Abstract
Introduction:
Sulphonylureas (SU) are metabolised predominantly by cytochrome p450 (CYP) 2C9 and 2C19 enzymes. In pharmacokinetic studies, certain SU such as gliclazide appear to be metabolised mainly via CYP2C19, while others such as glyburide by CYP2C9. The CYP2C9*3 variant has been associated with reduced treatment failure, however, the effect of CYP2C19 variants on SU response have not been examined. Loss-of-function CYP2C19 *2 and *3 variants are common in Chinese occurring in 40% and 7% respectively, whereas CYP2C9 variants are relatively uncommon.
Aim:
To examine the effect of CYP2C19 *2 and *3 variants on SU treatment failure in Chinese patients with type 2 diabetes.
Methods:
476 incident SU monotherapy users were identified from the Hong Kong Diabetes Registry between 1999 to 2007 with median follow up of 3 years. Treatment failure was defined as progression to i) combined oral antidiabetic drug therapy ii) insulin use or iii) a treatment haemoglobin A1c (HbA1c) >7.5% (58 mmol/mol). The combined effect of CYP2C19*2 and *3 variants on SU treatment failure was evaluated using Cox proportional hazards model with age, gender, baseline HbA1c as covariates.
Results:
192 (41%) patients were CYP2C19 wild-type carriers, 209 (45%) were *1/*2 or *1/*3 heterozygotes and 66 (14%) were CYP2C19 poor metabolisers (*2/*2 or *2/*3 or *3/*3). There were no differences in age, gender, diabetes duration or baseline HbA1c between genotypes groups. In univariate analysis, each copy of loss of function CYP2C19 allele was associated with reduced risk of SU monotherapy failure (HR 0.87, 95% CI 0.75 to 0.99, p = 0.04) under a proportional hazard model. This effect was attenuated following adjustment for covariates. In subgroup analysis, patients treated with gliclazide modified release (n=75) with one or more loss of function CYP2C19 alleles were at lower risk of treatment failure following adjustment for covariates (HR 0.50, 95% CI 0.27-0.91, p = 0.02)
Conclusions:
CYP2C19 loss-of-function variants may be associated with lower risk of SU treatment failure. These findings require confirmation in larger pharmacogenetic studies and may influence personalisation of glucose lowering therapies.
