SGLT-2 inhibitors in diabetes: a focus on renoprotection

Abstract

Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels.Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections.Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term. SGLT-2 INHIBITORS IN DIABETES: A FOCUS ON RENOPROTECTIONREV ASSOC MED BRAS 2020; 66(SUPPL 1):S17-S24 PALAVRAS-CHAVE: Diabetes mellitus. Insuficiência renal crônica. Hipoglicemiantes. Inibidores do transportador 2 de sódio-glicose.

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.…”

“…The exit of sodium through the pump decreases intracellular sodium, leading to entry of tubular sodium inside the cell. After reabsorption, glucose moves passively inside the interstitial space utilizing the glucose transporters GLUT1 and GLUT2, expressed on the basolateral membrane of the proximal tubular cells [3,10] (Figure 1).…”

“…Despite the fact that diabetic kidney disease depends on the interaction of multiple factors and processes, the main pathways implicated in its pathophysiology are: Glomerular hyper iltration (imposed by metabolic alterations that include hyperglycemia and hyperaminoacidemia), in lammatory processes and an increase in oxidative stress [3,8]. These pathophysiological pathways culminate by generating structural and functional alterations, manifested typically with albuminuria, a decrease in the glomerular iltration rate and hypertension [10].…”

“…The latter results in an increase of sodium delivery to the macula densa, leading to a local liberation of adenosine and as a consequence, intracellular calcium, generating vasoconstriction of the afferent arteriole [3,10,20,25]. Eventually, there is a reduction in glomerular hyper iltration and in intraglomerular hypertension, attenuating albuminuria, which are the primary pathophysiological mechanisms of diabetic kidney disease, explaining the bene its beyond reducing serum glucose [10]. It is worth mentioning that the mechanism of SGLT2 inhibitors is different from the ones seen in RAAS blockers, given that these agents also decrease intraglomerular pressure by causing vasodilation of the efferent arteriole [26,27].…”

“…SGLT2 inhibitors are also capable of reducing renal energy requirements, reducing renal hypoxia. Similarly, they pose an anti-in lammatory, antioxidant and anti-ibrotic action, given a reduction in glycogen end products, the expression of pro in lammatory molecules and reactive oxygen species [10,21] (Figure 3). SGLT2 inhibitors have demonstrated anti-in lammatory effects by reducing serum levels of IL-6 and leptin, decreasing C reactive protein (CRP) levels, increasing adiponectin and inhibition the IL-1β secretion by macrophages via the ROS-NLRP3-caspase-1 pathway [25].…”