Exploring zibotentan plus dapagliflozin for cirrhosis

Data from the cirrhosis subpopulation in the ZENITH-CKD trial suggest that a combination of zibotentan and dapagliflozin may positively affect liver health. The authors argue that the mechanistic argument for this combination therapy is strong and should be further evaluated.

Dr Phil Ambery (AstraZeneca, Sweden) and co-investigators aimed to explore the effect of the endothelin A receptor antagonist zibotentan in combination with the SGLT2 inhibitor dapagliflozin on liver cirrhosis among participants included in the phase 2b ZENITH-CKD study [1]. “Zibotentan is the most selective endothelin A receptor antagonist yet developed” [2]. Of the 447 trial participants from 18 countries, 66 had an elevated metabolic dysfunction-associated steatotic liver disease (MASLD; previously NAFLD) Fibrosis Score (>0.675). Participants were divided into 3 groups, according to the treatment received: zibotentan 0.25 mg plus dapagliflozin 10 mg (n=10), zibotentan 1.5 mg plus dapagliflozin 10 mg (n=29), and placebo plus dapagliflozin 10 mg (n=27).

At week 12, the median MASLD Fibrosis Score had dropped by only 0.09 points in the high-dose zibotentan arm but by 0.56 points in the low-dose zibotentan arm. In the placebo arm, the median MASLD Fibrosis Score was reduced by 0.26 points (see Figure). “The fluid retention associated with zibotentan may masque the effect on the fibrosis score in the high-dose arm,” argued Dr Ambery. “Furthermore, in the phase 2a ZEAL study, investigating the combination of zibotentan and dapagliflozin in participants with liver cirrhosis, a positive signal on the hepatic venous pressure gradient was seen.”

Figure: Median MASLD Fibrosis Score analysis at baseline and week 12 in liver cirrhosis patients treated with zibotentan and/or dapagliflozin [1]



Dapa, dapagliflozin; NFS, non-alcoholic fatty liver disease fibrosis score; PBO, placebo; Zibo, zibotentan.

Dr Ambery concluded that early, positive effects on health markers were observed after 12 weeks of treatment with zibotentan and dapagliflozin among participants with chronic kidney disease and elevated MASLD Fibrosis Scores.

1. 
   
   1. Ambery P, et al. Reductions in the NFS from the ZENITH CKD trial support exploration of zibotentan dapagliflozin in cirrhosis. LB19, UEG Week 2024, 12–15 October, Vienna, Austria.
   2. Davenport AP, et al. Parmacological reviews. 2016;68(2):357-418.

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Posted on 28 November 202428 November 2024