Kidney Week

Abstract: SA-PO1162

Impact of Zibotentan and Dapagliflozin Combination Therapy on Lipid Biomarkers in Individuals with CKD

Session Information

• CKD: SGLT2 Inhibitors and GLP-1 RAs for Kidney Health
  November 08, 2025 | 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

• Wasehuus, Victor, Steno Diabetes Center Copenhagen, Herlev, Capital Region of Denmark, Denmark

Victor Wasehuus, MD

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

Johannes David Smeijer, MD, MSc

• Ambery, Philip D., BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Philip D. Ambery, MD, MBChB

• Greasley, Peter J., BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Peter J. Greasley, PhD

• Wijkmark, Emma, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Emma Wijkmark

• Cigarrán Guldris, Secundino, Hospital Ribera Polusa, Lugo, Spain

Secundino Cigarrán Guldris, PhD

• Gorriz, Jose L., Department of Nephrology, University Clinical Hospital Valencia, Valencia, Spain

Jose L. Gorriz, MD

• Soler, Maria Jose, Hospital Universitari Vall d'Hebron, Barcelona, Spain

Maria Jose Soler, MD, PhD

• Rossing, Peter, Steno Diabetes Center Copenhagen, Herlev, Capital Region of Denmark, Denmark

Peter Rossing, MD, DrMed

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

Hiddo Jan L. Heerspink, PhD

Background

Endothelin receptor antagonists (ERAs) have beneficial effects on the kidneys and can alter lipid profiles. Zibotentan, a selective ERA, combined with the sodium-glucose cotransporter 2 inhibitor dapagliflozin, reduced albuminuria in individuals with chronic kidney disease (CKD) in the ZENITH-CKD trial. However, the impact of combination therapy on lipid biomarkers has not been fully characterized.

Methods

A post-hoc analysis of ZENITH-CKD, a randomized, double-blind, multicenter trial in adults with chronic kidney disease (CKD) (eGFR ≥20 mL/min/1.73m²; UACR 150-5000 mg/g). Participants were randomized to receive dapagliflozin 10 mg alone (n=148) or zibotentan (0.25 mg or 1.5 mg) plus dapagliflozin 10 mg (n=220) for 12 weeks. Changes from baseline in proprotein convertase subtilisin/kexin type 9 (PCSK9), lipoprotein(a) (Lp(a)), LDL cholesterol (LDL-C), apolipoprotein B (ApoB), and the LDL-C/ApoB ratio were evaluated. Due to the absence of a dose-dependent effect, the zibotentan arms were combined.

Results

Mean age was 63 years, 28% were female and 60% had type 2 diabetes. Median UACR was 565 mg/g and mean eGFR was 48 mL/min/1.73m². Lipid biomarker levels at baseline were similar across the groups (Table 1). When compared with dapagliflozin, zibotentan/dapagliflozin combination therapy significantly lowered PCSK9 (-8.74%; 90% CI: -12.40, -4.92), Lp(a) (-8.20%; 90% CI: -13.92, -2.10), and ApoB (-7.36%; 90% CI: -10.63, -3.97). A reduction in LDL-C was observed but did not reach statistical significance, while a numerical increase in LDL-C/ApoB ratio was likewise observed (Table 1).

Conclusion

In individuals with CKD, combination therapy with zibotentan and dapagliflozin improved key lipid parameters, notably reducing PCSK9, Lp(a) and ApoB levels, compared to dapagliflozin alone. These findings suggest potential cardiovascular benefits beyond albuminuria reduction.

Funding

• Commercial Support – AstraZeneca

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20254v0pgyza