Endothelin Receptor Antagonist Ambrisentan, SGLT2 Inhibitor Henagliflozin, and Their Combination in IgA Nephropathy: A Randomized Crossover Trial.

Abstract

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. This open-label randomized crossover trial enrolled adults with immunoglobulin A nephropathy (IgA nephropathy), estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2, 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/day, henagliflozin 10 mg/day, and combination), each for 4 weeks followed by a 4-week washout. Primary endpoint was correlation between treatments in 24-hour UPCR changes. Secondary endpoints included eGFR change. Safety endpoints included fluid retention (body weight change). Sixty-five patients were enrolled, with a mean baseline eGFR of 69 ml/min/1.73 m2 (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). Mean reduction in eGFR from baseline was -4.7 ml/min/1.73 m2 (95% CI, -6.9 to -2.6) with combination therapy, which was significantly greater than with ambrisentan (-0.5 ml/min/1.73 m2; 95% CI, -2.8 to 1.9) but comparable with henagliflozin (-3.5 ml/min/1.73 m2; 95% CI, -5.8 to -1.2). Less fluid retention occurred with combination treatment versus ambrisentan alone. Combining an ERA with an SGLT2 inhibitor further reduced proteinuria versus SGLT2 inhibitor alone, with less fluid retention than ERA alone.