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

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.