GLP-1s for MASH: Semaglutide Becomes Second FDA-Approved Treatment
In August 2025, semaglutide (Wegovy) received FDA approval for MASH with liver fibrosis—the second drug ever approved for this condition, and the first GLP-1.
FDA Approved August 2025Semaglutide improved both MASH resolution and liver fibrosis in a Phase 3 trial of 1,197 patients. At 72 weeks, 37% achieved fibrosis improvement vs. 23% on placebo. Combined with its benefits for diabetes, obesity, and cardiovascular disease, this makes semaglutide a triple-threat for metabolic patients.
Understanding MASH
MASH (metabolic dysfunction-associated steatohepatitis)—formerly called NASH (nonalcoholic steatohepatitis)—is a serious liver disease. It's the advanced stage of fatty liver disease, characterized by liver inflammation and scarring (fibrosis).
Left untreated, MASH can progress to cirrhosis (permanent scarring), liver failure, liver cancer, and death. It's the leading cause of liver-related mortality and an increasingly common reason for liver transplantation.
The Treatment Gap
Until March 2024, there was no FDA-approved medication for MASH. The only "treatment" was lifestyle modification—weight loss through diet and exercise. While effective when achieved, sustained weight loss is difficult for most patients.
The first approval came in March 2024: resmetirom (Rezdiffra), a thyroid hormone receptor agonist. Now semaglutide becomes the second—and the first GLP-1.
MASH Treatment Timeline
The ESSENCE Trial
Semaglutide's approval was based on the ESSENCE trial, a Phase 3 study published in the New England Journal of Medicine.
Sanyal AJ, Newsome PN, et al. "Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis." N Engl J Med. 2025;392(21):2089-2099.
PubMed: 40305708 →Study Design
1,197 patients with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomized 2:1 to receive once-weekly semaglutide 2.4 mg or placebo for 240 weeks. Results from a planned interim analysis at 72 weeks were the basis for approval.
Primary Endpoints
| Endpoint | Semaglutide | Placebo | Difference |
|---|---|---|---|
| MASH resolution without worsening fibrosis | 62.9% | 34.1% | +28.8% |
| Fibrosis improvement ≥1 stage | 37.0% | 22.5% | +14.5% |
| Both endpoints achieved | 32.8% | 16.2% | +16.6% |
These results were highly statistically significant (p<0.001 for both primary endpoints).
"There is a major unmet need for therapeutics for patients with MASH who have started scarring down their liver, but have not yet progressed to cirrhosis. Semaglutide met the criteria for regulatory approval by showing improvement in liver histology." — Arun J. Sanyal, MD, Director, Stravitz-Sanyal Institute for Liver Disease, VCU
How Semaglutide Helps the Liver
MASH develops through multiple pathways: insulin resistance, lipotoxicity, oxidative stress, and inflammation. Semaglutide addresses several of these:
Weight loss: Reduces visceral fat and hepatic fat content. In the ESSENCE trial, participants lost an average of 10.5% body weight.
Improved insulin sensitivity: Reduces insulin resistance, a key driver of hepatic fat accumulation.
Direct liver effects: Some evidence suggests GLP-1 receptors in the liver may mediate direct anti-inflammatory and anti-fibrotic effects, though this is less established.
Reduced de novo lipogenesis: May decrease the liver's production of new fat.
Semaglutide vs. Resmetirom
With two MASH drugs now approved, how do they compare?
Resmetirom (Rezdiffra)
Thyroid hormone receptor-β agonist. Once-daily oral pill. MASH resolution: 26-30%. Fibrosis improvement: 24-26%. Annual cost: ~$47,400.
Semaglutide (Wegovy)
GLP-1 receptor agonist. Once-weekly injection. MASH resolution: 63%. Fibrosis improvement: 37%. Annual cost: ~$15,000-18,000.
On efficacy alone, semaglutide appears stronger. But direct head-to-head comparison isn't available, and trial designs differed. Semaglutide's results were at 72 weeks; resmetirom's primary results were at 52 weeks.
Key advantages of semaglutide: also treats obesity, type 2 diabetes, and reduces cardiovascular events. Most MASH patients have metabolic comorbidities that semaglutide addresses simultaneously.
Tirzepatide in the Pipeline
Tirzepatide (Mounjaro/Zepbound), the dual GIP/GLP-1 agonist, showed even more impressive results in a Phase 2 MASH trial:
| Outcome (52 weeks) | Tirzepatide 15mg | Placebo |
|---|---|---|
| MASH resolution | 62% | 10% |
| Fibrosis improvement ≥1 stage | 51% | 30% |
The SYNERGY-OUTCOMES trial (Phase 3) is now underway, comparing tirzepatide and retatrutide (a triple agonist) for major adverse liver outcomes. Results expected ~2028.
Loomba R, et al. "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis." N Engl J Med. 2024.
NEJM →The Bigger Picture: Metabolic Disease Convergence
MASH doesn't exist in isolation. Most patients with MASH also have obesity, type 2 diabetes, hypertension, and/or cardiovascular disease. Historically, these were treated separately with different medications.
Semaglutide's MASH approval represents a paradigm shift. One medication can now treat:
✓ Obesity (weight loss)
✓ Type 2 diabetes (glycemic control)
✓ Cardiovascular risk (SELECT trial)
✓ MASH with fibrosis (liver protection)
For patients with multiple metabolic conditions—which is most MASH patients—this simplifies treatment considerably.
The approval is for noncirrhotic MASH with moderate to advanced fibrosis (F2-F3). It's not approved for patients with decompensated cirrhosis or early-stage fatty liver without fibrosis. A 48-week trial of semaglutide in patients with cirrhosis showed it did NOT reverse cirrhosis, though it was safe to use.
Diagnosis Challenge
One barrier to MASH treatment: diagnosis requires liver biopsy. Many patients with MASH are undiagnosed because routine blood tests and imaging don't definitively identify it.
Importantly, neither resmetirom nor semaglutide prescribing information requires liver biopsy for diagnosis. Non-invasive tests (FibroScan, blood biomarkers) can identify patients likely to benefit. But many clinicians are still learning how to diagnose MASH without biopsy.
Access and Insurance
Many patients already taking semaglutide for diabetes or obesity will benefit from its liver effects without needing additional approval. The MASH indication expands access for patients who have MASH but don't meet criteria for diabetes or obesity indications.
Insurance coverage varies. Some plans may require prior authorization or step therapy (trying lifestyle modification first). The MASH indication may help patients who were denied coverage for obesity get approved based on liver disease.
Semaglutide is now the second FDA-approved treatment for MASH and arguably the most practical first-line option for patients with metabolic comorbidities. Its ability to simultaneously address obesity, diabetes, cardiovascular risk, and liver disease makes it uniquely suited for the typical MASH patient. With tirzepatide in Phase 3 trials, even more effective options may be coming.