Effects of zibotentan and dapagliflozin combined in patients with compensated cirrhosis: A randomized placebo‐controlled exploratory study

作者：Juan Carlos García‐Pagán, Lise Lotte Gluud, Mattias Mandorfer, Jörn M. Schattenberg, Andrea De Gottardi, Annalisa Berzigotti, José Ignacio Fortea, Agustı́n Albillos, Edilmar Alvarado‐Tápias, Marco Berning, Paweł Petryszyn, Emilia Henricson, Niklas Berglind, Min Lin, Kevin Persson, Anne‐Kristina Mercier, Phil Ambery, Jaime Bosch, Jan Oscarsson, Don C. Rockey · 发表于：British Journal of Clinical Pharmacology · 年份：2025 · DOI：10.1002/bcp.70332 · 被引用次数：1 · 研究领域：Liver Disease and Transplantation、Organ Transplantation Techniques and Outcomes、Liver Disease Diagnosis and Treatment

AIMS: receptor antagonist zibotentan and the selective SGLT2i dapagliflozin were investigated. METHODS: Patients with compensated cirrhosis (Child-Pugh A) were randomized 1:1 to zibotentan 2.5 mg plus dapagliflozin 10 mg (zibo/dapa) or placebo in a 6-week parallel, double-blind Phase II study. The absolute change in hepatic venous pressure gradient (HVPG) from baseline to week 6 was evaluated in the full analysis set using analysis of covariance. RESULTS: In 28 participants (n = 14 per group), median age was 64 years (range: 37-78), common causes of cirrhosis were metabolic dysfunction-associated steatotic (46%) or alcohol-associated liver disease (39%), and 46% were receiving stable doses of non-selective beta-blockers. Baseline HVPG was 6.5-19 mmHg, and 16/28 had clinically significant portal hypertension. Absolute change in HVPG at week 6 was not different between groups (1.02 mmHg [90% CI -0.31, 2.35]). There was a trend towards decreased HVPG in patients with baseline HVPG ≥12 mmHg receiving zibo/dapa. Systolic and diastolic blood pressure were also reduced by zibo/dapa vs. placebo. Three mild adverse events (peripheral oedema) were reported (zibotentan/dapagliflozin, n = 2; placebo, n = 1). No serious adverse events or drug-induced liver injuries were observed. CONCLUSIONS: Combined zibo/dapa was well tolerated and had a good safety profile in patients with compensated cirrhosis, but had no conclusive effect on HVPG.