What is the evidence for using GLP-1 (Glucagon-Like Peptide-1) agonists in the management of MAFLD (Metabolic Associated Fatty Liver Disease)?

GLP-1 Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

GLP-1 receptor agonists (GLP-1RAs) cannot currently be recommended specifically as MASLD-targeted therapies due to insufficient evidence from large, well-conducted phase III trials demonstrating histological improvement. 1

Current Evidence and Recommendations

Official Position on GLP-1RAs in MASLD

• GLP-1RAs are safe to use in patients with MASLD, including those with compensated cirrhosis, and should be used for their approved indications of type 2 diabetes and obesity, as they improve cardiometabolic outcomes 1
• In the absence of formal demonstration of histological improvement in large phase III trials, GLP-1RAs cannot be specifically recommended as MASLD-targeted therapies (Level of Evidence 5, strong recommendation) 1
• When substantial weight loss is induced by GLP-1RAs, hepatic histological benefits could be expected, although this has not been extensively documented 1

Safety Profile

• GLP-1RAs have demonstrated safety in patients with MASLD, including those with compensated cirrhosis 1
• Baseline liver function tests should be obtained in patients with known liver disease, and periodic monitoring is reasonable during treatment 2

Potential Benefits in MASLD

Indirect Mechanisms of Action

• GLP-1RAs primarily affect the liver indirectly, as hepatocytes, Kupffer cells, and stellate cells do not express the canonical GLP-1 receptor 3
• These medications reduce appetite and body weight, decrease postprandial lipoprotein secretion, and attenuate systemic and tissue inflammation, which may contribute to improvement in MASLD 3, 4

Weight Loss Effects

• Weight loss is a key mechanism by which GLP-1RAs may benefit MASLD patients 1
• The LEAN trial (Liraglutide Efficacy and Action in Non-alcoholic steatohepatitis) showed more frequent resolution of NASH with liraglutide compared to placebo, though the study was small 1
• Studies have demonstrated that GLP-1RAs reduce hepatic fat and steatosis 1, 3

Clinical Considerations

Patient Selection

• The American Diabetes Association suggests that semaglutide may be particularly beneficial for patients with MASLD or NASH as it can improve both metabolic parameters and liver histology 2
• In patients with advanced fibrosis (F2-F4), semaglutide may be considered as part of metabolic management, though not specifically as liver-directed therapy 2

Monitoring

• Weight loss from semaglutide should be monitored carefully in patients with cirrhosis 2
• Common adverse events include gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain 5

Emerging Evidence and Future Directions

Dual and Triple Receptor Agonists

• Newer agents like tirzepatide (dual GIP/GLP-1 receptor agonist) are being studied in MASLD with ongoing trials 6, 4
• Triple GIP/GLP-1/glucagon receptor agonists are in development and may offer additional benefits 6

Research Gaps

• Ongoing trials in people with obesity will further clarify the safety of GLP-1RAs 3
• Pivotal studies underway in people with NASH will define whether GLP-1-based medicines represent effective and safe therapies for MASLD 3, 4

Practical Approach

• For patients with MASLD who also have type 2 diabetes or obesity, GLP-1RAs are appropriate treatment options for these indications 1
• The primary focus for MASLD management should remain lifestyle modifications, with GLP-1RAs considered as metabolic therapy rather than specific MASLD treatment 1
• In patients achieving substantial weight loss with GLP-1RAs, monitor for potential liver histological improvements 1, 4