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.
Zhou
K
K
Dundee Diabetes Genetics Group, Biomedical Research Institute, University of Dundee, Dundee, UK.
Donnelly
L
L
Burch
L
L
Tavendale
R
R
Doney
A S F
AS
Leese
G
G
Hattersley
A T
AT
McCarthy
M I
MI
Morris
A D
AD
Lang
C C
CC
Palmer
C N A
CN
Pearson
E R
ER
D000368:Aged; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000493:pharmacokinetics; D065729:Cytochrome P-450 CYP2C9; D030541:Databases, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012606:Scotland; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*
D013453:Sulfonylurea Compounds; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases