Efficacy and Safety of Atrasentan in Patients with IgA Nephropathy Receiving Sodium-Glucose Cotransporter 2 Inhibitors: Placebo-Controlled, Crossover Trial.

Abstract

Patients with IgA nephropathy and proteinuria are at risk of kidney failure despite use of guideline recommended renin-angiotensin system and sodium-glucose cotransporter 2 inhibition. Atrasentan reduces proteinuria in IgA nephropathy, but its efficacy as adjunct to renin-angiotensin system and sodium-glucose cotransporter 2 inhibition has not been rigorously tested. Atrasentan provided a clinically meaningful reduction in proteinuria in adults with IgA nephropathy treated with renin-angiotensin system and sodium-glucose cotransporter 2 inhibitors. Atrasentan, a highly selective endothelin-A receptor antagonist, is approved for proteinuria reduction in adults with IgA nephropathy. Renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are guideline recommended, yet the additional benefit of atrasentan has not been rigorously determined. We performed a randomized, double-blind, placebo-controlled crossover study of atrasentan in adults with IgA nephropathy, eGFR ≥30 ml/min per 1.73 m2, and urinary protein >0.5 g/d while on maximal, stable RASi and SGLT2i. Participants were randomized 1:1 to either sequence AB or sequence BA (0.75 mg atrasentan [A] once daily during period 1 and matching placebo [B] during period 2 or vice versa), with a 12-week washout period in between. The primary end point was the change in urinary protein-to-creatinine ratio (UPCR) to week 12. The secondary end point was the change in UPCR to week 24. Safety end points included the type, incidence, severity, seriousness, and relatedness of adverse events (AEs). We recruited 54 participants with mean age 48 years (SD 12), 43% female, mean eGFR 63 ml/min per 1.73 m2 (SD 22), and median UPCR 1.0 g/g (Q1-Q3, 0.7-1.4). Treatment with atrasentan versus placebo resulted in a difference in geometric mean percentage change in UPCR at week 12 of -25.3% (95% confidence interval, -36.8 to -11.7; P < 0.001). The treatment difference in UPCR between atrasentan versus placebo during treatment period 2 at week 24 was -26.4% (95% confidence interval, -45.8 to -0.0). There was one unrelated serious adverse event. Fluid retention events were uncommon, and none required hospitalization. There were no study drug discontinuations due to treatment-related adverse events and no deaths. Atrasentan provided a clinically meaningful reduction in proteinuria in adults with IgA nephropathy and proteinuria ≥0.5 g/d treated with RASi and SGLT2i therapy. Atrasentan was well tolerated, and no new safety signals emerged. NCT05834738.