Metformin and the Risk of Infection: From Epidemiology to Immunology

Metformin is the first-line pharmacologic therapy for type 2 diabetes mellitus (T2DM). Beyond its glucose-lowering effects, emerging evidence suggests that metformin may confer protection against infections through immunomodulatory and anti-inflammatory mechanisms. This chapter summarizes current evidence on the association between metformin use and infection risk, explores underlying biological mechanisms, and identifies gaps for future research. In vitro experimental studies demonstrate that metformin activates AMP-activated protein kinase (AMPK), enhances mitochondrial homeostasis, and reduces oxidative stress and pro-inflammatory cytokine production, leading to improved immune regulation. Observational studies consistently report reduced risks of respiratory infections, sepsis, and all-cause mortality among metformin users compared with other antidiabetic agents. During the COVID-19 pandemic, metformin use was associated with lower hospitalization and mortality in patients with T2DM. However, heterogeneity across studies and residual confounding limit causal inference. To date, evidence from randomized controlled trials investigating the benefits of metformin on risk of infection is limited, with high-quality trial data pertaining solely to COVID-19. In conclusion, metformin may exert pleiotropic benefits beyond glycemic control by modulating inflammatory and immune pathways, potentially reducing infection susceptibility and severity. While current evidence is encouraging, randomized controlled trials and mechanistic studies are needed to confirm causality and clarify optimal therapeutic contexts. Metformin thus represents a promising candidate for repurposing as an adjunctive therapy in infection prevention and management among patients with diabetes and potentially broader populations.