GLP-1 RAs Lower Risk of Liver Damage and Death in Alcohol Use, reveals research

GLP-1 receptor agonists have attracted interest for their glucose-lowering and weight-reducing action as well as through anecdotal evidence of reduced alcohol cravings among users. As excessive alcohol consumption is a major cause of liver disease and death, researchers aimed to ascertain whether GLP-1 RAs might offer quantifiable clinical benefits in such a population. The research replicated a target trial with data based on actual cases of veterans with alcohol use disorder history, defined as a positive Alcohol Use Disorders Identification Test–Concise (AUDIT-C) screen.

The study evaluated data through January 3, 2017, to September 30, 2024, with follow-up continuing through death, occurrence of liver-related outcomes, or end of the study. Each treatment-initiating participant was matched with a comparable patient who did not take GLP-1 RAs to provide equivalent comparisons.

The high-volume study employed electronic health records of the U.S. Veterans Affairs to simulate a target trial. It comprised 8040 new GLP-1 RA users with a positive AUDIT-C score, each 1:1 matched with 8040 non-users with a positive alcohol screen. The main outcome was a composite of four serious conditions: hepatic decompensation, hepatocellular carcinoma (HCC), liver-related death, and all-cause mortality. The secondary outcome assessed the odds of persistent harmful alcohol use, again measured in terms of follow-up AUDIT-C scores. Semaglutide, which is also widely prescribed GLP-1 RA, was also examined by dose to see if higher dosing provided greater protection against bad outcomes.

Key Findings

• Users of GLP-1 RA had a 30% reduced chance of having liver-related events and/or dying (adjusted hazard ratio [aHR] 0.70, 95% CI 0.56–0.87).

• All-cause mortality was lowered by 57% among users of GLP-1 RA (aHR 0.43, 95% CI 0.37–0.49).

Among Semaglutide users, every 1 mg/week increase in dose was linked with:

• A 50% reduced risk of liver-related outcomes (aHR 0.50, 95% CI 0.29–0.88)

• A 67% reduced risk of mortality (aHR 0.33, 95% CI 0.19–0.58)

• The use of GLP-1 RA was linked to 25% lower odds of positive testing for harmful alcohol use during follow-up (adjusted odds ratio [aOR] 0.75, 95% CI 0.68–0.82)

This real-world evidence target trial emulation demonstrated that GLP-1 RA therapy substantially decreased the risk of complications related to the liver, all-cause death, and dangerous use of alcohol in U.S. veterans with alcohol misuse. The results provide encouraging evidence of the potential for GLP-1 RA repurposing for more general use in liver disease prevention and substance use disorder treatment, supporting future clinical investigation and consideration in practice.

Reference:

John BV, Bastaich D, Marchetti D, Perumalswami P, Mustafa MZ, Dahman B; Veterans Analysis of Liver Disease (VALID) group of investigators. 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. Am J Gastroenterol. 2025 Jun 10. doi: 10.14309/ajg.0000000000003585. Epub ahead of print. PMID: 40488647.