Gene‐Guided Therapy in Type 2 Diabetes Mellitus: An Integrative Review of the Pharmacogenetics of Metformin and Sodium‐Glucose Cotransporter‐2 Inhibitors

BACKGROUND: Inter-individual variability in the therapeutic response to antidiabetic drugs is still a big problem in the management of type 2 diabetes mellitus (T2DM). Genetic polymorphisms of drug transporters, metabolizing enzymes and molecular targets have become significant factors in drug efficacy, pharmacokinetics and adverse effects. This review aims to provide a summary of the current evidence on the pharmacogenomics of metformin and sodium-glucose cotransporter-2 (SGLT2) inhibitors and their implications for precision medicine in T2DM. METHODS: Published human studies examining genetic polymorphisms related to the various effects of metformin and SGLT2 inhibitors in patients with T2DM were systematically searched in PubMed, Scopus and EBSCO and analysed using an integrative review. Qualitative synthesis was used to compare the pharmacogenetic profiles of the two drug classes and to look for potential biomarkers for precision therapy. RESULTS: Metformin has the most comprehensive pharmacogenetic evidence, including variants in SLC22A1 (OCT1), SLC22A2 (OCT2), SLC22A3 (OCT3), SLC47A1 (MATE1), SLC47A2 (MATE2), ATM and other genes that affect drug disposition, glycemic response and adverse effects. However, pharmacogenetic research on SGLT2 inhibitors is still scarce. Modest variations in drug exposure, glucose homeostasis and cardiorenal or hepatic outcomes have been reported for variants of UGT1A9, UGT2B4, SLC5A2, PNPLA3, and some glucose transporters, but most of these effects have not been strong enough to recommend routine genotype-based therapy. Metformin has more robust and consistent pharmacogenetic associations overall, while SGLT2 inhibitors have emerging but less definitive associations. CONCLUSION: Pharmacogenomics has great promise to enhance the selection of antidiabetic drugs, maximize therapeutic effect and minimize side effects. There is current evidence for the clinical relevance of several pharmacogenetic markers for metformin, but evidence for SGLT2 inhibitors is preliminary. Further, large, prospective, multiethnic studies and genotype-based clinical trials are needed to confirm candidate biomarkers and to help incorporate pharmacogenomics into precision medicine for T2DM.