Loss‐of‐Function CYP2C9 Variants Improve Therapeutic Response to Sulfonylureas in Type 2 Diabetes: A Go‐DARTS Study

Sulfonylureas are metabolized mainly by the cytochrome p450 2C9 (CYP2C9) enzyme. Two CYP2C9 variants—*2 (Arg144Cys) and *3 (Ile359Leu)—are associated with reduced enzyme activity and impaired substrate metabolism. We identified 1,073 incident users of sulfonylureas in Tayside, Scotland, and assessed the impact of the combined CYP2C9*2 and CYP2C9*3 genotypes on early and sustained sulfonylurea response. We found that patients with two copies of a loss‐of‐function allele were 3.4 times ( P = 0.0009) more likely to achieve a treatment hemoglobin A 1c (HbA 1c ) level <7% than patients with two wild‐type CYP2C9 alleles. This corresponds to a 0.5% ( P = 0.003) greater reduction in HbA 1c concentration. In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy ( P = 0.04; per‐allele hazard ratio 0.79; 95% confidence interval 0.63–0.99). In conclusion, CYP2C9 loss‐of‐function alleles are associated with greater response to sulfonylureas and decreased failure of therapy consistent with the pharmacokinetic role of CYP2C9 . Clinical Pharmacology & Therapeutics (2010) 87 1, 52–56. doi: 10.1038/clpt.2009.176