Sodium-Glucose Co-transporter-2 Inhibitors and Nephroprotection in Diabetic Patients: More Than a Challenge

Abstract

Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a novel class of oral hypoglycemic agents that increase urinary glucose excretion by suppressing glucose reabsorption at the renal proximal tubule. SGLT2is lower glycated hemoglobin (HbA1c) without increasing the risk of hypoglycemia, induce weight loss and improve various metabolic parameters including BP, lipid profile, albuminuria and uric acid. Several clinical trials have shown that SGLT2is (empagliflozin, dapagliflozin canagliflozin, and ertugliflozin) improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes. Effects of SGLT2is on the kidney can be explained by multiple pathways. SGLT2is may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT2is are associated with a reduction in glomerular hyperfiltration, an effect which is mediated by the increase in natriuresis, the re-activation of tubule-glomerular feedback and independent of glycemic control. In this review, we will focus on renal results of major cardiovascular and renal outcome trials and we will describe direct and indirect mechanisms through which SGLT2is confer renal protection.

Keywords: CKD; SGLT2i; cardiovascular risk; clinical trials; renal risk; review; type 2 diabetes.

Figure 1

Molecular and pharmacokinetics characteristics of the principal SGLT2 inhibitors. Phlorizin was the first SGLT2 inhibitor discovered. Later, several gliflozins have been developed, keeping the active center of phlorizin and implementing structural changes in order to achieve a better bioavailability, selectivity for SGLT2 and decrease their side effects. Only four molecules have received Food and Drug Administration approval for the treatment of type 2 diabetes namely dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin.

Figure 2

Central role of the kidney in glucose metabolism. The kidneys intervene in glucose homeostasis regulation through three main mechanisms: the glucose reabsorption via sodium co-transporters (SGLTs), the gluconeogenesis with endogenous glucose production and the utilization of glucose. The right side of the figure shows the mechanism of sodium and glucose reabsorption through the SGLT and GLUT transporters in the kidney. SGLTs, which are mainly located on the brush border (luminal side) of epithelial tubular cells, enables the transfer of both sodium and glucose from the lumen into the tubular cells. Sodium is transported along with glucose through the SGLTs. Next, glucose enters blood circulation through an active transport mechanism mediated by GLUTs, which are located on the basolateral membrane of the epithelial tubular cells. Sodium is actively exchanged between tubular cells and blood circulation through a Na+/K+/ATPase pump. The different phases of renal gluconeogenesis and glycolysis are depicted on the left side of the figure.