Abstract
BackgroundMetformin is one of the most commonly used drugs for type 2 diabetes mellitus (T2DM). Despite its efficacy and safety, metformin is frequently associated with highly variable glycemic responses, which is hypothesized to be the result of genetic variations in its transport by organic cation transporters (OCTs). This systematic review aims to highlight and summarize the overall effects of OCT1 polymorphisms on therapeutic responses to metformin and to evaluate their potential role in terms of interethnic differences with metformin responses.Methods/designWe will systematically review observational studies reporting on the genetic association between OCT1 polymorphisms and metformin responses in T2DM patients. A comprehensive search strategy formulated with the help of a librarian will be used to search MEDLINE via PubMed, Embase, and CINAHL for relevant studies published between January 1990 and July 2017. Two review authors will independently screen titles and abstracts in duplicate, extract data, and assess the risk of bias with discrepancies resolved by discussion or arbitration of a third review author. Mined data will be grouped according to OCT1 polymorphisms, and their effects on therapeutic responses to metformin will be narratively synthesized. If sufficient numbers of homogeneous studies are scored, meta-analyses will be performed to obtain pooled effect estimates. Funnel plots analysis and Egger’s test will be used to assess publication bias. This study will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.DiscussionThis review will summarize the genetic effects of OCT1 polymorphisms associated with variabilities in glycemic responses to metformin. The findings of this study could help to develop genetic tests that could predict a person’s response to metformin treatment and create personalized drugs with greater efficacy and safety.Systematic review registrationRegistration number: PROSPERO, CRD42017079978
Highlights
DiscussionThis review will summarize the genetic effects of organic cation transporter 1 (OCT1) polymorphisms associated with variabilities in glycemic responses to metformin
Metformin is one of the most commonly used drugs for type 2 diabetes mellitus (T2DM)
This review will summarize the genetic effects of organic cation transporter 1 (OCT1) polymorphisms associated with variabilities in glycemic responses to metformin
Summary
Type 2 diabetes a chronic degenerative metabolic disease represents a major medical and public health problem. Several lines of evidence based on pharmacogenetic research have demonstrated that genetic variation is one of the major factors affecting metformin responses [41]. It is well known that genetic polymorphisms in gene encoding drug-metabolism enzymes and drug transporters contribute to interindividual variabilities in the pharmacokinetics/pharmacodynamics profiles of clinical drugs [42]. The most studied transporter regarding the impact of genetic variation on metformin action has been OCT1. This study will systematically review worldwide reports that have investigated an association between any OCT1 genetic polymorphism and therapeutic response to metformin in T2DM patients. Understanding the diversity of genetic markers associated with drug response across different global populations is essential to set ethnicity-specific reference for adverse drug reactions and identify patient groups whose genetic characteristics put them at special risk from either excessive or reduced pharmacologic effects of metformin.
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