Abstract: FR-OR020
Effects of Zibotentan and Dapagliflozin Combination Therapy on Albuminuria and Fluid Parameters in CKD: Results from the ZODIAC Trial
Session Information
- CKD: Identifying Risks and Optimizing Outcomes
November 07, 2025 | Location: Room 362A, Convention Center
Abstract Time: 04:40 PM - 04:50 PM
Category: CKD (Non-Dialysis)
- 2302 CKD (Non-Dialysis): Clinical, Outcomes, and Trials
Authors
- Wasehuus, Victor, Steno Diabetes Center Copenhagen, Herlev, Capital Region of Denmark, Denmark
- Smeijer, Johannes David, Universitair Medisch Centrum Groningen, Groningen, GR, Netherlands
- Jongs, Niels, Universitair Medisch Centrum Groningen, Groningen, GR, Netherlands
- Sayer, Matthew, Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom
- Dhaun, Neeraj, Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom
- Bjornstad, Petter, University of Washington School of Medicine, Seattle, Washington, United States
- Casillas, Daniel Isaiah, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Cherney, David, University of Toronto, Toronto, Ontario, Canada
- Kendrick, Jessica B., University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, United States
- Greasley, Peter J., Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- van Raalte, Daniël H., Amsterdam UMC Locatie AMC, Amsterdam, NH, Netherlands
- Rossing, Peter, Steno Diabetes Center Copenhagen, Herlev, Capital Region of Denmark, Denmark
- Heerspink, Hiddo Jan L., Universitair Medisch Centrum Groningen, Groningen, GR, Netherlands
Background
Endothelin receptor antagonists (ERA) reduce albuminuria, but may cause fluid retention, limiting their broader use in chronic kidney disease (CKD). Sodium-glucose co-transporter 2 (SGLT2) inhibitors also attenuate albuminuria, have diuretic effects, and provide cardio-kidney protection. We evaluated whether combining the ERA zibotentan with the SGLT2 inhibitor dapagliflozin leads to greater albuminuria reduction compared to either monotherapy alone, while also mitigating zibotentan-induced fluid retention in individuals with CKD.
Methods
We conducted a randomized, double-blind, placebo-controlled, crossover trial in adults with CKD (eGFR ≥30 mL/min/1.73m2, urine albumin-to-creatinine ratio (UACR) 100-3500 mg/g). Participants received placebo, zibotentan 1.5 mg/day (zibo), dapagliflozin 10 mg/day (dapa), and their combination (zibo/dapa) in one of two randomized sequences across three 4-week treatment periods, each separated by a 4-week washout. The primary endpoint was percent change from baseline in UACR at end of each treatment period. Secondary endpoints included changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), body weight, fluid volumes by bioimpedance, and adverse events.
Results
A total of 27 participants were randomized (mean age 63 years, 11% female, median UACR 304 mg/g, mean eGFR 71 mL/min/1.73m2). At the end of treatment zibo/dapa reduced UACR by a greater extent; by -48.9% (95%CI: -73.5, -1.8; p=0.04) compared with placebo, by 20.6% (95%CI: -53.4, 35.3; p=0.39) compared with zibo and by 37.7% (95%CI: -65.4, 12.2; p=0.11) compared with dapa. Zibo alone increased fluid retention which was mitigated with zibo/dapa (Table 1). Six fluid retention adverse events were observed with zibo versus one with placebo and none with dapa or zibo/dapa (Table 1).
Conclusion
Zibo/dapa combination therapy reduced albuminuria in an additive manner, mitigated fluid retention, and was well tolerated. These findings support zibo/dapa combination as a promising strategy for kidney protection.
Funding
- Commercial Support – AstraZeneca