Pharmacogenetics of Allelic Variants of CYP2C9 and Clinical Implications among Mexican Patients with Diabetes Mellitus Type 2 Undergoing Treatment with Glibenclamide and Metformin

Abstract

Diabetes  Mellitus Type 2 (DMT2) is a major public health concern in Mexico as well as globally.  The majority of Mexican patients with diabetes mellitus type 2 (DMT2) (67.9-85.0%) are prescribed sulphonylureas (SUs), which are metabolized by cytochrome P450 2C9. The polymorphisms of CYP2C9 are thought to be responsible for the extensive variability found in SU responses. The current chapter aims todescribe CYP2C9 polymorphisms (*2, *3 and IVS8-109T) within a sample of Mexican patients with DMT2, while suggesting the potential clinical implications in terms of glibenclamide response variability. The study included 248 patients with DMT2 who initially consented to be studied, those included in the study were treated with glibenclamide (n=11), glibenclamide combined with metformin (n=112) or metformin (n=76), and were subsequently genotyped using a reverse transcription quantitative polymerase chain reaction (PCR), endpoint allelic discrimination and PCR amplifying enzymatic restriction fragment long polymorphism. Glibenclamide significantly reduced the pre-prandial glucose (P<0.01) and the percentage of glycated hemoglobin (%HbA1c; P<0.01) for IVS8-109A>T compared with combined glibenclamide and metformin treatment. Concerning the various treatments with respect to the different genotypes, the percentages obtained were as follows: Glibenclamide A/A, HbA1c<6.5=33.3%; glibenclamide + metformin A/A, HbA1c<6.5=24.6%; gliben-clamide A/T, HbA1c<6.5=33.3%; glibenclamide + metformin A/T, HbA1c<6.5=25%; glibenclamide T/T, HbA1c<6.5=100%; and glibenclamide + metformin T/T, HbA1c<6.5=12.5%. Overall, these findings show that, while genetically customised prescriptions remain a desirable goal for increasing therapeutic success, neither allelic variants nor dosages evidenced a strong correlation with biomarker levels within the studied population; thus, more precise experimental and observational investigations are needed.