Toward Precision Metformin Therapy: OCT1 Pharmacogenomics and a Genotype-Guided Clinical Algorithm in Type 2 Diabetes Mellitus
Authors
##plugins.themes.bootstrap3.article.sidebar##
##plugins.themes.bootstrap3.article.main##
Abstract
Objective: To systematically evaluate the influence of organic cation transporter 1 genetic polymorphisms on therapeutic response to metformin and to assess their relevance for personalized management of type 2 diabetes mellitus. Design: A Systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses 2020 principles using an integrative synthesis approach. Subjects/Patients: Adults with type 2 diabetes mellitus receiving metformin monotherapy or predominant metformin-based therapy across diverse ethnic populations. Methods: PubMed was searched for open access human studies evaluating SLC22A1 polymorphisms and glycemic outcomes. Fifteen studies including prospective cohorts, randomized pharmacogenetic subanalyses and observational designs were included. Data on Organic Cation Transporter 1 variants metformin exposure and glycemic endpoints were extracted and synthesized. Results: Reduced function organic cation transporter 1 variants were consistently associated with diminished glycemic response to metformin. Carriers exhibited smaller reductions in glycated hemoglobin, delayed attainment of glycemic targets, and a higher likelihood of treatment escalation, with a clear gene dose effect and hepatic organic cation transporter 1 mediated uptake emerging as the principal determinant of therapeutic efficacy. Conclusion: Organic cation transporter 1 genetic polymorphisms are a key determinant of interindividual variability in metformin response. Integrating organic cation transporter 1 pharmacogenomics into clinical algorithms may enhance therapeutic optimization and precision care in type 2 diabetes mellitus.
##plugins.themes.bootstrap3.article.details##
Copyright (c) 2026 Dr. Suhena Sarkar, MD, Dr. Birupaksha Biswas, MD
This work is licensed under a Creative Commons Attribution 4.0 International License.
Creative Commons License All articles published in Annals of Medicine and Medical Sciences are licensed under a Creative Commons Attribution 4.0 International License.
[1] Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007 May;117(5):1422-31. doi: 10.1172/JCI30558. PMID: 17476361; PMCID: PMC1857259.
[2] Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenomics J. 2009 Aug;9(4):242-7. doi: 10.1038/tpj.2009.15. Epub 2009 Apr 21. PMID: 19381165.
[3] Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt T, Sehrt D, Sabolić I, Koepsell H, Brockmöller J. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther. 2009 Sep;86(3):299-306. doi: 10.1038/clpt.2009.92. Epub 2009 Jun 17. PMID: 19536068.
[4] Dujic T, Causevic A, Bego T, Malenica M, Velija-Asimi Z, Pearson ER, Semiz S. Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes. Diabet Med. 2016 Apr;33(4):511-4. doi: 10.1111/dme.13040. Epub 2015 Dec 24. PMID: 26605869; PMCID: PMC5064645.
[5] Sundelin E, Gormsen LC, Jensen JB, Vendelbo MH, Jakobsen S, Munk OL, Christensen M, Brøsen K, Frøkiaer J, Jessen N. Genetic Polymorphisms in Organic Cation Transporter 1 Attenuates Hepatic Metformin Exposure in Humans. Clin Pharmacol Ther. 2017 Nov;102(5):841-848. doi: 10.1002/cpt.701. Epub 2017 Jun 1. PMID: 28380657.
[6] Reséndiz-Abarca CA, Flores-Alfaro E, Suárez-Sánchez F, Cruz M, Valladares-Salgado A, Del Carmen Alarcón-Romero L, Vázquez-Moreno MA, Wacher-Rodarte NA, Gómez-Zamudio JH. Altered Glycemic Control Associated with Polymorphisms in the SLC22A1 (OCT1) Gene in a Mexican Population with Type 2 Diabetes Mellitus Treated with Metformin: A Cohort Study. J Clin Pharmacol. 2019 Oct;59(10):1384-1390. doi: 10.1002/jcph.1425. Epub 2019 Apr 23. PMID: 31012983
[7] Stage TB, Brøsen K, Christensen MM. A Comprehensive Review of Drug-Drug Interactions with Metformin. Clin Pharmacokinet. 2015 Aug;54(8):811-24. doi: 10.1007/s40262-015-0270-6. PMID: 25943187.
