(A) SGLT2 inhibitors regulate inflammation and glycolysis through SGLT2 receptors. The binding of an SGLT2 inhibitor to the SGLT2 receptor blocks glucose reabsorption from the luminal side of proximal tubular epithelial cells in the kidney, leading to low intracellular glucose, and consequently, less glucose transport across the basolateral side into the blood by GLUT2 (4). Reduced sodium reabsorption at this site also lessens ATPase activity and the conversion of ATP to ADP, which generates energy for solute transport. Further, low intracellular glucose activates AMPK, which phosphorylates regulatory proteins that inhibit mTORC1 signaling (21). Importantly, suppression of mTORC1 may block stimulatory actions to promote expression of inflammatory mediators and glycolysis at this site. (B) SGLT2 inhibitors may also modulate inflammation, intracellular glucose levels, and EPO production through non-receptor-mediated pathways. In a variety of cells from the kidney (e.g., proximal tubular epithelial cells, podocytes, fibroblasts) and the cardiovascular system (e.g., cardiac myocytes, endothelial cells), SGLT2 inhibitors may have off-target effects. SGLT2 inhibitors can putatively bind mTORC1 intracellularly to inhibit expression of inflammatory mediators and/or glycolysis depending on cell type (19). Cardiac myocytes contain GLUT1 and GLUT4 that can be blocked by intracellular interaction with SGLT2 inhibitors and, consequently, lower glucose transfer into the cell along with AMPK activation that may also inhibit mTORC1 (20). Conversely, SGLT2 inhibitors can dock with SIRT1 and increase its activity to oppose expression of inflammatory mediators (22, 23). In kidney medullary interstitial fibroblasts, SIRT1 and hypoxia could activate HIF-2α and thereby increase EPO production (25).