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

Aims 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. Material and Methods 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. Results 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]). Conclusion 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.