Glucagon-like peptide-1 receptor agonists but not dipeptidyl peptidase-4 inhibitors reduce alcohol intake.

BACKGROUND: Despite growing preclinical evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be repurposed to treat alcohol use disorder (AUD), clinical evidence is scarce. Additionally, the potential impact of dipeptidyl peptidase-4 inhibitors (DPP-4Is) on alcohol intake is largely unknown. METHODS: We conducted a large cohort study using 2008-2023 electronic health records data from the U.S. Department of Veterans Affairs. Changes in Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores were compared between propensity-score-matched GLP-1RA recipients, DPP-4I recipients, and unexposed comparators. We further tested the effects of two DPP-4Is, linagliptin and omarigliptin, on binge-like alcohol drinking in mice and operant oral alcohol self-administration in alcohol-dependent rats, models previously used to show a significant effect of the GLP-1RA semaglutide in reducing alcohol intake. RESULTS: GLP-1RA recipients reported a greater reduction in AUDIT-C scores than unexposed individuals [difference-in-difference: 0.09(0.03,0.14), p=0.0025] and DPP-4I recipients [difference-in-difference: 0.11(0.05,0.17), p=0.0002]. Reductions in drinking were more pronounced among individuals with baseline AUD [GLP-1RA vs. unexposed: 0.51(0.29,0.72), p<0.0001; GLP-1RA vs. DPP-4I: 0.65(0.43,0.88), p<0.0001] and baseline hazardous drinking [GLP-1RA vs. unexposed: 1.38(1.07,1.69), p<0.0001; GLP-1RA vs. DPP-4I: 1.00(0.68,1.33), p<0.0001]. There were no differences between DPP-4I recipients and unexposed individuals. The latter results were confirmed via a reverse translational approach. Specifically, neither linagliptin nor omarigliptin reduced alcohol drinking in mice or rats. The rodent experiments also confirmed target engagement as both DPP-4Is reduced blood glucose levels. CONCLUSION: Convergent findings across humans, mice, and rats indicate that GLP-1RAs but not DPP-4Is reduce alcohol consumption and may be efficacious in treating AUD.