Endothelin Receptor Antagonist Ambrisentan, Sodium-Glucose Cotransporter 2 Inhibitor Henagliflozin, and Their Combination in IgA Nephropathy: A Randomized Crossover Trial.
Qinlan Chen, Pei Chen, Lijun Liu et al.
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In 30 seconds
This open-label randomized crossover trial evaluated ambrisentan, henagliflozin, and their combination in adults with IgA nephropathy and persistent proteinuria despite maximal renin-angiotensin system blockade. Each treatment was given for 4 weeks, with washout periods. Combination therapy reduced 24-hour UPCR by -44% (95% CI, -52 to -34), similar to ambrisentan alone (-48%; 95% CI, -56 to -39) and greater than henagliflozin alone (-21%; 95% CI, -33 to -6). Fluid retention was lower with combination therapy than with ambrisentan alone, although eGFR fell more than with ambrisentan.
Key findings
- Mean 24-hour UPCR reduction was -44% with combination therapy, similar to -48% with ambrisentan and greater than -21% with henagliflozin alone.
- UPCR responses to either single agent were not correlated with responses to combination therapy.
- Combination therapy reduced eGFR by -4.7 ml/min per 1.73 m 2, more than ambrisentan (-0.5 ml/min per 1.73 m 2) and comparably to henagliflozin (-3.5 ml/min per 1.73 m 2).
- Less fluid retention occurred with combination therapy than with ambrisentan alone.
Why it matters
The findings suggest that combining an endothelin receptor antagonist with an SGLT2 inhibitor can reduce proteinuria more than SGLT2 inhibition alone, without the same degree of fluid retention reported with endothelin receptor antagonist monotherapy. The accompanying short-term eGFR decline is relevant when interpreting the proteinuria response and underscores the need to consider both efficacy and safety outcomes.
What to keep in mind
Each treatment period lasted 4 weeks, so the trial does not establish longer-term effects on kidney function or disease progression.