GLP-1 Medications and MASH (Metabolic Dysfunction-Associated Steatohepatitis)

What Is MASH?

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD). The nomenclature was updated in 2023 by a multi-society consensus to more accurately reflect the metabolic drivers of the disease and to reduce stigma associated with the term "nonalcoholic."

MASH is characterized by fat accumulation in the liver (steatosis) accompanied by inflammation (hepatitis) and liver cell damage (ballooning), which can lead to progressive fibrosis (scarring). If untreated, MASH can advance to cirrhosis, liver failure, and hepatocellular carcinoma (liver cancer). MASH is now considered one of the leading causes of liver transplantation in the United States.

The condition is strongly associated with obesity, type 2 diabetes, insulin resistance, and metabolic syndrome. An estimated 6 to 8 million adults in the United States may have MASH with moderate-to-advanced fibrosis, though the exact prevalence is difficult to determine because MASH can only be definitively diagnosed through liver biopsy. Many people with MASH are undiagnosed because the condition is often asymptomatic in its earlier stages.

There is no single widely adopted noninvasive test that definitively diagnoses MASH, though combinations of blood-based biomarkers, imaging techniques such as FibroScan (transient elastography), and MRI-based methods are used to assess liver fat, inflammation, and fibrosis severity. Liver biopsy remains the reference standard for confirming MASH and staging fibrosis.

Current FDA-Approved Treatments for MASH

As of this writing, the FDA has approved one medication specifically for MASH. On March 14, 2024, the FDA granted accelerated approval to Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic MASH with moderate-to-advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Rezdiffra is an oral thyroid hormone receptor-beta (THR-beta) selective agonist and is the first drug approved for MASH.

Rezdiffra's approval was based on the MAESTRO-NASH trial, a phase 3 study in which the drug demonstrated statistically significant improvements in MASH resolution and fibrosis improvement compared to placebo at 52 weeks on liver biopsy endpoints. Because the approval was granted under the accelerated pathway, continued approval is contingent on verification of clinical benefit in an ongoing confirmatory trial.

Prior to Rezdiffra's approval, there were no FDA-approved pharmacological treatments for MASH. Management relied primarily on lifestyle modifications, including weight loss of 7 to 10 percent or more of body weight through diet and exercise, which studies have shown can improve liver histology in some patients. Bariatric surgery has also demonstrated improvements in MASH in patients with severe obesity, but it is a major surgical intervention with its own risks.

It is important to note that no GLP-1 receptor agonist is currently FDA-approved for the treatment of MASH. Any use of GLP-1 medications for MASH is considered investigational or off-label.

GLP-1 Receptor Agonists Under Investigation for MASH

Despite the absence of an FDA-approved indication, GLP-1 receptor agonists have generated substantial clinical interest as potential treatments for MASH due to their effects on body weight, insulin resistance, and inflammation, all of which are central to MASH pathophysiology. Two agents in particular have been studied or are being studied in dedicated MASH trials.

Semaglutide was evaluated in a phase 2 trial published in the New England Journal of Medicine in 2021 (Newsome et al.). This randomized, double-blind, placebo-controlled study enrolled 320 patients with biopsy-confirmed NASH (now MASH) and liver fibrosis stages F1 through F3. Patients received subcutaneous semaglutide at doses of 0.1 mg, 0.2 mg, or 0.4 mg daily (note: these are daily doses, different from the weekly dosing used in Ozempic or Wegovy) or placebo for 72 weeks.

The highest dose of semaglutide (0.4 mg daily) resulted in NASH resolution without worsening of fibrosis in 59 percent of patients, compared to 17 percent with placebo. However, the study did not demonstrate a statistically significant improvement in fibrosis stage, which is considered the most clinically important endpoint because fibrosis progression drives long-term liver outcomes. While the results were considered promising for MASH resolution, the fibrosis findings were a notable limitation.

Tirzepatide has been evaluated in the SYNERGY-NASH trial (published in the New England Journal of Medicine in 2024), a phase 2 randomized, double-blind, placebo-controlled study in patients with biopsy-confirmed MASH and moderate-to-severe fibrosis (stages F2 and F3). The trial evaluated multiple doses of tirzepatide over 52 weeks. Results showed that tirzepatide at the highest dose (15 mg weekly) achieved MASH resolution without worsening of fibrosis in a significantly greater proportion of patients compared to placebo. Importantly, tirzepatide also demonstrated improvements in fibrosis of at least one stage in a meaningfully greater proportion of patients versus placebo, a result that distinguished it from the earlier semaglutide phase 2 data.

Additionally, Eli Lilly has initiated the SURMOUNT-MASH trial (NCT06309992), a phase 3 study evaluating tirzepatide in participants with MASH. This trial is designed to generate the data that could potentially support an FDA submission for a MASH indication. The study is ongoing, and results are not yet available as of this writing.

Clinical Trial Data in Context

The clinical trial data for GLP-1 receptor agonists in MASH should be interpreted with appropriate caution.

The semaglutide phase 2 data demonstrated meaningful MASH resolution but did not show statistically significant fibrosis improvement. A phase 3 trial would be needed to confirm whether higher doses, longer treatment durations, or different formulations of semaglutide could achieve fibrosis improvement. As of this writing, no phase 3 trial of semaglutide specifically for a MASH indication has reported results.

The tirzepatide SYNERGY-NASH data were more encouraging on the fibrosis endpoint, but this was a phase 2 study with a relatively small sample size and 52-week duration. Phase 3 confirmation through the SURMOUNT-MASH trial is required before any conclusions about efficacy can be drawn at a regulatory level. Phase 2 results do not always replicate in larger phase 3 studies.

It is also worth noting that the endpoints used in MASH trials, particularly histological improvement assessed by liver biopsy, involve a degree of variability and subjectivity. Additionally, the relationship between histological improvement at 52 or 72 weeks and long-term clinical outcomes (such as prevention of cirrhosis, liver failure, or death) has not been fully established, which is one reason the FDA used the accelerated approval pathway for Rezdiffra rather than a traditional approval.

Important Caveats

No GLP-1 receptor agonist, including semaglutide (Ozempic, Wegovy), tirzepatide (Mounjaro, Zepbound), liraglutide (Victoza, Saxenda), or any other agent in this class, is FDA-approved for the treatment of MASH. Any claims that a GLP-1 medication is an approved treatment for MASH or fatty liver disease are inaccurate as of this writing.

Patients with suspected or diagnosed MASH should consult a hepatologist or gastroenterologist for disease evaluation and management. The only FDA-approved pharmaceutical treatment for MASH is currently Rezdiffra (resmetirom), which is indicated for a specific subset of patients with noncirrhotic MASH and moderate-to-advanced fibrosis.

While weight loss from any means, including GLP-1 medications, may improve liver fat and inflammation, this should not be conflated with an established treatment for MASH. The decision to use any medication for an off-label purpose should be made in consultation with a healthcare provider who can weigh the potential benefits and risks for the individual patient.

Patients should be cautious about information sources that overstate the evidence for GLP-1 medications in MASH. The clinical data are promising but preliminary, and the regulatory process exists to ensure that treatments are proven safe and effective before they are marketed for specific conditions.

This content is for informational purposes only and does not constitute medical advice. Individuals should consult a qualified healthcare provider to discuss whether any treatment is appropriate for their specific medical situation.