Effects of combined treatment with zibotentan and dapagliflozin compared to dapagliflozin alone in patients with diabetic and non‐diabetic chronic kidney disease

Abstract Aims To evaluate whether type 2 diabetes status modifies the efficacy and safety of combining zibotentan (zibo), a selective endothelin receptor antagonist, and dapagliflozin (dapa) compared to placebo plus dapagliflozin in individuals with chronic kidney disease (CKD). Methods and Materials We conducted a post hoc analysis of the ZENITH‐CKD trial, a multicentre 12‐week, double‐blind, randomized, active‐controlled, phase 2b study involving 447 participants with CKD (261 with and 186 without type 2 diabetes). Participants were assigned to zibotentan (0.25 or 1.5 mg) plus dapagliflozin 10 mg or placebo plus dapagliflozin 10 mg. Changes in urinary albumin‐to‐creatinine ratio (UACR) and markers of fluid retention (bodyweight and B‐type natriuretic peptide [BNP]) were compared in participants with and without type 2 diabetes. Results Zibo/dapa 0.25/10 mg changed UACR by −37.7% (90% CI: −40.4, −23.4) compared to placebo/dapa in participants without diabetes and by −17.9% (90% CI: −31.3, −2.0) in participants with diabetes (p‐interaction 0.096). Effects of zibo/dapa 1.5/10 mg on UACR were consistent regardless of diabetes status (−34.0% (90% CI: −45.0, −20.8) vs. −33.0% (90% CI: −42.2, −22.5), p‐interaction 0.921). Changes in body weight and BNP did not differ by diabetes status. Fluid retention occurred in five participants with diabetes assigned to zibo/dapa 1.5/10 mg and one participant with diabetes in the zibo/dapa 0.25/10 mg group. Fluid retention did not occur in those without diabetes in both zibo/dapa groups. With placebo/dapa, fluid retention occurred in one participant without diabetes and in none with diabetes. Conclusions Combination therapy with zibotentan and dapagliflozin demonstrated consistent efficacy and safety across CKD patients with and without type 2 diabetes.