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

TY - JOUR

T1 - Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: A Go-DARTS study

AU - Zhou, K.

AU - Donnelly, L.

AU - Burch, L.

AU - Tavendale, R.

AU - Doney, A. S. F.

AU - Leese, G.

AU - Hattersley, A. T.

AU - McCarthy, M. I.

AU - Morris, A. D.

AU - Lang, C. C.

AU - Palmer, C. N. A.

AU - Pearson, E. R.

PY - 2010/1

Y1 - 2010/1

N2 - 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.

AB - 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.

KW - HEALTHY-VOLUNTEERS

KW - GLUCOSE RESPONSE

KW - POLYMORPHISMS

KW - INSULIN

KW - MELLITUS

KW - EFFICACY

KW - KINETICS

KW - IMPACT

UR - https://www.scopus.com/pages/publications/72849111539

U2 - 10.1038/clpt.2009.176

DO - 10.1038/clpt.2009.176

M3 - Article

C2 - 19794412

SN - 0009-9236

VL - 87

SP - 52

EP - 56

JO - Clinical Pharmacology & Therapeutics

JF - Clinical Pharmacology & Therapeutics

IS - 1

ER -