Is Resmetirom (a selective thyroid hormone receptor beta agonist) an appropriate first-line treatment for an adult patient with Non-Alcoholic Fatty Liver Disease (NAFLD), possibly with metabolic syndrome, insulin resistance, or type 2 diabetes?

Resmetirom in NAFLD/MASLD

Resmetirom should be considered as first-line MASLD-targeted pharmacotherapy for adults with non-cirrhotic MASH and significant liver fibrosis (stage F2 or F3), as it is the only medication with demonstrated histological efficacy on both steatohepatitis and fibrosis in large phase III trials with acceptable safety. 1, 2

When to Use Resmetirom

Primary Indication

• Adults with non-cirrhotic MASH and fibrosis stage F2 or F3 are the target population, ideally with biopsy-proven MASH performed within the last 12 months 2, 1
• Resmetirom demonstrated NASH resolution in 24.2% (80 mg dose) and 25.9% (100 mg dose) versus 14.2% with placebo (P < 0.001), and improved fibrosis in 25.9% (80 mg) and 29.9% (100 mg) versus 9.7% with placebo (P < 0.001) 3

Non-Invasive Test Thresholds for Treatment Eligibility

When liver biopsy is unavailable, use these parameters to identify F2-F3 fibrosis 2, 1:

• VCTE (FibroScan): 10-15 kPa (LSM values) 2, 1
• MRE: 3.0-4.3 kPa 2, 1
• ELF score: 9.2-10.4 (when used with another NIT) or ≥9.8 when used in isolation 1, 2
• Use at least 2 concordant tests to reduce false positives when relying solely on non-invasive testing 1

Key Baseline Characteristics from MAESTRO-NASH

The pivotal trial enrolled patients with 1:

• CAP ≥280 dB/m and LSM ≥8.5 kPa on prescreening
• At least 3 cardiometabolic risk factors
• Median baseline LSM: 12 kPa (IQR 10-15)
• Median ELF: 9.7 (IQR 9.2-10.4)
• 68% had type 2 diabetes, 79% hypertension, 71% dyslipidemia

Who Should NOT Receive Resmetirom

Absolute Exclusions 1

• Established cirrhosis or suspected cirrhosis based on:

  • History of fibrosis stage F4 on liver biopsy
  • Imaging showing portal hypertension, ascites, portosystemic collaterals, or varices
  • Clinical manifestations of hepatic decompensation (ascites, varices, hepatic encephalopathy)
  • VCTE stiffness >20 kPa or MRE >5 kPa or ELF >11.3 1

• Significant alcohol use: PeTH >200 ng/mL suggests MetALD or alcoholic liver disease 1

Rationale for Cirrhosis Exclusion

The MAESTRO-OUTCOMES trial (NCT05500222) is currently evaluating resmetirom in compensated cirrhosis, and efficacy/safety data in this population are not yet available 1. The drug should not be used in cirrhotic patients until these data are published.

Resmetirom vs. Other Therapies

Why Resmetirom is First-Line for MASH-Targeted Therapy

• Resmetirom is the ONLY medication with robust demonstration of histological efficacy on both steatohepatitis AND fibrosis from large Phase III trials 1, 2
• Vitamin E cannot be recommended due to lack of robust Phase III evidence and potential long-term risks 1
• Pioglitazone is safe but cannot be recommended as MASH-targeted therapy due to lack of robust Phase III demonstration of histological efficacy 1, 4

Role of GLP-1 Receptor Agonists

• GLP-1RAs (semaglutide, liraglutide) should be used for their approved indications (type 2 diabetes, obesity) as they improve cardiometabolic outcomes and are safe in MASH, including compensated cirrhosis 1, 5, 2
• However, GLP-1RAs cannot be recommended as MASH-targeted therapies because they lack formal demonstration of histological improvement in large Phase III trials 2
• In practice: Use GLP-1RAs for diabetes/obesity management alongside resmetirom for liver-directed therapy 3

Other Diabetes Medications

• SGLT2 inhibitors and metformin are safe in MASLD and should be used for their respective indications (diabetes, heart failure, CKD), but insufficient evidence exists to recommend them as MASH-targeted therapies 1
• Metformin showed no difference from placebo in steatosis, fibrosis, or NASH resolution in systematic reviews 6

Practical Implementation Algorithm

Step 1: Screen for MASLD

• Identify patients with steatosis on imaging or suspected by cardiometabolic risk factors 1
• Exclude other causes of liver disease 4
• Measure PeTH to exclude significant alcohol use 1

Step 2: Assess Fibrosis Burden

• Calculate FIB-4 score in all MASLD patients 2
• Important caveat: FIB-4 correlated poorly in MAESTRO-NASH (median 1.3 in F2-F3 patients), so do not use FIB-4 alone to exclude patients from treatment 1
• If FIB-4 suggests risk, proceed to liver stiffness measurement (VCTE or MRE) or ELF testing 2

Step 3: Determine Treatment Eligibility

• If biopsy available showing F2 or F3 within 12 months: Consider resmetirom regardless of NIT values (provided no portal hypertension) 1
• If no biopsy: Use NITs with thresholds above to identify F2-F3 disease 2
• Exclude cirrhosis using criteria listed above 1

Step 4: Initiate Resmetirom

• Dosing: 80 mg or 100 mg orally once daily 3
• Continue lifestyle interventions (≥7-10% weight loss, Mediterranean diet, 150 min/week moderate exercise) 5
• Optimize cardiometabolic comorbidities with GLP-1RAs, statins, antihypertensives as indicated 5, 3

Monitoring Treatment Response

Biochemical Markers

• ALT reduction ≥17 U/L (or ≥20% decline) correlates with histologic response, though many patients show histologic improvement without ALT normalization 2
• Monitor lipid profiles: Resmetirom reduces LDL-C, apolipoprotein-B, and triglycerides 7, 8

Non-Invasive Tests

• VCTE stiffness reductions >30% may indicate meaningful clinical response, but changes typically require ≥1 year to manifest 2
• Serial monitoring with same modality used for diagnosis 2

Thyroid Function

• Resmetirom decreases prohormone FT4 and increases sex hormone binding globulin, but these are expected pharmacodynamic effects without clinical thyroid dysfunction 2

Safety Profile

Common Adverse Effects 2, 3

• Gastrointestinal side effects
• Gallstone-related complications
• Generally well tolerated in clinical trials

Cardiovascular Benefits

• Favorable cardiovascular profile with reduction in atherogenic lipids 7, 8
• No clinically relevant QT prolongation at doses up to 2× maximum recommended dose 2

Common Pitfalls to Avoid

1. Do not rely on FIB-4 alone to exclude patients from treatment—it underperformed in the MAESTRO-NASH population 1

2. Do not use resmetirom in cirrhotic patients until MAESTRO-OUTCOMES data are available 1

3. Do not use ELF <9.8 in isolation without confirmatory testing, as it has low positive predictive value in unselected populations 1

4. Do not withhold GLP-1RAs or statins in patients receiving resmetirom—these should be used for their cardiometabolic indications alongside liver-directed therapy 1, 5, 3

5. Do not expect rapid changes in liver stiffness—meaningful reductions typically require ≥1 year 2