#1568 Cardiometabolic benefits of low dose zibotentan and dapagliflozin 10 mg in the ZENITH-CKD study

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Abstract Background and Aims Positive effects of endothelin receptor antagonists on blood pressure and urinary albumin excretion have been well described, although their use in a wider population of patients with chronic kidney disease with increased cardiovascular risk has been limited by potential fluid retention. Here we present the effects of low dose zibotentan in combination with dapagliflozin on a range of cardiometabolic risk factors. Method In a post-hoc analysis of the ZENITH-CKD trial, a randomized, double-blind, active-controlled trial conducted in 170 clinical sites in 19 countries, adults with a urinary albumin-creatinine ratio (UACR) of 150 to 5000 mg/g and eGFR ≥20 mL/min/1.73 m2 not on SGLT2i were randomized to zibotentan/dapagliflozin, 0.25 mg/10 mg, zibotentan/dapagliflozin, 1.5 mg/10 mg, or placebo/dapagliflozin 10 mg. 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 (NCT04724837). Results Data from the full analysis set is presented including 91 participants treated with 0.25 mg zibotentan and 10 mg dapagliflozin, and 177 participants treated with 10 mg dapagliflozin and placebo. UACR reduction for 0.25 mg zibotentan and 10 mg dapagliflozin was −47.7%, for 10 mg dapagliflozin alone it was −28.3%, making an adjusted mean difference for the combination versus dapagliflozin alone of −27.0%. Cardiometabolic markers are shown in the table. Conclusion In the ZENITH-CKD study zibotentan used at low dose combined with dapagliflozin had incremental effects versus dapagliflozin alone on a range of cardiometabolic risk markers including blood pressure, LDL cholesterol, HbA1c and uric acid, without a significant increase in fluid retention.