What is MASH (Metabolic Dysfunction-Associated Steatohepatitis)?
MASH is the most severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), a condition characterized by fat accumulation in the liver due to metabolic dysfunction. Most patients with MASH are asymptomatic in early stages. Symptoms in later stages may include fatigue, itchy skin, abdominal swelling, shortness of breath and jaundice. If left untreated, MASH can progress to fibrosis, cirrhosis, liver cancer and ultimately liver failure requiring liver transplant
Diagnosing MASH remains challenging, especially in early stages when symptoms are absent, minimal, or mimic other conditions like cirrhosis, obesity or type 2 diabetes.
In 2023, the medical community shifted terminology from NAFLD/NASH to MASLD/MASH to better reflect the metabolic roots of the disease.
As of 2025, MASLD affects approximately 33.7% of U.S. adults, while MASH impacts an estimated 1.0% to 7.9%, depending on diagnostic methods and disease progression. It’s not entirely clear what causes MASLD and MASH to develop in some people and not others, but the conditions are closely linked to cardiodiabesity – a cluster of conditions including obesity, diabetes and cardiovascular disease – and may have genetic links.
MASH (fatty liver) treatment development challenges
Key challenges currently facing MASH treatment development include:
- Limited efficacy of current therapies: While drugs like Resmetirom have shown promise, the improvement over placebo remains modest—typically around 20–30% for MASH resolution and 10–15% for fibrosis improvement. This highlights the need for more potent or combination therapies.
- Challenges in treating cirrhotic MASH: Patients with advanced fibrosis (stage 4) represent the highest disease burden and risk for liver-related consequences. However, most current therapies are focused on non-cirrhotic MASH, leaving a significant gap in treatment options for the most advanced population.
- Reliance on invasive diagnostics: Liver biopsy remains the gold standard for assessing disease progression and treatment efficacy. Despite advances in non-invasive technologies (NITs), they still lack the sensitivity and specificity needed to fully replace biopsy, complicating patient recruitment and retention in trials.
- Standardization of biopsy handling: Variability in biopsy sample preparation — such as fixation type and exposure time — can affect histological assessments and data reliability. This is especially critical as AI tools begin to assist in fibrosis scoring, requiring consistent sample quality.
- Complex disease pathophysiology: MASH involves multiple overlapping mechanisms — lipotoxicity, inflammation, immune cell infiltration, and fibrosis. This complexity makes it difficult to develop single-target therapies, pushing the field toward combinatorial approaches that address multiple pathways simultaneously.
What does fatty liver treatment look like in the near future?
Advancements in non-invasive diagnostics — such as ultrasound and MRI elastography — are making it easier to detect liver stiffness and scarring, potentially replacing biopsies in the future.
Meanwhile, the drug development pipeline is heating up. Over 500 therapies are currently in development globally, with several showing promise:
- Pegozafermin (89bio): A fibroblast growth factor 21 (FGF21) analog in Phase III trials, Pegozafermin has shown strong efficacy in reducing liver fibrosis and resolving MASH without worsening fibrosis. It also boasts a favorable safety profile with minimal gastrointestinal side effects
- Efruxifermin (Akero Therapeutics): Another FGF21 analog, Efruxifermin has demonstrated reversal of cirrhosis in long-term trials and is being tested in multiple Phase III studies. It targets both liver and adipose tissue to correct metabolic imbalances
- Denifanstat (Sagimet): A fatty acid synthase (FASN) inhibitor, Denifanstat directly reduces hepatic fat accumulation — a key driver of MASH. It has shown significant histologic improvements in Phase IIb trials and is now in Phase III
- Efimosfermin Alfa (Boston Pharmaceuticals): A long-acting FGF21 fusion protein, Efimosfermin alfa is being developed for once-monthly dosing and has shown promising Phase II results. It is entering Phase III trials soon
- VK2809 (Viking Therapeutics): A thyroid hormone receptor-β agonist, VK2809 achieved MASH resolution in up to 75% of patients in Phase IIb trials. It is being considered for combination therapy with GLP-1 agents
- Resmetirom (Madrigal Pharmaceuticals): The first FDA-approved treatment for MASH, Resmetirom is a thyroid hormone receptor-β agonist. While already on the market, ongoing trials aim to expand its indications and validate long-term safety
- Lanifibranor (Inventiva Pharma): An oral peroxisome proliferator-activated receptor (PPAR) agonist has shown improved cardiovascular biomarkers in a Phase 2b trial, including dyslipidemia, insulin resistance, inflammation, and high blood pressure. It’s a promising option for patients with a high cardiovascular risk profile.
In addition to Resmetirom is another promising class of drugs: glucagon-like peptide-1 (GLP-1) agonists.
Can GLP-1 medications treat MASH?
GLP-1 medications like semaglutide and tirzepatide are currently used to treat diabetes and obesity.
These medications are emerging as a transformative treatment for metabolic dysfunction-associated steatohepatitis (MASH). In August 2025, the FDA approved Wegovy® (semaglutide) as the first GLP-1 therapy indicated for MASH in adults with moderate-to-advanced liver fibrosis. This approval was based on results from the Phase 3 ESSENCE trial, which showed that 63% of patients receiving Wegovy achieved MASH resolution without worsening fibrosis, and 37% experienced fibrosis improvement without worsening steatohepatitis — significantly outperforming placebo groups.
This milestone expands the clinical utility of GLP-1s beyond metabolic and cardiovascular health into hepatology, offering a much-needed therapeutic option for the estimated 15 million U.S. adults affected by MASH. The approval also underscores the growing recognition of liver disease as part of the broader metabolic syndrome spectrum. As GLP-1 therapies continue to evolve — with oral formulations and combination regimens in development — their role in liver health is expected to grow even further.
Going forward with MASH
As multiple therapies approach approval, it’s estimated that the MASH treatment market could swell to $108.4 billion worldwide by 2030. This expansion will create a paradigm shift within the industry as we devise the right proactive strategies to identify the patients who would benefit most from these therapies. Encouragingly, earlier detection combined with more effective therapies — such as Rezdiffra and Wegovy — could significantly transform care and outcomes for millions living with MASH.
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This article was created with the assistance of AI tools. It was reviewed, edited, and fact-checked by Evernorth’s editorial team and subject matter experts.
Originally published on 3/11/2024 and updated on 10/21/2025.
