Renoprotective Mechanism of Sodium-Glucose Cotransporter 2 Inhibitors: Focusing on Renal Hemodynamics

Abstract

Diabetic kidney disease (DKD) is a prevalent renal complication of diabetes mellitus that ultimately develops into end-stage kidney disease (ESKD) when not managed appropriately. Substantial risk of ESKD remains even with intensive management of hyperglycemia and risk factors of DKD and timely use of renin-angiotensin-aldosterone inhibitors. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce hyperglycemia primarily by inhibiting glucose and sodium reabsorption in the renal proximal tubule. Currently, their effects expand to prevent or delay cardiovascular and renal adverse events, even in those without diabetes. In dedicated renal outcome trials, SGLT2 inhibitors significantly reduced the risk of composite renal adverse events, including the development of ESKD or renal replacement therapy, which led to the positioning of SGLT2 inhibitors as the mainstay of chronic kidney disease management. Multiple mechanisms of action of SGLT2 inhibitors, including hemodynamic, metabolic, and anti-inflammatory effects, have been proposed. Restoration of tubuloglomerular feedback is a plausible explanation for the alteration in renal hemodynamics induced by SGLT2 inhibition and for the associated renal benefit. This review discusses the clinical rationale and mechanism related to the protection SGLT2 inhibitors exert on the kidney, focusing on renal hemodynamic effects.

Keywords: Diabetes mellitus; Hemodynamics; Renal insufficiency; Sodium-glucose transporter 2 inhibitors.

Fig. 1

Hemodynamic changes following sodium-glucose cotransporter 2 (SGLT2) inhibition in the kidney. ① SGLT2 is responsible for 80% to 90% glucose reabsorption in the early proximal tubule, and SGLT1 reabsorbs the remaining 10% of the filtered glucose under physiologic conditions. ② Under hyperglycemic condition, glucose filtration is increased, which leading to increased sodium and glucose reabsorption via SGLT2 upregulation. SGLT2 inhibitor primarily blocks the action of SGLT2, ③ resulting in increased delivery of sodium and glucose to the distal renal tubule. ④ In type 1 diabetes mellitus or hyperfiltration state, increased sodium delivery to the tubular epithelial cells of the macular densa induces adenosine production which activates adenosine A1 receptor, triggering an increase in cytosolic Ca²⁺. ⑤ Restoration of tubuloglomerular feedback ultimately results in afferent arteriolar vasoconstriction. ⑥ In type 2 diabetes mellitus on renin-angiotensin-aldosterone system (RAAS) blockade, SGLT2 inhibition may act on renal arterioles in a different way. SGLT2 inhibitors increased production of adenosine and prostaglandin ⑦ which resulting in efferent vasodilation on RAAS blockade.