneficial effects in reducing the risk for developing vascular complications associated with diabetes, the glycemic response to metformin is highly variable. Genetic factors, along with factors such as various comorbidities and body weight, contribute to this variability. In this chapter, we focus on genetic polymorphisms that associate with metformin pharmacokinetics as well as poor glycemic response to the drug. In particular, genetic polymorphisms in membrane transporters that play a role in metformin absorption, disposition, and response are highlighted. Studies in healthy volunteers, prediabetic and diabetic patients, and patients with polycystic ovary disease are described. Using genome-wide data, it is estimated that the heritability of glycemic response to metformin is around 30 %. The first genome-wide association study of metformin glycemic response in patients with type 2 diabetes reveals a locus in chromosome 11. Finally, we provide an overview of future directions for metformin pharmacogenomic studies to further elucidate genetic loci and targets for metformin action.