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CYP2C19 Loss‐of‐function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes
Author(s) -
Wang Ke,
Yang Aimin,
Shi Mai,
Tam Claudia C. H.,
Lau Eric S. H.,
Fan Baoqi,
Lim Cadmon K. P.,
Lee Heung Man,
Kong Alice P. S.,
Luk Andrea O. Y.,
Tomlinson Brian,
Ma Ronald C. W.,
Chan Juliana C. N.,
Chow Elaine
Publication year - 2022
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2446
Subject(s) - cyp2c19 , medicine , odds ratio , hazard ratio , pharmacogenetics , sulfonylurea , type 2 diabetes , cyp2c9 , confidence interval , logistic regression , proportional hazards model , genotype , diabetes mellitus , pharmacology , allele , retrospective cohort study , endocrinology , cytochrome p450 , genetics , biology , insulin , gene , metabolism
Sulfonylureas (SUs) are predominantly metabolized by cytochrome p450 2C9 (CYP2C9) and cytochrome p450 2C19 (CYP2C19) enzymes. CYP2C9 polymorphisms are associated with greater treatment response and hypoglycemic risk in SU users. However, there are no large scale pharmacogenetic studies investigating the effect of loss‐of‐function alleles CYP2C19*2 and CYP2C19*3 , which occur frequently in East Asians. Retrospective pharmacogenetic analysis was performed in 11,495 genotyped patients who were enrolled in the Hong Kong Diabetes Register between 1995 and 2017, with follow‐up to December 31, 2019. The associations of CYP2C19 polymorphisms with SU treatment failure, early HbA1c response, and severe hypoglycemia were analyzed by Cox regression or logistic regression assuming an additive genetic model. There were 2341 incident SU users that were identified (mean age 59 years, median diabetes duration 9 years), of which 324 were CYP2C19 poor metabolizers ( CYP2C19 *2/*2 or *2/*3 or *3/*3 ). CYP2C19 poor metabolizers had lower risk of SU treatment failure (hazard ratio 0.83, 95% confidence interval (CI) 0.72–0.97, P = 0.018) and were more likely to reach the HbA1c treatment target < 7% (odds ratio 1.52, 95% CI 1.02–2.27, P = 0.039) than wild‐type carriers ( CYP2C19 *1/*1 ) following adjustment for multiple covariates. There were no significant differences in severe hypoglycemia rates among different CYP2C19 genotype groups. CYP2C19 polymorphisms should be considered during personalization of SU therapy.