Mofo Mato Edith Pascale, Guewo-Fokeng Magellan, Essop M Faadiel, Owira Peter Mark Oroma
Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa Laboratory of Public Health Research Biotechnology (LAPHER-Biotech) Laboratory of Molecular Medicine and Metabolism (LMMM), Biotechnology Centre, University of Yaounde I, Yaounde, Cameroon Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
Medicine (Baltimore). 2018 Jul;97(27):e11349. doi: 10.1097/MD.0000000000011349.
Metformin is one of the most commonly used drugs for the treatment of type 2 diabetes mellitus (T2DM). Despite its widespread use, there are considerable interindividual variations in metformin response, with about 35% of patients failing to achieve initial glycemic control. These variabilities that reflect phenotypic differences in drug disposition and action may indeed be due to polymorphisms in genes that regulate pharmacokinetics and pharmacodynamics of metformin. Moreover, interethnic differences in drug responses in some cases correspond to substantial differences in the frequencies of the associated pharmacogenomics risk allele.
This study aims to highlight and summarize the overall effects of organic cation transporter 1(OCT1) polymorphisms on therapeutic responses to metformin and to evaluate the potential role of such polymorphisms in interethnic differences in metformin therapy.
We conducted a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We searched for PubMed/MEDLINE, Embase, and CINAHL, relevant studies reporting the effects of OCT1 polymorphisms on metformin therapy in T2DM individuals. Data were extracted on study design, population characteristics, relevant polymorphisms, measure of genetic association, and outcomes. The presence of gastrointestinal side effects, glycated hemoglobin A1 (HbA1c) levels, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) concentrations after treatment with metformin were chosen as measures of the metformin responses. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO).
According to the data extracted, a total of 34 OCT1 polymorphisms were identified in 10 ethnic groups. Significant differences in the frequencies of common alleles were observed among these groups. Met408Val (rs628031) variant was the most extensively explored with metformin responses. Although some genotypes and alleles have been associated with deleterious effects on metformin response, others indeed, exhibited positive effects.
Genetic effects of OCT1 polymorphisms on metformin responses were population specific. Further investigations in other populations are required to set ethnicity-specific reference for metformin responses and to obtain a solid basis to design personalized therapeutic approaches for T2DM treatment.
二甲双胍是治疗2型糖尿病（T2DM）最常用的药物之一。尽管其广泛应用，但二甲双胍反应存在相当大的个体差异，约35%的患者未能实现初始血糖控制。这些反映药物处置和作用表型差异的变异性可能确实归因于调节二甲双胍药代动力学和药效学的基因多态性。此外，在某些情况下，药物反应的种族间差异对应于相关药物基因组学风险等位基因频率的显著差异。
本研究旨在突出并总结有机阳离子转运体1（OCT1）多态性对二甲双胍治疗反应的总体影响，并评估此类多态性在二甲双胍治疗种族间差异中的潜在作用。
我们根据系统评价和Meta分析的首选报告项目（PRISMA）指南进行了系统评价。我们检索了PubMed/MEDLINE、Embase和CINAHL，查找报告OCT1多态性对T2DM个体二甲双胍治疗影响的相关研究。提取了关于研究设计、人群特征、相关多态性、基因关联测量和结果的数据。选择二甲双胍治疗后胃肠道副作用的发生情况、糖化血红蛋白A1（HbA1c）水平、空腹血糖（FPG）和餐后血糖（PPG）浓度作为二甲双胍反应的测量指标。本系统评价方案已在国际前瞻性系统评价注册库（PROSPERO）注册。
根据提取的数据，在10个种族群体中总共鉴定出34种OCT1多态性。在这些群体中观察到常见等位基因频率存在显著差异。Met408Val（rs628031）变异体是对二甲双胍反应研究最广泛的。虽然一些基因型和等位基因与二甲双胍反应的有害影响相关，但其他一些确实表现出积极影响。
OCT1多态性对二甲双胍反应的遗传效应具有人群特异性。需要在其他人群中进行进一步研究，以建立种族特异性的二甲双胍反应参考标准，并为设计T2DM治疗的个性化治疗方法获得坚实基础。
