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Treatment with the endothelin receptor antagonist (ERA) Zibotentan 0.25 mg/day in combination with dapagliflozin reduced albuminuria more than dapagliflozin alone with minimal fluid retention in patients with chronic kidney disease (CKD). We assessed the effects of zibotentan-dapagliflozin combination on albuminuria according to the presence or absence of diabetes and according to baseline kidney function.
We performed a post-hoc analysis of the ZENITH-CKD trial, a randomized, double-blind, placebo-controlled trial conducted in 170 clinical sites in 19 countries, where adults with a urinary albumin-creatinine ratio (UACR) of 150 to 5000 mg/g and eGFR ≥20 mL/min/1.73m2 not on SGLT2i were randomized to zibotentan/dapagliflozin: 0.25 mg/10 mg zibotentan/dapagliflozin, 1.5 mg/10 mg zibotentan/dapagliflozin, and dapagliflozin 10 mg. The primary efficacy endpoint was change from baseline to week 12 in log-transformed UACR, assessed using mixed model repeated measures (in patients who received at least one dose of study treatment). Effects on fluid retention events, defined as body weight increase from baseline >3% (of which at least 2.5% from total body water) or BNP increase >100% to 200 pg/mL without atrial fibrillation or 100% increase to 400 pg/mL with atrial fibrillation were assessed as well. (NCT04724837).
From April 28, 2021, to January 17, 2023, 447 patients were randomized and received 0.25 mg/10 mg zibotentan/dapagliflozin (n=91), 1.5 mg/10 mg zibotentan/dapagliflozin (n=179), or 10 mg dapagliflozin/placebo (n=177). Overall, 58% of patients had type 2 diabetes, mean baseline eGFR was 47 mL/min/1.73m2, and baseline geometric mean UACR was 538 mg/g. The effects of zibotentan/dapagliflozin combinations versus dapagliflozin/placebo on albuminuria were consistent irrespective of baseline diabetes status or kidney function (Table 1). No increased rates of fluid retention were observed for 0.25 mg/10 zibotentan-dapagliflozin combination compared to dapagliflozin/placebo in patients with or without diabetes or baseline UACR > 700 mg/g or 700 mg/g (Table 1). Absolute rates of fluid retention were higher among those with eGFR≤45 mL/min/1.73m2 compared to those with eGFR>45 mL/min1.73m2, but 0.25/10 mg zibotentan/dapagliflozin did not increase these events compared to dapagliflozin alone.
ZENITH-CKD confirmed 0.25 mg/10 mg zibotentan/dapagliflozin was highly effective in reducing albuminuria and was well tolerated irrespective of baseline diabetes status or kidney function.