TOPLINE:

Adding dapagliflozin (dapa) to the endothelin A receptor antagonist zibotentan (zibo) did not reduce hepatic venous pressure gradient (HVPG) or fluid retention in patients with compensated or decompensated cirrhosis and clinically significant portal hypertension, according to 6-week results of a phase 2 study.

METHODOLOGY:

• Endothelin A receptor antagonists such as zibo have been shown to reduce intrahepatic resistance, but at the possible cost of fluid retention; in contrast, SGLT2 inhibitors such as dapa may normalize extracellular water volume and counteract fluid retention. Researchers therefore hypothesized that adding dapa might lower HVPG while minimizing fluid retention.
• In a study known as ZEAL Part B, the study investigators enrolled 177 adults with compensated or decompensated cirrhosis with clinically significant portal hypertension, Model for End-Stage Liver Disease scores < 15, and/or Child-Pugh scores < 10. The mean age of the participants was 61 years, 52% were male.
• Participants were randomly assigned to a once-daily combination of 1 mg zibo and 10 dapa; 2.5 mg zibo and 10 mg dapa; 5 mg zibo and 1.0 mg dapa; 10 mg dapa only; or placebo.
• The primary endpoint was the change in HVPG from baseline to 6 weeks; secondary endpoints included body weight changes, blood pressure changes, and use of loop diuretics.

TAKEAWAY:

• In the 154 patients who completed 6 weeks of treatment, no significant change in HVPG occurred in any of the active treatment groups including the dapa monotherapy group compared with the placebo group.
• The highest dose of zibo (5 mg) was associated with a significantly higher incidence of fluid retention events (41.7%) than with 2.5 mg zibo (26.5%), 1 mg zibo (20.6%), dapa monotherapy (17.6%), or placebo (17.1%).
• However, patients treated with dapa monotherapy had fewer fluid retention events than patients in the placebo group.
• Overall serious adverse event rates were similar across the groups, with no cases of drug-induced liver injury, increased risk for orthostatic hypotension, or deaths.
• A total of two mild heart failure events occurred, one each in the 1-mg and 2.5-mg zibo/dapa combination groups.

IN PRACTICE:

Although dapa could not counteract the zibo-induced fluid retention, it showed potential effects against fluid retention on its own, the researchers of the study wrote in their abstract. “We hypothesize that any increased intrahepatic vasodilation by zibo was counteracted by an increased blood volume,” they added.

SOURCE:

The study was presented by Mattias Mandorfer, MD, Medical University of Vienna, Vienna, Austria, at The Liver Meeting 2025: American Association for the Study of Liver Diseases (AASLD).

LIMITATIONS:

The findings were limited in part by the small sample size and relatively short study period.

DISCLOSURES:

The study was supported by AstraZeneca. Mandorfer disclosed serving as a speaker, consultant, or advisory board member for AstraZeneca, AbbVie, Boehringer Ingelheim, Echosens, Eli Lilly and Company, Gilead Sciences, Ipsen, Takeda, and W.L. Gore. He reported receiving grants and research support from Echosens.