Recent Treatment Options for MASLD
Clarification: MASLD vs. Lipodystrophy
The question appears to contain a terminology error: "Multi-Acquired Systemic Lipodystrophy Disorder (MASLD)" does not exist as a medical entity. MASLD refers to Metabolic dysfunction-Associated Steatotic Liver Disease, not lipodystrophy. These are entirely different conditions with distinct pathophysiology and treatment approaches. I will address MASLD (the liver disease) as this aligns with the current medical literature and guidelines provided.
First-Line Treatment: Lifestyle Modifications
All patients with MASLD should achieve sustained weight loss through dietary and behavioral therapy, with targets of >5% to reduce liver fat, 7-10% to improve inflammation, and >10% to improve fibrosis. 1
Specific Dietary Recommendations:
- Adopt a Mediterranean dietary pattern with limitation of ultra-processed foods rich in sugars and saturated fat 1
- Completely avoid sugar-sweetened beverages 1
- Engage in ≥150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity physical activity 1
Pharmacological Treatment for Non-Cirrhotic MASH
MASH-Targeted Therapy
For adults with non-cirrhotic MASH with significant liver fibrosis (stage ≥F2), resmetirom should be considered as the primary MASH-targeted therapy if locally approved, as it demonstrated histological efficacy on steatohepatitis and fibrosis in phase III trials with acceptable safety. 1
Important limitation: Resmetirom cannot be recommended for patients with MASH-related cirrhosis due to lack of evidence in this population 1
Treatment Based on Comorbidities (F0-F3 Fibrosis)
The preferred pharmacological approach depends on metabolic comorbidities:
For Patients with Type 2 Diabetes:
- First choice: GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) or dual GIP/GLP-1 agonists (tirzepatide) 1, 2, 3
- Alternative: SGLT2 inhibitors (empagliflozin, dapagliflozin) for cardiovascular and renal protection 1
- Continue metformin if already prescribed (glomerular filtration rate >30 mL/min), as it may improve transplant-free survival in advanced fibrosis 1
Critical distinction: GLP-1 receptor agonists cannot currently be recommended as MASH-targeted therapies due to absence of formal demonstration of histological improvement in large phase III trials, but they are preferred for treating diabetes in MASLD patients due to cardiometabolic benefits 1, 2
For Patients with Obesity (without diabetes):
- GLP-1 receptor agonists or GIP/GLP-1 agonists are preferred as they induce substantial weight loss that may provide hepatic histological benefits 2, 3
For Patients with Dyslipidemia:
- Standard lipid-lowering agents should be used according to cardiovascular risk 1
Treatment for Compensated Cirrhosis (F4)
For patients with MASLD-related compensated cirrhosis:
- Check indication for liver transplantation if decompensation or hepatocellular carcinoma develops 1
- Use insulin for diabetes management in cases of decompensated cirrhosis 1
- GLP-1 receptor agonists and tirzepatide can be used cautiously in Child-Pugh A cirrhosis, with tirzepatide prioritized based on superior liver outcome data 3
- Contraindications: GLP-1 receptor agonists are contraindicated in Child-Pugh C cirrhosis and require extreme caution in Child-Pugh B 3
Special Considerations for Cirrhosis:
- Target moderate weight reduction (3-5%) rather than the standard 7-10% goal to avoid worsening sarcopenia 3
- Ensure high-protein intake (1.2-1.5 g/kg/day) during weight loss to prevent sarcopenia 3
- Bariatric interventions require special caution in compensated cirrhosis 1
Bariatric Surgery
In adults with non-cirrhotic MASLD who have an approved indication, bariatric surgery should be considered, as it induces long-term beneficial effects on the liver and is associated with remission of type 2 diabetes and improvement of cardiometabolic risk factors. 1
Treatments NOT Recommended
The following cannot be recommended based on current evidence:
- Vitamin E: Despite prior use, it cannot be recommended due to lack of robust demonstration of histological efficacy in large phase III trials and potential long-term risks 1
- Non-incretin-based weight-loss agents (orlistat, phentermine-topiramate, naltrexone-bupropion): Controlled trials have been inconclusive 1
- Nutraceuticals: Insufficient evidence of effectiveness and safety 1
- Pioglitazone: While R-enantiomers are being studied, standard pioglitazone is not currently recommended as monotherapy 1
Risk Stratification for Treatment Decisions
Use FIB-4 score as initial screening: If FIB-4 indicates indeterminate or high risk, proceed to liver stiffness measurement or Enhanced Liver Fibrosis (ELF) testing to identify clinically significant fibrosis (≥F2) 2
Patients with clinically significant fibrosis (≥F2) on noninvasive testing qualify for preferential GLP-1 or GIP/GLP-1 agonist therapy if they have diabetes 2
Common Pitfalls to Avoid
- Do not delay treatment waiting for liver biopsy confirmation in patients with high-risk noninvasive test results and diabetes requiring treatment 2
- Do not discontinue GLP-1 receptor agonists in patients who develop compensated cirrhosis, as they remain safe in this population 2
- Do not discontinue metformin in patients with cirrhosis unless hepatic decompensation or renal failure occurs, as discontinuation may increase mortality 1
- Do not use aggressive weight loss targets in cirrhotic patients without adequate protein supplementation 3
Monitoring and Long-Term Considerations
For patients on resmetirom: Data on sustainability of histological benefits, individual prediction of response, liver-related outcomes, and long-term safety (bone density, endocrine functions, cardiovascular and oncological safety) are currently not available 1
Future research priorities include: Defining non-response and stopping rules for MASH-targeted pharmacotherapy, evaluating additive or synergistic effects of combining drugs for MASH and cardiometabolic comorbidities, and developing effective treatments for MASH-related cirrhosis 1