Endothelin Receptor Antagonist Ambrisentan, Sodium-Glucose Cotransporter 2 Inhibitor Henagliflozin, and Their Combination in IgA Nephropathy

KEY POINTS: Proteinuria responses to endothelin receptor antagonists and sodium-glucose cotransporter 2 inhibitors were not correlated. Ambrisentan-henagliflozin combination therapy reduced proteinuria similarly to ambrisentan monotherapy but exceeded henagliflozin alone. Combination therapy resulted in markedly less fluid retention and weight gain compared with endothelin receptor antagonist monotherapy. BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors and endothelin receptor antagonists (ERAs) can reduce proteinuria and may slow kidney progression in IgA nephropathy. Their potential synergistic efficacy and safety are unclear. METHODS: This open-label randomized crossover trial enrolled adults with IgA nephropathy, eGFR >30 ml/min per 1.73 m 2 , and 24-hour urine protein-creatinine ratio (UPCR) ≥0.44 g/g or 24-hour urine protein ≥0.5 g, despite maximal renin-angiotensin system blockade. Treatments were given in random order (ambrisentan 5 mg/d, henagliflozin 10 mg/d, and combination), each for 4 weeks followed by a 4-week washout. Primary end point was correlation between treatments in 24-hour UPCR changes. Secondary end points included eGFR change. Safety end points included fluid retention (body weight change). RESULTS: Sixty-five patients were enrolled, with a mean baseline eGFR of 69 ml/min per 1.73 m 2 (SD=23) and a median 24-hour UPCR of 0.8 g/g (0.6-1.3). No correlation was found in 24-hour UPCR reduction between single-agent therapy and combination therapy (ambrisentan, r =0.13, P = 0.97; henagliflozin, r =0.04, P = 1.00). After treatment, the mean reduction in 24-hour UPCR was -44% with combination therapy (95% confidence interval [CI], -52 to -34), which was similar to ambrisentan alone (-48%; 95% CI, -56 to -39) but significantly superior to henagliflozin alone (-21%; 95% CI, -33 to -6). The mean reduction in eGFR from baseline was -4.7 ml/min per 1.73 m 2 (95% CI, -6.9 to -2.6) with combination therapy, which was significantly greater than with ambrisentan (-0.5 ml/min per 1.73 m 2 ; 95% CI, -2.8 to 1.9) but comparable with henagliflozin (-3.5 ml/min per 1.73 m 2 ; 95% CI, -5.8 to -1.2). Less fluid retention occurred with combination treatment versus ambrisentan alone. CONCLUSIONS: Combining an ERA with an SGLT2 inhibitor further reduced proteinuria versus SGLT2 inhibitor alone, with less fluid retention than ERA alone. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2400080435).