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 language | English |
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Pages (from-to) | 52-56 |
Number of pages | 5 |
Journal | Clinical Pharmacology & Therapeutics |
Volume | 87 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jan 2010 |
Keywords
- HEALTHY-VOLUNTEERS
- GLUCOSE RESPONSE
- POLYMORPHISMS
- INSULIN
- MELLITUS
- EFFICACY
- KINETICS
- IMPACT