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.

Beyond the Glycaemic Control of Dapagliflozin: Microangiopathy and Non-classical Complications

“…This decrease in BP associated with dapagliflozin appears to be largely explained by intravascular volume depletion, due to its diuretic and natriuretic properties [ 1 ]. However, a direct vasodilatory effect on the efferent arteriole, modulation of the renin–angiotensin–aldosterone system and the sympathetic nervous system, as well as increased urinary excretion of uric acid have also been suggested [ 4 , 20 ]. Importantly, the decrease in BP is independent of the estimated glomerular filtration rate [ 21 ].…”

“…Patients with T2DM have a high residual risk of developing renal complications despite intensive glycaemic control, the use of renin–angiotensin–aldosterone system inhibitors, and BP and lipid control [ 4 , 33 ]. However, the emergence of SGLT2i has led to the discovery of new mechanisms of nephroprotection, both renal and extrarenal [ 4 , 19 ] (Fig. 1 ).…”

“…This process activates tubuloglomerular feedback, which ultimately leads to correction of vasodilation of the afferent arteriole and, as a consequence, to a decrease in intraglomerular pressure and diabetes-related hyperfiltration . In addition, sodium chloride delivery to the distal nephron reduces the GFR by increasing the hydrostatic pressure in Bowman's space [ 4 , 19 ]. Furthermore, the use of SGLT2i is associated with a reduction in biomarkers of inflammation and fibrosis in tubular cells and a reduction in their oxygen demand, enhancing the protective effect on tubular cells.…”

“…Furthermore, dapagliflozin has been associated with both cardiovascular (CV) and renal benefits along with a good safety profile, including a low risk of hypoglycaemia [ 1 ]. Its use may also be beneficial in the prevention of microvascular complications such as renal disease or retinopathy in patients with T2DM [ 4 – 10 ].…”

Diabetes mellitus in dialysis and renal transplantation

“…These include improving glycaemia, promotion of diuresis and natriuresis, blood pressure reduction and modulation of the sympathetic nervous and rennin–angiotensin–aldosterone systems. 122 …”