Pleiotropic effects of SGLT2 inhibitors: A focus on macrophage-mediated action

SGLT2 inhibitors, initially developed for type 2 diabetes management, have primarily demonstrated pleiotropic benefits in cardiovascular, renal, pulmonary, digestive and endocrine/metabolic, et al. Emerging evidence highlights their immunomodulatory effects on macrophages, key players in disease pathogenesis. This review summarizes the mechanisms by which dapagliflozin, empagliflozin, and canagliflozin regulate macrophage polarization, metabolic reprogramming, and inflammatory responses. These drugs suppress pro-inflammatory M1 macrophage activation, promote anti-inflammatory M2 phenotypes, and reduce the release of cytokines (e.g., IL-1β, IL-6,TNF-α) through pathways such as NF-κB, AMPK/mTOR, and JAK/STAT. In cardiovascular diseases, they attenuate atherosclerosis (AS) and myocardial fibrosis by limiting macrophage infiltration and foam cell formation. Renal protection is mediated via reduced macrophage-driven inflammation and fibrosis in diabetic and non-diabetic kidney injury. Additionally, their anti-inflammatory effects extend toothers like non-alcoholic fatty liver disease and inflammatory bowel disease. Collectively, SGLT2 inhibitors exhibit multi-organ protective potential through macrophage modulation, positioning them as promising immunomodulatory agents beyond glucose-lowering therapy.