Search for Genetic Determinants of Sulfonylurea Efficacy in Type 2 Diabetic Patients from China

Aims/hypothesis: The aim of this study was to investigate whether genetic variance can influence the efficacy of glibenclamide in patients with type 2 diabetes.

Methods: A total of 747 patients with type 2 diabetes was enrolled from the Xiaoke Pills Clinical Trial, which is a double-blind, randomised controlled trial. All the patients had been treated with glibenclamide for 48 weeks, with strict drug dose adjustment and data collection. Treatment failure was confirmed when patients reached the criteria for terminating their participation in the study (fasting blood glucose level ≥ 7.0 mmol/l on two consecutive tests 4 weeks after reaching the pre-set maximal dose or maximal tolerated dose). Using this cohort, we tested 44 single-nucleotide polymorphisms (SNPs) in 27 gene regions. The genes in our study were involved in the metabolism of sulfonylureas, islet beta cell function, insulin resistance and beta cell growth and differentiation. A logistic regression model was used to evaluate the relationship between genetic variants and treatment failure over a period of 48 weeks.

Results: We found that no SNP reached the significance level of p < 0.00125 if Bonferroni correction was performed for multiple testing in the logistic regression model used in this pharmacogenetic study. Participants with the minor allele C of rs10811661 in CDKN2A/CDKN2B showed a significantly greater reduction in fasting blood glucose (TT vs TC vs CC: 9.3% (0-20.0%) vs 9.2% (0.9-20.5%) vs 12.7% (5.2-24.4%), p = 0.008) after the initial 4 weeks of treatment independent of age, sex and BMI. There was a significant difference in beta cell function among carriers of different genotypes of rs10811661.

Conclusions/interpretation: Our study demonstrated that the CDKN2A/CDKN2B gene may be nominally associated with the efficacy of glibenclamide, and that CDKN2A/CDKN2B is associated with beta cell function.