SGLT2 inhibitors - proposed mechanism for renal protection

Last edited 05/2021 and last reviewed 11/2022

• evidence is emerging about the added value of sodium-glucose cotransporter 2 (SGLT2) inhibitors, beyond their glucose-lowering effect, when they are used to treat patients with or without diabetes who have proteinuria and declining kidney function
  
  
• various mechanisms have been proposed to explain the renoprotective effect of SGLT2 inhibitors
  • including a reduction in pressure within the glomerular capillaries, with resulting protection of glomerular podocytes, which are the targets of injury in most, if not all, proteinuric kidney diseases

• preventing angiotensin II-mediated constriction of the efferent arteriole by blockade of the renin-angiotensin system is the cornerstone of antiproteinuric therapy to limit progressive podocyte injury and loss in diabetic and nondiabetic kidney disease
  
  
• as well as due to constriction of the efferent arteriorole, hyperfiltration also occurs through loss of regulation of the afferent arteriole
  • thought that the beneficial effects in renal disease of SGLT2 inhibitors is thought to be primarily mediated through constriction of the afferent arteriole and prevention of hyperfiltration (1)
    • SGLT2 inhibition reduces reabsorption of glucose and sodium within the proximal tubule, which reestablishes sodium delivery to the macula densa and leads to a correction of hyperfiltration through tubuloglomerular feedback and afferent vasoconstriction
    • dysfunctional podocytes cannot sufficiently counteract elevated glomerular capillary pressure, suggesting that SGLT2-mediated afferent arteriole vasoconstriction may be beneficial
    • effect of SGLT2 inhibitors appears to be consistent across all levels of kidney function, down to an estimated GFR of 30 ml per minute per 1.73 m2 of body-surface area, whereas glucose-lowering effects are directly proportional to glomerular filtration and are substantially decreased when kidney function declines, underscoring the importance of regulating glomerular hemodynamics in progressive renal disease

Reference:

1. Benzing C, Salant T. Insights into Glomerular Filtration and Albuminuria. N Engl J Med 2021;384:1437-46 DOI: 10.1056/NEJMra1808786