Effect of CYP2C9 gene polymorphisms on response to treatment with sulfonylureas in a cohort of Egyptian type 2 diabetes mellitus patients

Abstract

Oral hypoglycemics are a widely prescribed group of drugs for the management of type 2 diabetes mellitus. Sulfonylureas (SUs) are the cornerstone of type 2 diabetes pharmacotherapy. The enzyme cytochrome P450 2C9 (CYP2C9) is the main enzyme that catalyzes the biotransformation of SUs. It is encoded by the polymorphic gene CYP2C9 with two allelic variants namely CYP2C9*2 and CYP2C9*3 coding for variant allozymes with reportedly decreased metabolic capacity resulting in decreased SUs clearance and consequently prolonged and exacerbated action. The aim of this study was to investigate the influence of genetic polymorphisms of CYP2C9 on the response to glibenclamide, a second-generation sulfonylurea. Hundred type 2 diabetic patients were enrolled in the study. Genotyping was done on the LightCycler 2 by real-time polymerase chain reaction (PCR) hybridization probe assay. The results are the following: 53 patients were carriers of the wild genotype (CYP2C9*1/*1), 20 were heterozygous for the variant CYP2C9*2 allele (CYP2C9*1/*2), 18 were heterozygous for the variant CYP2C9*3 allele (CYP2C9*1/*3), and 9 were double heterozygous for both mutant alleles (CYP2C9*2/*3); of those double mutant genotype patients, two were also homozygous for the mutant CYP2C9*2 allele (CYP2C9*2/*2) and one patient was homozygous for the mutant CYP2C9*3 allele (CYP2C9*3/*3). Although there was no significant difference in drug dosage between the four groups, there was however a significant association of the CYP2C9*2/*3 genotype with better glycemic control. As conclusion, the better glycemic control observed can probably be attributed to slower metabolism of SUs by the carriers of the CYP2C9*2/*3 genotype and consequently longer half-life or exacerbated effect of the SUs administered.

Frequency of CYP2C9 (*2, *3 and IVS8‑109A>T) allelic variants, and their clinical implications, among Mexican patients with diabetes mellitus type 2 undergoing treatment with glibenclamide and metformin

“…Reports from healthy Swedish populations (25) consider its carriers to be lower rate metabolizers, whereas studies on Ecuadorians regard them to possess an increased CYP2C9 hydroxylation capacity (26). When comparing the frequency of variant *1 / *2 in the Mexican population from the present study with those from other regions of the world identified in previous studies, significant differences were identified respect to Europe (0.06 vs. 0.18-0.24; P<0.05) and Africa (0.06 vs. 0.20; P<0.05), but not respect to India (21,32-38). As for *1 / *3 , statistical differences were identified in the Mexican population when compared with European countries (32-38), India (39), China (40), Japan (41) and Egypt (21) (P<0.05; Table IV).…”

“…The first stage of the present study described the variability and substantial diversity of the distribution of CYP2C9 within samples from Mexican patients with DMT2 and those from other populations; however, the effect of this genetic factor accounts for only 40% of the glibenclamide response variability (17), and it has only been studied in two other populations (20,21). The function of these polymorphisms in differential glibenclamide dosages, their effect on the variability of the response monitored by HbA1c (considered to be the main efficacy biomarker in the present study) and also on the most relevant adverse glibenclamide reaction (including hypoglycemia), have yet to be reported.…”

“…The glibenclamide group was not large; however, statistically the number of patients used was legitimately and properly applied. Glycemic control had been previously reported through measuring fasting glucose levels in the only two previous studies examining CYP2C9 including glibenclamide-treated patients with DMT2 (20,21). None of them belonged to any Mexican populations, where control was reported through measuring fasting glucose levels (<110 mg/dl) and associated with CYP2C9 through Xi2 in order to compare genotype frequencies between controlled and uncontrolled patients.…”

“…Replication and confirmation of these studies is necessary, thus fasting glucose, HbA1c description and investigatory analysis were performed on a Mexican population. The present study took into account the analysis performed by Salam et al (21) to compare results from different studies. The participants used in the present study had been previously diagnosed with DMT2 according to World Health Organization and American Diabetes Association criteria (30).…”

Variation of CYP2C9 Gene and Glycemic Control in Diabetic Patients: A Literature Review

“…The next study determined the impact of CYP2C9 polymorphism on response of treatment in Egyptian patients with DMT2 [13]. The genotype frequencies are 53 patients who were carriers of CYP2C9 *1/*1 (wild-type), 20 patients who were carriers of CYP2C9 *1/*2 (heterozygous for CYP2C9*2), 18 carriers of CYP2C9 *1/*3 (heterozygous for CYP2C9*3) and 9 patient carriers of CYP2C9 *2/*3 (double heterozygous for both mutant alleles).…”