For many years, the primary recommendation for managing fatty liver disease was limited to lifestyle changes such as diet and exercise. However, the therapeutic landscape for the more severe form, metabolic dysfunction-associated steatohepatitis (MASH), has dramatically changed with the recent approval of targeted medications. Previously known as nonalcoholic steatohepatitis (NASH), MASH is an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by liver inflammation and scarring, or fibrosis. While lifestyle interventions remain crucial, these new drug therapies offer a powerful tool to directly combat the disease's progression.
Resmetirom (Rezdiffra): A Targeted Thyroid Hormone Receptor Agonist
Resmetirom (brand name Rezdiffra) was the first drug specifically approved by the FDA for treating MASH with moderate to advanced liver fibrosis (stage F2 or F3). This oral, once-daily medication offers a novel approach by targeting a specific protein involved in metabolism within the liver itself.
Mechanism of Action
Resmetirom is a selective thyroid hormone receptor-beta (THR-β) agonist. In the liver, the THR-β receptor is critical for regulating fat metabolism. By activating this receptor, Rezdiffra significantly boosts the liver's ability to process and clear accumulated fat. This targeted action reduces both liver fat and inflammation, which are key drivers of MASH progression. By acting primarily in the liver, it avoids systemic effects that might be seen with other thyroid hormone treatments.
Efficacy and Target Population
Clinical trials have shown Rezdiffra's effectiveness in resolving MASH and improving fibrosis in a significant portion of patients. The approval is based on improvements observed in liver biopsies at 12 months in noncirrhotic adults with F2 or F3 fibrosis. It is not currently approved for patients with decompensated cirrhosis.
Semaglutide (Wegovy): A GLP-1 Receptor Agonist
In August 2025, the FDA approved another major therapy for MASH: a weekly injectable form of semaglutide (brand name Wegovy). Primarily known for its use in weight loss and diabetes management, semaglutide's benefits in MASH are driven largely by its effect on cardiometabolic health.
Mechanism of Action
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. While its direct effect on the liver is less pronounced than resmetirom, its primary benefit stems from promoting significant weight loss and improving metabolic factors like insulin resistance. These metabolic improvements lead to a reduction in liver fat and inflammation. Semaglutide does not directly target fibrotic pathways, but its metabolic effects can reduce the progression of fibrosis over time.
Efficacy and Target Population
Clinical trials demonstrated that a greater percentage of patients receiving semaglutide achieved resolution of MASH without worsening fibrosis compared to placebo. It is indicated for adults with noncirrhotic MASH and moderate to advanced fibrosis (F2-F3), and should be used alongside diet and exercise.
Off-Label and Investigational Treatments
Older Therapies
Historically, other medications have been used off-label for MASH with varying success, though they lack specific FDA approval for this condition.
- Pioglitazone: This thiazolidinedione, used for type 2 diabetes, can improve insulin sensitivity and liver function tests, as well as reduce liver fat and inflammation. However, it comes with side effects like weight gain and fluid retention, and its effect on fibrosis has been inconsistent.
- Vitamin E: High doses of vitamin E have been shown to improve liver inflammation in some non-diabetic patients but without a significant effect on fibrosis. Concerns about potential safety issues with long-term high-dose use remain.
Combination and Future Therapies
Due to the complex nature of MASH, a single drug may not be a complete solution for all patients. Research is actively exploring new and combination therapies. Novel drug classes being investigated include FXR agonists, FGF21 analogs, and pan-PPAR agonists, aiming to address different aspects of the disease pathophysiology.
Comparison of MASH Pharmacological Therapies
| Feature | Resmetirom (Rezdiffra) | Semaglutide (Wegovy) | Pioglitazone (Off-label) |
|---|---|---|---|
| Mechanism | Selective THR-β agonist (liver fat metabolism) | GLP-1 receptor agonist (metabolic improvement, weight loss) | PPAR-γ agonist (insulin sensitivity) |
| Administration | Oral, once daily | Subcutaneous injection, weekly | Oral, once daily |
| Primary Effect | Direct reduction of liver fat and inflammation | Indirect reduction of liver fat via weight loss and metabolic changes | Improvement of insulin resistance, reduces liver fat |
| Fibrosis Impact | Resolution or improvement shown in clinical trials | Improves fibrosis without worsening steatohepatitis in some patients | Variable effect, may reduce progression but not consistently proven to reverse |
| Side Effects | Diarrhea, nausea, pruritus, potential hepatotoxicity | Nausea, diarrhea, vomiting, constipation, potential gallbladder issues | Weight gain, fluid retention, potential cardiovascular risk |
| FDA Approval for MASH | Yes (moderate/advanced fibrosis, noncirrhotic) | Yes (moderate/advanced fibrosis, noncirrhotic) | No (used off-label for T2D/insulin resistance) |
The Foundational Role of Lifestyle Modifications
Regardless of medication use, lifestyle changes remain the cornerstone of treatment for fatty liver disease and MASH. The medications are intended to be used in conjunction with, not in place of, a healthy diet and regular exercise. A 7–10% body weight loss can significantly improve liver inflammation and fibrosis.
- Balanced Diet: Reducing calorie intake, particularly from saturated fats and sugars, is critical. A Mediterranean-style diet or a low-carbohydrate approach has shown promise.
- Regular Exercise: Aim for at least 150 minutes of moderate-intensity activity per week. Exercise helps reduce liver fat, even without significant weight loss.
- Weight Management: Sustained weight loss is one of the most effective strategies for reversing liver damage in fatty liver disease.
- Alcohol Limitation: Abstaining from or significantly reducing alcohol consumption is essential for liver health.
Conclusion: A New Era for MASH Treatment
For those asking "what drug is used to reverse fatty liver?", the answer is now more complex and hopeful than ever before. With the FDA approval of Resmetirom (Rezdiffra) and Semaglutide (Wegovy), there are finally targeted pharmaceutical interventions for noncirrhotic MASH patients with moderate to advanced fibrosis. These drugs, combined with continued adherence to lifestyle changes, represent a significant advancement in the fight against this progressive liver disease. While challenges remain, including treatment of patients with cirrhosis and further exploring combination therapies, the future of MASH treatment is increasingly optimistic. It is important for patients to discuss these options with a healthcare provider to determine the best course of action for their individual needs. For more information, the American Liver Foundation provides comprehensive resources on liver health and disease at liverfoundation.org.
