The renal effects of SGLT2 inhibitors and a mini-review of the literature

Abstract

Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM). The glucosuria-induced caloric loss as well as the osmotic diuresis significantly decrease body weight and blood pressure, respectively. Given that SGLT2 inhibitors do not interfere with insulin action and secretion, their efficacy is sustained despite the progressive β-cell failure in T2DM. They are well tolerated, with a low risk of hypoglycemia. Their most frequent adverse events are minor: genital and urinal tract infections. Recently, it was demonstrated that empagliflozin presents a significant cardioprotective effect. Although the SGLT2 inhibitors' efficacy is affected by renal function, new data have been presented that some SGLT2 inhibitors, even in mild and moderate renal impairment, induce significant HbA1c reduction. Moreover, recent data indicate that SGLT2 inhibition has a beneficial renoprotective effect. The role of this review paper is to explore the current evidence on the renal effects of SGLT2 inhibitors.

Keywords: SGLT transporters; SGLT2 inhibitors; albuminuria; glucosuria; hyperfiltration; renal impairment; renoprotection; tubulointerstitial fibrosis; type 2 diabetes.

Figure 1.

A model for renal glucose reabsorption. The sodium-potassium ATPase pump that is located is at the tubular cells of the S1 and S3 segment of the proximal convoluted tubule is a primary active counter-transporter. Its function is to export sodium to the interstitium and import potassium. ATP-ADP transformation provides the required energy for this function. Therefore, this pump creates the sodium gradient needed for the operation of the secondary active SGLT cotransporter which imports both sodium and glucose from the tubular lumen into tubular cells. Glucose moves against its electrochemical gradient following sodium transportation along its gradient. Intracellular glucose passive diffusion to the interstitium is facilitated by GLUTs which are located at the basolateral membrane of the tubular cells. Concerning SGLTs, SGLT1 is found at the S3 segment and has 2:1 sodium to glucose stoichiometry, whereas SGLT2 is located at the S1 segment and has 1:1 stoichiometry. SGLTs are on the brush border of tubular cells. The pharmacological effect of SGLT2 inhibitors, which block SGLT2 transporters, is also shown. Thus they induce glucosuria. ADP, adenosine diphosphate; ATP, adenosine triphosphate; GLUT, glucose transporter; SGLT, sodium-glucose linked transporter.