Sulfonylurea pharmacogenomics in Type 2 diabetes: the influence of drug target and diabetes risk polymorphisms

The sulfonylureas stimulate insulin release from pancreatic b cells, and have been a cornerstone of Type 2 diabetes pharmacotherapy for over 50 years. Although sulfonylureas are effective antihyperglycemic agents, interindividual variability exists in drug response (i.e., pharmacodynamics), disposition (i.e., pharmacokinetics) and adverse effects. The field of pharmacogenomics has been applied to sulfonylurea clinical studies in order to elucidate the genetic underpinnings of this response variability. Historically, most studies have sought to determine the influence of polymorphisms in drug-metabolizing enzyme genes on sulfonylurea pharmacokinetics in humans. More recently, polymorphisms in sulfonylurea drug target genes and diabetes risk genes have been implicated as important determinants of sulfonylurea pharmacodynamics in patients with Type 2 diabetes. As such, the purpose of this review is to discuss sulfonylurea pharmacogenomics in the setting of Type 2 diabetes, specifically focusing on polymorphisms in drug target and diabetes risk genes, and their relationship with interindividual variability in sulfonylurea response and adverse effects.