SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits

Abstract

In recent years, following the publication of results from several RCTs, first on cardiovascular and more recently on renal outcomes, SGLT2is have become the standard of care to prevent diabetic kidney disease and slow its progression. This narrative review focuses on biological mechanisms, both renal and extrarenal, underlying kidney protection with SGLT2is. Furthermore, data from cardiovascular as well as renal outcome trials, mostly conducted in diabetic patients, are presented and discussed to provide an overview of current uses as well as the future therapeutic potential of these drugs.

Keywords: SGLT2 inhibitors; kidney disease; kidney protection.

Figure 1

Renal and extrarenal mechanisms of action by SGLT2is. Selective inhibition of SGLT2 in proximal renal tubule prevents glucose reabsorption and entails several potentially favorable effects. Glycosuria concurs to euglycemia, lowers HbA1c, and reduces glucotoxicity, preserving beta cell function. As for extra-glycemic effects, SGLT2is promote diuresis and natriuresis and determine a mild reduction in extracellular fluid, especially interstitial fluid. Effective blood volume and blood pressure reduction ensues. Abbreviations: MoA, mechanisms of action; RAAS, renin angiotensin aldosterone system; SNS, sympathetic nervous system.

Figure 2

SGLT2is and renal protection: from biological mechanisms to clinical benefits. Renal protection by SGLT2 inhibitors is likely multifactorial. In the short term, SGLT2is promote diuresis and natriuresis as well as tubuloglomerular feedback activation, resulting in afferent arteriole vasoconstriction and a reduction in intraglomerular pressure, filtration fraction, and eGFR. Over a longer term, SGLT2is induce a reduction in inflammatory as well as interstitial fibrosis biomarkers together with an increase in hematocrit and mitigation of hypoxia in tubular cells. These changes result in a reduction in blood pressure and urine excretion and GFR preservation over time.

Figure 3

Proposed systemic renal-protective pathways with SGLT2 inhibitors. The potential pathways linking SGLT2is with blood pressure reduction and vascular stiffness improvement involve the intravascular volume depletion via osmotic diuresis due to glycosuria, the lowering of blood glucose (and glucotoxicity), blood serum uric acid levels, and body mass. SGLT2is increase glucose concentrations in the proximal tubules, wherein glucose competes with urates for the transporter GLUT9, reducing urate reabsorption and then increasing renal uric acid excretion as a direct effect. This was speculated to be an indirect effect of SGLT2is on URAT1, as a consequence of the glycemia reduction on insulin amount and other mechanisms not insulin-mediated. It was demonstrated that restoration of the integrity of the endothelial glycocalyx in human cells, possibly resulting in atheroprotective effect and contrasting endothelial dysfunction mediated by oxidative stress and inflammation, leads to a reduction in arterial stiffness. An emerging hypothesis states that sustaining salt storage in the glycocalyx contributes to developing hypertension due to impaired excretory ability of sodium at the kidney level. Furthermore, SGLT2is inhibit NHE in tubular cells, acting as a proximal diuretic; and also inhibit endothelial NHE, leading to decreased intracellular calcium, increasing endothelial NOS and NO levels, allowing vasodilatation. Abbreviations: GLUT, glucose transporter; NHE, Na+/H+ exchanger; NOS, nitrite oxide synthase; NO, nitrite oxide; SGLT2is; sodium-glucose cotransporter 2 inhibitors; URAT, urate transporter.