Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD.

Abstract

Endothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with chronic kidney disease (CKD). Combining ERAs with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have diuretic effects, offers a promising strategy to mitigate fluid retention. In this post-hoc analysis of the ZENITH-CKD trial, we assessed fluid dynamics in patients with CKD treated with the ERA zibotentan alone, and in combination with the SGLT2 inhibitor dapagliflozin. In ZENITH-CKD, 508 patients with CKD (estimated glomerular filtration rate ≥ 20 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio of 150-5000 mg/g) were randomized to treatment with placebo, dapagliflozin 10 mg plus placebo, zibotentan (0.25, 1.5 or 5 mg) plus dapagliflozin 10 mg and zibotentan 5 mg plus placebo. We evaluated correlations between changes in fluid retention markers and bioimpedance-measured extracellular fluid (ECF) in response to zibotentan treatment. We used Cox proportional hazards regression to assess the association between zibotentan/dapagliflozin treatment, baseline characteristics, and fluid retention, and the relationship between zibotentan plasma exposure and fluid retention. After 3 weeks of treatment with zibotentan 0.25, 1.5 or 5 mg plus dapagliflozin 10 mg, changes in body weight (β=0.36 [95%CI 0.26,0.45]) per kg, B-type natriuretic peptide (β=0.38 [95%CI 0.22, 0.54]) per doubling, and hemoglobin (β=-0.29 [95%CI -0.48, -0.10]) per g/dL were independently associated with changes in ECF. Higher doses of zibotentan were associated with significantly higher risk of fluid retention compared to dapagliflozin alone (zibotentan 5 mg HR 8.50 (95%CI 3.40, 21.30). The hazard ratio attenuated when zibotentan was combined with dapagliflozin (HR zibotentan/dapagliflozin 5/10 mg 3.09 [95%CI 1.08, 8.80], zibotentan/dapagliflozin 1.5/10 mg 2.70 [95%CI 1.44, 5.07] and zibotentan/dapagliflozin 0.25/10 mg HR 1.21 [95%CI 0.50, 2.91]). The risk of fluid retention was higher with higher zibotentan exposure and lower eGFR. High doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin.