Exploratory associations between co-occurring opioid and alcohol use disorders and GIP/GLP-1 receptor agonist treatment

BACKGROUND: Co-occurring opioid and alcohol use disorders (OUD + AUD) are associated with morbidity, yet medications for these disorders remain underused. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (RA), prescribed for metabolic disease, may influence substance-related outcomes. This study aims to estimate associations between GIP/GLP-1 RA prescriptions, first-line AUD and OUD medications and several adverse healthcare outcomes among those with co-occurring OUD + AUD. METHODS: We conducted a retrospective cohort study using de-identified electronic health records from Oracle Health Real-World Data (149 U.S. health systems; 2014-2024). Among 107,217 patients aged ≥12 years with dual OUD + AUD diagnoses, time-varying exposures included medications for OUD (MOUD), medications for AUD (MAUD), and GIP/GLP-1 RA prescriptions. Outcomes over 2 years included overdoses and intoxications, SUD-related hospitalizations, detoxification, positive drug screens, mental health events, incident liver conditions, and liver biomarkers. Marginal structural survival models with stabilized inverse probability of treatment weighting estimated adjusted hazard ratios (aHRs) overall and stratified by MOUD/MAUD status, type 2 diabetes (T2DM), and obesity. RESULTS: GIP/GLP-1 RA prescriptions are associated with lower risk of all-drug overdose among patients not receiving MOUD/MAUD (aHR 0.61; 95% CI 0.32-0.98). In stratified analyses, lower overdose risk is observed among patients with T2DM receiving MAUD only (aHR 0.15; 95% CI 0.01-0.41) and among those receiving both MOUD and MAUD (T2DM: aHR 0.46; 95% CI 0.24-0.87; obesity: aHR 0.19; 95% CI 0.04-0.97). Protective associations for SUD-related hospitalization are observed across most strata. CONCLUSIONS: In this large EHR cohort, GIP/GLP-1 RA prescriptions are linked to reduced overdose and hospitalization risk among patients with co-occurring OUD + AUD. Findings are exploratory and limited by small subgroup sizes; prospective studies are needed to confirm benefit and evaluate safety.