Semaglutide for NASH liver disease: the 2021 phase 2 trial

Why this study matters

NASH stands for non-alcoholic steatohepatitis. It is a form of fatty liver disease with inflammation, and over time it can lead to scarring of the liver, called fibrosis. Researchers now often use the newer name MASH. It is closely linked to higher body weight and type 2 diabetes. This was one of the first trials to ask whether semaglutide (Wegovy, Ozempic) could help the liver itself, not just body weight. Canadian readers who live with both a higher body weight and fatty liver disease may want to know what this early trial did and did not show.

Who was in the study

The trial enrolled 320 adults with NASH confirmed by liver biopsy. A biopsy is a small tissue sample taken with a needle. Everyone had liver fibrosis at stage F1, F2 or F3. Stages run from F0 (no scarring) to F4 (cirrhosis), so these people had mild to advanced scarring but not cirrhosis. Of the 320, 230 had stage F2 or F3 fibrosis. The main results were measured only in those 230 people. The trial ran for 72 weeks. The summary we reviewed does not say which countries took part.

What the researchers did

This was a randomized, double-blind, phase 2 trial. Randomized means a computer decided by chance which treatment each person got. Double-blind means neither the participants nor the study doctors knew who was getting the medicine. Phase 2 means it was a mid-stage trial designed to test doses and look for early signs of benefit, not a final confirmation trial.

People were assigned in a 3:3:3:1:1:1 ratio to one of three doses of semaglutide injected under the skin once a day (0.1 mg, 0.2 mg or 0.4 mg) or to a matching placebo. A placebo is an inactive injection that looks the same. There were 80 people in the 0.1 mg group, 78 in the 0.2 mg group, 82 in the 0.4 mg group and 80 in the placebo group.

The main outcome was resolution of NASH with no worsening of fibrosis, judged on a repeat biopsy. The key secondary outcome was an improvement of at least one fibrosis stage with no worsening of NASH.

What they found

The primary result was clear. NASH resolved without worse fibrosis in 59% of the 0.4 mg group, compared with 17% of the placebo group (R32-C35). The chance of seeing a gap that large if the medicine did nothing was less than 1 in 1,000 (P less than 0.001).

The fibrosis result was different. Fibrosis improved by at least one stage in 43% of the 0.4 mg group and 33% of the placebo group. The P value was 0.48, meaning a gap that size could easily happen by chance. So the trial did not show that semaglutide improved liver scarring (R32-C36).

Mean weight loss was 13% in the 0.4 mg group and 1% in the placebo group. The published summary we reviewed does not report a confidence interval for the between-group differences.

Side effects and people who stopped

Stomach and gut effects were more common at the highest dose. Comparing the 0.4 mg group with placebo: nausea 42% versus 11%, constipation 22% versus 12%, and vomiting 15% versus 2%.

Cancers (malignant neoplasms) were reported in 3 people taking semaglutide (1%) and none taking placebo. Growths of any kind (benign, malignant or unspecified) were reported in 15% of people in the semaglutide groups and 8% in the placebo group. The authors saw no pattern in specific organs. The summary we reviewed does not report how many people stopped treatment.

What this study does not tell you

• It used daily injections at doses of 0.1 to 0.4 mg. That is not the weekly 2.4 mg regimen tested later in the ESSENCE trial, so the results do not transfer directly.
• It did not show a significant improvement in fibrosis. Resolving NASH is not the same as reversing scarring.
• It was a phase 2 trial, so it was designed to explore, not to confirm.
• The main results apply only to people with F2 or F3 fibrosis. People with cirrhosis were not included.
• Biopsy results at 72 weeks do not tell you whether people avoided liver failure, transplant or death later on.
• The trial was funded by the maker of semaglutide.

What it means in Canada

This is early research on a liver outcome, not a weight-loss trial. It helped set up the larger ESSENCE trial that came later. For information about how semaglutide is used and what it is approved for, see semaglutide in Canada. For questions about paying for treatment, see public drug coverage by province.

Related reading

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

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