Pharmacogenetics of sulfonylureas

Despite tremendous efforts and recent advances in the understanding of the molecular biology and genetics of type 2 diabetes (T2D), its translation into clinical practice remains limited primarily to monogenic forms of diabetes. Pharmacogenetics, which focuses on the relationship between individual gene variants and their influence on drug action or side effect, may substantially improve patients’ health by enabling application of therapies targeted to patient subgroups. The present review focuses on the pharmacogenetic aspects of treatment with the widely used oral antidiabetic drugs-sulfonylureas (SUs). Initially, the review addresses two dramatic clinical applications of pharmacogenetics in diabetes-extreme sensitivity to SUs in patients with HNF1A MODY and SU treatment in patients with neonatal diabetes due to mutations in the potassium channel genes KCNJ11 (encoding Kir6.2) and ABCC8 (encoding SUR1). In addition to monogenic forms, pharmacogenetic aspects of treatment with SUs in polygenic T2D will be elaborated as well. Whereas pharmacodynamic variation in polygenic T2D is attributed to genetic variants in ABCC8/KCNJ11 and TCF7L2, known to be strongly associated with T2D, variants in CYP2C9 encoding sulfonylurea metabolising cytochrome P450 isoenzyme 2C9 play a major role in pharmacokinetic variation in polygenic T2D. Despite currently lacking large-scale population studies addressing the pharmacogenomics of SUs, it is our hope that given the recently established international collaborative efforts in this field, the next few years will see pharmacogenomics of SUs in T2D mirror the success seen in monogenic diabetes.