Association of GLP-1 receptor agonist use with long-term outcomes in patients with opioid use disorder

Opioid use disorder (OUD) is a major public health challenge with high overdose mortality and healthcare utilization. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer cardiometabolic and neurobiological benefits, including modulation of reward pathways linked to addiction. Preclinical and early clinical data suggest GLP-1RAs may reduce substance-seeking behaviors, but realworld outcomes in OUD remain unclear. We conducted a retrospective cohort study using the TriNetX US Collaborative Network to identify adults aged ≥18 years diagnosed with OUD between January 1, 2016, and October 30, 2025. GLP-1RA exposure was defined as a prescription within 1 month up to the date of OUD diagnosis. Propensity score matching (1:1) balanced demographic and clinical covariates, including medication for opioid use disorder (MOUD) treatments. Primary outcomes were all-cause mortality and opioid overdose; secondary outcomes included inpatient admissions and emergency department (ED) visits over 6-month to 5-year intervals. Among 473,906 individuals with OUD, 8,737 (1.8%) received a GLP-1RA; after propensity score matching, 8,052 patients remained in each cohort with wellbalanced baseline characteristics (all standardized mean differences ≤0.10). GLP-1RA use was associated with lower 5-year all-cause mortality (4.9% vs 10.9%; HR 0.63, p < 0.001) and reduced overdose risk (3.0% vs 4.8%; HR 0.81, p = 0.01). In addition, GLP-1RA therapy was linked to fewer inpatient admissions (HR 0.73) and ED visits (HR 0.83), both with p < 0.001. These findings suggest that GLP-1RA use was associated with lower mortality, overdose risk, and healthcare utilization, supporting further investigation of GLP-1RAs as potential adjunctive therapies for OUD.