[8] Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CN, Pearson ER. Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. Diabetes. 2015 May;64(5):1786-93. doi: 10.2337/db14-1388. Epub 2014 Dec 15. PMID: 25510240; PMCID: PMC4452716.
[9] Christensen MMH, Højlund K, Hother-Nielsen O, Stage TB, Damkier P, Beck-Nielsen H, Brøsen K. Steady-state pharmacokinetics of metformin is independent of the OCT1 genotype in healthy volunteers. Eur J Clin Pharmacol. 2015 Jun;71(6):691-697. doi: 10.1007/s00228-015-1853-8. Epub 2015 May 5. PMID: 25939711.
[10] DeGorter MK, Kim RB. Hepatic drug transporters, old and new: pharmacogenomics, drug response, and clinical relevance. Hepatology. 2009 Oct;50(4):1014-6. doi: 10.1002/hep.23233. PMID: 19787812.
[11] Umamaheswaran G, Praveen RG, Damodaran SE, Das AK, Adithan C. Influence of SLC22A1 rs622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients. Clin Exp Med. 2015 Nov;15(4):511-7. doi: 10.1007/s10238-014-0322-5. Epub 2014 Dec 10. PMID: 25492374.
[12] Moreno-González JG, Reza-López SA, González-Rodríguez E, Siqueiros-Cendón TS, Escareño Contreras A, Rascón-Cruz Q, Leal-Berumen I. Genetic Variants of SLC22A1 rs628031 and rs622342 and Glycemic Control in T2DM Patients from Northern Mexico. Genes (Basel). 2025 Jan 24;16(2):139. doi: 10.3390/genes16020139. PMID: 40004467; PMCID: PMC11855146.
[13] Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CN, Pearson ER. Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. Diabetes. 2015 May;64(5):1786-93. doi: 10.2337/db14-1388. Epub 2014 Dec 15. PMID: 25510240; PMCID: PMC4452716.
[14] Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013 Feb 14;494(7436):256-60. doi: 10.1038/nature11808. Epub 2013 Jan 6. PMID: 23292513; PMCID: PMC3573218.
[15] Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010 Jul;120(7):2355-69. doi: 10.1172/JCI40671. Epub 2010 Jun 23. PMID: 20577053; PMCID: PMC2898585.
[16] Flory JH, Keating SJ, Siscovick D, et al. Identifying prevalence and risk factors for metformin non-persistence: a retrospective cohort study using an electronic health record. BMJ Open 2018;8:e021505. doi:10.1136/ bmjopen-2018-021505
[17] Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-2701. doi: 10.2337/dci18-0033. Epub 2018 Oct 4. PMID: 30291106; PMCID: PMC6245208.
[18] Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, D'Alessio DA, Davies MJ. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Feb;43(2):487-493. doi: 10.2337/dci19-0066. Epub 2019 Dec 19. Erratum in: Diabetes Care. 2020 Jul;43(7):1670. doi: 10.2337/dc20-er07. PMID: 31857443; PMCID: PMC6971782.
[19] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17. PMID: 26378978.
[20] Franke RM, Gardner ER, Sparreboom A. Pharmacogenetics of drug transporters. Curr Pharm Des. 2010;16(2):220-30. doi: 10.2174/138161210790112683. PMID: 19835554.
[21] Pearson ER. Personalized medicine in diabetes: the role of 'omics' and biomarkers. Diabet Med. 2016 Jun;33(6):712-7. doi: 10.1111/dme.13075. PMID: 26802434; PMCID: PMC4879510.
[22] Lauschke VM, Ingelman-Sundberg M. Emerging strategies to bridge the gap between pharmacogenomic research and its clinical implementation. NPJ Genom Med. 2020 Mar 5;5:9. doi: 10.1038/s41525-020-0119-2. PMID: 32194983; PMCID: PMC7057970.