Is semaglutide (Glucagon-like peptide-1 (GLP-1) receptor agonist) indicated for the treatment of transaminitis (elevated liver enzymes) and fatty liver disease?

Semaglutide for Transaminitis and Fatty Liver Disease

Semaglutide has strong evidence supporting its use for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), particularly in patients with fibrosis, though it is not yet FDA-approved specifically for this indication.

Evidence for Semaglutide in Liver Disease

Semaglutide has emerged as the GLP-1 receptor agonist with the most robust evidence for treating NASH and fibrosis:

• In a 72-week study of 320 patients with biopsy-proven NASH, semaglutide at 0.4 mg daily achieved NASH resolution without worsening fibrosis in 59% of patients versus 17% on placebo 1
• Among different GLP-1 receptor agonists, semaglutide has shown the strongest evidence for benefit in patients with NASH and fibrosis 2
• Recent clinical evidence demonstrates that semaglutide treatment improves liver steatosis and fibrosis markers in patients with NAFLD 3, 4, 5

Clinical Benefits on Liver Parameters

Semaglutide provides multiple benefits for patients with fatty liver disease:

• Reduces hepatic fat content and inflammation 2
• Improves liver enzyme levels (transaminitis) 2, 4
• Decreases surrogate markers of liver fibrosis, including:
  • Controlled Attenuation Parameter (CAP) scores
  • Fibrosis-4 (FIB-4) scores
  • NAFLD fibrosis scores 3, 5

Comparative Effectiveness

A multi-institutional cohort study found semaglutide superior to other antidiabetic medications for liver outcomes:

• Lower risk of major adverse liver outcomes compared to SGLT2 inhibitors (aHR 0.73), DPP-4 inhibitors (aHR 0.72), and thiazolidinediones (aHR 0.76) 6
• Reduced all-cause mortality compared to these same medication classes 6

Treatment Algorithm for NAFLD/NASH

Based on current guidelines, the following approach is recommended:

1. For NAFL or NASH with minimal fibrosis (F0-F1):

   • Lifestyle modifications are first-line
   • No specific pharmacotherapy for liver disease is indicated 1

2. For NASH with significant fibrosis (F2-F3):

   • Lifestyle modifications plus pharmacotherapy
   • Among GLP-1 receptor agonists, semaglutide has the best evidence 1
   • Consider pioglitazone (especially in patients with diabetes) 1
   • Consider vitamin E 800 IU/day (primarily in non-diabetic patients) 1

3. For NASH cirrhosis (F4):

   • Pharmacotherapy should be individualized and used with caution
   • Evidence for efficacy in cirrhosis is limited 1

Important Considerations and Caveats

• Semaglutide is not yet FDA-approved specifically for NAFLD/NASH treatment
• Common side effects include gastrointestinal symptoms (nausea, vomiting, constipation) 1, 5
• Gradual dose titration helps mitigate adverse effects 1
• GLP-1 receptor agonists have been associated with increased risk of pancreatitis and gallbladder disease 1
• Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1
• Weight loss achieved with semaglutide likely contributes significantly to its beneficial effects on liver parameters 5

In conclusion, while semaglutide shows promising results for treating transaminitis and fatty liver disease, it should be considered as part of a comprehensive approach that includes lifestyle modifications, particularly for patients with significant fibrosis (F2-F3) where the evidence is strongest.