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Combination of ERA and SGLT2 inhibitor reduced albuminuria in patients with chronic kidney disease: ZENITH-CKD trial
Netherlands: A combination of zibotentan and dapagliflozin reduced albuminuria with an acceptable safety and tolerability profile, according to phase IIb ZENITH-CKD trial. Therefore, it could be an option to reduce the progression of chronic kidney disease (CKD) in patients already receiving currently recommended therapy.
"By week 12 of treatment, patients on 1.5 mg zibotentan plus dapagliflozin had a -33.7% difference in urinary albumin-to-creatinine ratio (UACR) versus dapagliflozin (Farxiga) added onto placebo," the researchers reported in The Lancet.
In previous studies, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) have been shown to reduce albuminuria and glomerular filtration rate (GFR) decline in CKD patients. Prof Hiddo J L Heerspink, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, and colleagues assessed the albuminuria-lowering safety and efficacy of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin.
ZENITH-CKD was a randomised, multicentre, double-blind, active-controlled clinical trial, conducted in 170 clinical practice sites in 18 countries. It included adults with an estimated GFR (eGFR) of 20 mL/min per 1·73 m2 or greater and a UACR of 150–5000 mg/g. 449 participants were randomly assigned in the ratio of 2:1:2 to 12 weeks of daily treatment with zibotentan 1·5 mg plus dapagliflozin 10 mg (n=179), zibotentan 0·25 mg plus dapagliflozin 10 mg (n=91), dapagliflozin 10 mg plus placebo (n=177) as an adjunct to angiotensin receptor blockers or angiotensin-converting enzyme inhibitors if tolerated.
The primary endpoint of the study was determined as 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 and defined as an increase in body weight of at least 3% from baseline or a rise 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.
Based on the study, the researchers reported the following findings:
- 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% for zibotentan 1·5 mg plus dapagliflozin and –27·0% for zibotentan 0·25 mg plus dapagliflozin.
- Fluid-retention events were observed in 18% of 179 participants in the zibotentan 1·5 mg plus dapagliflozin group, 9% of 91 in the zibotentan 0·25 mg plus dapagliflozin group, and 8% of 177 in the dapagliflozin plus placebo group.
Zibotentan was described as the most potent and selective endothelin A receptor antagonist developed to date. However, endothelin A receptor antagonists cause oedema and fluid retention, so it was paired with an SGLT2 inhibitor, which has both renoprotective properties and diuretic effects. Other ERAs in development or on the market today include sparsentan and atrasentan.
"The fluid retention profile of a low-dose combination supports further clinical trials," the researchers wrote. "Results of these larger and longer studies in high-risk CKD populations are awaited."
MSc. Biotechnology
Medha Baranwal joined Medical Dialogues as an Editor in 2018 for Speciality Medical Dialogues. She covers several medical specialties including Cardiac Sciences, Dentistry, Diabetes and Endo, Diagnostics, ENT, Gastroenterology, Neurosciences, and Radiology. She has completed her Bachelors in Biomedical Sciences from DU and then pursued Masters in Biotechnology from Amity University. She has a working experience of 5 years in the field of medical research writing, scientific writing, content writing, and content management. She can be contacted at  editorial@medicaldialogues.in. Contact no. 011-43720751
Dr Kamal Kant Kohli-MBBS, DTCD- a chest specialist with more than 30 years of practice and a flair for writing clinical articles, Dr Kamal Kant Kohli joined Medical Dialogues as a Chief Editor of Medical News. Besides writing articles, as an editor, he proofreads and verifies all the medical content published on Medical Dialogues including those coming from journals, studies,medical conferences,guidelines etc. Email: drkohli@medicaldialogues.in. Contact no. 011-43720751