Medical Policy

Policy Num:       05.001.051
Policy Name:     Pharmacologic Treatments for Metabolic Dysfunction-Associated Steatohepatitis
Policy ID:           [05.001.051] [Ac / B/ M+/ P-] [5.01.13]

Last Review:      November 13, 2025
Next Review:     November 20, 2026
 

Related Policies:

11.001.009- Noninvasive Techniques for the Evaluation and Monitoring of Patients With Chronic Liver Disease

Pharmacologic Treatments for Metabolic Dysfunction-Associated Steatohepatitis

Summary

Description

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD) and a part of the larger spectrum of liver disease. MASH is differentiated from other causes of steatohepatitis by the presence of metabolic dysfunction and exclusion of excessive alcohol intake. The clinical burden of MASH is related not only to the risk of cirrhosis and hepatocellular carcinoma, but also cardiovascular disease, chronic kidney disease, type 2 diabetes, and extrahepatic cancers. Although lifestyle modifications are the primary treatments for MASH, pharmacotherapeutic options are promising. Resmetirom, a liver-directed thyroid hormone receptor beta-selective agonist, was the first agent to receive FDA approval in adults with noncirrhotic MASH and moderate to advanced fibrosis in March 2024. This approval was quickly followed by the approval of semaglutide for the same indication in August 2025.

Summary of Evidence

For individuals with metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced fibrosis who receive resmetirom, the evidence includes an ongoing phase 3 randomized controlled trial (RCT). Relevant clinical outcomes include change in disease status, quality of life, hospitalizations, treatment-related mortality, and treatment-related morbidity; however, the FDA has outlined an accelerated approval pathway allowing for conditional approval based on achievement of either of 2 histologic endpoints (improvement in liver fibrosis stage or resolution of MASH) considered to be reasonably likely to predict clinical benefit. Although results for the clinical endpoints from the phase 3 MAESTRO-NASH trial are not yet available, week 52 histological results in 966 patients indicate significantly improved MASH resolution and fibrosis improvement with either resmetirom 80 mg or 100 mg daily compared with placebo. Safety findings identify diarrhea and nausea as the most common adverse effects with no documented resmetirom-related liver injury. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with MASH and moderate to advanced fibrosis who receive semaglutide, the evidence includes an ongoing phase 3 RCT and a nonrandomized study. Relevant clinical outcomes include change in disease status, quality of life, hospitalizations, treatment-related mortality, and treatment-related morbidity; however, the FDA has outlined an accelerated approval pathway allowing for conditional approval based on achievement of either of 2 histologic endpoints (improvement in liver fibrosis stage or resolution of MASH) considered to be reasonably likely to predict clinical benefit. Although results for the clinical endpoints from the phase 3 ESSENCE trial are not yet available, week 72 histological results in the first 800 enrolled patients indicate significantly improved MASH resolution and fibrosis improvement with 2.4 mg subcutaneous semaglutide once weekly compared with placebo. Secondary benefits included weight loss and reductions in liver stiffness and inflammatory markers. Gastrointestinal adverse events were more common with semaglutide, but serious adverse events and discontinuation rates were similar between groups. In the nonrandomized trial comparing semaglutide with endoscopic sleeve gastroplasty, semaglutide was superior in improving Fibrosis-4 (FIB-4) scores in patients with metabolic dysfunction-associated liver disease (MASLD) and fibrosis but the analysis is heavily limited by the small number of patients with fibrosis at baseline and the baseline differences between groups. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether the use of resmetirom and semaglutide improve the net heath outcome in individuals with metabolic dysfunction-associated steatohepatitis (MASH).

Policy Statements

Resmetirom may be considered medically necessary if all of the following conditions are met::

In conjunction with lifestyle intervention including diet, weight loss, and exercise, the member has the diagnosis of Metabolic dysfunction-associated steatohepatitis (MASH) diagnosis based upon the following criteria

• Adults age 18 or older
• Biopsy confirmed MASH - Stage F2 to F3 fibrosis based on histology. No evidence of cirrhosis.
• imaging-based noninvasive liver disease assessment with vibration-controlled transient elastrography (VCTE) liver stiffness measurement of 8 kPa to 15 kPa
• Stable body weight (±5%) for at least 3 months
• If diabetic, HbA1c ≤ 9.5% and stable glucose-lowering therapy.

Semaglutide may be considered medically necessary if all of the following conditions are met:

In conjunction with lifestyle intervention including diet, weight loss, and exercise, the member has the diagnosis of Metabolic dysfunction-associated steatohepatitis (MASH) diagnosis based upon the following criteria

• Adults aged 18 or older
• Histologically confirmed MASH/NASH with fibrosis stage F2–F3. No evidence of cirrhosis
• BMI ≥ 25 kg/m².
• Stable body weight for at least 3 months.
• If diabetic, HbA1c ≤ 10%.
• Liver biopsy within 6 months prior to screening or during screening.
• non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS) ≥4 with a score of 1 or more in steatosis, lobular inflammation, and hepatocyte ballooning or imaging-based noninvasive liver disease assessment with vibration-controlled transient elastrography (VCTE) liver stiffness measurement of ≥8.5 kPa

Resmetirom and semaglutide are considered investigational for MASH when cirrhosis is present.

