Can GLP-1 medicines help fatty liver disease (MASH)? What the trials found

MASLD, MASH and fibrosis in plain words

The names changed recently, which makes this topic confusing. Here is what they mean.

• MASLD (metabolic dysfunction-associated steatotic liver disease) is the new name for what used to be called non-alcoholic fatty liver disease, or NAFLD. It means too much fat in the liver, linked to things like excess weight, high blood sugar or high blood fats. It is estimated to affect about 30% of adults worldwide.³
• MASH (metabolic dysfunction-associated steatohepatitis) is the more serious form, formerly called NASH. The fat comes with inflammation and damage to liver cells. About 20% of people with MASLD are estimated to have MASH.³
• Fibrosis is scarring. Ongoing inflammation can slowly lay down scar tissue in the liver. Doctors grade it in stages from F0 (none) to F4, which is cirrhosis. Both trials here enrolled people at stage F2 or F3, meaning moderate or advanced scarring but not cirrhosis.^1,2

Scarring matters because MASH with fibrosis can progress to cirrhosis or liver cancer.³ That is why these trials judged success by looking at liver tissue under a microscope.

How the trials measured success

Both trials took a liver biopsy, a small sample of liver tissue taken with a needle, at the start and again at the end. Pathologists then checked two things:

• MASH resolution without worsening of fibrosis: the inflammation and cell damage cleared, and scarring did not get worse.
• Fibrosis improvement without worsening of MASH: scarring dropped by at least one stage, and the inflammation did not get worse.

Phase 2 vs phase 3: why it matters

A phase 2 trial is a medium-sized study meant to find the right dose and check for a signal. A phase 3 trial is larger and is designed to confirm whether a treatment works. Phase 3 results carry much more weight. ESSENCE (semaglutide) is phase 3. SYNERGY-NASH (tirzepatide) is phase 2. That means the two sets of numbers should not be lined up as a head-to-head contest.

ESSENCE: semaglutide, phase 3

ESSENCE assigned 1,197 adults with biopsy-confirmed MASH and F2 or F3 fibrosis to weekly semaglutide 2.4 mg or placebo, in a 2:1 ratio, for a planned 240 weeks. The results so far come from a planned check at week 72 in the first 800 participants.¹ In that group, the average age was 56, 57.1% were women, the average BMI was 34.6, and 55.5% had type 2 diabetes.³

Both main goals were met. Inflammation cleared without worse scarring in 62.9% on semaglutide vs 34.3% on placebo, a difference of 28.7 percentage points. Scarring improved without worse inflammation in 36.8% vs 22.4%, a difference of 14.4 points.¹

Both together, inflammation cleared and scarring improved, happened in 32.7% on semaglutide vs 16.1% on placebo. Average weight change was −10.5% with semaglutide and −2.0% with placebo. Stomach and gut side effects were more common with semaglutide.¹

SYNERGY-NASH: tirzepatide, phase 2

SYNERGY-NASH randomly assigned 190 adults with biopsy-confirmed MASH and F2 or F3 fibrosis to weekly tirzepatide at 5 mg, 10 mg or 15 mg, or placebo, for 52 weeks. Of these, 157 had a usable biopsy at week 52. The researchers filled in missing results by assuming those people would look like the placebo group.²

All three doses beat placebo on the main goal, clearing MASH without worse scarring. Scarring improved by at least one stage in about half of people on tirzepatide vs 30% on placebo. Because each group was small, the ranges around those fibrosis numbers were wide. The most common side effects were stomach and gut events, mostly mild or moderate.²

What these results do not show yet

• No outcome data yet. Biopsy changes are early signs. ESSENCE is continuing to 240 weeks, and its second part is built around clinical outcomes rather than biopsies. SYNERGY-NASH was not designed to measure those.^1,3
• Placebo groups improved too. In ESSENCE, about a third of people on placebo saw MASH clear. Biopsy readings vary, and some people improve with time or small weight changes. The gap between groups is the fairest measure.
• Not a head-to-head comparison. The trials differed in size, length, phase and analysis. Comparing their percentages directly would be misleading. For a true comparison on weight, see semaglutide vs tirzepatide.
• Specific population. Adults with MASH and F2 or F3 scarring confirmed by biopsy. Not people with cirrhosis, and not people with simple fatty liver and no scarring.
• Industry funded. Novo Nordisk funded ESSENCE and Eli Lilly funded SYNERGY-NASH. Each company makes the drug its trial tested.^1,2

The practical takeaway

For adults with MASH and moderate or advanced scarring, the phase 3 ESSENCE trial shows that semaglutide improved liver tissue more than placebo over 72 weeks. Early phase 2 data for tirzepatide point the same way, but need confirming in larger trials. Many people with MASH also have type 2 diabetes or heart risk, which these medicines have been studied for separately. See GLP-1s and type 2 diabetes and the SELECT heart trial.

Whether a GLP-1 medicine is right for your liver, and how your liver should be monitored, are questions for your doctor or liver specialist.