Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors effectively slow chronic kidney disease (CKD) progression and reduce cardiovascular events. However, their efficacy across all CKD subgroups remains uncertain. Major clinical trials primarily included overweight or obese patients with advanced CKD, where sodium retention, volume expansion and glomerular hyperfiltration are key disease drivers. In contrast, many underrepresented CKD subgroups, such as Alport syndrome or most immune-mediated glomerular disorders, often affect lean individuals whose CKD progression is not linked to these mechanisms. Emerging evidence suggests that the renal benefits of SGLT2 inhibitors may depend on body mass index (BMI), with greater effects observed in patients with higher BMI, while those with BMI <25 may show minimal/no benefit. This raises concerns about their applicability in lean, non-diabetic CKD patients, whose disease progression may involve alternative pathways, such as inflammation, autoimmunity or genetic abnormalities. Animal studies further suggest that SGLT2 inhibitors provide limited renal protection in certain genetic and immune-mediated kidney diseases. Additionally, molecular data indicate that SGLT2 expression is predominantly restricted to the proximal tubule, implying a limited role in CKD driven by non-hyperfiltration mechanisms. While SGLT2 inhibitors have revolutionized CKD treatment in diabetes, obesity and heart failure, their role in lean, non-diabetic patients remains unclear. Dedicated clinical trials are needed to assess their efficacy in underrepresented CKD subgroups, including pediatric patients, and ensure evidence-based, personalized treatment strategies.