FDA Approves Semaglutide for MASH: The ESSENCE Trial Results

On August 15, 2025, the FDA granted accelerated approval to semaglutide (Wegovy) for the treatment of adults with metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis. This makes Wegovy the first GLP-1 medication approved for MASH and only the second drug ever approved for this condition.

The approval was based on the landmark ESSENCE trial, published in the New England Journal of Medicine.

What is MASH?

MASH (formerly called NASH—nonalcoholic steatohepatitis) is a severe form of fatty liver disease where fat accumulation in the liver causes inflammation and progressive scarring (fibrosis). If untreated, it can progress to cirrhosis, liver cancer, and liver failure requiring transplant.

MASH is closely linked to metabolic conditions including obesity, Type 2 diabetes, high triglycerides, and high LDL cholesterol. Many patients are asymptomatic until significant damage has occurred.

The ESSENCE Trial: Key Results

ESSENCE was a phase 3, randomized, double-blind, placebo-controlled trial enrolling 1,197 adults with biopsy-confirmed MASH and stage F2-F3 fibrosis across 253 sites in 37 countries.

Participants were randomized 2:1 to receive weekly subcutaneous semaglutide 2.4 mg or placebo for up to 240 weeks. The FDA approval was based on Part 1 results at week 72.

Primary Endpoints

A third of participants (33%) achieved both endpoints—resolution of MASH and improvement in fibrosis—compared to 16% on placebo.

Why This Matters

The ESSENCE trial represented a significant advance over semaglutide's earlier Phase 2b results, which showed MASH resolution but not fibrosis improvement.

"The Essence Trial demonstrated, for the first time, improvement in fibrosis with semaglutide, a key endpoint in the treatment of individuals with MASH and moderate to severe fibrosis," noted Dr. Paul Kwo of Stanford in the American College of Gastroenterology's analysis.

Fibrosis improvement is clinically important because fibrosis stage is the strongest predictor of liver-related mortality in MASH. Reversing or halting fibrosis progression can prevent progression to cirrhosis.

Accelerated Approval: What That Means

This is an accelerated approval based on improvement in histological endpoints (liver biopsy findings), not yet on clinical outcomes like reduced cirrhosis, liver failure, or death.

Part 2 of the ESSENCE trial is ongoing and will evaluate whether semaglutide reduces the risk of liver-related clinical events over 240 weeks (approximately 5 years). Results are expected in 2029.

If Part 2 does not confirm clinical benefit, the FDA could withdraw the approval.

Semaglutide vs. Resmetirom

With two approved options, clinicians now have choices. Here's how they compare:

For patients with MASH who also have obesity, diabetes, or cardiovascular disease—which is the majority—semaglutide offers treatment of multiple conditions simultaneously. For those who prefer oral medication or don't have weight issues, resmetirom may be preferable.

Combination therapy is likely to be explored in future trials.

Insurance Implications

This approval may improve insurance coverage for patients with MASH. Previously, many patients with clear indications for semaglutide were denied coverage because obesity alone is often not covered.

A documented MASH diagnosis with stage F2-F3 fibrosis now provides an additional pathway to coverage for Wegovy specifically.

Safety Profile

The safety profile was consistent with semaglutide's known effects in obesity and diabetes trials. The most common side effects were gastrointestinal:

• Nausea
• Diarrhea
• Vomiting
• Constipation
• Abdominal pain

Approximately 10% of patients discontinued due to adverse events. The same contraindications apply: do not use if you have a personal or family history of medullary thyroid carcinoma or MEN2 syndrome.

What We Don't Know

• Long-term clinical outcomes: Will histological improvement translate to fewer liver transplants, less cirrhosis, and reduced mortality? Part 2 results expected 2029.
• Effects in cirrhosis: Patients with cirrhosis were excluded. Safety and efficacy in this population is unknown.
• Optimal duration: Is this lifelong treatment? What happens if stopped?
• Combination with resmetirom: Would dual therapy be more effective?