The Effect of CYP2C9 Genotype Variants in Type 2 Diabetes on the Pharmacological Effectiveness of Sulfonylureas, Diabetic Retinopathy, and Nephropathy

Abstract

Aim

Type 2 diabetes (T2D), as a major cause of morbidity and mortality, is predicted to have a prevalence of 629 million by 2045. As diabetic patients show considerable inter-individual variation in response to antidiabetic treatment, this study aimed to investigate the gene polymorphism of cytochrome P450 as well as the effectiveness and safety of glibenclamide and gliclazide for different genotypes of CYP2C9. Besides, the chronic side effects of T2D including retinal microvasculature complications or retinopathy and renal dysfunction due to nephropathy in different genotypes were considered.

Patients and Methods

The participants including 80 T2D patients treated with glibenclamide or gliclazide were recruited from university hospitals of Ahvaz Jundishpur University of Medical Sciences, Ahvaz, in the southwest of Iran. Blood samples were collected from the patients at 2.5h after the morning dose of glibenclamide and 12h after the last dose of gliclazide. Genotyping from the extracted DNA was, then, performed using PCR-RFLP. The plasma level of glibenclamide and gliclazide was, in turn, measured by the reverse-phase high-pressure liquid chromatography.

Results

The results showed that the wild-type allele, i.e., CYP2C9*1, occurred in the highest frequency (0.8), while the frequency rates of the mutant allele, i.e., CYP2C9*2 and CYP2C9*3, were 0.15 and 0.05, respectively. Moreover, no significant association was found between any of the genotypes as well as the clinical and biochemical characteristics of the patients. The findings also showed that the plasma level of sulfonylureas (i.e., glibenclamide and gliclazide) was the highest in the patients with the CYP2C9*3 allele. It was also found that 75.9% of the patients with variant genotypes had experienced hypoglycemia events. Furthermore, in the absence of wild type allele, a significant increase was observed in retinopathy (p=0.039) and nephropathy (p=0.05).

Conclusion

The findings can provide guidelines for the optimal management of the treatment protocols with sulfonylurea intended to control the T2D complications.

Keywords:

• CYP2C9
• glibenclamide
• gliclazide
• retinopathy
• nephropathy

Ethics Approval and Consent to Participate

In this clinical experimental study, all peripheral blood samples were collected and used by the ethical rules confirmed by the ethics committee of Ahvaz Jundishapur University of Medical Sciences (Code no: IR.AJUMS.REC.139.221). Ethical issues (including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors. Written informed consent was also obtained from all patients. Data were anonymously and confidentially retrieved with compliance with the Declaration of Helsinki.

Acknowledgments

We thank the patients and nurses in diabetic specific clinics at Imam Khomeini and Golestan Hospitals affiliated to Ahvaz Jundishpur University of Medical Sciences, Ahvaz, Iran for their contribution to the research. The study was supported by the grant provided by the Deputy of Research Affairs at Ahvaz Jundishpur University of Medical Sciences.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest.