Relative efficacy of GLP-1 and GLP-1/GIP receptor agonists in the prevention of alcohol-use disorders using a target trial emulation approach.

Henney, Alex E ORCID: 0000-0002-8066-9470, Riley, David R ORCID: 0000-0002-0905-6524, Heague, Megan, Roberts, Carl A ORCID: 0000-0003-4275-601X, Hydes, Theresa J ORCID: 0000-0002-7768-6886, Anson, Matthew ORCID: 0000-0001-9991-7369, Hughes, David M ORCID: 0000-0002-1287-9994, Alam, Uazman ORCID: 0000-0002-3190-1122 and Cuthbertson, Daniel J ORCID: 0000-0002-6128-0822 (2026) Relative efficacy of GLP-1 and GLP-1/GIP receptor agonists in the prevention of alcohol-use disorders using a target trial emulation approach. Diabetes, obesity & metabolism, 28 (1). pp. 137-150. ISSN 1462-8902, 1463-1326

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Abstract

<h4>Aims</h4>There is growing evidence that the GLP-1 system is implicated in alcohol and other substance use disorders, and that GLP-1-based therapies may have therapeutic relevance in alcohol use disorder (AUD). We aimed to determine the impact of GLP-1 based therapies on incident AUDs in a real-world setting in patients with T2D.<h4>Material and methods</h4>We conducted emulation target trials based on a real-world network of electronic health records (EHRs) from over 120 million patients in the United States of America. Four target trials were emulated among eligible patients with type 2 diabetes (T2D) who had no prior AUD diagnosis by comparing tirzepatide, semaglutide, liraglutide, and dulaglutide with DPP4 inhibitors (DPP4i). First-ever diagnosis of AUD occurred within an 18-month follow-up period and was examined using Kaplan-Meier survival analyses. Four target trial cohorts were generated and compared with a reference arm of patients treated with DPP4i: cohort (1) treatment with tirzepatide; cohort (2) treatment with semaglutide; cohort (3) treatment with liraglutide; and cohort (4) treatment with dulaglutide. Cohorts underwent propensity score matching 1:1 for confounders. We examined rates of incident AUD (ICD-10 code F10) and performed head-to-head analyses of the incretin-based therapies. We also performed sensitivity analyses relating to whether treatment was adjunctive therapy with metformin and by treatment adherence.<h4>Results</h4>After propensity-score matching, we identified four target trials of patients treated with tirzepatide (n = 7165), semaglutide (n = 20 198), liraglutide (n = 6565), and dulaglutide (n = 19 061); 1:1 with the reference (DPP4i) patients. Tirzepatide and semaglutide (but not liraglutide or dulaglutide) were associated with significant risk reduction of incident AUD compared to DPP4i (hazard ratio 0.47 [95% confidence interval 0.29, 0.75] and 0.68 [0.52, 0.89], respectively). Head-to-head comparison revealed tirzepatide had a significant risk reduction compared to liraglutide in incident AUD (0.47 [0.24, 0.92]).<h4>Conclusion</h4>In patients with T2D, tirzepatide and semaglutide treatment is associated with a lower incidence of AUD; robust randomised, controlled evidence for the use of these drugs for this novel indication is appropriate.

Item Type:	Article
Uncontrolled Keywords:	Humans, Diabetes Mellitus, Type 2, Alcoholism, Receptors, Gastrointestinal Hormone, Recombinant Fusion Proteins, Hypoglycemic Agents, Treatment Outcome, Drug Therapy, Combination, Adult, Aged, Middle Aged, Female, Immunoglobulin Fc Fragments, Male, Glucagon-Like Peptide 1, Glucagon-Like Peptides, Incretins, Dipeptidyl-Peptidase IV Inhibitors, Liraglutide, Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences > Inst. Life Courses & Medical Sciences (T&R staff) Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences > Cardiovascular & Metabolic Medicine Faculty of Health & Life Sciences > Inst. Population Health Faculty of Health & Life Sciences > Inst. Population Health > Psychology Faculty of Health & Life Sciences > Inst. Population Health > Inst. Population Health (T&R Staff)
Depositing User:	Symplectic Admin
Date Deposited:	13 Oct 2025 13:27
Last Modified:	04 Jan 2026 13:21
DOI:	10.1111/dom.70169
Open Access URL:	http://doi.org/10.1111/dom.70169
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3194822
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