SGLT2 inhibitors: anti-diabetic drug discovery based on transporter inhibition

Abstract

SGLT2 inhibitors exert their anti-diabetic actions by inhibiting renal glucose reabsorption and increasing glucose excretion into urine. They selectively inhibit Na⁺/glucose cotransporter SGLT2 in proximal convoluted tubules in kidney. The drugs have been developed by modifying phlorizin, a natural O-glycoside, to obtain C-glycosides with high metabolic stability, and high affinity and selectivity to SGLT2. They are filtered by glomerulus in kidney to be excreted into glomerular filtrate and bind to SGLT2 on the apical membrane of renal tubules to inhibit it. SGLT2 inhibitors reduce glucotoxicity by lowering blood sugar of diabetic patients to improve the diabetic symptoms and disease state. The decrease of cardiovascular death and their renal protective effects have been reported and proved by large scale clinical studies, promising the significant contribution of SGLT2 inhibitors in the treatment of patients with diabetes mellitus.