Resmetirom and semaglutide are considered investigational for MASH without moderate or advanced fibrosis.

Resmetirom and semaglutide are considered investigational for all steatotic liver disease that is not MASH.

Policy Guidelines

In June 2023, the traditional nomenclature for non-alcoholic liver diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) was updated to more accurately reflect the underlying pathophysiology of the disease states. The modern terms, metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), respectively are the preferred terminology replacing NAFLD and NASH. This policy consistently uses the modern nomenclature.

Resmetirom

Dosing and Administration

The recommended dose of resmetirom is based on actual body weight. For individuals <100 kg the dose is 80 mg once daily and for individuals ≥100 kg the dose is 100 mg once daily.

Interactions

Concomitant use of resmetirom with strong CYP2C8 inhibitors is not recommended. If resmetirom is used concomitantly with a moderate CYP2C8 inhibitor, it is recommended that the dose of resmetirom be reduced to 60 mg once daily (if weight is <100 kg) or 80 mg once daily (if weight is ≥100 kg). The use of resmetirom in individuals with decompensated cirrhosis (consistent with moderate to severe hepatic impairment) should be avoided.

On Treatment Monitoring (from AASLD Practice Guidelines October 2024)

• Hepatic function panel testing should be obtained at baseline and at periodic intervals (eg, 3, 6, and 12 months) to determine response and adverse events while on resmetirom therapy. Resmetirom should be discontinued if hepatotoxicity develops, as defined by the AASLD drug-induced liver injury practice guidance. There are insufficient data to make a recommendation on monitoring after 12 months of resmetirom treatment but continued monitoring with hepatic function panel testing every 6 months is suggested.
• Among persons with known thyroid disease, standard laboratory monitoring (eg, TSH and free T₄) per established guidelines is recommended while receiving resmetirom therapy.
• Resmetirom can be used concurrently with statins; however, practitioners should be aware of the maximum recommended daily dosages, including atorvastatin 40 mg/d, pravastatin 40 mg/d, rosuvastatin 20 mg/d, and simvastatin 20 mg/d. Continued attention to comorbidity management including hyperlipidemia is recommended, particularly if the statin dose is modified at the outset of resmetirom therapy.
• In persons whose treatment candidacy was determined by liver stiffness measurements (VCTE ), a repeat measurement at 12 months of therapy is recommended to assess for treatment response.

Reauthorization

Rezdiffra will be approved based on all of the following criteria:
a. Documentation of positive clinical response to Rezdiffra therapy (e.g., improvement in or stabilization of fibrosis)
-AND

b. Patient has not progressed to cirrhosis
-AND

c. Prescribed by or in consultation with a gastroenterologist or hepatologist

Authorization will be issued for 12 months

Semaglutide

Dosing and Administration

The recommended dose of semaglutide is 2.4 mg subcutaneously once weekly. Treatment should be initiated at 0.25 mg once weekly for 4 weeks then 0.5 mg for weeks 5 to 8, 1 mg weeks 9 to 12, 1.7 mg weeks 13 to 16, with full dose anticipated from week 17 onward. If gastrointestinal adverse reactions are intolerable, dose escalation should be delayed for 4 weeks.

Boxed Warning

Semaglutide is associated with risk of thyroid C-cell tumors in rodents. It is unknown whether semaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Semaglutide is contraindicated in individuals with a personal or family history of MTC or in individuals with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

On Treatment Monitoring (no published guidelines for MASH)

• Hepatic function panel testing should be obtained at baseline and at periodic intervals (eg, 3, 6, and 12 months) to determine response and adverse events while on semaglutide therapy.
• Among persons with known thyroid disease, standard laboratory monitoring (eg, TSH and free T₄) per established guidelines is recommended while receiving semaglutide therapy.
• HgA1c quarterly if diabetes control is suboptimal, otherwise every 6-12 months

Reauthorization

Semaglutide will be approved based on all of the following criteria:
a. Documentation of positive clinical response to semaglutide therapy (e.g., improvement in or stabilization of fibrosis)
-AND

b. Patient has not progressed to cirrhosis
-AND

c. Prescribed by or in consultation with a gastroenterologist or hepatologist

Authorization will be issued for 12 months

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Background

Metabolic Dysfunction-Associated Steatohepatitis

Disease Background

Steatotic liver disease (SLD) is a generic term for the accumulation of lipids in liver parenchymal cells (i.e., fatty liver). The primary risk factors for SLD include alcohol, insulin resistance, and obesity. In 2023, a global consensus conference described 5 subclasses of SLD: metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD); alcohol-associated liver disease (ALD); SLD with specific etiology (e.g., drug-induced); cryptogenic SLD, and MASLD with increased alcohol intake (MetALD).^1, MASLD is characterized by hepatic steatosis (>5%) along with at least one cardiometabolic risk factor, no other causes of SLD, and minimal or no alcohol consumption. Cardiometabolic criteria are summarized in Table 1.

