Effect of varenicline on major adverse liver outcomes in alcohol‐associated liver disease: An exploratory analysis

Abstract

Background: Varenicline, a partial agonist of the α4β2 nicotinic acetylcholine receptor, is effective for smoking cessation and has shown promise in treating alcohol use disorder (AUD). However, its impact on patients with concurrent alcohol-associated liver disease (ALD) remains understudied. We aimed to evaluate the association between varenicline use and long-term clinical outcomes in this population. Methods: We conducted a retrospective cohort study using the TriNetX federated network of deidentified electronic health records. Adults with diagnoses of both ALD and AUD were included. Patients prescribed varenicline were compared to those receiving FDA-approved AUD pharmacotherapies (acamprosate or naltrexone), using 1:1 propensity score matching based on demographics, comorbidities, medications, and laboratory values. The primary outcome was major adverse liver outcomes (MALO); secondary outcomes included all-cause mortality and other liver-related complications. Hazard ratios (HRs) were estimated using Cox proportional hazards models over a five-year follow-up period. Results: A total of 1278 patients were included after matching. Varenicline use was associated with lower all-cause mortality (14.4% vs. 17.4%; HR 0.75, 95% CI 0.57-0.99) and a significantly reduced risk of hepatic encephalopathy (3.5% vs. 6.7%; HR 0.47, 95% CI 0.28-0.79). Although overall MALO rates were similar between groups (17.3% vs. 17.6%; HR 0.89, 95% CI 0.66-1.20), subgroup analyses revealed reduced MALO incidence among females and all-cause mortality among individuals aged ≥65 years. Conclusion: In this real-world cohort study, varenicline use was associated with improved survival and a lower risk of hepatic encephalopathy compared to standard AUD pharmacotherapies in patients with co-occurring ALD and AUD. These findings support further investigation of varenicline as a potential therapeutic option, ideally through randomized controlled trials.