Metformin is a synthetic biguanide (two coupled molecules of guanidine) that is mainly absorbed in the upper small intestine and exhibits flip–flop pharmacokinetics with limited oral bioavailability 19, 20. However, reassuring data were provided in a long-term follow-up study showing similar anthropometrics in children exposed or not to metformin in utero 18. While in utero exposure to metformin was considered safe, some studies have found higher occurrence of small for gestational age birthweight and increased risk of childhood obesity 17. As metformin crosses the placenta and circulates in the developing fetus, the long-term effects of fetal exposure to metformin have raised concerns about the potential risk to growth and development of the fetus, and later, on offspring health 16. It is important to note that metformin is increasingly being used during pregnancy for the management of gestational diabetes mellitus and in those with polycystic ovary syndrome or T2DM 15. Administered orally as an immediate-release or extended-release formulation, the usual dose of metformin (0.5–2.5 g daily) is effective for long-term glycaemic control, with notable changes in HbA 1c from baseline 1, 2. Metformin is now used daily by >200 million patients with T2DM worldwide as monotherapy or in combination with sulfonylureas or dipeptidyl peptidase 4 inhibitors 1, 2. In addition, metformin moderately reduces body weight gain, possibly through upregulation of the anorectic cytokine growth differentiation factor 15 (refs. The benefits of metformin therapy in T2DM have been well documented it has long-term safety and efficacy data, low risk of hypoglycaemia, cardiovascular benefits, mortality benefits, additive or synergistic effects in combination therapy, low cost and wide availability 1, 2, 10, 11, 12. In 1957, the French physician Jean Sterne introduced the clinical use of metformin for the treatment of adult-onset diabetes mellitus 3, 4. ![]() Interestingly, in the past few years, the use of metformin has been explored for the management of patients with T2DM and obesity who contract influenza 6 or COVID-19 (refs. In 1949, metformin (called flumamine at that time) was used for the treatment of an epidemic influenza outbreak in the Philippines and was noted to lower blood levels of glucose in some of the patients with influenza 5. Metformin was first synthesized in 1922, and the first report of it being used to lower blood levels of glucose (in rabbits) was published in 1929 (refs. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.įor the past 60 years, metformin (1,1-dimethylbiguanide hydrochloride) has been the most commonly used glucose-lowering agent and has become the first-line medication for individuals newly diagnosed with type 2 diabetes mellitus (T2DM) in many clinical guidelines 1, 2. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. ![]() Initial studies have shown that metformin targets hepatic mitochondria however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients.
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