Table 1. Cardiometabolic Criteria for MASLD in Adults^1,

The subset of MASLD individuals with steatohepatitis are considered to have metabolic dysfunction-associated steatohepatitis (MASH, formerly nonalcoholic steatohepatitis [NASH]).^2,1, MASH is a more severe form of MASLD and is associated with lobular inflammation and apoptosis.^3, Approximately 20% of people with MASLD have MASH, and as MASH progresses fibrosis and cirrhosis can occur. MASH severity can be graded by use of the nonalcoholic fatty liver disease activity score (NAS), an 8-point scale classifying the severity of steatosis (score: 0-3), lobular inflammation (score: 0-3) and ballooning (score: 0-2), with greater scores equating more severe disease. In addition, the stage of fibrosis is also important for assessing the risk for severe liver disease as well as to guide management. Fibrosis severity is strongly correlated with morbidity and mortality. The stages of fibrosis are summarized Table 2.

Table 2. Fibrosis Stages^4,

Current Standard of Care

Treatment options for MASH have evolved significantly, with several promising pharmacologic agents emerging alongside lifestyle interventions.^5,6,7, Lifestyle modification—including weight loss through a hypocaloric diet and physical activity—remains the cornerstone of MASH management. These approaches can reduce hepatic steatosis and improve insulin sensitivity, even in the absence of pharmacotherapy. For individuals with biopsy-confirmed MASH and fibrosis (≥F2), pharmacologic options are increasingly considered. Pioglitazone and vitamin E have shown reduction in steatohepatitis without improvement in fibrosis, and concerns about efficacy and safety limit their use. Ursodeoxycholic acid (UDCA) has demonstrated biochemical improvements but lacks consistent histological efficacy. Recent clinical trials have introduced novel agents targeting key metabolic pathways. Glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide) and dual incretin agonists (e.g., tirzepatide) have shown robust effects on steatosis, inflammation, and weight reduction, with some evidence of fibrosis improvement. Resmetirom, a liver-specific thyroid hormone receptor belta-agonist, is the first FDA-approved drug for non-cirrhotic MASH with moderate to advanced fibrosis, demonstrating histological and biochemical benefits. Semaglutide Is the second FDA-approved agent for MASH.

Regulatory Status

Rezdiffra™ (resmetirom, Madrigal Pharmaceuticals, Inc.) was approved by the FDA in March 2024 for treatment of adults with MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), in conjunction with diet and exercise. The indication was approved under accelerated approval based on improvement of MASH and fibrosis. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.^8,

Wegovy® (semaglutide, Novo Nordisk) received an additional approval by the FDA in August 2025 for treatment of adults with MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), in conjunction with diet and exercise. The indication was approved under accelerated approval based on improvement of MASH and fibrosis. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.^9, Other indications for Wegovy include the reduction of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight; reduction of excess body weight and maintenance of weight reduction long term in adults and pediatric patients 12 years and older. The Ozempic® brand of semaglutide is also approved for type 2 diabetes indications.

Rationale

This evidence review was created in September 2025 with a search of the PubMed database. The most recent literature update was performed through September 4, 2025.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to individuals and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Metabolic Dysfunction-associated Steatohepatitis with Moderate to Advanced Fibrosis

Clinical Context and Therapy Purpose

Metabolic dysfunction-associated steatohepatitis (MASH), is a progressive liver disease characterized by the presence of at least 5% hepatic steatosis, along with hepatocellular damage and inflammation. This condition can develop into advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), all of which are linked to significant morbidity and mortality. In the United States, MASH ranks among the leading causes of HCC and is the second most common reason for liver transplantation after hepatitis C.^10, Once MASH advances to clinically significant fibrosis (stages F2 and F3), the risk of serious clinical outcomes rises. Cardiovascular incidents are the primary cause of death in individuals with MASH, with non-liver cancers being the second leading cause.^11,12, Liver-related complications also contribute to the overall mortality, though to a lesser extent.^13,

The purpose of resmetirom and semaglutide in patients who have MASH is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is adults (≥18 years of age) with noncirrhotic MASH with moderate to advanced (F2 or F3) fibrosis.

