✓ FDA APPROVED August 15, 2025
Wegovy (semaglutide 2.4 mg) approved for MASH with moderate to advanced fibrosis (F2-F3)
First GLP-1 receptor agonist approved for this indication
For decades, there were no FDA-approved medications for metabolic dysfunction-associated steatohepatitis (MASH), the progressive liver disease affecting nearly 15 million Americans. In March 2024, resmetirom (Rezdiffra) became the first approved treatment. Now, semaglutide has become the second—and the first GLP-1 medication—to receive FDA approval for MASH.
Here's what the clinical trial showed and what it means for patients with fatty liver disease.
What is MASH?
MASH—formerly called nonalcoholic steatohepatitis (NASH)—is a severe form of fatty liver disease characterized by:
- Fat accumulation in the liver (steatosis)
- Inflammation (hepatitis)
- Progressive scarring (fibrosis)
If untreated, MASH can progress to cirrhosis, liver cancer, liver failure requiring transplant, and death. Approximately 6% of U.S. adults (14.9 million people) have MASH, and prevalence is rising alongside obesity and type 2 diabetes.
Most patients with MASH are asymptomatic in early stages, leading to delayed diagnosis. By the time symptoms appear, significant liver damage may have already occurred. Effective treatments that can halt or reverse fibrosis progression are critical.
The ESSENCE Trial
The FDA approval was based on Part 1 of the ESSENCE trial, published in the New England Journal of Medicine in April 2025.
Trial Design
| Design | Phase 3, multicenter, randomized, double-blind, placebo-controlled |
| Participants | 800 adults (Part 1 interim) / 1,197 total enrolled |
| Inclusion | Biopsy-confirmed MASH with fibrosis stage F2 or F3 |
| Exclusion | Cirrhosis (F4) |
| Treatment | Semaglutide 2.4 mg weekly vs. placebo (2:1 randomization) |
| Duration | 72 weeks (Part 1); 240 weeks planned (Part 2) |
| Sites | 253 clinical sites across 37 countries |
Primary Endpoints
The FDA requires two histological (biopsy-proven) endpoints for MASH approval:
- Resolution of steatohepatitis without worsening of fibrosis
- Improvement in fibrosis (≥1 stage) without worsening of steatohepatitis
The Results
| Endpoint | Semaglutide | Placebo | Difference |
|---|---|---|---|
| MASH resolution (no worsening fibrosis) | 62.9% | 34.1% | +29 percentage points |
| Fibrosis improvement (≥1 stage, no MASH worsening) | 36.6% | 22.4% | +14 percentage points |
| Both endpoints achieved | 32.8% | 16.2% | +17 percentage points |
These differences were statistically significant (P<0.001 for both primary endpoints).
Additional Findings
- 83.5% of semaglutide patients maintained the target 2.4 mg dose through week 72
- Significant improvements in weight, blood sugar, and lipid levels
- Consistent benefits regardless of baseline diabetes status
A prior Phase 2b trial of semaglutide showed MASH resolution but not fibrosis improvement. The ESSENCE trial is the first to demonstrate that semaglutide can improve both disease activity AND fibrosis—a crucial distinction for preventing progression to cirrhosis.
Safety Profile
The safety profile was consistent with previous semaglutide trials:
| Adverse Event | Notes |
|---|---|
| Nausea | Most common, typically during dose escalation |
| Diarrhea | Usually mild to moderate |
| Vomiting | More common during early treatment |
| Constipation | May persist in some patients |
| Abdominal pain | Generally mild |
| Discontinuation due to AEs | Approximately 10% |
Semaglutide should not be used by individuals with a personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2, or known hypersensitivity to semaglutide.
How This Compares to Resmetirom
Semaglutide is the second FDA-approved MASH treatment after resmetirom (Rezdiffra), which was approved in March 2024.
| Feature | Semaglutide (Wegovy) | Resmetirom (Rezdiffra) |
|---|---|---|
| Mechanism | GLP-1 receptor agonist | Thyroid hormone receptor-beta agonist |
| Administration | Weekly injection | Daily oral tablet |
| Weight loss | Significant (~15-20%) | Minimal |
| Other benefits | Diabetes, CV risk, kidney protection | Liver-specific |
| FDA status | Accelerated approval | Accelerated approval |
Dr. Paul Kwo, co-editor-in-chief of Evidence-Based GI, notes: "The future will likely belong to combination therapy—optimizing both liver disease treatment and cardiovascular risk reduction."
What Comes Next: Part 2
The current approval is accelerated, meaning it's based on a surrogate endpoint (liver histology) that is reasonably likely to predict clinical benefit. Full approval requires confirmation that semaglutide actually prevents progression to cirrhosis, liver failure, and death.
Part 2 of the ESSENCE trial extends to 240 weeks (approximately 5 years) and will evaluate:
- Progression to cirrhosis
- Liver-related events (ascites, encephalopathy, variceal bleeding)
- Need for liver transplant
- Overall mortality
Results are expected in 2029.
What This Means for Patients
For patients with MASH and significant fibrosis:
- A new treatment option exists—especially valuable for those with obesity or diabetes who could benefit from semaglutide's metabolic effects
- Insurance coverage may improve—having a liver disease indication may help patients access semaglutide when denied for weight loss alone
- Lifestyle remains important—the trial included reduced-calorie diet and increased physical activity as adjuncts
- Approval is for F2-F3 fibrosis only—not cirrhosis (F4)
- This is accelerated approval pending long-term outcome data
- Not all patients respond; individual results vary
Semaglutide (Wegovy) is now the first GLP-1 medication approved for MASH with moderate to advanced fibrosis. The ESSENCE trial showed 63% of patients achieved resolution of steatohepatitis (vs. 34% placebo) and 37% saw fibrosis improvement (vs. 22% placebo) at 72 weeks. This accelerated approval provides a second treatment option for the 15 million Americans with MASH, with long-term outcome data expected in 2029. For patients with metabolic syndrome who need both liver protection and weight loss, this approval is particularly significant.
Sources
- FDA. "FDA Approves Treatment for Serious Liver Disease Known as 'MASH'." August 15, 2025.
- Sanyal AJ, et al. "Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis." New England Journal of Medicine. 2025;392(21):2089-2099.
- Novo Nordisk. "Wegovy approved by FDA for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis." Press release. August 15, 2025.
- AJMC. "FDA Approves Semaglutide for MASH With Fibrosis." December 2025.
- American College of Gastroenterology. "Semaglutide for the treatment of metabolic dysfunction-associated steatohepatitis." September 2025.
- HCPLive. "MASH/MASLD in 2025: Year in Review." December 2025.
- Docwire News. "FDA Grants Accelerated Approval of Semaglutide for Treatment of MASH With Liver Fibrosis." 2025.
- ClinicalTrials.gov. ESSENCE trial (NCT04822181).
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