CYP2C19 Loss-of-function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes

Abstract

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.

Figure 1

Kaplan‐Meier survival plots of time to SU treatment failure by CYP2C19 genotype groups. (a) Plot for overall SU users. (b) Plot for SU monotherapy users. SU, sulfonylurea; EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.

Figure 2

Associations of CYP2C19 polymorphisms with (ⅰ) SU treatment failure, (ⅱ) reaching treatment target (HbA1c < 7%), and (ⅲ) severe hypoglycemia among overall SU users. †Adjusted models were adjusted for covariates including therapy group (monotherapy or dual therapy), baseline age, sex, diabetes duration, baseline HbA1c, body mass index, estimated glomerular filtration rate, average SU daily dose, baseline use of antihypertensive drug and baseline use of lipid‐lowering drug. CI, confidence interval; HR, hazard ratio; OR, odds ratio; SU, sulfonylurea.