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

Aims Endothelin A (ET A ) 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 ET A 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.