Association of GLP-1 Receptor Agonists with Liver-Related Outcomes and All-Cause Mortality in Patients with Harmful Alcohol Use: A Target Trial Emulation Study

Background and Aims: Anecdotal observations report a decrease in craving for alcohol among patients taking glucagon-like peptide-1 receptor agonists (GLP-1RA). We aimed t o 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 U.S. Veterans with positive alcohol use disorders-concise score (AUDIT-C), comparing new initiators of GLP-1RA 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-matched 1:1 with a patient not on a GLP-1RA. The primary outcomes were the time to a composite outcome of decompensation, HCC, liver-related death, and all-cause mortality. The secondary outcome was the proportion of patients with positive AUDIT-C scores. Results: We matched 8040 patients with positive AUDIT-C initiated on GLP-1 RA with 8040 non-initiators. GLP-1 RA use was associated with a lower risk of composite liver-related outcomes (adjusted hazard ratio [aHR], 0.70; 95% CI 0.56-0.87), and death (aHR 0.43, 95% CI 0.37-0.49). Among Semaglutide users, a 1 mg/week 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 (aOR 0.75, 95% CI 0.68-0.82). Conclusions and Relevance: 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.