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

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 Adults1,

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 Stages4,

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 Steatohepatitis16,

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.

Review of Evidence 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.

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.

Table 12. Observational Comparative Study Characteristics

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

Table 13. Observational Comparative Study Resultsa

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.

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