What antifibrotic therapies are currently under investigation for metabolic dysfunction‑associated steatotic liver disease (MASLD)?

Antifibrotic Therapies Under Investigation for MASLD

Resmetirom is currently the only FDA-approved antifibrotic therapy for MASLD with significant fibrosis (stage ≥F2), while several other agents remain under investigation but lack robust Phase III evidence for direct antifibrotic effects. 1

Currently Approved Antifibrotic Therapy

Resmetirom (Thyroid Hormone Receptor-β Agonist)

• Resmetirom is the first and only medication with demonstrated histological efficacy on both steatohepatitis and fibrosis in large Phase III registrational trials with acceptable safety and tolerability profiles. 1, 2
• Indicated for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥F2, specifically F2-F3). 1, 2
• Weight-based dosing: 80 mg for patients <100 kg and 100 mg for patients ≥100 kg body weight. 1
• Critical limitation: No MASH-targeted pharmacotherapy can currently be recommended for cirrhotic stage disease. 1
• Long-term efficacy data, sustainability of histological benefits, and liver-related outcomes remain unavailable. 1

Agents Under Investigation Without Current Antifibrotic Recommendation

GLP-1 Receptor Agonists (Semaglutide, Liraglutide, Tirzepatide)

• GLP-1RAs cannot currently be recommended as MASH-targeted therapies due to absence of formal demonstration of histological improvement in large, well-conducted Phase III trials. 1, 3, 2
• However, they are safe to use 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, 3
• Substantial weight loss induced by GLP-1RAs could potentially yield hepatic histological benefits, though this has not been extensively documented. 1, 3
• The American Diabetes Association suggests preferential use in patients with biopsy-proven MASH or high-risk fibrosis based on noninvasive tests. 3

Pioglitazone (PPAR-γ Agonist)

• Pioglitazone cannot be recommended as a MASH-targeted therapy given the lack of robust demonstration of histological efficacy on steatohepatitis and liver fibrosis in large Phase III trials. 1, 2
• Safe to use in adults with non-cirrhotic MASH for metabolic indications. 1
• May be considered in combination with GLP-1RAs for patients with biopsy-proven MASH or high fibrosis risk. 3

SGLT2 Inhibitors (Empagliflozin, Dapagliflozin)

• Insufficient evidence to recommend as MASH-targeted therapies, though safe to use in MASLD for approved indications (type 2 diabetes, heart failure, chronic kidney disease). 1, 3
• Should be used for cardiovascular and renal protection in appropriate patients. 3

Vitamin E

• Cannot be recommended as MASH-targeted therapy given lack of robust demonstration of histological efficacy from large Phase III trials and potential long-term risks. 1

Agents Explicitly Not Recommended

Saroglitazar

• Explicitly excluded from 2024 EASL-EASD-EASO guidelines because large Phase III trials have not demonstrated histological efficacy on steatohepatitis or fibrosis. 4
• Strong guideline recommendation against use as MASH-targeted therapy. 4

Emerging Therapeutic Strategies Under Investigation

Novel Antifibrotic Compounds

• Multiple anti-inflammatory and direct antifibrotic agents are under investigation, though anti-inflammatory and antifibrotic effects of monotherapy appear less robust in current trials. 5, 6
• Combination therapeutic approaches are being explored to address the heterogeneity of MASLD. 5, 7

Agents Targeting Gut-Liver Axis

• FXR agonists, PPAR agonists (beyond pioglitazone), and other agents acting on systemic metabolic pathways remain under investigation. 7

Clinical Algorithm for Patient Selection

Step 1: Risk Stratification

• Calculate FIB-4 score in all MASLD patients. 3, 2
• If FIB-4 indicates indeterminate or high risk, proceed to liver stiffness measurement (VCTE or MRE) or ELF testing. 3, 2

Step 2: Identify Significant Fibrosis (≥F2)

• VCTE: 10-15 kPa suggests F2-F3. 2
• MRE: 3.0-4.3 kPa suggests F2-F3. 2
• ELF score: 9.2-10.4 suggests F2-F3. 2
• Historical liver biopsy within 12 months showing MASH with F2-F3 qualifies for treatment regardless of noninvasive test values. 1

Step 3: Treatment Selection

• If F2-F3 fibrosis confirmed and non-cirrhotic: Consider resmetirom (if locally approved). 1, 2
• If cirrhotic: No MASH-targeted pharmacotherapy recommended; focus on metabolic management and surveillance. 1
• If type 2 diabetes or obesity present: Use GLP-1RAs or dual GIP/GLP-1 agonists for metabolic indications. 3, 4
• If cardiovascular/renal disease present: Use SGLT2 inhibitors for cardio-renal protection. 3, 4

Critical Pitfalls to Avoid

• Do not delay treatment waiting for liver biopsy confirmation in patients with high-risk noninvasive test results who require metabolic therapy. 3
• Do not discontinue GLP-1RAs in patients who develop compensated cirrhosis, as they remain safe in this population. 3
• Do not use saroglitazar as MASH-targeted therapy, even if approved in certain countries for diabetic dyslipidemia. 4
• Do not prescribe resmetirom for cirrhotic patients, as no evidence supports efficacy or safety in this population. 1
• Rule out autoimmune liver disease before initiating therapy, as several MASH trials have inadvertently included these cases. 1