Metformin: update on mechanisms of action and repurposing potential

This Review highlights the latest advances in our understanding of the mechanisms of action of metformin. Potential repurposing of metformin for other indications is also discussed. 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. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. 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. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. 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. 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. 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.

Automated summary

This Review presents the latest advances in understanding the mechanisms of action of metformin and discusses its potential repurposing for other indications. Metformin is currently the first-line medication for treating type 2 diabetes in most guidelines and is widely used by over 200 million patients. Its therapeutic action involves complex mechanisms that are not fully understood. Although the liver was initially identified as the main organ involved, increasing evidence suggests the involvement of other sites, including the gastrointestinal tract, gut microbial communities, and tissue-resident immune cells. The molecular mechanisms of metformin vary depending on the dose and duration of treatment, and recent studies have revealed a novel action on the lysosome surface at low concentrations. Considering its efficacy and safety in diabetes, attention has been given to using metformin as adjunct therapy for cancer, age-related diseases, inflammatory diseases, and COVID-19.