Interventions

The therapy being considered is resmetirom (Rezdiffra, Madrigal Pharmaceuticals, Inc.) and semaglutide (Wegovy, Novo Nordisk). ­Resmetirom and semaglutide are prescribed in combination with diet and exercise for the treatment of adults with MASH and moderate to advanced liver fibrosis, specifically stages F2 to F3. Resmetirom is a thyroid hormone receptor-beta (THR-β) agonist, administered orally once daily. In individuals with MASH, THR-β function in the liver is compromised, resulting in decreased mitochondrial function and β-oxidation of fatty acids, which contributes to increased fibrosis. Resmetirom activates THR-β in the liver, thereby reducing intrahepatic triglycerides, enhancing mitochondrial function, and ultimately decreasing fibrosis. Semaglutide is a GLP-1 receptor agonist which regulates appetite and caloric intake in the brain—the exact mechanism for MASH is not fully understood. It is administered as a weekly subcutaneous injection.

Comparators

The relevant comparators are standard medical management (lifestyle interventions, bariatric/weight-loss surgery, pharmacotherapy). Pioglitazone and vitamin E have been studied in patients with MASH, but are not considered standard care.

Outcomes

Owing to the unmet need for a treatment for MASH, the FDA has outlined an accelerated approval pathway allowing for conditional approval based on achievement of either of 2 histologic endpoints (improvement in liver fibrosis stage or resolution of MASH) considered to be reasonably likely to predict clinical benefit (Table 3).^14, Full FDA approval is based on reduction in clinical outcomes (all-cause mortality, liver transplantation, worsening of Model For End Stage Liver Disease (MELD) Score ≥15, hepatic encephalopathy, variceal hemorrhage, and ascites complications).^15,

Noninvasive risk score including the Fibrosis-4 (FIB-4), AST to platelet ratio index (APRI), and NAFLD fibrosis score (NAFLD) may help predict risk of more advanced liver disease and may be reported as surrogate outcomes.

.

Table 3. Histologic Primary Endpoints Relevant to Metabolic Dysfunction-Associated Steatohepatitis^16,

      NAS: Nonalcoholic fatty liver disease activity score.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Population Reference No. 1 

Resmetirom

Randomized Controlled Trials

Trial characteristics and results are summarized in Tables 4 and 5, respectively. Limitations can be found in Tables 6 and 7.

The phase 3 MAESTRO-NASH study (Harrison et al [2024]) is an ongoing, double-blind, RCT comparing resmetirom to placebo in patients with biopsy-proven MASH and significant fibrosis.^17, Patients included in the trial were adults with steatohepatitis, stage 1B to 3 fibrosis, and a NAS of at least 4 with at least 3 metabolic risk factors including: large waist or body mass index (BMI) ≥30 kg/m² (except for Asian patients who met criteria for obesity with BMI ≥27.5 kg/m²); dyslipidemia; hypertension; type 2 diabetes or documented insulin resistance.^18, Patients with alcohol consumption exceeding 20 g/day for women or 30 g/day for men and those with hemoglobin A1c (HbA1c) over 9% were excluded.^17, Notably patients were allowed GLP-1 agonist therapy if receiving stable doses for 24 weeks prior to biopsy; however, GLP-1 agonist initiation or titration was not allowed during the first 52 weeks of the study. Patients were randomized to resmetirom 80 mg daily, resmetirom 100 mg daily, or placebo. At baseline, the mean age was 56.6 years and most patients were White (89.3%), with a high incidence of metabolic risk factors (hypertension, 78.1%; dyslipidemia, 71.3%; and type 2 diabetes, 67.0%). A total of 21.1% of the patients were Hispanic; only 2.0% of the patients were Black. Most patients had F3 fibrosis (61.9%)—33.0% of patients had F2 fibrosis and 5.1% had F1B fibrosis. The dual primary endpoints of MAESTRO-NASH were MASH resolution (achievement of a hepatocellular ballooning score of 0, a lobular inflammation score of 0 or 1, and a reduction in the NAS by ≥2) with no fibrosis worsening and fibrosis improvement (≥1 stage) with no worsening NAS assessed at week 52 of treatment. The clinical primary endpoint is a composite outcome composed of all-cause mortality, liver transplant, and significant hepatic events including histologic progression to cirrhosis (time to event), which will be assessed at month 54 of treatment.^18, Both primary biopsy endpoints were significantly improved with resmetirom compared with placebo. The incidence of serious adverse events with similar with resmetirom and placebo with diarrhea and nausea the most commonly reported adverse events. There were no reports of resmetirom-related liver injury.

In order to expand the overall size of the safety database, the FDA evaluated the phase 3 MAESTRO-NAFLD-1 RCT (Harrison et al [2023]; NCT04197479) conducted in patients with MASLD and presumed MASH.^19,19, Patients were randomized to 3 double-blind arms (resmetirom 100 mg, n=325; resmetirom 80 mg, n=327; or placebo, n=320) or open-label resmetirom 100 mg (n=171). The primary endpoint was treatment-emergent adverse events (TEAEs) in this 52-week trial. Incidence of TEAEs was similar among groups: 86.5% of open-label resmetirom 100 mg-treated patients, 86.1% of double-blind resmetirom 100 mg-treated patients, 88.4% of resmetirom 80 mg-treated patients, and 81.8% of placebo-treated patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment.

