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

Mehdi Farokhnia, M.D., M.P.H.

Featured Paper of the Month – July 2025

Published in Journal of Clinical Investigation by Mehdi Farokhnia and Lorenzo Leggio of the NIDA IRP Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section.

Summary

Glucagon-like peptide-1 (GLP-1) is a naturally produced hormone that regulates blood sugar, appetite, and food intake. The development and clinical adoption of potent GLP-1 receptor agonists (GLP-1RAs), like semaglutide and tirzepatide, has revolutionized the management of diabetes and obesity. Increasing evidence also suggests that these medications help people reduce their alcohol intake and GLP-1RAs could possibly be repurposed to treat alcohol use disorder (AUD). Electronic health records, when combined with rigorous statistical methods, provide a valuable resource to study the effects of approved medications for new indications. In the present study, we investigated the associations between the receipt of GLP-1RAs and change in alcohol use, using real-world electronic health record data from the largest integrated healthcare system in the U.S., the Department of Veterans Affairs (VA). Compared to unexposed comparators, GLP-1RA recipients showed a greater reduction in AUD identification test-consumption (AUDIT-C) scores from baseline to follow-up. AUDIT-C is a validated and widely used 3-item questionnaire on alcohol use frequency and quantity with scores denoting severity of alcohol use. We also studied the effects of another class of GLP-1 therapies, known as dipeptidyl peptidase-4 inhibitors (DPP-4Is), which inhibit the degradation of GLP-1 and, therefore, increase endogenous GLP-1 levels. Unlike GLP-1RAs, receipt of DPP-4Is was not associated with changes in alcohol intake. We confirmed and corroborated the latter results via a reverse translational approach by showing that the DPP-4Is linagliptin and omarigliptin did not reduce alcohol intake in validated experimental models in mice or rats, despite reducing blood glucose levels. These findings provide convergent evidence across humans, mice, and rats that GLP-1RAs, but not DPP-4Is, reduce alcohol consumption and may be efficacious in treating AUD.

Publication Information

Farokhnia, Mehdi; Tazare, John; Pince, Claire L; Bruns, Nicolaus; Gray, Joshua C; Re, Vincent Lo; Fiellin, David A; Kranzler, Henry R; Koob, George F; Justice, Amy C; Vendruscolo, Leandro F; Rentsch, Christopher T; Leggio, Lorenzo

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

In: J Clin Invest, vol. 135, no. 9, 2025, ISSN: 1558-8238.

Abstract | Links

@article{pmid40048376,

title = {Glucagon-like peptide-1 receptor agonists, but not dipeptidyl peptidase-4 inhibitors, reduce alcohol intake},

author = {Mehdi Farokhnia and John Tazare and Claire L Pince and Nicolaus Bruns and Joshua C Gray and Vincent Lo Re and David A Fiellin and Henry R Kranzler and George F Koob and Amy C Justice and Leandro F Vendruscolo and Christopher T Rentsch and Lorenzo Leggio},

doi = {10.1172/JCI188314},

issn = {1558-8238},

year  = {2025},

date = {2025-05-01},

urldate = {2025-05-01},

journal = {J Clin Invest},

volume = {135},

number = {9},

abstract = {BACKGROUNDDespite growing preclinical evidence that glucagon-like peptide1 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.METHODSWe 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 2 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.RESULTSGLP-1RA recipients reported a greater reduction in AUDIT-C scores than unexposed individuals (difference-in-difference [DiD]: 0.09 [95% CI: 0.03, 0.14], P = 0.0025) and DPP-4I recipients (DiD: 0.11 [95% CI: 0.05,0.17], P = 0.0002). Reductions in drinking were more pronounced among individuals with baseline AUD (GLP-1RA versus unexposed: 0.51 [95% CI: 0.29,0.72], P < 0.0001; GLP-1RA versus DPP-4I: 0.65 [95% CI: 0.43,0.88], P < 0.0001) and baseline hazardous drinking (GLP-1RA versus unexposed: 1.38 [95% CI: 1.07,1.69], P < 0.0001; GLP-1RA versus DPP-4I: 1.00 [95% CI: 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 engagemhent, as both DPP-4Is reduced blood glucose levels.CONCLUSIONConvergent findings across humans, mice, and rats indicated that GLP-1RAs, but not DPP-4Is, reduce alcohol consumption and may be efficacious in treating AUD.FUNDINGThis work was supported by the National Institutes of Health Intramural Research Program (ZIA DA000635, ZIA DA000644, ZIA DA000602), National Institute on Alcohol Abuse and Alcoholism extramural funding (R01 AA030041, P01 AA029545, U01 AA026224, U24 AA020794, U01 AA020790, U10 AA013566), the U.S. Department of Veterans Affairs (I01BX004820), and an Alkermes Pathways Research Award.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

BACKGROUNDDespite growing preclinical evidence that glucagon-like peptide1 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.METHODSWe 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 2 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.RESULTSGLP-1RA recipients reported a greater reduction in AUDIT-C scores than unexposed individuals (difference-in-difference [DiD]: 0.09 [95% CI: 0.03, 0.14], P = 0.0025) and DPP-4I recipients (DiD: 0.11 [95% CI: 0.05,0.17], P = 0.0002). Reductions in drinking were more pronounced among individuals with baseline AUD (GLP-1RA versus unexposed: 0.51 [95% CI: 0.29,0.72], P < 0.0001; GLP-1RA versus DPP-4I: 0.65 [95% CI: 0.43,0.88], P < 0.0001) and baseline hazardous drinking (GLP-1RA versus unexposed: 1.38 [95% CI: 1.07,1.69], P < 0.0001; GLP-1RA versus DPP-4I: 1.00 [95% CI: 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 engagemhent, as both DPP-4Is reduced blood glucose levels.CONCLUSIONConvergent findings across humans, mice, and rats indicated that GLP-1RAs, but not DPP-4Is, reduce alcohol consumption and may be efficacious in treating AUD.FUNDINGThis work was supported by the National Institutes of Health Intramural Research Program (ZIA DA000635, ZIA DA000644, ZIA DA000602), National Institute on Alcohol Abuse and Alcoholism extramural funding (R01 AA030041, P01 AA029545, U01 AA026224, U24 AA020794, U01 AA020790, U10 AA013566), the U.S. Department of Veterans Affairs (I01BX004820), and an Alkermes Pathways Research Award.