A Review of the Impact of Pharmacogenetics and Metabolomics on the Efficacy of Metformin in Type 2 Diabetes

Abstract

Metformin is the most often prescribed drug for people with type 2 diabetes (T2D). More than 120 million patients with T2D use metformin worldwide. However, monotherapy fails to achieve glycemic control in a third of the treated patients. Genetics contribute to some of the inter-individual variations in glycemic response to metformin. Numerous pharmacogenetic studies have demonstrated that variations in genes related to pharmacokinetics and pharmacodynamics of metformin's encoding transporters are mainly associated with metformin response. The goal of this review is to evaluate the current state of metformin pharmacogenetics and metabolomics research, discuss the clinical and scientific issues that need to be resolved in order to increase our knowledge of patient response variability to metformin, and how to improve patient outcomes. Metformin's hydrophilic nature and absorption as well as its action mechanism and effectiveness on T2D initiation are discussed. The impacts of variations associated with various genes are analysed to identify and evaluate the effect of genetic polymorphisms on the therapeutic activity of metformin. The metabolic pattern of T2D and metformin is also indicated. This is to emphasise that studies of pharmacogenetics and metabolomics could expand our knowledge of metformin response in T2D.

Identification of Transporter Polymorphisms Influencing Metformin Pharmacokinetics in Healthy Volunteers

“…For patients with DM2, metformin is the most often recommended medication. Metformin is used by more than 120 million type 2 diabetes patients globally [ 26 ]. However, individual differences in the pharmacological response to metformin are significant.…”

“…Some interindividual variations in the glycaemic response to metformin are influenced by genetics. Numerous pharmacogenetic investigations have shown that differences in the genes that encode the transporters responsible for the pharmacokinetics and pharmacodynamics of metformin are often related to metformin response [ 26 ]. Metformin’s total exposure and efficacy can be increased or decreased by certain genetic polymorphisms; hence, these variations must be examined to get the optimal therapeutic outcome.…”

“…However, it is not the real environment of metformin therapy, where patients usually present comorbidities and concomitant treatment that can influence the response to metformin. Therefore, future perspectives should include studies exploring the relationship between metformin and its metabolites and type 2 diabetes risk and symptoms, which may shed light on the disease’s pathophysiological features and lead to the identification of novel, reliable biomarkers that may aid in the early detection and treatment of type 2 diabetes [ 26 ].…”

Метформін — Препарат Першої Лінії Антигіперглікемічної Терапії: Від Механізмів Дії До Рекомендацій NICE

“…Рекомендації такого федерального американського консультативного комітету, як Національна комісія з клінічної допомоги (National Clinical Care Co��ission), передбачають широке застосування метформіну в осіб з переддіабетом з метою попередження розвитку ЦД [9]. Такі наполегливі рекомендації зумовили те, що зараз в усьому світі метформін приймають >120 млн хворих на ЦД [10].…”

Metabolomic analysis of serum samples from a clinical study on ipragliflozin and metformin treatment in Japanese patients with type 2 diabetes: Exploring human metabolites associated with visceral fat reduction

“…8 Metformin has been used for several decades as the first-line therapy for T2D in the United States. However, only a few studies 9 have performed metabolomic analyses on metformin-treated patients. Moreover, although visceral fat accumulation is associated with insulin resistance and various metabolic complications, 10 no metabolomic studies evaluating visceral fat content reduction by SGLT2 inhibitors have been reported.…”