What medications are used to treat liver fibrosis?

Medication for Liver Fibrosis

Currently, there is no FDA-approved medication specifically for treating liver fibrosis itself, but resmetirom is recommended for non-cirrhotic MASH with significant fibrosis (stage ≥2), and lifestyle modifications combined with management of underlying metabolic conditions remain the cornerstone of treatment. 1

Primary Pharmacological Approach

For Non-Alcoholic Steatohepatitis (NASH) with Fibrosis

Resmetirom should be considered for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2). 1, 2 This thyroid hormone receptor-beta agonist demonstrated histological improvement in both steatohepatitis and fibrosis in phase 3 trials, with 18% and 23% of patients achieving at least 1-stage fibrosis improvement at 10 mg and 25 mg doses respectively, compared to 12% with placebo. 1

Diabetes Medications with Liver Benefits

GLP-1 receptor agonists (semaglutide, tirzepatide) are strongly recommended when patients have comorbid type 2 diabetes or obesity. 1, 2, 3 Semaglutide at 0.4 mg/day achieved NASH resolution without worsening fibrosis in 59% versus 17% with placebo. 4

Pioglitazone (15-30 mg daily) improves liver histology in patients with biopsy-proven NASH, achieving fibrosis resolution in some cases (odds ratio 3.15). 1 However, it causes average weight gain of 2.7% and is contraindicated in decompensated cirrhosis. 1

SGLT2 inhibitors reduce steatosis by approximately 20% but their effect on liver histology remains unknown. 1

Cardiovascular Risk Management

Statins can be prescribed to patients with F2-F3 fibrosis and Child A or B cirrhosis for cardiovascular protection. 1 A meta-analysis of 121,058 patients showed statin use associated with 46% reduction in hepatic decompensation and 46% lower mortality in patients with cirrhosis. 1 Avoid statins in decompensated cirrhosis (Child C) or acute liver failure. 1

Failed or Not Recommended Therapies

Obeticholic acid (farnesoid X receptor agonist) was rejected by the FDA despite showing fibrosis improvement because severe pruritus and increased cardiovascular risk from elevated LDL-C outweighed benefits. 1

The following drugs failed phase 3 trials and development was discontinued: 1

• Selonsertib (ASK1 inhibitor) - STELLAR-3,4 trials
• Elafibranor (PPAR-α/δ agonist) - RESOLVE-IT trial

Omega-3 fatty acids are not recommended for NASH treatment due to inconsistent study results, though they may be used for hypertriglyceridemia with NAFLD. 1

Metformin has no major effect on steatohepatitis in randomized controlled trials, though observational studies suggest possible HCC risk reduction. 1

Essential Non-Pharmacological Management

Weight loss of 7-10% body weight is required to improve liver inflammation and fibrosis. 2 Weight loss of any magnitude provides benefit, with 5-10% reduction improving steatohepatitis and fibrosis. 3

Mediterranean diet is strongly recommended: limited ultra-processed foods, no sugar-sweetened beverages, increased fruits, vegetables, whole grains, legumes, nuts, and olive oil. 2

Physical activity target: 150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity exercise. 2

Bariatric surgery can be considered for NASH patients with obesity who do not respond to medical treatment and lifestyle modification. 1, 2

Special Populations and Contraindications

In decompensated cirrhosis (Child C):

• Avoid statins 1
• Pioglitazone is contraindicated 1
• GLP-1RAs have not been widely tested 1
• Metformin is contraindicated due to lactic acidosis risk 3

For compensated cirrhosis (Child A/B):

• Statins are safe and may provide hepatoprotective effects 1, 3
• SGLT2 inhibitors can be used 3
• GLP-1RAs are preferred for diabetes management 3

Monitoring and Surveillance

Use FIB-4 score followed by transient elastography to assess fibrosis progression. 1, 2 This stepwise approach rules out/in advanced fibrosis, which predicts liver-related outcomes. 1

Hepatocellular carcinoma surveillance is mandatory for MASH-related cirrhosis. 2, 3

Monitor for portal hypertension complications in cirrhotic patients. 1, 3

Critical Pitfalls to Avoid

• Do not use vitamin E in diabetic patients with NASH (evidence only supports use in non-diabetics) 3
• Do not continue pioglitazone if weight gain becomes problematic without combining with SGLT2 inhibitors or GLP-1RAs 1
• Do not assume any single drug will work in >50% of patients - combination therapy will likely be required 1
• Do not delay liver transplant evaluation if decompensation develops 1, 3