Metformin is a commonly prescribed drug used to treat type 2 diabetes. The drug works by decreasing the amount of glucose the liver produces, increasing the sensitivity of muscle cells to insulin, and delaying the absorption of glucose in the intestines. Approximately 50% - 55% of metformin is absorbed in the small intestines. Most of the drug is excreted in the urine, so a patient with renal impairment may need a lower dose of the drug. Common side effects include nausea, vomiting, and diarrhea. Metformin may increase the risk of vitamin B12 deficiency. A rare but serious complication of metformin treatment is lactic acidosis, which is characterized by a blood pH of less than 7.35 and a plasma lactate concentration of greater than 5.0 mmol/L. The risk of lactic acidosis increases with the dose of metformin. The current recommended maximum dose of metformin is 2.0 g per day.
References
[1]
Tokhirovna, E.G. (2024) The Role of Metformin (Gliformin) in the Treatment of Patients with Type 2 Diabetes Mellitus. European Journal of Modern Medicine and Practice, 4, 171-177.
[2]
Liang, D., Liu, L., Qi, Y., Nan, F., Huang, J., Tang, S., et al. (2024) Jin-gui-shen-qi Wan Alleviates Fibrosis in Mouse Diabetic Nephropathy via MHC Class II. Journal of Ethnopharmacology, 324, Article 117745. https://doi.org/10.1016/j.jep.2024.117745
[3]
Thomas, I. and Gregg, B. (2017) Metformin; a Review of Its History and Future: From Lilac to Longevity. Pediatric Diabetes, 18, 10-16. https://doi.org/10.1111/pedi.12473
[4]
Pawlyk, A.C., Giacomini, K.M., McKeon, C., Shuldiner, A.R. and Florez, J.C. (2014) Metformin Pharmacogenomics: Current Status and Future Directions. Diabetes, 63, 2590-2599. https://doi.org/10.2337/db13-1367
[5]
Marathe,, P.H., Wen, Y., Norton, J., Greene, D.S., Barbhaiya, R.H. and Wilding, I.R. (2000) Effect of Altered Gastric Emptying and Gastrointestinal Motility on Metformin Absorption. British Journal of Clinical Pharmacology, 50, 325-332. https://doi.org/10.1046/j.1365-2125.2000.00264.x
[6]
Graham, G.G., Punt, J., Arora, M., Day, R.O., Doogue, M.P., Duong, J.K., et al. (2011) Clinical Pharmacokinetics of Metformin. Clinical Pharmacokinetics, 50, 81-98. https://doi.org/10.2165/11534750-000000000-00000
[7]
Jabbour, S. and Ziring, B. (2011) Advantages of Extended-Release Metformin in Patients with Type 2 Diabetes Mellitus. Postgraduate Medicine, 123, 15-23. https://doi.org/10.3810/pgm.2011.01.2241
[8]
Cheng, M., Ren, L., Jia, X., Wang, J. and Cong, B. (2024) Understanding the Action Mechanisms of Metformin in the Gastrointestinal Tract. Frontiers in Pharmacology, 15, Article 1347047. https://doi.org/10.3389/fphar.2024.1347047
[9]
Corleto, K.A., Strandmo, J.L. and Giles, E.D. (2024) Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies. Pharmaceuticals, 17, Article 396. https://doi.org/10.3390/ph17030396
[10]
Zake, D.M., Kurlovics, J., Zaharenko, L., Komasilovs, V., Klovins, J. and Stalidzans, E. (2021) Physiologically Based Metformin Pharmacokinetics Model of Mice and Scale-Up to Humans for the Estimation of Concentrations in Various Tissues. PLOS ONE, 16, e0249594. https://doi.org/10.1371/journal.pone.0249594
[11]
Gong, L., Goswami, S., Giacomini, K.M., Altman, R.B. and Klein, T.E. (2012) Metformin Pathways. Pharmacogenetics and Genomics, 22, 820-827. https://doi.org/10.1097/fpc.0b013e3283559b22
[12]
He, L. (2020) Metformin and Systemic Metabolism. Trends in Pharmacological Sciences, 41, 868-881. https://doi.org/10.1016/j.tips.2020.09.001
[13]
Ningrum, V.D.A., Sadewa, A.H., Ikawati, Z., Yuliwulandari, R., Ikhsan, M.R. and Fajriyah, R. (2022) The Influence of Metformin Transporter Gene SLC22A1 and SLC47A1 Variants on Steady-State Pharmacokinetics and Glycemic Response. PLOS ONE, 17, e0271410. https://doi.org/10.1371/journal.pone.0271410
[14]
Tucker, G., Casey, C., Phillips, P., Connor, H., Ward, J. and Woods, H. (1981) Metformin Kinetics in Healthy Subjects and in Patients with Diabetes Mellitus. British Journal of Clinical Pharmacology, 12, 235-246. https://doi.org/10.1111/j.1365-2125.1981.tb01206.x
[15]
Jeong, Y. and Jusko, W.J. (2021) Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species. Pharmaceuticals, 14, Article 545. https://doi.org/10.3390/ph14060545
[16]
Heeren, L., Verelst, S., Desruelles, D. and Sabbe, M. (2024) Metformin-associated Lactic Acidosis: Which Elimination Therapy to Use in Case of Haemodynamic Instability? A Retrospective Cohort Study. Emergency Care and Medicine, 1, 87-94. https://doi.org/10.3390/ecm1020012
[17]
Nasri, H. and Rafieian-Kopaei, M. (2014) Metformin: Current Knowledge. Journal of Research in Medical Sciences: The Official Journal of Isfahan University of Medical Sciences, 19, Article 658.
