Glucagon-Like Peptide 1 Receptor Agonists are Associated With Reduced Risk of Hepatic Encephalopathy in Cirrhosis

GOALS: This retrospective cohort study investigates whether weight loss-dose glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy is associated with the risk of hepatic encephalopathy (HE) among patients with cirrhosis. BACKGROUND: Hepatic encephalopathy (HE) is associated with prolonged intestinal transit time. GLP-1 RA therapies, particularly at weight-loss-promoting doses, prolong gastrointestinal transit time, but there is limited data on HE risk in cirrhotic GLP-1 RA users. STUDY: Patients with cirrhosis from a single quaternary care medical center were examined between 2017 and 2024. The primary exposure was the presence or absence of therapeutic-dose GLP-1 RA treatment (≥1 mg/wk semaglutide or ≥7.5 mg/wk tirzepatide for ≥6 mo). The primary outcome was time to incident HE. Survival analyses were conducted with competing risks for death or liver transplantation, and adjusting for sociodemography and comorbidity. RESULTS: A total of n=2557 patients with cirrhosis, of which n=139 met GLP-1 RA use criteria. GLP-1 RA users were less likely to develop HE (3.6% vs. 18.7%, P<0.001) or experience mortality (2.9% vs. 14.5%, P<0.001) compared with nonusers. Multivariate analysis demonstrated a reduced of HE risk with GLP-1 RA use [Hazard Ratio (HR) 0.33, P=0.048]. A significant interaction was observed between GLP-1 RA use and liver cancer, with GLP-1 RA use increasing HE risk among patients with cirrhosis and liver cancer (HR 6.12, P=0.024) but reducing risk in those without liver cancer (HR 0.23, P=0.041). CONCLUSIONS: These findings suggest that GLP-1 RA use may be considered in patients with cirrhosis but without liver cancer to reduce events of HE. Further study is needed to clarify the mechanistic pathways of the observed effects.