What are the new emerging therapies for Metabolic Associated Fatty Liver Disease (MAFLD)?

Emerging Therapies for Metabolic Associated Steatotic Liver Disease (MASLD)

Resmetirom is currently the most promising MASH-targeted pharmacological therapy for non-cirrhotic patients with significant liver fibrosis (stage ≥2), showing histological effectiveness on steatohepatitis and fibrosis with an acceptable safety profile. 1, 2

Current First-Line Approaches

Lifestyle Modifications

Lifestyle modifications remain the cornerstone of MASLD treatment:

• Weight Loss Goals:

  • 5-7% weight loss decreases intrahepatic fat and inflammation 2

  • 10% weight loss improves liver fibrosis in 45% of patients 2

  • Progressive weight loss (<1 kg/week) is preferred over rapid weight loss 2

• Exercise Recommendations:

  • At least 150-240 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity physical activity 2, 3
  • Combine both aerobic exercise and resistance training for optimal reduction of liver fat 2
  • Exercise alone can reduce hepatic steatosis even without significant weight loss 2

• Dietary Approach:

  • Mediterranean diet pattern with daily consumption of vegetables, fruits, fiber-rich cereals, nuts, fish/white meat, and olive oil 2
  • Limit simple sugars, red/processed meats, and ultra-processed foods 2
  • Reduce carbohydrate intake, especially fructose 2
  • Complete alcohol abstinence is recommended 2

Emerging Pharmacological Therapies

1. Resmetirom

• Mechanism: Thyroid hormone receptor-β agonist
• Evidence: Demonstrated histological effectiveness on steatohepatitis and fibrosis 1, 2
• Recommendation: Consider for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2), if locally approved 1, 2

2. Incretin-Based Therapies

• GLP-1 Receptor Agonists (semaglutide, tirzepatide):
  • Shown to improve liver histology in MASH patients with or without diabetes 2
  • Particularly effective for patients with comorbid type 2 diabetes or obesity 1
  • Provide dual benefit for metabolic control and hepatic steatosis 2

3. Gut Microbiota Modulation

• Probiotics:
  • Short-term probiotic interventions appear safe and can improve liver steatosis 1
  • Mechanisms include modification of gut microbiota dysbiosis, reduced endotoxemia, and improved intestinal barrier function 1
  • Interindividual response variability exists; predictors of good response need further study 1

4. Bariatric Surgery

• Consider for patients with MASLD and obesity 1, 2
• Leads to significant weight loss and improvement in liver disease 2

Treatments Not Currently Recommended

Based on current evidence, the following are not recommended as specific therapies for MASLD:

• Vitamin E: Not recommended as a targeted therapy for steatohepatitis 2
• Pioglitazone: Not recommended due to lack of robust demonstration of histological efficacy 2
• Metformin: Not recommended as a specific treatment for liver disease in MASH 2
• Nutraceuticals: Insufficient evidence on effectiveness and safety 2

Management Algorithm for MASLD

1. Initial Assessment:

   • Evaluate fibrosis stage using blood-based scores (FIB-4) and imaging techniques (transient elastography) 1
   • Identify comorbidities (type 2 diabetes, obesity, metabolic syndrome)

2. For All Patients:

   • Implement lifestyle modifications (diet, exercise, alcohol abstinence)
   • Optimize management of metabolic comorbidities

3. For Patients with Obesity:

   • Consider incretin-based therapies if indicated for weight management
   • Consider bariatric surgery for eligible patients

4. For Patients with Non-Cirrhotic MASH and Significant Fibrosis (≥F2):

   • Consider resmetirom if locally approved 1, 2

5. For Patients with MASH-Related Cirrhosis:

   • No MASH-targeted pharmacotherapy currently recommended 1
   • Focus on nutritional counseling, surveillance for portal hypertension and HCC
   • Consider liver transplantation in decompensated cirrhosis 1

Monitoring and Follow-up

• Periodic monitoring of liver function tests
• Evaluation of fibrosis progression using non-invasive tests
• HCC surveillance every 6 months in patients with advanced fibrosis or cirrhosis 2
• Monitoring for treatment response and potential side effects

Future Research Directions

The EASL-EASD-EASO guidelines highlight several research priorities:

• Development of effective pharmacological treatments for MASH-related cirrhosis 1
• Identification of early predictors of non-response to pharmacological intervention 1
• Evaluation of potential additive or synergistic effects of combining drugs 1
• Determination of weight loss-independent mechanisms of MASLD improvement 1