Table 4. Summary of Key RCT Characteristics

      MASH: metabolic dysfunction-associated steatohepatitis; RCT: randomized controlled trial.

Table 5. Summary of Key RCT Results

   CI: confidence interval; LDL: low-density lipoprotein; MASH: metabolic dysfunction-associated steatohepatitis; LDL: low-density lipoprotein; NR: not reported; RCT: randomized controlled trial; TRAE: treatment-related adverse event. a MASH resolution with no fibrosis worsening at week 52. b Fibrosis improvement by ≥1 stage with no worsening of NAS at week 52. c LSM % change from baseline at week 24.

Table 6. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.  a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5. Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 7. Study Design and Conduct Limitations

   CI: confidence interval. The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other. b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other. e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

For individuals with metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced fibrosis who receive resmetirom, the evidence includes an ongoing phase 3 randomized controlled trial (RCT). Relevant clinical outcomes include change in disease status, quality of life, hospitalizations, treatment-related mortality, and treatment-related morbidity; however, the FDA has outlined an accelerated approval pathway allowing for conditional approval based on achievement of either of 2 histologic endpoints (improvement in liver fibrosis stage or resolution of MASH) considered to be reasonably likely to predict clinical benefit. Although results for the clinical endpoints from the phase 3 MAESTRO-NASH trial are not yet available, week 52 histological results in 966 patients indicate significantly improved MASH resolution and fibrosis improvement with either resmetirom 80 mg or 100 mg daily compared with placebo. Safety findings identify diarrhea and nausea as the most common adverse effects with no documented resmetirom-related liver injury. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Semaglutide

Randomized Controlled Trials

Trial characteristics and results are summarized in Tables 8 and 9, respectively. Limitations can be found in Tables 10 and 11.

The phase 3 ESSENCE study is an ongoing, double-blind, RCT comparing semaglutide to placebo in patients with biopsy-proven MASH and significant fibrosis. Sanyal et al published an interim analysis after enrollment of the first 800 patients at week 72.^20, Patients included in the trial had histologically documented steatohepatitis and liver fibrosis stage F2 or F3 and a NAS of at least 4. Patients with alcohol consumption exceeding 20 g/day for women or 30 g/day for men and those with HbA1c over 9.5% were excluded. Patients were randomized to weekly subcutaneous semaglutide 2.4 mg or placebo. At baseline, the mean age was 56.0 years and most patients were White (67.5%), with type 2 diabetes diagnosis in 55.9% of patients. Most patients had F3 fibrosis (68.8%) and the remainder had F2. The dual primary endpoints for this analysis were MASH resolution with no fibrosis worsening and fibrosis improvement (≥1 stage) with no worsening of steatohepatitis assessed at week 72 of treatment. Both primary biopsy endpoints were significantly improved with semaglutide compared with placebo. The percentage of patients who met the prespecified definition of a decrease in the enhanced liver fibrosis (ELF) score of 0.5 or more was 55.8% in the semaglutide group and 25.5% in the placebo group. The percentage of patients who met the response criteria for a decrease in liver stiffness of 30% or more was 52.0% with semaglutide and 30.3% with placebo. A total of 83.5% of patients maintained the target dose to week 72. Gastrointestinal adverse events were more common with semaglutide.

Table 8. Summary of Key RCT Characteristics

      RCT: randomized controlled trial; SC: subcutaneous.

Table 9. Summary of Key RCT Results

   AE: adverse event; CI: confidence interval; MASH: metabolic dysfunction-associated steatohepatitis; RCT: randomized controlled trial. a MASH resolution with no fibrosis worsening. b Fibrosis improvement by ≥1 stage with no worsening of steatohepatitis.

Table 10. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.  a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 11. Study Design and Conduct Limitations

   CI: confidence interval. The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other. b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other. e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Nonrandomized Trials

Kumar et al (2025) published a single-center, prospective, matched case-control study comparing endoscopic sleeve gastroplasty (ESG) with semaglutide in patients with MASLD.^22, Patients (N=273) with steatosis and at least one metabolic criterion per the AASLD undergoing ESG (n=220) or treatment with semaglutide (n=53) with at least 6 months follow-up were included. There were significant differences in baseline characteristics between groups at baseline. Patients in the semaglutide group were older, had lower BMI/weight, had more patients with elevated ALT, lower LDL, higher triglycerides, higher HbA1c, more type 2 diabetes, and higher Fibrosis-4 (FIB-4) scores. In a propensity score-matched analysis of FIB-4 scores in the subpopulation of those with baseline FIB-4 score greater than 1.3 (indicating fibrosis), semalgutide had significantly better improvement in FIB-4 scores (difference, 0.89; 95% CI, 0.70 to 1.07; p<.001) at 12 months; however, liver enzyme levels were similar between groups. The study is limited by the small number of patients with baseline fibrosis (29.2% with semaglutide and 0.4% with ESG), inability to fully control confounding factors, and use of FIB-4 as a surrogate outcomes.

