Effects of zibotentan and dapagliflozin combined in patients with compensated cirrhosis: A randomized placebo-controlled exploratory study.
Publisher DOI
PubMed ID
41362018
Abstract
Aims
Endothelin A (ETA) receptor antagonists may reduce cirrhosis-associated portal hypertension (PH). They are associated with fluid retention, which might be mitigated by sodium-glucose co-transporter 2 inhibitors (SGLT2is). Efficacy, safety and tolerability of combining the selective ETA 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.
Endothelin A (ETA) receptor antagonists may reduce cirrhosis-associated portal hypertension (PH). They are associated with fluid retention, which might be mitigated by sodium-glucose co-transporter 2 inhibitors (SGLT2is). Efficacy, safety and tolerability of combining the selective ETA 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.
Date Issued
2026-05
Publication Type
Article
Subject(s)
Subjects
Child‐Pugh A
•
ETA receptor antagonist
•
SGLT2 inhibitor
•
hepatic venous pressure gradient
Language(s)
en
Author(s)
Garcia-Pagan, Juan Carlos | |
Gluud, Lise Lotte | |
Mandorfer, Mattias | |
Schattenberg, Jörn M | |
Fortea, José Ignacio | |
Martínez, Agustin Albillos | |
Alvarado-Tapias, Edilmar | |
Berning, Marco | |
Petryszyn, Pawel | |
Henricson, Emilia | |
Berglind, Niklas | |
Lin, Min | |
Persson, Kevin | |
Mercier, Anne-Kristina | |
Ambery, Phil | |
Oscarsson, Jan | |
Rockey, Don C |
Additional Credits
Journal
British Journal of Clinical Pharmacology
Publisher
Wiley
ISSN
1365-2125
0306-5251
Related Collection(s)
Access(Rights)
restricted