What is the role of resmetirom (thyroid hormone receptor beta agonist) in the treatment of Metabolic Associated Fatty Liver Disease (MAFLD) in adults with obesity, insulin resistance, or type 2 diabetes?

Role of Resmetirom in MASLD

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

Patient Selection Criteria

Who Should Receive Resmetirom

Primary indication: Adults with non-cirrhotic MASH and fibrosis stage F2 or F3 (significant to advanced fibrosis) are the target population for resmetirom therapy. 1, 2

Specific qualifying criteria include:

• Biopsy-proven MASH with fibrosis stage F2 or F3 performed within the last 12 months 1, 2
• Non-invasive test thresholds indicating significant fibrosis:
  • Vibration-controlled transient elastography (VCTE/FibroScan): 10-15 kPa 1, 2
  • MR elastography (MRE): 3.0-4.3 kPa 1, 2
  • Enhanced Liver Fibrosis (ELF) score: 9.2-10.4 1, 2
• Documentation of at-risk steatohepatitis with significant fibrosis by validated non-invasive panels 1

Who Should NOT Receive Resmetirom

Absolute exclusions:

• Decompensated cirrhosis (Child-Pugh Class B or C) - resmetirom increases drug exposure in moderate to severe hepatic impairment, raising adverse reaction risk 3
• History of fibrosis stage F4 (cirrhosis) on liver biopsy 1
• Clinical manifestations of hepatic decompensation (ascites, varices, hepatic encephalopathy) 1
• Imaging evidence of portal hypertension, ascites, portosystemic collaterals, or varices 1

Relative exclusions requiring careful assessment:

• VCTE stiffness >20 kPa or MRE >5 kPa (suggests advanced cirrhosis) 1
• Platelet count <140,000/mL without alternative explanation 1
• ELF score >11.3 (increased risk for clinical outcomes) 1
• Hepatic nodularity on imaging 1
• Elevated bilirubin (unless Gilbert syndrome) or other synthetic dysfunction markers 1

Early stage disease exclusion: Patients with no fibrosis or early fibrosis (F0-F1) should NOT receive resmetirom as they are at very low risk for adverse liver-related outcomes and should be managed with lifestyle intervention alone. 1

Mechanism and Efficacy

Resmetirom is a selective thyroid hormone receptor-beta (THR-β) agonist that produces 83.8% of maximum response compared to T3, with preferential liver targeting (THR-β predominates in liver while THR-α mediates cardiac and bone effects). 3, 4

Demonstrated benefits from MAESTRO-NASH trial:

• Histological improvement in steatohepatitis and fibrosis regression 1, 5
• Reduction in liver fat content measured by MRI-PDFF and FibroScan CAP 3
• Improved lipid profiles 6
• Clinically meaningful quality of life improvements in histologic responders, with 35-41% meeting minimal clinically important difference thresholds in multiple domains 7

Monitoring Treatment Response

Non-Invasive Markers of Response

ALT reduction: A decrease of ≥17 U/L (or ≥20% decline) correlates with histologic response, though many patients show histologic improvement without ALT normalization - lack of ALT response should be interpreted cautiously. 1

Liver stiffness changes: Reductions in VCTE stiffness by >30% may indicate meaningful clinical response (coefficient of variation ~30%), though changes typically require ≥1 year to manifest. 1

MRI-PDFF: Substantial reductions in hepatic fat content are observed as early as 16 weeks and sustained at 52 weeks. 3

Important caveat: Data on sustainability of histological benefits, individual prediction of response, liver-related outcomes, and long-term safety are currently not available. 1

Integration with Other Therapies

GLP-1 Receptor Agonists

GLP-1RAs cannot be recommended as MASH-targeted therapies due to lack of formal demonstration of histological improvement in large phase III trials. 1, 8 However, they are safe in MASH (including compensated cirrhosis) and should be used for their approved indications of type 2 diabetes and obesity, as they improve cardiometabolic outcomes. 1, 8

• In patients achieving substantial weight loss with GLP-1RAs, hepatic histological benefit could be expected, though not extensively documented. 1
• GLP-1RAs or dual GIP/GLP-1 agonists are preferred adjunctive therapy for patients with MASLD who have type 2 diabetes or obesity with overweight. 8
• Combination therapy with pioglitazone plus GLP-1RA can be considered for biopsy-proven MASH or high-risk fibrosis. 8

Other Medications

Pioglitazone: Safe in non-cirrhotic MASH but cannot be recommended as MASH-targeted therapy due to lack of robust phase III trial evidence for histological efficacy. 1

SGLT2 inhibitors and metformin: Insufficient evidence as MASH-targeted therapies, but safe in MASLD and should be used for their respective indications (diabetes, heart failure, chronic kidney disease). 1

Vitamin E: Cannot be recommended as MASH-targeted therapy given lack of robust demonstration of histological efficacy in large phase III trials and potential long-term risks. 1

Practical Implementation Algorithm

Step 1: Risk stratification

• Calculate FIB-4 score in all MASLD patients 8, 9
• If FIB-4 indicates indeterminate or high risk, proceed to liver stiffness measurement or ELF testing 8

Step 2: Confirm fibrosis stage

• VCTE 10-15 kPa, MRE 3.0-4.3 kPa, or ELF 9.2-10.4 → likely F2-F3, consider resmetirom 1, 2
• Consider liver biopsy when non-invasive tests are discordant or to confirm diagnosis 1, 2

Step 3: Exclude cirrhosis

• Screen for clinical, laboratory, or imaging evidence of advanced cirrhosis or portal hypertension 1
• Exclude if VCTE >20 kPa, platelets <140,000/mL, ELF >11.3, or imaging shows nodularity/portal hypertension 1

Step 4: Initiate therapy if approved locally

• Start resmetirom 80 mg or 100 mg daily (dose-proportional exposure between these doses) 3
• Can be taken with or without food (food decreases Cmax by 33% but not clinically significant) 3

Step 5: Monitor response

• Assess ALT, liver stiffness, and MRI-PDFF at baseline and periodically (changes in stiffness require ≥1 year) 1
• Monitor for adverse effects, particularly gastrointestinal symptoms and gallstone-related complications 6
• Obtain baseline and periodic liver function tests 8

Step 6: Continue lifestyle modification

• Target ≥7-10% sustained weight loss through Mediterranean diet and ≥150 minutes weekly moderate-intensity exercise 9, 5
• Optimize management of diabetes, obesity, hypertension, and dyslipidemia 9

Safety Considerations

Common adverse effects: Gastrointestinal side effects and gallstone-related complications have been observed. 6

Pharmacodynamic effects:

• Decreases prohormone FT4 (observed at 4 weeks, sustained during treatment) 3
• Increases sex hormone binding globulin (SHBG) - clinical significance unknown 3
• No clinically relevant QT prolongation at doses up to 2× maximum recommended dose 3

Renal impairment: No dosage adjustment needed for mild or moderate renal impairment; not studied in severe renal impairment. 3

Hepatic impairment: Avoid in decompensated cirrhosis; no adjustment needed for Child-Pugh Class A. 3

Critical Gaps in Evidence

The MAESTRO OUTCOMES trial (NCT05500222) is near full enrollment and will provide efficacy and safety data in patients with compensated cirrhosis, which will guide future treatment decisions in this population. 1 Currently, no MASH-targeted pharmacotherapy can be recommended for adults with MASH at the cirrhotic stage. 1

Long-term data on prevention of cirrhosis, hepatocellular carcinoma, and liver-related mortality remain under investigation. 6