Do GLP-1 (Glucagon-like peptide-1) receptor agonists affect Liver Function Tests (LFTs)?

GLP-1 Receptor Agonists and Liver Function Tests

GLP-1 receptor agonists generally improve liver function markers rather than cause harm, with evidence showing reductions in transaminases and beneficial effects on hepatic steatosis, though mild isolated bilirubin elevations can occur in approximately 4% of patients. 1

Effects on Liver Enzymes and Bilirubin

Mild bilirubin elevations occur in a small subset of patients:

• In clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin (up to twice the upper limit of normal) occurred in 4.0% of liraglutide-treated patients versus 2.1% of placebo-treated patients 1
• These bilirubin elevations were isolated findings not accompanied by abnormalities in other liver tests, and their clinical significance remains unknown 1

Transaminase improvements are more commonly observed:

• Meta-analyses demonstrate that GLP-1 receptor agonists reduce circulating transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD) 2
• These reductions reflect improvements in hepatic steatosis and inflammation rather than drug-induced liver injury 3

Hepatobiliary Effects

Gallbladder-related complications represent the primary hepatobiliary concern:

• Post-marketing surveillance has identified elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, and cholelithiasis requiring cholecystectomy 1
• However, in controlled trials, the incidence of cholelithiasis (0.3%) and cholecystitis (0.2%) was identical between liraglutide and placebo groups 1
• These complications relate to delayed gastric emptying and altered bile composition rather than direct hepatotoxicity 2

Beneficial Effects on Liver Disease

GLP-1 receptor agonists demonstrate protective effects on liver outcomes:

• A large Scandinavian cohort study (91,479 GLP-1 receptor agonist users) showed an adjusted hazard ratio of 0.85 (95% CI: 0.75-0.97) for serious liver events, representing a reduction of 2.1 events per 10,000 person-years 4
• This benefit was driven primarily by reduced risk of compensated and decompensated cirrhosis (HR 0.85,95% CI: 0.75-0.97) 4
• In patients with chronic liver disease and type 2 diabetes who adhered to therapy, the 10-year risk of major adverse liver outcomes was 7.4% with GLP-1 receptor agonists versus 14.4% in non-users (RR=0.51,95% CI: 0.14-0.88) 5

Mechanisms of hepatic benefit include:

• Reduction in hepatic fat content by approximately 31% after 6 months of liraglutide therapy 6
• Resolution of non-alcoholic steatohepatitis (NASH) without worsening of liver fibrosis (WMD: 4.08,95% CI: 2.54-6.56) 3
• Decreased C-reactive protein levels (WMD: -0.41,95% CI: -0.78 to -0.04), indicating reduced systemic inflammation 3
• The LEAN trial demonstrated NASH resolution in 39% of liraglutide-treated patients versus 9% with placebo, with less progression of fibrosis 2

Clinical Monitoring Recommendations

Baseline and periodic monitoring should include:

• Obtain baseline liver function tests (ALT, AST, bilirubin, alkaline phosphatase) before initiating therapy 1
• Monitor for symptoms of cholecystitis (right upper quadrant pain, fever, nausea) during treatment 2, 1
• If isolated bilirubin elevation occurs without other liver test abnormalities, continue monitoring but recognize this is typically benign 1
• Lipase and amylase may increase (mean 33% and 15% respectively), but clinical significance is unclear without other signs of pancreatitis 1

Key Clinical Pitfalls

Avoid misinterpreting beneficial effects as toxicity:

• Transaminase reductions reflect therapeutic benefit on hepatic steatosis, not drug discontinuation signals 2, 3
• Isolated mild bilirubin elevations without other liver test abnormalities do not require drug cessation 1

Recognize true contraindications:

• GLP-1 receptor agonists are not contraindicated in patients with chronic liver disease; they may actually be beneficial 7, 5
• The primary hepatobiliary concern is gallbladder disease in susceptible patients, not hepatotoxicity 1