Association of Glucagon-Like Peptide-1 Receptor Agonists With Liver-Related Outcomes and All-Cause Mortality in Patients With Harmful Alcohol Use: A Target Trial Emulation Study.

INTRODUCTION: Anecdotal observations report a decrease in craving for alcohol among patients taking glucagon-like peptide-1 receptor agonists (GLP-1 RA). We aimed to assess liver-related outcomes and mortality among individuals with harmful alcohol use who received GLP-1 RAs. METHODS: We emulated a target trial using the electronic health records of US Veterans with positive alcohol use disorders-concise score (AUDIT-C), comparing new initiators of GLP-1 RA between 1/3/2017 and 9/30/2024, with controls, with follow-up until outcomes or study end. Each GLP-1 RA new user with a positive AUDIT-C screen was propensity score (PS) matched 1:1 with a patient not on a GLP-1 RA. The primary outcomes were the time to a composite outcome of decompensation, hepatocellular carcinoma, liver-related death, and all-cause mortality. The secondary outcome was the proportion of patients with positive AUDIT-C scores. RESULTS: We matched 8,040 patients with positive AUDIT-C initiated on GLP-1 RA with 8,040 noninitiators. GLP-1 RA use was associated with a lower risk of composite liver-related outcomes (adjusted hazard ratio [aHR], 0.70; 95% confidence interval [CI] 0.56-0.87) and death (aHR 0.43, 95% CI 0.37-0.49). Among semaglutide users, a 1 mg/wk dose increase was associated with a reduced risk of composite liver-related outcomes (aHR 0.50, 95% CI 0.29-0.88) and death (aHR 0.33, 95% CI 0.19-0.58). GLP-1 RA use was also associated with lower odds of positive AUDIT-C during follow-up (adjusted Odds ratio 0.75, 95% CI 0.68-0.82). DISCUSSION: In this observational target trial emulation study, GLP-1 RA use was associated with a lower risk of liver outcomes, death, and harmful alcohol use.