Kidney Week

Abstract: TH-PO1052

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

Session Information

• CKD: Therapeutic Advances
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2302 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Authors

• Smeijer, Johannes David, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Johannes David Smeijer, MD, MSc

• Åstrand, Magnus, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden

Magnus Åstrand, PhD

• Mercier, Anne-Kristina, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden

Anne-Kristina Mercier, PhD

• Greasley, Peter J., Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Peter J. Greasley, PhD

• Ambery, Philip D., Clinical Late Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Philip D. Ambery, MD

• Heerspink, Hiddo Jan L., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Hiddo Jan L. Heerspink, PhD

Group or Team Name

• Investigators of ZENITH-CDK Clinical Trial.

Background

Endothelin receptor antagonists (ERAs) effectively 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

Methods

In ZENITH-CKD, 508 patients with CKD (eGFR ≥ 20 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio (UACR) 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, as well as the relationship between zibotentan plasma exposure and fluid retention.

Results

After 3 weeks of treatment with zibotentan 0.25, 1.5 or 5 mg plus dapagliflozin 10 mg, changes in body weight, BNP, and hemoglobin were independently associated with changes in ECF. Higher doses of zibotentan significantly increased the risk of fluid retention compared to dapagliflozin alone (zibotentan 5 mg HR 9.13 [95%CI 3.40, 24.49]). The hazard ratio attenuated when zibotentan was combined with dapagliflozin (HR zibotentan/dapagliflozin 5/10 mg 3.61 (95%CI 1.26,10.33) and zibotentan/dapagliflozin 0.25/10 mg HR 0.99 (95%CI 0.37, 2.63). The risk of fluid retention increased with higher zibotentan exposure and lower eGFR.

Conclusion

High doses of zibotentan increased the risk of fluid retention which could be reduced with lower doses and addition of dapagliflozin. This risk was more pronounced at lower eGFR which highlights the need for combined use of low zibotentan doses and dapagliflozin in advanced CKD.

Funding

• Commercial Support – The ZENITH-CKD trial was sponsored by AstraZeneca