SGLT2 inhibition to address the unmet needs in diabetic nephropathy

Abstract

Summary Current treatment of diabetic nephropathy is effective; however, substantial gaps in care still remain and new therapies are urgently needed to reduce the global burden of the complication. Desirable properties of an “ideal” new drug should include primary prevention of microalbuminuria, additive/synergistic anti‐proteinuric effect in combination therapy with renin angiotensin system blockers, reduction of chronic kidney disease progression to lower the risk of end‐stage renal disease, and cardiovascular protection. Growing evidence suggests that sodium‐glucose cotransporter 2 inhibitors (SGLT2i) may fulfil many of these criteria and represent novel tools to cover the unmet needs in diabetic nephropathy care. However, the underlying mechanisms of SGLT2i renal benefits are still poorly understood and promising results from cardiovascular outcome trials with SGLT2i need confirmation in dedicated renal outcome trials.

The future of diabetic kidney disease management: what to expect from the experimental studies?

“…The particular efficacy of RAS blockers in the treatment of DKD is due to their ability to reduce not only systemic blood pressure, but also glomerular capillary pressure via vasodilation of the efferent arteriole. Similarly, SGLT2i are believed to slow DKD progression predominantly by reducing glomerular capillary pressure via vasoconstriction of the afferent arteriole [11]. Therefore, RAS blockers and SGLT2i appears to have complementary positive effects on renal hemodynamic.…”

SGLT2 Inhibitors and nephroprotection in diabetic kidney disease: From mechanisms of action to the latest evidence in the literature

“…SGLT2 are low af inity and high capacity glucose co-transporters localized in the lumen of proximal tubular cells, exerting their action speci ically in the S1 segment of the proximal tubule; they conduct glucose and sodium inside the cells and are responsible for the reabsorption of 80% to 90% of the iltered glucose. The remaining 10% to 20% is reabsorbed by SGLT1, high af inity and low capacity glucose co-transporters, expressed in the distal part of the proximal tubule; they exert their action speci ically in the S2 and S3 segments of the proximal tubule [3,5,10,20,21]. The entry of sodium inside the cells through SGLT1 and 2 is driven by a concentration gradient of sodium generated by the sodium-potassium ATPase (Na-K ATPase) pump, located in the basolateral membrane.…”

“…Additionally, the reabsorption of proximal sodium produces a decrease in the availability of sodium in the distal tubules and the decrease in the sodium reaching the macular densa, leading to a reduction in the hydro-lysis of ATP and the production of adenosine. Adenosine is a potent vasoconstrictor, and its reduction, such as in the hyperglycemic state, causes vasodilatation of the afferent arteriole, increasing intra-glomerular pressure and iltration [3,5,20,22]. The previously mentioned changes at the glomerular level produce in lammation and oxidative stress, with an increase in the production of pro in lammatory cytokines and reactive oxygen species (ROS).…”

“…Diabetic kidney disease (DKD) is considered a major microvascular complication as it leads to ends stage kidney disease (ESKD), contributing to increased mortality [1][2][3][4]. Patients with DKD and ESKD can have a mortality risk that is 3 to 12 times higher than patients without these complications [5]. There is evidence suggesting that poor glycemic control can explain the pathogeny of the structural damage of the nephrons that occurs primarily in the mesangium, later on progressing to diffuse damage, capable of progressing to ESKD [6,7].…”

Network Pharmacology Study Reveals the Mechanism of Astragali Radix in Treatment of Diabetic Nephropathy

“…Moreover, the patients with ESRD often need hemodialysis or kidney transplantation to restore the normal kidney function [3]. At present, the therapies for DN mainly focus on controlling the blood pressure and glycemic, and regulating the renin-angiotensin system (RAS) to control the further development of DN [4]. Furthermore, DN is an extremely complicated pathophysiological process, in which multiple biological and pathological processes are involved [5].…”