Repurposing Metformin for Vascular Disease

Metformin has been used as an oral anti-hyperglycaemic drug since the late 1950s; however, following the release in 1998 of the findings of the 20-year United Kingdom Prospective Diabetes Study (UKPDS), metformin use rapidly increased and today is the first-choice anti-hyperglycaemic drug for patients with type 2 diabetes (T2D). Metformin is in daily use by an estimated 150 million people worldwide. Historically, the benefits of metformin as an anti-diabetic and cardiovascular-protective drug have been linked to effects in the liver, where it acts to inhibit gluconeogenesis and lipogenesis, as well as reduce insulin resistance and enhance peripheral glucose utilization. However, direct protective effects on the endothelium and effects in the gut prior to metformin absorption are now recognized as important. In the gut, metformin modulates the glucagon-like peptide-1 (GLP-1) - gut-brain axis and impacts the intestinal microbiota. As the apparent number of putative tissue and cellular targets for metformin has increased, so has the interest in re-purposing metformin to treat other diseases that include polycystic ovary syndrome (PCOS), cancer, neurodegenerative diseases, and COVID-19. Metformin is also being investigated as an anti-ageing drug. Of particular interest is whether metformin provides the same level of vascular protection in individuals other than those with T2D, including obese individuals with metabolic syndrome, or in the setting of vascular thromboinflammation caused by SARS-CoV-2. In this review, we critically evaluate the literature to highlight clinical settings in which metformin might be therapeutically repurposed for the prevention and treatment of vascular disease.

Automated summary

Metformin, originally used as an oral anti-hyperglycaemic drug, has become the first-choice treatment for type 2 diabetes (T2D) following the release of the UKPDS findings in 1998. It is estimated that around 150 million people worldwide use metformin daily. In addition to its well-known effects in the liver, metformin is now recognized for its direct protective effects on the endothelium and its impact on the gut, including modulation of the gut-brain axis and effects on the intestinal microbiota. The expanding list of potential targets for metformin has led to interest in its repurposing for the treatment of other diseases, including polycystic ovary syndrome (PCOS), cancer, neurodegenerative diseases, and COVID-19.