What are the treatment options and recommended medications for metabolic dysfunction‑associated steatohepatitis (MASLD)?

Treatment of MASLD: Comprehensive Management Strategy

The cornerstone of MASLD treatment is achieving sustained weight loss of 7–10% through dietary modification and exercise, with pharmacologic therapy reserved for patients with non-cirrhotic MASH and significant fibrosis (stage F2 or higher). 1, 2

Non-Pharmacological Management: First-Line for All Patients

Weight Loss Targets

• Achieve 5% weight reduction to decrease hepatic steatosis 1, 2
• Achieve 7–10% sustained weight loss to improve liver inflammation and resolve steatohepatitis 1, 2
• Achieve >10% weight reduction to improve fibrosis 1, 2
• These targets represent the only intervention with Level 1 evidence for improving liver injury 3

Dietary Modifications

• Adopt a Mediterranean dietary pattern emphasizing vegetables, fruits, low-fat dairy, nuts, olive oil, legumes, and unprocessed fish or poultry 1, 2
• Completely eliminate sugar-sweetened beverages 1, 2
• Minimize ultra-processed foods rich in sugars and saturated fats 1, 2
• Create a 500–1000 kcal/day deficit to achieve gradual weight loss 4

Physical Activity

• Prescribe ≥150 minutes/week of moderate-intensity or ≥75 minutes/week of vigorous-intensity aerobic activity 1, 2
• Physical activity reduces steatosis even without significant weight loss 3

Alcohol Avoidance

• Advise complete alcohol avoidance, especially in patients with advanced fibrosis or cirrhosis 2

Pharmacologic Management: Non-Cirrhotic MASH with Significant Fibrosis

MASH-Targeted Therapy

Resmetirom is the first FDA-conditionally approved agent (March 2024) for adults with non-cirrhotic MASH and fibrosis stage F2/F3. 2, 5

• Phase III data demonstrate superior histologic resolution of steatohepatitis and fibrosis with acceptable safety 2
• Use only where locally approved and according to label 2

Dual-Benefit Therapies for Comorbid Conditions

For Type 2 Diabetes or Obesity

GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) and the GLP-1/GIP co-agonist tirzepatide are preferred first-line agents in non-cirrhotic MASH, providing both glycemic control and hepatic benefit. 2, 5

• Semaglutide received FDA conditional approval for MASH with moderate-to-advanced fibrosis 2, 5
• These agents improve cardiometabolic outcomes and are safe in MASH, including compensated cirrhosis 2

Alternative Glucose-Lowering Agents

• SGLT2 inhibitors (empagliflozin, dapagliflozin) are alternative options showing moderate reductions in liver fat content and serum ALT 2
• Metformin should be continued in patients with compensated cirrhosis (if eGFR >30 mL/min) because discontinuation may increase mortality 2
• However, metformin alone does not improve MASH histology 2

Lipid Management

• Statins are safe and should be used for dyslipidemia in patients with MASLD; they remain cardioprotective and should not be withheld solely because of liver disease 2, 3

Weight-Loss Medications

• Incretin-based agents (GLP-1 agonists, tirzepatide) are favored for their combined metabolic and hepatic effects 2
• Non-incretin weight-loss drugs (orlistat, phentermine-topiramate, naltrexone-bupropion) are NOT recommended due to inconclusive efficacy data 2

Pharmacologic Management: Cirrhotic Disease

No MASH-targeted pharmacotherapy is currently recommended for patients with cirrhosis. 2

Glucose Management in Cirrhosis

• Metformin may be used in compensated cirrhosis if eGFR >30 mL/min; it is contraindicated in decompensated disease 2
• Insulin is the preferred glucose-lowering agent in decompensated cirrhosis when other options are unsuitable 2
• GLP-1 agonists and SGLT2 inhibitors can be used cautiously in compensated cirrhosis with close monitoring 2

Nutrition in Cirrhosis

• Provide a high-protein diet (1.2–1.5 g/kg body weight/day) with total calories ≥35 kcal/kg/day 2
• Offer a late-evening snack to reduce overnight fasting and preserve muscle mass in sarcopenic or decompensated patients 2
• In compensated cirrhosis with obesity, a moderate weight-loss plan emphasizing protein intake and physical activity is acceptable to avoid sarcopenia 2

Surgical and Endoscopic Options

Bariatric Surgery

Bariatric surgery is indicated for non-cirrhotic MASLD patients with BMI >40 kg/m² or BMI >35 kg/m² plus comorbidities. 2, 5

• Yields durable liver improvement, diabetes remission, and better cardiometabolic risk profiles 2
• In compensated cirrhosis, bariatric surgery may be considered after multidisciplinary assessment for portal hypertension 2

Endoscopic Procedures

• Metabolic/bariatric endoscopic procedures are NOT recommended pending further validation 2

Monitoring and Surveillance

Non-Invasive Assessment

• Use FIB-4 score and transient elastography to assess fibrosis stage; fibrosis stage ≥F2 identifies patients at risk for liver-related outcomes and determines eligibility for therapy 2
• Repeat non-invasive fibrosis tests (e.g., FIB-4, elastography) to monitor disease progression 2
• Changes in non-invasive markers (e.g., MRI-PDFF relative reduction by >30%, ALT reduction by >17 U/L) have been associated with resolution of steatohepatitis 1
• Liver biopsy is not suited for routine monitoring due to invasiveness but may be reserved for select cases requiring precise histologic information 1, 2

Cirrhosis-Specific Surveillance

• Conduct regular surveillance for portal hypertension and hepatocellular carcinoma in cirrhotic patients 2
• Provide nutritional counseling to prevent sarcopenia 2
• Evaluate for liver transplantation in decompensated cirrhosis or when HCC develops 2

Multidisciplinary Care Approach

Implement a multidisciplinary team (hepatology, endocrinology, nutrition, cardiology, surgery) to address the intertwined liver disease, diabetes, obesity, and cardiovascular risk. 1, 2

• This approach improves both hepatic and extra-hepatic outcomes 1, 2
• Given the multidirectional connections between MASLD and cardiometabolic comorbidities, all components must be appropriately targeted 1

Common Pitfalls to Avoid

• Do NOT impose aggressive caloric restriction in patients with sarcopenia or decompensated cirrhosis, as it worsens muscle loss 2
• Do NOT prescribe metformin in decompensated cirrhosis or when eGFR <30 mL/min due to lactic-acidosis risk 2
• Do NOT withhold statins solely because of liver disease; they remain safe and cardioprotective 2, 3
• Do NOT discontinue metformin in compensated cirrhosis with type 2 diabetes, as this may increase mortality 2
• Do NOT use nutraceuticals as there is insufficient evidence of their effectiveness 1

Evidence Limitations

• Improved mortality has not been demonstrated for any treatment-induced histological changes; further long-term follow-up studies are needed 1
• There is little evidence that improving diet quality beneficially impacts clinical liver-related outcomes, despite strong evidence for histological improvement 1
• Benefits of physical activity on histological outcomes and liver-related clinical outcomes are less robust compared to well-documented cardiometabolic benefits 1