[18]
Bu, Y., Peng, M., Tang, X., Xu, X., Wu, Y., Chen, A.F., et al. (2022) Protective Effects of Metformin in Various Cardiovascular Diseases: Clinical Evidence and AMPK-dependent Mechanisms. Journal of Cellular and Molecular Medicine, 26, 4886-4903. https://doi.org/10.1111/jcmm.17519
[19]
McCreight, L.J., Bailey, C.J. and Pearson, E.R. (2016) Metformin and the Gastrointestinal Tract. Diabetologia, 59, 426-435. https://doi.org/10.1007/s00125-015-3844-9
[20]
Forslund, K., Hildebrand, F., Nielsen, T., Falony, G., Le Chatelier, E., Sunagawa, S., et al. (2015) Disentangling Type 2 Diabetes and Metformin Treatment Signatures in the Human Gut Microbiota. Nature, 528, 262-266. https://doi.org/10.1038/nature15766
[21]
Fatima, M., Sadeeqa, S. and Rashid Nazir, S.U. (2018) Metformin and Its Gastrointestinal Problems: A Review. Biomedical Research, 29, 2285-2289. https://doi.org/10.4066/biomedicalresearch.40-18-526
[22]
Kelly, C.J., Verdegaal, A.A., Anderson, B.W., Shaw, W.L., Bencivenga-Barry, N.A., Folta-Stogniew, E., et al. (2023) Metformin Inhibits Digestive Proteases and Impairs Protein Digestion in Mice. Journal of Biological Chemistry, 299, Article 105363. https://doi.org/10.1016/j.jbc.2023.105363
[23]
Inzucchi, S.E., Lipska, K.J., Mayo, H., Bailey, C.J. and McGuire, D.K. (2014) Metformin in Patients with Type 2 Diabetes and Kidney Disease. Journal of the American Medical Association, 312, 2668-2675. https://doi.org/10.1001/jama.2014.15298
[24]
Dawed, A.Y., Zhou, K., van Leeuwen, N., Mahajan, A., Robertson, N., Koivula, R., et al. (2019) Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by SLC29A4) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI Direct Study. Diabetes Care, 42, 1027-1033. https://doi.org/10.2337/dc18-2182
[25]
Nakrani, M.N., Wineland, R.H. and Anjum, F. (2020) Physiology, Glucose Metabolism. StatPearls Publishing.
