Role of GLP-1 Agonists in Metabolic Associated Steatotic Liver Disease (MASLD)
GLP-1 receptor agonists (GLP-1RAs) are recommended as first-line pharmacological therapy for patients with non-cirrhotic MASLD/MASH (F0-F3), particularly when locally approved and in patients with comorbid obesity or type 2 diabetes. 1
Efficacy in MASLD Management
- GLP-1RAs (semaglutide, liraglutide, dulaglutide) are preferred pharmacological options for treating MASLD/MASH without cirrhosis (F0-F3) according to the 2024 EASL-EASD-EASO clinical practice guidelines 1
- These agents reduce hepatic fat and steatosis, helping decrease inflammation associated with MASLD and metabolic dysfunction-associated steatohepatitis (MASH) 2, 3
- GLP-1RAs significantly reduce liver fat content (weighted mean difference -3.17%), body weight, waist circumference, and liver enzymes (ALT, GGT) compared to placebo or active agents 4
- The LEAN trial demonstrated that liraglutide led to more frequent resolution of NASH and less progression of fibrosis compared to placebo in patients with NAFLD/NASH 2
Mechanism of Action in Liver Disease
- GLP-1RAs improve MASLD primarily through indirect mechanisms, as hepatocytes, Kupffer cells, and stellate cells do not express the canonical GLP-1 receptor 5
- These agents reduce appetite and body weight, decrease postprandial lipoprotein secretion, and attenuate systemic and tissue inflammation, all contributing to improvement in MASLD 5
- GLP-1RAs decrease systemic inflammation and improve endothelium-dependent vasodilation, which may contribute to their hepatoprotective effects 2
Clinical Outcomes
- Recent evidence shows GLP-1 agonist use in MASLD patients is associated with reduced risk of:
- Major cardiovascular events (HR 0.594 at 7 years)
- Clinically significant portal hypertension events (HR 0.463 at 7 years)
- All-cause mortality (HR 0.303 at 7 years) 6
- Among GLP-1RAs, semaglutide has the strongest evidence for benefit in patients with NASH and fibrosis 1
- While GLP-1RAs can reduce steatosis and steatohepatitis histological signs (inflammatory cell infiltration and hepatocyte ballooning), their effect on improving fibrosis is more limited 3
Treatment Recommendations
- For patients with MASLD/MASH without cirrhosis (F0-F3), GLP-1RAs are recommended as first-line pharmacological therapy when locally approved 1
- For patients with MASLD/MASH with compensated cirrhosis (F4), pharmacotherapy should be individualized with caution 1
- GLP-1RAs should be considered particularly for MASLD patients with comorbid type 2 diabetes or obesity 1
- Combination therapy approaches using GLP-1RAs with antifibrotic drugs or dual agonists (GIP/GLP-1 or GLP-1/glucagon) may provide greater improvement than monotherapy 3
Limitations and Considerations
- Most common adverse effects are gastrointestinal (nausea, vomiting, dyspepsia, diarrhea, gastrointestinal reflux, and constipation) 2
- GLP-1RAs may cause gallbladder disorders and rare cases of pancreatitis, requiring caution in patients with a history of these conditions 2
- When initiating GLP-1RAs, start at a low dose and titrate slowly to minimize gastrointestinal side effects 2
- While GLP-1RAs show promise in MASLD management, they should be used as part of a comprehensive approach that includes lifestyle modifications 1