Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial

• Published in: The Lancet (British edition) 2023-11, Vol.402 (10416), p.2004-2017
• Main Authors: Heerspink, Hiddo J L, Kiyosue, Arihiro, Wheeler, David C, Lin, Min, Wijkmark, Emma, Carlson, Glenn, Mercier, Anne-Kristina, Åstrand, Magnus, Ueckert, Sebastian, Greasley, Peter J, Ambery, Phil
• Format: Article
• Language: English
• Subjects: Active control; Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin; Angiotensin-converting enzyme inhibitors; Antidiabetics; Atrial Fibrillation - drug therapy; Body water; Brain natriuretic peptide; Clinical medicine; Clinical trials; Creatinine; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diuretics; Double-Blind Method; Endothelin ETA receptors; Enzyme inhibitors; Epidermal growth factor receptors; Female; Fibrillation; Glomerular Filtration Rate; Health services; Heart failure; Humans; Kidney diseases; Kidneys; Male; Middle Aged; Patients; Peptides; Peptidyl-dipeptidase A; Placebos; Prostate cancer; Receptors; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - drug therapy; Retention; Safety; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Zenith
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(23)02230-4

In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin. ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries. Adults (≥18 to ≤90 years) with an estimated GFR (eGFR) of 20 mL/min per 1·73 m or greater and a urinary albumin-to-creatinine ratio (UACR) of 150-5000 mg/g were randomly assigned (2:1:2) to 12 weeks of daily treatment with zibotentan 1·5 mg plus dapagliflozin 10 mg, zibotentan 0·25 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as adjunct to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if tolerated. The primary endpoint was a change from baseline in log-transformed UACR (zibotentan 1·5 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest, defined as an increase in bodyweight of at least 3% (at least 2·5% must have been from total body water) from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation. This trial is registered with ClinicalTrials.gov, NCT04724837, and is completed. Between April 28, 2021, and Jan 17, 2023, we assessed 1492 participants for eligibility. For the main analysis, we randomly assigned 449 (30%) participants, 447 (99%) of whom (mean age 62·8 years [SD 12·1], 138 [31%] female, 309 [69%] male, 305 [68%] White, mean eGFR 46·7 mL/min per 1·73 m [SD 22·4], and median UACR 565·5 mg/g [IQR 243·0-1212·6]) received treatment with zibotentan 1·5 mg plus dapagliflozin (n=179 [40%]), zibotentan 0·25 mg plus dapagliflozin (n=91 [20%]), or dapagliflozin plus placebo (n=177 [40%]). Zibotentan 1·5 mg plus dapagliflozin and zibotentan 0·25 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study. At week 12, the difference in UACR versus dapagliflozin plus placebo was -33·7% (90% CI -42·5 to -23·5; p