Amelioration of endothelial dysfunction by sodium glucose co‐transporter 2 inhibitors: pieces of the puzzle explaining their cardiovascular protection

Sodium glucose co‐transporter 2 inhibitors (SGLT‐2is) improve cardiovascular outcomes in both diabetic and non‐diabetic patients. Preclinical studies suggest that SGLT‐2is directly affect endothelial function in a glucose‐independent manner. The effects of SGLT‐2is include decreased oxidative stress and inflammatory reactions in endothelial cells. Furthermore, SGLT2is restore endothelium‐related vasodilation and regulate angiogenesis. The favourable cardiovascular effects of SGLT‐2is could be mediated via a number of pathways: (1) inhibition of the overactive sodium‐hydrogen exchanger; (2) decreased expression of nicotinamide adenine dinucleotide phosphate oxidases; (3) alleviation of mitochondrial injury; (4) suppression of inflammation‐related signalling pathways (e.g., by affecting NF‐κB); (5) modulation of glycolysis; and (6) recovery of impaired NO bioavailability. This review focuses on the most recent progress and existing gaps in preclinical investigations concerning the direct effects of SGLT‐2is on endothelial dysfunction and the mechanisms underlying such effects.