Semaglutide for NASH-related cirrhosis: 2023 phase 2 trial results

Why this study matters

NASH (non-alcoholic steatohepatitis, now often called MASH) is fatty liver disease with inflammation. When scarring becomes severe, it is called cirrhosis. Compensated cirrhosis means the liver is heavily scarred but still doing its job. Earlier trials tested semaglutide (Wegovy, Ozempic) in people with milder scarring. This trial asked whether the same weekly 2.4 mg dose used for weight management could help once cirrhosis had developed. The answer matters for Canadian readers with advanced fatty liver disease, and it was not the answer many hoped for.

Who was in the study

The trial enrolled 71 adults between 18 June 2019 and 22 April 2021 at 38 centres in Europe and the United States. Everyone had NASH-related cirrhosis confirmed by liver biopsy (a small tissue sample) and a BMI of 27 or higher. BMI (body mass index) compares weight with height.

The mean age was 59.5 years and the mean BMI was 34.9. Of the 71 people, 49 (69%) were female and 22 (31%) were male. Most, 53 people (75%), had diabetes. Forty-seven people were assigned to semaglutide and 24 to placebo. The trial ran for 48 weeks.

What the researchers did

This was a double-blind, placebo-controlled, phase 2 trial. Randomized means chance decided who got which treatment, in a 2:1 ratio. Double-blind means patients, doctors and the people reading the biopsies did not know who was on the medicine. Placebo means an inactive injection that looked the same. Phase 2 means a mid-sized trial designed to look for a signal, not to give a final answer. Randomization was balanced by whether people had type 2 diabetes.

People injected semaglutide 2.4 mg or placebo under the skin once a week. The main outcome was the share of people whose liver fibrosis improved by at least one stage without their NASH getting worse, judged by a repeat biopsy at 48 weeks. Everyone randomized was counted (intention-to-treat). If a person's follow-up biopsy was missing, they were counted as not responding.

What they found

After 48 weeks, fibrosis improved without worse NASH in 5 of 47 people (11%) on semaglutide and 7 of 24 (29%) on placebo (R32-C38). The odds ratio was 0.28, with a 95% confidence interval of 0.06 to 1.24 and a P value of 0.087. An odds ratio below 1 points toward fewer responses with the medicine, but the confidence interval, which is the range where the true value most likely lies, stretched from well below 1 to above 1. That means the trial could not tell whether semaglutide helped, harmed or made no difference to scarring (R32-C37).

There was also no significant difference in the share of people whose NASH resolved (P = 0.29). Liver and kidney function stayed stable in both groups.

Side effects and people who stopped

Adverse events were reported by 42 people (89%) on semaglutide and 19 (79%) on placebo. Serious adverse events occurred in 6 (13%) and 2 (8%). The most common side effects were nausea (45% versus 17%), diarrhoea (19% versus 8%) and vomiting (17% versus none). There were no liver decompensation events (such as fluid build-up or bleeding) and no deaths. Three people on semaglutide and none on placebo stopped because of adverse events; the percentages were not extracted. The authors reported no new safety concerns.

What this study does not tell you

• With 71 people, the trial was small. A wide confidence interval means it could miss a real benefit or a real harm.
• It ran for 48 weeks. The absence of decompensation in this sample does not prove long-term safety.
• Its results differ from those in people with milder fibrosis, but the populations and endpoints also differ, so the trials are not simply contradictory.
• Three quarters of participants had diabetes, so results in people without diabetes are less certain.
• It measured biopsy changes, not liver failure, transplant or death.
• The trial was funded by the maker of semaglutide.

What it means in Canada

This trial is the reason careful summaries say semaglutide's liver benefit has been shown in people with moderate to advanced scarring, not in people who already have cirrhosis. For how semaglutide is used in Canada, see semaglutide in Canada. For funding questions, see public drug coverage by province.

Related reading

Other studies in this library that bear on the same question.

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