[26]
Nawaz, A., Zhang, P., Li, E., Gilbert, R.G. and Sullivan, M.A. (2021) The Importance of Glycogen Molecular Structure for Blood Glucose Control. iScience, 24, Article 101953. https://doi.org/10.1016/j.isci.2020.101953
[27]
American Diabetes Association (2010) Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 33, S62-S69. https://doi.org/10.2337/dc10-s062
[28]
Rahman, M.S., Hossain, K.S., Das, S., Kundu, S., Adegoke, E.O., Rahman, M.A., et al. (2021) Role of Insulin in Health and Disease: An Update. International Journal of Molecular Sciences, 22, 6403. https://doi.org/10.3390/ijms22126403
[29]
Sansome, D.J., Xie, C., Veedfald, S., Horowitz, M., Rayner, C.K. and Wu, T. (2019) Mechanism of Glucose-Lowering by Metformin in Type 2 Diabetes: Role of Bile Acids. Diabetes, Obesity and Metabolism, 22, 141-148. https://doi.org/10.1111/dom.13869
[30]
Hostalek, U., Gwilt, M. and Hildemann, S. (2015) Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention. Drugs, 75, 1071-1094. https://doi.org/10.1007/s40265-015-0416-8
[31]
Duong, J.K., Kroonen, M.Y.A.M., Kumar, S.S., Heerspink, H.L., Kirkpatrick, C.M., Graham, G.G., et al. (2017) A Dosing Algorithm for Metformin Based on the Relationships between Exposure and Renal Clearance of Metformin in Patients with Varying Degrees of Kidney Function. European Journal of Clinical Pharmacology, 73, 981-990. https://doi.org/10.1007/s00228-017-2251-1
[32]
Barnett Collins, J.D. (2022) The Effect of Oleic Acid on Metformin Transport and Toxicity in a Caco-2 Cell Model. Doctoral Dissertation, Research Space@Auckland.
[33]
Sugandh, F., Chandio, M., Raveena, F., Kumar, L., Karishma, F., Khuwaja, S., et al. (2023) Advances in the Management of Diabetes Mellitus: A Focus on Personalized Medicine. Cureus, 15, e43697. https://doi.org/10.7759/cureus.43697
[34]
Tarry-Adkins, J.L., Grant, I.D., Ozanne, S.E., Reynolds, R.M. and Aiken, C.E. (2021) Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis. Diabetes Therapy, 12, 1901-1914. https://doi.org/10.1007/s13300-021-01058-2
[35]
De Broe, M.E. and Jouret, F. (2020) Does Metformin Do More Benefit or Harm in Chronic Kidney Disease Patients? Kidney International, 98, 1098-1101. https://doi.org/10.1016/j.kint.2020.04.059
[36]
Rena, G., Hardie, D.G. and Pearson, E.R. (2017) The Mechanisms of Action of Metformin. Diabetologia, 60, 1577-1585. https://doi.org/10.1007/s00125-017-4342-z
[37]
Ting, R.Z. (2006) Risk Factors of Vitamin B12 Deficiency in Patients Receiving Metformin. Archives of Internal Medicine, 166, 1975. https://doi.org/10.1001/archinte.166.18.1975
[38]
DeFronzo, R., Fleming, G.A., Chen, K. and Bicsak, T.A. (2016) Metformin-associated Lactic Acidosis: Current Perspectives on Causes and Risk. Metabolism, 65, 20-29. https://doi.org/10.1016/j.metabol.2015.10.014
[39]
Sundelin, E., Jensen, J.B., Jakobsen, S., Gormsen, L.C. and Jessen, N. (2020) Metformin Biodistribution: A Key to Mechanisms of Action? The Journal of Clinical Endocrinology & Metabolism, 105, 3374-3383. https://doi.org/10.1210/clinem/dgaa332
[40]
Sachar, M., Kumar, V., Gormsen, L.C., Munk, O.L. and Unadkat, J.D. (2020) Successful Prediction of Positron Emission Tomography–Imaged Metformin Hepatic Uptake Clearance in Humans Using the Quantitative Proteomics–informed Relative Expression Factor Approach. Drug Metabolism and Disposition, 48, 1210-1216. https://doi.org/10.1124/dmd.120.000156
[41]
Alemón-Medina, R., Altamirano-Bustamante, N., Lugo-Goytia, G., García-Álvarez, R., Rivera-Espinosa, L., Torres-Espíndola, L.M., et al. (2021) Comparative Bioavailability and Pharmacokinetics between the Solid Form of Metformin vs a Novel Liquid Extemporaneous Formulation in Children. Dose-Response, 19, Article 155932582110331. https://doi.org/10.1177/15593258211033140
[42]
Hasanein, A.I. (2022) Therapeutic Drug Monitoring of (Metformin and Glimepiride) on Diabetic Patients’ Plasma by Using LC/MS/MS in Relation with Their Genetic Polymorphism. Master’s Thesis, University of Petra.
[43]
Sheleme, T. (2021) Clinical Pharmacokinetics of Metformin. In: Metformin—Pharmacology and Drug Interactions, IntechOpen. https://doi.org/10.5772/intechopen.99343
