What is the role of GLP-1 (Glucagon-like peptide-1) analogs, such as liraglutide (Victoza) or semaglutide (Ozempic), in the treatment of non-alcoholic fatty liver disease (NAFLD)?

GLP-1 Receptor Agonists in NAFLD Treatment

GLP-1 receptor agonists (GLP-1RAs) show significant promise for treating non-alcoholic fatty liver disease (NAFLD), with semaglutide demonstrating NASH resolution in 59% of patients compared to 17% on placebo in the most recent high-quality trial. 1

Efficacy of GLP-1RAs in NAFLD

• GLP-1RAs, particularly semaglutide and liraglutide, have demonstrated effectiveness in improving liver histology in patients with biopsy-proven NASH 1
• Semaglutide (0.4 mg/day) achieved NASH resolution without worsening fibrosis in 59% of patients versus 17% in placebo group (p<0.001) 1
• Liraglutide has shown reversal of steatohepatitis and amelioration of fibrosis progression in a proof-of-concept study with 52 subjects with biopsy-proven NASH 1
• The LEAN trial demonstrated more frequent resolution of NASH (9/23 versus 2/22; p=0.019) and less progression of fibrosis (2/23 versus 8/22; p=0.04) with liraglutide compared to placebo 1

Mechanisms of Action in NAFLD

• GLP-1RAs improve NAFLD through multiple mechanisms:
  • Reduction of hepatic fat and steatosis 1
  • Weight loss, which correlates with degree of steatosis improvement 1
  • Decrease in epicardial adipose tissue thickness (36% reduction with liraglutide in one study) 1
  • Improvement in metabolic parameters and insulin sensitivity 2
  • Reduction in inflammation markers such as CRP (WMD:-0.41,95% CI-0.78 to -0.04, p=0.002) 3

Clinical Application Algorithm

1. Patient Selection:

   • Prioritize patients with:
     • Biopsy-proven NASH 1
     • NAFLD with type 2 diabetes mellitus (T2DM) 1
     • NAFLD with obesity 1

2. GLP-1RA Selection:

   • For patients with T2DM and NAFLD:

     • Follow American Diabetes Association guidelines for GLP-1RA use 1
     • Consider semaglutide (strongest evidence) or liraglutide 1

   • For non-diabetic patients with NAFLD:

     • Evidence is stronger for overweight/obese patients 1
     • Use is premature in lean NAFLD patients until further data are available 1

3. Monitoring:

   • Assess liver enzymes (ALT, AST) 2
   • Monitor weight loss (significant predictor of response) 1
   • Consider AST to platelet ratio to evaluate fibrosis progression 2
   • Watch for gastrointestinal side effects (nausea, constipation, vomiting) 1

Comparative Efficacy

• GLP-1RAs compared to other treatments:
  • Superior to sitagliptin for weight reduction and liver inflammation improvement 2
  • Similar efficacy to pioglitazone for liver inflammation, but with weight loss rather than weight gain 2
  • Can be combined with pioglitazone to prevent weight gain while maintaining anti-inflammatory benefits 1

Important Considerations and Limitations

• No GLP-1RAs are currently FDA-approved specifically for NAFLD treatment 1
• Semaglutide showed NASH resolution but did not demonstrate significant improvement in fibrosis in the largest trial 1
• Dose-dependent gastrointestinal side effects occur more frequently with higher doses 1
• Most studies have been conducted in overweight/obese populations, limiting generalizability to lean NAFLD patients 1
• Long-term studies (beyond 3 years) are still needed 1
• Meta-analysis of 16 RCTs (2,178 patients) confirms GLP-1RAs significantly improve histologic resolution of NASH (WMD:4.08,95%CI 2.54-6.56, p<0.00001) 3

Combination Approaches

• For optimal outcomes in high-risk patients with NAFLD:
  • Combine GLP-1RAs with structured weight loss programs 1
  • Consider combination with SGLT2 inhibitors in diabetic patients 1
  • For patients requiring pioglitazone, adding GLP-1RAs can prevent weight gain while maintaining benefits 1