Patients diagnosed with fatty liver disease may still be told that the main options are monitoring liver enzymes, losing weight through diet and exercise, and reducing alcohol intake. The condition is now generally called metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD. Its inflammatory form is called metabolic dysfunction-associated steatohepatitis (MASH), formerly NASH.¹

Lifestyle modification remains foundational, but it is no longer the entire treatment conversation. For selected adults with noncirrhotic MASH and moderate-to-advanced fibrosis, FDA-approved medications can improve MASH and fibrosis on liver histology. Both current MASH drug indications received accelerated approval, however, so ongoing studies are still determining whether these improvements translate into fewer cases of cirrhosis, liver failure, transplantation, or liver-related death.^2–4

GLP-1–Based Therapy

Semaglutide (Wegovy): FDA-Approved for MASH

Wegovy injection is FDA-approved for adults with noncirrhotic MASH and moderate-to-advanced fibrosis consistent with stages F2-F3. This indication applies to the injectable formulation, not Wegovy tablets, and the medication is prescribed in conjunction with a reduced-calorie diet and increased physical activity. Approval was granted under the FDA’s accelerated approval pathway based on improvement in MASH and fibrosis.³

In the phase 3 ESSENCE trial, approximately 63% of patients receiving once-weekly semaglutide achieved MASH resolution without worsening of fibrosis, compared with approximately 34% receiving placebo. Fibrosis improvement without worsening of MASH occurred in approximately 37% versus 22%, respectively. Patients receiving semaglutide also lost an average of approximately 10.5% of their body weight, compared with 2% in the placebo group.⁵

These results demonstrate meaningful improvement in liver inflammation, metabolic health, and fibrosis for appropriately selected patients. They do not mean that every patient will respond, that all fibrosis will disappear, or that semaglutide is FDA-approved for uncomplicated liver fat or mild F0-F1 disease.^3,5

The MASH indication may also create a different insurance-coverage pathway from a prescription submitted only for weight management. A patient whose plan excludes weight-loss medications may still be evaluated under the plan’s criteria for treatment of noncirrhotic F2-F3 MASH. This does not guarantee coverage. Insurers may require prior authorization, documentation of fibrosis severity, supporting laboratory or imaging results, specialist evaluation, or biopsy findings, depending on the individual plan.^3,6

When semaglutide is clinically appropriate, the associated weight loss can also help address obesity, insulin resistance, diabetes, and other metabolic factors that contribute to MASLD progression.^2,5

Tirzepatide (Zepbound): Promising but Not Specifically FDA-Approved for MASH

Tirzepatide has also produced encouraging liver results. In the phase 2 SYNERGY-NASH trial involving patients with MASH and F2-F3 fibrosis, tirzepatide produced significantly higher rates of MASH resolution without worsening fibrosis than placebo. The trial also showed evidence of fibrosis improvement, although larger and longer studies are needed to establish effects on liver-related clinical outcomes.⁷

As of June 2026, Zepbound is not FDA-approved specifically for MASLD or MASH. Its current FDA indications include chronic weight management and treatment of moderate-to-severe obstructive sleep apnea in adults with obesity. It may still be an appropriate option when a patient independently meets one of its approved indications.⁸

In a head-to-head obesity trial involving adults without diabetes, tirzepatide produced greater average weight loss than semaglutide at 72 weeks. That finding supports its effectiveness as an obesity treatment, but it should not be interpreted as proof that tirzepatide produces better liver outcomes than semaglutide.⁹

Rezdiffra (Resmetirom): Targeted Liver Therapy

Rezdiffra became the first FDA-approved medication for adults with noncirrhotic NASH/MASH and moderate-to-advanced F2-F3 fibrosis. It is used in conjunction with diet and exercise and was approved under the accelerated approval pathway based on improvement in MASH and fibrosis.⁴

Rezdiffra is a thyroid hormone receptor-beta agonist with liver-directed activity. Activation of these receptors affects metabolic pathways involved in liver fat and lipid metabolism. Although the medication preferentially targets the receptor subtype found predominantly in the liver, measurable changes in thyroid laboratory values can occur, so it should not be described as having no systemic thyroid effects.⁴

A biopsy is not explicitly required by the FDA-approved Rezdiffra indication. The pivotal clinical trial enrolled patients with biopsy-confirmed disease, but AASLD guidance allows clinicians to identify appropriate F2-F3 candidates using reliable noninvasive evidence or biopsy findings, depending on the clinical circumstances. Insurance companies may impose their own documentation requirements.^4,10

In the phase 3 MAESTRO-NASH trial, MASH resolution without worsening fibrosis occurred in 25.9% of patients receiving 80 mg of resmetirom and 29.9% receiving 100 mg, compared with 9.7% receiving placebo. Improvement of fibrosis by at least one stage without worsening of disease activity occurred in 24.2%, 25.9%, and 14.2%, respectively.¹¹

Rezdiffra also reduced LDL cholesterol by approximately 14%-16% in the pivotal trial. This is a favorable metabolic effect, but it should not yet be described as proven prevention of heart attack, stroke, or other cardiovascular events because dedicated cardiovascular-outcome evidence has not established that benefit.¹¹

Safety and medication interactions must be reviewed before treatment. Rezdiffra labeling includes warnings concerning possible hepatotoxicity and gallbladder-related adverse events. It can also increase exposure to certain statins, which may require statin dose limits and closer monitoring. Use should be avoided in patients with decompensated cirrhosis.⁴