The evidence for semaglutide in MASH with moderate to advanced fibrosis includes the ongoing phase 3 ESSENCE trial. Among the first 800 patients analyzed at week 72, 2.4 mg of weekly semaglutide led to significantly improved MASH resolution and fibrosis improvement. Secondary benefits included weight loss and reductions in liver stiffness and inflammatory markers. Gastrointestinal adverse events were more common with semaglutide, but serious adverse events and discontinuation rates were similar between groups. A nonrandomized trial comparing semaglutide with endoscopic sleeve gastroplasty found semaglutide to be superior in improving FIB-4 scores in patients with MASLD and fibrosis but the analysis is heavily limited by the small number of patients with fibrosis at baseline and the baseline differences between groups.

Table 12. Observational Comparative Study Characteristics

      ESG: endoscopic sleeve gastroplasty; MASLD, metabolic dysfunction-associated steatotic liver disease; 

Table 13. Observational Comparative Study Results^a

   ALT: alanine aminotransferase; AST: aspartate aminotransferase; CI: confidence interval; Diff: difference; HR: hazard ratio; NNT: number needed to treat; OR: odds ratio; RCT: randomized controlled trial; RR: relative risk; TBWL, total body weight loss. a All results reported are change from baseline at 12 months.

Section Summary: Metabolic Dysfunction-associated Steatohepatitis with Moderate to Advanced Fibrosis

The evidence for resmetirom in MASH with moderate to advanced fibrosis includes the ongoing phase 3 MAESTRO-NASH study conducted in patients with biopsy-proven MASH. Although results for the clinical endpoints are not yet available, week 52 histological results in 966 patients indicate significantly improved MASH resolution and fibrosis improvement with either resmetirom 80 mg or 100 mg daily compared with placebo. Safety findings identify diarrhea and nausea as the most common adverse effects with no documented resmetirom-related liver injury.

The evidence for semaglutide in MASH with moderate to advanced fibrosis includes the ongoing phase 3 ESSENCE trial. Among the first 800 patients analyzed at week 72, 2.4 mg of weekly semaglutide led to significantly improved MASH resolution and fibrosis improvement. Secondary benefits included weight loss and reductions in liver stiffness and inflammatory markers. Gastrointestinal adverse events were more common with semaglutide, but serious adverse events and discontinuation rates were similar between groups. A nonrandomized trial comparing semaglutide with endoscopic sleeve gastroplasty found semaglutide to be superior in improving FIB-4 scores in patients with MASLD and fibrosis but the analysis is heavily limited by the small number of patients with fibrosis at baseline and the baseline differences between groups.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Association for the Study of Liver Diseases

The American Association for the Study of Liver Diseases (AASLD) published guidelines for assessment and management of NALD (now MASLD) in 2023.^2, The guidelines recommend that patients with hepatic steatosis or MASLD based on the presence of obesity and metabolic risk factors should undergo primary risk assessment with fibrosis-4 (FIB-4) index as they consider this the most valid noninvasive test. Patients with FIb-4 scores less than 1.3 are unlikely to have advanced fibrosis. High-risk individuals, such as those with type 2 diabetes, medically complicated obesity, family history of cirrhosis, or more than mild alcohol consumption, should be screened for advanced fibrosis. Vibration-controlled elastography (VCTE) or ultrasound-based methods such as acoustic radio force impulse are favored over magnetic resonance elastography (MRE), as initial secondary assessments due to cost considerations. The Enhanced Liver Fibrosis (ELF) test is approved for prognostication when advanced fibrosis is suspected, although it can be ordered for secondary risk assessment, particularly because the availability of elastography may be limited in some settings. Weight loss, including the option for bariatric surgery, is recommended as the primary management strategy. The guidelines do discuss pharmacotherapeutic options for MASH including, vitamin E, pioglitazone, SGLT-2 inhibitors, tirzepatide, liraglutide, and semaglutide. Of these agents, only semaglutide was noted to potentially slow fibrosis progression, most other agents were noted to have "no proven impact on fibrosis."

Following FDA approval of resmetirom, the AASLD updated their guidelines with specific recommendations for use of resmetirom.^23, The AASLD recommended resmetriom in patients with:

• liver histology and MASH F2 to F3 or;

• imaging-based noninvasive liver disease assessment with vibration-controlled transient elastrography liver stiffness measurement of 8 kPa to 15 kPa or magnetic resonance elastography liver stiffness measurement of 3.1 kPA to 4.4 kPa.

