Avosentan

To analyse the efficacy and safety of endothelin receptor antagonists for people with diabetic kidney disease.

Randomized controlled trials comparing endothelin receptor antagonists with placebo in people with diabetic kidney disease were identified through PubMed, Embase and the Cochrane Library. We used a random‐effect model to calculate the mean difference or risk ratio with the 95% CI.

Seven studies with a total of 4730 participants were included. Overall, endothelin receptor antagonists significantly reduced albuminuria compared with placebo (standardized mean difference –0.48, 95% CI –0.64 to –0.33). Atrasentan, in particular, effectively reduced albuminuria (standardized mean difference –0.58, 95% CI –1.00 to –0.17) and the risk of composite renal endpoints (risk ratio 0.65; 95% CI 0.49 to 0.88), with insignificant change in the rate of congestive heart failure (risk ratio 1.40, 95% CI 0.76 to 2.56) and mortality (risk ratio 1.11, 95% CI 0.77 to 1.61). In contrast, although avosentan reduced albuminuria (standardized mean difference –0.47, 95% CI –0.57 to –0.36) and the risk of composite renal endpoints (risk ratio 0.63, 95% CI 0.42 to 0.94), it was associated with a significant increase in congestive heart failure risk (risk ratio 2.61, 95% CI 1.36 to 5.00) and an insignificant increase in mortality risk (risk ratio 1.50, 95% CI 0.81, 2.78). No significant change in efficacy or safety outcomes with bosentan was detected. Dose–response analysis indicated that 0.75 mg/day atrasentan is expected to be optimal for renoprotection, with maximal albuminuria reduction and minimal fluid retention events.

Among the endothelin receptor antagonists, atrasentan and avosentan, but not bosentan, are effective for renoprotection in people with diabetic kidney disease. Compared with other types and doses, atrasentan 0.75 mg/day is the most promising, with maximal albuminuria reduction and minimal fluid retention. Vigilant monitoring of congestive heart failure risk is needed in future clinical practice. (PROSPERO registration no. CRD42020169840).

Endothelin-1 (ET-1) is the most potent vasoconstrictor, and is involved in the renal regulation of salt and water homeostasis. When produced in excess in the kidney, ET-1 promotes proteinuria and tubulointerstitial injury. There is great interest in the clinical use of endothelin receptor antagonists (ERAs) in chronic kidney disease (CKD), mainly in diabetic nephropathy (DN). Areas covered: Physiopathological actions of ET-1 on the kidney. Both dual ETAR/ET_BR (bosentan) or ET_AR specific endothelin antagonists (avosentan and atrasentan, among others), which have progressed to early clinical development, with particular emphasis on atrasentan. Expert opinion: Different phase I and II clinical trials with ERAs in DN, mostly with atrasentan, have shown that these drugs have a marked anti-proteinuric effect on residual proteinuria when administered as add-on therapy in addition to ACEi or ARAII treatment. In the past few years, a series of randomized controlled trials investigating new approaches to DN have provided negative or inconclusive data, or even were terminated due to safety concerns or lack of efficacy. Therefore, we eagerly but cautiously await the results of the ongoing SONAR trial with atrasentan in more than 4,000 patients including assessment of renal and cardiovascular hard-end points (estimated primary completion date, July 2018).