Our Assessment and Monitoring Approach

We can begin with a review of liver enzymes, platelet count, metabolic risk factors, prior imaging, medication history, and alcohol exposure. We may calculate a validated fibrosis-risk score such as FIB-4 and arrange FibroScan, also called vibration-controlled transient elastography, when appropriate.^2,10

FibroScan is a noninvasive test that measures liver stiffness and provides a controlled attenuation parameter estimate of liver fat. It can help identify patients at low or increased risk of clinically significant fibrosis. However, it estimates fibrosis risk rather than perfectly reproducing a biopsy-defined fibrosis stage, and results must be interpreted alongside laboratory findings, imaging, medical history, and the overall clinical picture.^2,10

Based on this assessment, available biopsy findings, and current prescribing guidance, we can determine whether a patient appears to meet the criteria for Wegovy injection or Rezdiffra and coordinate care with a gastroenterologist or hepatologist when needed. Liver biopsy may still be appropriate when noninvasive results are uncertain, competing liver diseases are suspected, or the result would materially change treatment.^3,4,10,12

Follow-up laboratory testing and noninvasive fibrosis assessments may be used to monitor safety and trends over time. No single blood test or FibroScan result can independently prove histologic resolution, however, so treatment response should be evaluated using the complete clinical picture.^10,12

Comprehensive Management Strategy

• Early or mild disease, generally F0-F1: Emphasize sustainable nutrition changes, regular physical activity, weight management, diabetes control, cardiovascular-risk reduction, and individualized alcohol counseling. GLP-1–based treatment may be used when the patient separately meets an approved indication such as obesity, or type 2 diabetes. Mild steatosis by itself does not establish eligibility for the FDA-approved MASH indications.^2,3,8
• Noncirrhotic MASH with F2-F3 fibrosis: Consider Wegovy injection, Rezdiffra, or an individualized treatment strategy after confirming that the patient appears to meet the applicable indication and after reviewing contraindications, medication interactions, comorbidities, treatment goals, and insurance criteria.^3,4,10,12
• Possible combination treatment: Semaglutide and resmetirom act through different pathways and may sometimes be considered when a patient has separate reasons to receive each therapy. However, the combination has not been directly studied for additive histologic efficacy or long-term safety, and there is no combination-specific FDA approval. It should therefore be described as an individualized, approach rather than an established standard regimen.¹²
• Metabolic optimization: Treat obesity, diabetes, dyslipidemia, and hypertension according to current evidence-based standards. GLP-1 receptor agonists, dual GIP/GLP-1 therapy, or SGLT2 inhibitors may be appropriate depending on the patient’s diabetes, obesity, cardiovascular, and kidney indications. Statins are considered safe in MASLD and compensated cirrhosis and should not be withheld when indicated for cardiovascular-risk reduction.²
• Cirrhosis or suspected F4 disease: Refer to hepatology for specialized management. Patients may require evaluation for portal hypertension, liver decompensation, hepatocellular carcinoma surveillance, transplantation risk, and other cirrhosis-specific care. The current MASH indications for Wegovy and Rezdiffra apply to noncirrhotic disease and should not be automatically extrapolated to F4 cirrhosis.^2–4

Important Safety Considerations

These medications are not appropriate for every patient. Wegovy has a boxed warning concerning thyroid C-cell tumors observed in rodents and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Its labeling also includes warnings concerning pancreatitis, gallbladder disease, volume-depletion kidney injury, severe gastrointestinal adverse reactions, diabetic retinopathy complications, and other risks.³

Medication selection should account for pregnancy or plans for pregnancy, cirrhosis status, gastrointestinal disease, gallbladder history, concurrent diabetes medications, statins and other drug interactions, kidney function, and the patient’s broader medical history. Treatment should be prescribed and monitored by a qualified healthcare professional after an individualized risk-benefit assessment.^3,4,8

This material is for general educational purposes and does not replace individualized diagnosis or medical care. FDA indications, professional guidance, and insurance criteria may change.

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References

1. Kanwal F, Neuschwander-Tetri BA, Loomba R, Rinella ME. Metabolic dysfunction-associated steatotic liver disease: update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease. Hepatology. 2024;79(5):1212-1219. doi:10.1097/HEP.0000000000000670
2. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835. doi:10.1097/HEP.0000000000000323
3. National Library of Medicine. Wegovy (semaglutide) injection and tablets: prescribing information. DailyMed. Revised May 2026. Accessed June 21, 2026. View current prescribing information.
4. National Library of Medicine. Rezdiffra (resmetirom): prescribing information. DailyMed. Updated December 22, 2025. Accessed June 21, 2026. View current prescribing information.
5. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258
6. Centers for Medicare & Medicaid Services. Drug plan rules. Medicare.gov. Accessed June 21, 2026. View Medicare drug-plan rules.
7. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391(4):299-310. doi:10.1056/NEJMoa2401943
8. National Library of Medicine. Zepbound (tirzepatide): prescribing information. DailyMed. Updated April 22, 2026. Accessed June 21, 2026. View current prescribing information.
9. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025;393:26-36. doi:10.1056/NEJMoa2416394
10. Chen VL, Morgan TR, Rotman Y, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology. 2025;81(1):312-320. doi:10.1097/HEP.0000000000001112
11. Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000
12. Bansal MB, Patton HM, Morgan TR, et al. Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: November 2025 updates to AASLD Practice Guidance. Hepatology. 2026;83(5):1326-1340. doi:10.1097/HEP.0000000000001608