Kidney-Protective Effects of SGLT2 Inhibitors

The sodium-glucose cotransporter 2 (SGLT2) inhibitors have become an integral part of clinical practice guidelines to slow the progression of CKD in patients with and without diabetes mellitus. Although initially developed as antihyperglycemic drugs, their effect on the kidney is multifactorial resulting from profuse glycosuria and natriuresis consequent to their primary site of action. Hemodynamic and metabolic changes ensue that mediate kidney-protective effects, including (1) decreased workload of proximal tubular cells and prevention of aberrant increases in glycolysis, contributing to a decreased risk of AKI; (2) lowering of intraglomerular pressure by activating tubular glomerular feedback and reductions in BP and tissue sodium content; (3) initiation of nutrient-sensing pathways reminiscent of starvation activating ketogenesis, increased autophagy, and restoration of carbon flow through the mitochondria without production of reactive oxygen species; (4) body weight loss without a reduction in basal metabolic rate due to increases in nonshivering thermogenesis; and (5) favorable changes in quantity and characteristics of perirenal fat leading to decreased release of adipokines, which adversely affect the glomerular capillary and signal increased sympathetic outflow. Additionally, these drugs stimulate phosphate and magnesium reabsorption and increase uric acid excretion. Familiarity with kidney-specific mechanisms of action, potential changes in kidney function, and/ or alterations in electrolytes and volume status, which are induced by these widely prescribed drugs, will facilitate usage in the patients for whom they are indicated.