More than Glucose Elimination: Additional Benefits of SGLT2 Inhibitors in Glomerular Diseases

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have consistent nephroprotective effects across diverse patient populations, including those with glomerular disease without diabetes mellitus. These somehow unexpected benefits cannot be solely explained by glycosuria and intrarenal hemodynamic effects. Experimental evidence largely supports the effects of SGLT2 inhibitors on several pathways, many of them outside the kidneys. This review explores the mechanisms underlying these benefits, focusing on those of importance in primary and secondary glomerulonephritis. In addition to glucose homeostasis, SGLT2 inhibitors exert local and systemic effects that mimic nutrient deprivation, impacting inflammation, immunity, autophagy, hypoxia responses, ferroptosis, lipotoxicity, and energy metabolism. Sodium-glucose cotransporter 2 inhibitors modulate inflammatory pathways through suppression of cytokines and NLR family pyrin domain containing 3 inflammasome activity, mechanisms relevant to immunoglobulin A glomerulonephritis, lupus nephritis, and anti-neutrophil cytoplasmic antibody-associated vasculitis. They also influence immune cell metabolism, inhibit T-cell activation, and potentially modulate B-cell and macrophage polarization. There is evidence that autophagy may show a dual role in glomerular disease. It could activate innate and adaptive immunity, so triggering the disease, or may protect podocytes, so reducing proteinuria and the risk of progression. Sodium-glucose cotransporter 2 inhibition also modulates the hypoxia inducible factor axis and reduces ferroptosis, possibly contributing to attenuate hypoxia-induced kidney damage. The upregulation of ketogenesis and activation of nutrient-sensing pathways (adenosine monophosphate-activated protein kinase-activated protein kinase, sirtuins, and mammalian target of rapamycin) further supports their role in metabolic reprogramming. Finally, they contribute to preserve gerosuppressor functions by increasing kidney Klotho, a protein with anti-aging, and-inflammatory, and antifibrotic effects, and liver betaine. Although direct clinical evidence on the specific molecular pathways targeted by SGLT2 inhibitors in glomerulonephritis remains limited, preclinical data and emerging human observations suggest SGLT2 inhibitors may offer therapeutic advantages beyond non-specific kidney-cardiovascular protection.