First real-world evidence of sparsentan efficacy in patients with IgA nephropathy treated with SGLT2 inhibitors

Background Sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy (IgAN). Following the publication of the PROTECT trial, sparsentan recently received approval for the treatment of IgAN in Europe. However, it remains uncertain whether an additive effect can be observed in the context of existing treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors, given that the PROTECT study did not investigate this dual therapy approach. Methods A total of 23 patients with IgAN were treated with sparsentan via the Managed Access Programme between December 2023 and August 2024. The patients were stable on maximum tolerated doses of renin–angiotensin system (RAS) and SGLT2 inhibitors, with an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m² and a urine protein/creatinine ratio (UPCR) >0.75 g/g. Results In the 23 patients, median (IQR) baseline eGFR (CKD-EPI) was 42 mL/min/1.73 m2 (32–63) and median baseline UPCR was 1.5 g/g (0.9–1.8). After initiation of sparsentan, UPCR significantly decreased (P < 0.0001) to a median of 0.85 g/g (0.42–1.15) in the 2-week follow-up and further declined (P = 0.001) to a median of 0.60 g/g (0.32–0.82) after 14 weeks, equivalent to a relative reduction in proteinuria up to 62% (45–74). A similar significant reduction was observed for the urine albumin/creatinine ratio. No drug-related serious adverse events were reported. Conclusions In this real-world setting, sparsentan shows a significant impact on proteinuria, leading to a relative reduction of 62% in UPCR after 14 weeks and beyond, even in patients already receiving SGLT2 inhibitors.