Mechanisms of renoprotective action of sodium-glucose cotransporter-2 inhibitors (gliflozins): a clinician’s view

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a group of drugs that block the enzyme responsible for the reabsorption of glucose and sodium in the proximal part of the nephron. They appeared in clinical practice about a decade ago for the treatment of type 2 diabetes mellitus, but the first clinical studies showed the potential of these agents in preventing cardiovascular and renal events. Among the main mechanisms of the renoprotective effect of SGLT2i, the following are distinguished now: 1)reduction of hyperfiltration/pressure in the glomerulus (narrowing of the afferent and dilation of the efferent arterioles); 2) metabolic shift towards the use of free fatty acids for obtaining energy (increasing energy efficiency and reducing lipotoxic damage to cells); 3) antihypoxic effect (direct— due to a decrease in oxygen needs and indirect— due to an increase in hemoglobin); 4) reduction of pressure and fluid overload; 5) anti-inflammatory and antifibrotic effects; 6)other effects (decrease in glycaemia, body weight, uric acid level, etc.). Presumably, SGLT2i administration causes a universal cellular reaction (autophagic flux), which leads to improved energy efficiency, reduces cellular stress and increases the resistance of cells to overload. The significance of various mechanisms in the formation of the overall effect differs depending on the main cause of kidney damage, concomitant pathology, metabolic characteristics of the patient, degree of kidney ischemia, etc. It is different not only in each individual patient, but, probably, in the same patient at different stages of the disease. However, the implementation of these mechanisms allows preventing the development/progression of kidney failure and prolonging the life of patients.