Association of the Reduced Function Met420del Polymorphism of SLC22A1 with Metformin-Induced Gastrointestinal Intolerance in Ethiopian Patients with Type 2 Diabetes Mellitus

Abstract

Abraham Degaga,1,2 Sisay Sirgu,3 Hasniza Zaman Huri,2 Maw Shin Sim,4 Navin Kumar Loganadan,5 Tedla Kebede,6 Birhanemeskel Tegene,7 Ephrem Engidawork,1 Workineh Shibeshi1 1Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of Clinical Pharmacy & Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia; 3Department of Internal Medicine, Diabetes and endocrinology unit, Saint Paul Hospital Millennium Medical College, Addis Ababa, Ethiopia; 4Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia; 5Department of Pharmacy, Putrajaya Hospital, Putrajaya, Malaysia; 6Department of Internal Medicine, Diabetes and endocrinology unit, Addis Ababa University, Addis Ababa, Ethiopia; 7Department of Microbiology, Saint Paul Hospital Millennium Medical College, Addis Ababa, EthiopiaCorrespondence: Workineh Shibeshi, Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, P.O.Box 9086, Addis Ababa, Ethiopia, Tel [phone], Email [email protected]: Despite its widespread use and favored profile, there are extensive variations in the treatment outcome of metformin therapy. Furthermore, studies reported that the inter-individual variability in the occurrence of metformin treatment associated side effects were related to the differences in individual genetic profiles. Thus, this study aimed to evaluate whether the reduced function methionine deletion at codon 420 (Met420del) variant of SLC22A1 (rs72552763) is associated with metformin induced gastrointestinal intolerance in Ethiopian patients with type 2 diabetes mellitus (T2DM).Patients and Methods: A retrospective observational study was conducted on 47 T2DM patients on metformin treatment for < 3 years to assess the association of SLC22A1 (rs72552763) polymorphism with metformin induced gastrointestinal intolerance. Accordingly, 24 metformin tolerant and 23 metformin intolerant individuals with T2DM were recruited. Genotyping of rs72552763 was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association to metformin induced gastrointestinal intolerance was assessed based on switching to a new class of glucose lowering agents or failure to up titrate dose due to metformin induced gastrointestinal intolerance. Chi-square, logistic regression and Mann–Whitney statistical tests were used as appropriate. Statistical significance was set at p < 0.05.Results: In our study, no significant association was observed between rs72552763 and metformin induced gastrointestinal intolerance. We found that the female gender and physical inactivity were risk factors for metformin gastrointestinal intolerance.Conclusion: Our study found that the Met420del variant of SLC22A1 (rs72552763) was not associated with metformin induced gastrointestinal intolerance in Ethiopian patients with T2DM. This is the study first to investigate the association of rs72552763 with metformin intolerance in the Ethiopian population with T2DM. However, the findings need to be cautiously interpreted given the relatively small sample size. In addition, a more complete investigation of SLC22A1 variants would be required to fully assess the effect of the gene on metformin induced gastrointestinal intolerance as several variants with a more severe loss of function have been described.Keywords: metformin intolerance, SLC22A1 gene, rs72552763, Ethiopia

Keywords

• metformin intolerance
• slc22a1 gene
• rs72552763
• ethiopia