Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: A Go-DARTS study

K. Zhou, L. Donnelly, L. Burch, R. Tavendale, A. S. F. Doney, G. Leese, A. T. Hattersley, M. I. McCarthy, A. D. Morris, C. C. Lang, C. N. A. Palmer, E. R. Pearson (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    109 Citations (Scopus)

    Abstract

    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 HbA1c 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.

    Original languageEnglish
    Pages (from-to)52-56
    Number of pages5
    JournalClinical Pharmacology & Therapeutics
    Volume87
    Issue number1
    DOIs
    Publication statusPublished - Jan 2010

    Keywords

    • HEALTHY-VOLUNTEERS
    • GLUCOSE RESPONSE
    • POLYMORPHISMS
    • INSULIN
    • MELLITUS
    • EFFICACY
    • KINETICS
    • IMPACT

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