الفهرس 
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Abstract
Background: In Egypt, diabetes mellitus is a considered a health burden with 7.5 million patients in 2013 which expected to double by 2040. Moreover, Egypt has the highest number of Type 2 Diabetic patients in the Middle east and North Africa. Among different hypoglycemic agents, Metformin and sulfonylureas such as Glimepiride are usually co-prescribed as a combination therapy due to their acceptable efficacy and low cost.
Metformin must be uptaken into hepatocytes in order to initiate its pharmacological actions. Organic cation transport 1 (OCT1), encoded by SLC22A1 gene, is the main transport of metformin. Sulfonylureas are regarded as insulin secretagogues which enhance insulin release from pancreatic B-cells through binding to a specific Sulfonylurea Receptor 1(SUR1), encoded by ABCC8 gene. Mutations in such genes could affect the efficacy of each medication.
Aims: Determine minor allele frequency (MAF) of SLC22A1 rs622342, and ABCC8 rs757110 genetic variants in an Egyptian population. Investigate the influence of such genetic variants on the efficacy of metformin and glimepiride combination therapy in type 2 diabetic patients.
Methods: This was an observational non-interventional pharmacogenetic study on Egyptian patients, receiving metformin and glimepiride as combination therapy for at least 6 months whom were included and genotyped. Patients were classified into either responders or non-responders based on their Glycated Hemoglobin (HbA1c) level. Efficacy and response were defined as the ability of both drugs to decrease HbA1c to the controlled levels (less than 7%). Patients with HbA1c less than 7% were considered responders and otherwise they were regarded as non-responders. Logistic regression model was used to assess the association. Final model was adjusted for patients’ characteristics such as age, gender, Treatment duration, Metformin daily dose, Glimepiride daily dose, and BMI.
Results: A total number of 150 T2DM patients were screen and only 127 T2DM patients receiving combination therapy were included and divided into 93 responders (HbA1c<7%) and 34 non-responders (HbA1c≥7%). Minor allele frequencies for ABCC8 rs757110 and SLC22A1 rs622342 were 0.271 and 0.189, respectively. Both variants were in equilibrium with Hardy-Weinberg Equilibrium. SLC22A1 rs622342 was found to be associated with metformin response in combination therapy, in which AA-allele carriers were 2.7 times more responsive to metformin in combination therapy than C-allele carriers (Odds Ratio= 2.718, p=0.028, 95% CI = 1.112-6.385). However, ABCC8 rs757110 showed no influence on glimepiride efficacy.
Conclusion: Genotyping of SLC22A1 rs622342, but not ABCC8 rs757110, is a good predictor for metformin response in combination therapy in T2DM patients. MAF of SLC22A1 rs622342 was first to be described in Egyptian population and its MAF was different that of Caucasians suggesting that Egyptians should not be considered as Caucasians, but they should be regarded as a distinctive population.
Recommendation: We recommend conducting more pharmacogenetic studies in Egyptian T2DM populations with larger sample size to increase the power of determining association of genetic variants with response and to have larger genetic panel as well.