The guidelines also state resmetirom "may be used" for liver stiffness values outside the recommended ranges or with other noninvasive liver disease assessment consistent with F2 to F3.^23, The guidelines include recommendations for concomitant medications stating, "While these [GLP-1 and GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists] pharmaceutical agents are not currently approved for the treatment of MASH, phase 2 randomized, placebo-controlled clinical trials of liraglutide, semaglutide, and tirzepatide have demonstrated their efficacy in reducing steatohepatitis without worsening fibrosis and, in the case of tirzepatide, decreasing fibrosis without worsening of steatohepatitis as well. Although not FDA approved for the treatment of MASH, vitamin E and pioglitazone may also improve steatohepatitis." Notably, of the GLP-1/GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists, only semaglutide has received FDA approval at this time.^9,

American Diabetes Association

The 2025 standards of care in diabetes from the American Diabetes Association (ADA) include recommendations for MASH.^24, They recommend screening adults with type 2 diabetes or prediabetes for risk of cirrhosis related to MASH using a calculated FIB-4 and make the following MASLD management recommendations:

• "Adults with type 2 diabetes or prediabetes, particularly with overweight or obesity, who have metabolic dysfunction–associated steatotic liver disease (MASLD) should be recommended lifestyle changes using an interprofessional approach that promotes weight loss, ideally within a structured nutrition plan and physical activity program for cardiometabolic benefits and histological improvement.

• In adults with type 2 diabetes, MASLD, and overweight or obesity, consider using a glucagon-like peptide 1 (GLP-1) receptor agonist (RA) or a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA for the treatment of obesity with potential benefits in MASH as an adjunctive therapy to lifestyle interventions for weight loss.

• In adults with type 2 diabetes and biopsy-proven MASH or those at high risk for liver fibrosis (based on noninvasive tests), pioglitazone, a GLP-1 RA, or a dual GIP and GLP-1 RA is preferred for glycemic management because of potential beneficial effects on MASH.

• Combination therapy with pioglitazone plus GLP-1 RA can be considered for the treatment of hyperglycemia in adults with type 2 diabetes with biopsy proven MASH or those at high risk of liver fibrosis (identified with noninvasive tests) because of potential beneficial effects on MASH.

• For consideration of treatment with a thyroid hormone receptor-beta agonist in adults with type 2 diabetes or prediabetes with MASLD with moderate (F2) or advanced (F3) liver fibrosis on liver histology, or by a validated imaging-based or blood-based test, refer to a gastroenterologist or hepatologist with expertise in MASLD management.

• In adults with type 2 diabetes and MASLD, use of glucose-lowering therapies other than pioglitazone or GLP-1 RAs may be continued as clinically indicated, but these therapies lack evidence of benefit in MASH."

A 2025 consensus statement from the ADA (Cusi et al [2025]) on the need for screening and intervention in MASLD included the following recommendations for MASLD management:^25,

Table 14. ADA Consensus Recommendations for Management of People with Diabetes and MASLD.^25,

      ADA: American Diabetes Association; CV: cardiovascular; CVD: cardiovascular disease; GLP-1 RA: glucagon-like peptide 1 receptor agonist; SGLT2i: sodium-glucose cotransporter 2 inhibitors.

European Association for the Study of the Liver et al

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and the European Association for the Study of Obesity (EASO) developed comprehensive guidelines for MASLD management.^26, Recommendations for non-glucose-lowering pharmacotherapy include:

• "If approved locally and dependent on the label, adults with non-cirrhotic MASH with significant liver fibrosis (stage ≥2) should be considered for treatment with resmetirom as a MASH-targeted therapy, as this treatment demonstrated histological efficacy on steatohepatitis and fibrosis in a large phase III registrational trial with an acceptable safety and tolerability profile (LoE 2, strong recommendation, consensus).

• Treatment with resmetirom, if approved locally, may be considered for individuals with MASLD who are noncirrhotic and with documentation of either: (A) advanced fibrosis; (B) at-risk steatohepatitis with significant fibrosis (by liver biopsy, when available, or by non-invasive panels validated for that purpose); or (C) risk of adverse liverrelated outcomes (e.g. by elastography- or biomarkerdefined thresholds) (LoE 3, open recommendation, consensus).

• No MASH-targeted pharmacotherapy can currently be recommended for adults with MASH at the cirrhotic stage (LoE 5, weak recommendation, strong consensus). Given the lack of robust demonstration of histological efficacy on steatohepatitis and liver fibrosis derived from large phase III trials and potential long-term risks, vitamin E cannot be recommended as a MASH-targeted therapy (LoE 2, weak recommendation, strong consensus)."

At the time of writing, the GLP-1RA were not recommended as MASH-targeted therapies due to the lack of phase 3 evidence; however, they were considered safe to use for their respective indications. Similar recommendations were made for pioglitazone, metformin, and SGLT2 inhibitors.

Global Consensus Recommendations

Younossi et al (2025) published recommendations from a Delphi consensus of 61 guidelines published from 2018 to 2025.^27, Recommendations for resmetirom are summarized in Table 15. No MASH-specific guidelines were developed for GLP-1 RAs pending approval of these agents.

Table 15. Global Consensus Recommendations for Resmetirom.

