Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review

Abstract

Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.

The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management

“…By inhibiting SGLT2, SGLT2 inhibitors lower renal reabsorption of filtered glucose and reduce the renal threshold for glucose, thereby increasing urinary glucose excretion [ 19 , 21 – 27 ]. This reduces HbA1c by approximately 0.6–1.0% [ 8 , 28 ]. SGLT2 inhibitors increase sodium delivery to distal tubules through blocking SGLT2-dependent glucose and sodium reabsorption, which is thought to increase tube-ball feedback and decrease intraglomerular pressure.…”

“…SGLT2 inhibitors increase sodium delivery to distal tubules through blocking SGLT2-dependent glucose and sodium reabsorption, which is thought to increase tube-ball feedback and decrease intraglomerular pressure. This may affect a variety of physiological functions, comprising reducing cardiac preload and afterload and downregulating sympathetic nerve activity [ 4 , 19 , 21 – 28 ]. Metabolism is shifted to gluconeogenesis and ketosis, which are thought to have protective effects on the heart and kidneys [ 28 ].…”

“…This may affect a variety of physiological functions, comprising reducing cardiac preload and afterload and downregulating sympathetic nerve activity [ 4 , 19 , 21 – 28 ]. Metabolism is shifted to gluconeogenesis and ketosis, which are thought to have protective effects on the heart and kidneys [ 28 ]. SGLT2 inhibitors can reduce glucotoxicity in renal tubular cells by reducing mitochondrial dysfunction and inflammation, and also reduce renal hypoxia by reducing tubular energy and oxygen demand [ 28 ].…”

“…Metabolism is shifted to gluconeogenesis and ketosis, which are thought to have protective effects on the heart and kidneys [ 28 ]. SGLT2 inhibitors can reduce glucotoxicity in renal tubular cells by reducing mitochondrial dysfunction and inflammation, and also reduce renal hypoxia by reducing tubular energy and oxygen demand [ 28 ].…”

Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis

“…Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of lower blood glucose drugs that increase urinary glucose excretion by inhibiting glucose reabsorption at the proximal tubule in the kidney [ 23 , 24 , 25 ]. Recent studies suggested that SGLT2 inhibitor treatment can reduce hepatic lipid levels and alleviate NAFLD, and has blood glucose-lowering effects [ 26 , 27 ].…”