Low doses of zibotentan with dapagliflozin improve albuminuria in patients with CKD

Dapagliflozin administration with zibotentan decreased urine albumin to creatinine ratio (UACR) in patients with chronic kidney disease (CKD). A low dose of zibotentan did not lead to increased fluid retention.

Prof. Hiddo Heerspink (UMC Groningen, the Netherlands) presented the results of the phase 2 ZENITH-CKD trial (NCT04724837) [1,2]. Previous studies found that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduced the risk of a composite kidney endpoint [3]. Another trial with the endothelin receptor antagonist atrasentan showed a reduced risk of a composite kidney outcome and reduced albuminuria. However, endothelin receptor antagonists can cause fluid retention, which may lead to heart failure. “In the SONAR trial with atrasentan, there was indeed a tendency towards an increased risk of heart failure,” Prof. Heerspink explained [4]. The researchers hypothesised that using dapagliflozin may ameliorate the fluid retention caused by endothelin receptor antagonist like zibotentan.

The ZENITH-CKD trial included part A (5 mg of zibotentan or placebo, plus 10 mg dapagliflozin) and part B (0.25 mg or 1.5 mg zibotentan or placebo, plus 10 mg dapagliflozin). Part A was discontinued at an interim analysis point due to safety concerns and updated clinical guidelines, making part B the main study. The study enrolled 447 participants from 18 countries and over 160 sites. The primary outcome was UACR change.

Dapagliflozin alone reduced UACR by 28.3%. Zibotentan (0.25 mg) decreased UACR by an additional 27.0% (90% CI -38.4 to -13.6; P=0.002), and 1.5 mg zibotentan decreased the UACR by an additional 33.7% (90% CI -42.5 to -23.4; P<0.001). Fluid retention was similar in the 0.25 mg zibotentan group and the dapagliflozin alone group.

Lower doses of zibotentan with dapagliflozin may thus be a viable treatment regimen for CKD; a new, phase 3 clinical trial called ‘ZENITH High Proteinuria’ is now recruiting.

1. Heerspink HJ, et al. ZENITH-CKD: A Phase 2B Study of Zibotentan in Combination with Dapagliflozin and Dapagliflozin Alone in Patients with CKD. FR-OR112, ASN Kidney Week 2023, 2–5 November, Philadelphia, PA, USA.
2. Heerspink HJ, et al. Lancet. 2023;Nov 3. DOI:10.1016/S0140-6736(23)02230-4.
3. Heerspink HJ, et al. N Engl J Med 2020;383:1436­-1446.
4. Heerspink HJ, et al. Lancet. 2019;May 11;393(10184):1937-1947.

 

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Posted on 28 November, 202331 January, 2024