      ALT: alanine aminotransferase: MASH: metabolic dysfunction-associated steatohepatitis; NIT: noninvasive test; VCTE: vibration-controlled transient elastography.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 16.

Table 16. Summary of Key Trials

      NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

References

1. Kanwal F, Neuschwander-Tetri BA, Loomba R, et al. 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. May 01 2024; 79(5): 1212-1219. PMID 38445559
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. May 01 2023; 77(5): 1797-1835. PMID 36727674
3. American Gastroenterological Association. Metabolic dysfunction-associated steatotic liver disease (MASLD) toolkit. https://gastro.org/clinical-guidance/guideline-toolkits/metabolic-dysfunction-associated-steatotic-liver-disease-masld-toolkit/. Accessed September 8, 2025.
4. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. Jun 2005; 41(6): 1313-21. PMID 15915461
5. Jamal F, Elshaer A, Odeh NB, et al. Resmetirom in the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis. Life (Basel). Aug 18 2025; 15(8). PMID 40868953
6. Kumar A. MASLD Pharmacotherapy: Current Standards, Emerging Treatments, and Practical Guidance for Indian Physicians. J Assoc Physicians India. Jul 2025; 73(7): e45-e60. PMID 40836732
7. Peverelle M, Mbelle M, Joshi D. New Names, New Drugs, Better Outcomes in Steatotic Liver Disease. Br J Hosp Med (Lond). Aug 25 2025; 86(8): 1-18. PMID 40847981
8. Food and Drug Administration. Label: REZDIFFRA (resmetirom) oral use tablets. 2024; https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217785s000lbl.pdf. Accessed September 9, 2025.
9. Food and Drug Administration. Label: WEGOVY (semaglutide) injection. 2025; https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215256. Accessed September 8, 2025.
10. Koh JH, Ng CH, Nah B, et al. NASH is the Leading Cause of Hepatocellular Carcinoma in Liver Transplant Candidates. Clin Gastroenterol Hepatol. Jan 2024; 22(1): 197-199.e3. PMID 37245718
11. Shroff H, VanWagner LB. Cardiovascular Disease in Nonalcoholic Steatohepatitis: Screening and Management. Curr Hepatol Rep. Sep 2020; 19(3): 315-326. PMID 33585157
12. Konyn P, Ahmed A, Kim D. Causes and risk profiles of mortality among individuals with nonalcoholic fatty liver disease. Clin Mol Hepatol. Feb 2023; 29(Suppl): S43-S57. PMID 36417893
13. Tomeno W, Imajo K, Takayanagi T, et al. Complications of Non-Alcoholic Fatty Liver Disease in Extrahepatic Organs. Diagnostics (Basel). Nov 07 2020; 10(11). PMID 33171865
14. Food and Drug Administration. Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure. Accessed September 7, 2025.
15. Department of Health and Human Services. Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment: guidance for industry. Silver Spring, MD: Food and Drug Administration, December 2018. https://www.fda.gov/media/119044/download. Accessed September 9, 2025.
16. Younossi ZM, Loomba R, Anstee QM, et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology. Jul 2018; 68(1): 349-360. PMID 29222917
17. 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. Feb 08 2024; 390(6): 497-509. PMID 38324483
18. Center for Drug Evaluation and Research Application Number: 217785Orig1s000 Integrated Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217785Orig1s000IntegratedR.pdf. Accessed September 4, 2025.
19. Harrison SA, Taub R, Neff GW, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. Nov 2023; 29(11): 2919-2928. PMID 37845512
20. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. Jun 05 2025; 392(21): 2089-2099. PMID 40305708
21. Sanyal AJ, Van Natta ML, Clark J, et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. N Engl J Med. Oct 21 2021; 385(17): 1559-1569. PMID 34670043
22. Kumar S, Lahooti A, Hajifathalian K, et al. Prospective, Matched Case-Control Study of Endoscopic Sleeve Gastroplasty and Semaglutide in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease at One Year. Dig Dis Sci. Jul 08 2025. PMID 40629230
23. 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. Jan 01 2025; 81(1): 312-320. PMID 39422487
24. ElSayed NA, McCoy RG, Aleppo G, et al. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes-2025. Diabetes Care. Jan 01 2025; 48(1 Suppl 1): S59-S85. PMID 39651988
25. Cusi K, Abdelmalek MF, Apovian CM, et al. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in People With Diabetes: The Need for Screening and Early Intervention. A Consensus Report of the American Diabetes Association. Diabetes Care. Jul 01 2025; 48(7): 1057-1082. PMID 40434108
26. Tacke F, Horn P, Wai-Sun Wong V, et al. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. Sep 2024; 81(3): 492-542. PMID 38851997
27. Younossi ZM, Zelber-Sagi S, Lazarus JV, et al. Global Consensus Recommendations for Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis. Gastroenterology. Oct 2025; 169(5): 1017-1032.e2. PMID 40222485

Codes

Policy History