Association of GLP ‐1 Receptor Agonist Use With Safety Outcomes in Individuals With Opioid Use Disorder: A Target Trial Emulation

Aims To evaluate the association between glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) initiation and adverse gastrointestinal, renal, respiratory and psychiatric outcomes among individuals with opioid use disorder (OUD). Materials and Methods This retrospective cohort study was conducted using the MarketScan Commercial Claims and Encounters database (2016–2023) following a target trial emulation framework. Participants were aged 18 years or older with OUD and eligible for GLP‐1 RA treatment for type 2 diabetes or obesity. Ten prespecified safety outcomes were assessed. For each prespecified outcome, separate analytic cohorts of GLP‐1 RA users and non‐users were created based on time‐conditional propensity score matching. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated comparing GLP‐1 RA users with non‐users, with follow‐up until outcome occurrence, disenrollment or end of the study period (December 2023), whichever came first. Results For each prespecified outcome, the size of the matched cohorts varied from 1472 to 2329 GLP‐1 RA users (and an equal number of non‐users), depending on outcome‐specific eligibility criteria. For the gastrointestinal outcomes, GLP‐1 RA use was associated with a lower risk of pancreatitis (aHR, 0.65; 95% CI, 0.45–0.93), with no increased risk of gastroparesis. No increased risks were observed for renal (AKI) or respiratory (aspiration pneumonitis) outcomes. Among psychiatric outcomes, lower risks were observed for insomnia (0.78; 0.68–0.89) and anxiety (0.76; 0.67–0.86), with no increased risk for depression, stress‐related disorders, eating disorders and suicidal behaviour or ideation. Findings were generally consistent across subgroups stratified by age, sex and type 2 diabetes status. Conclusions In a large cohort of commercially insured individuals with OUD, GLP‐1 RA initiation was not associated with increased adverse gastrointestinal, renal, respiratory or psychiatric outcomes and was associated with lower risks of pancreatitis, insomnia and anxiety. While the possibility of residual confounding cannot be excluded, these data support the safety of GLP‐1 RAs when used for approved indications in patients with OUD and inform ongoing repurposing efforts.