S797 Gastrointestinal Adverse Events of Glucagon-Like Peptide-1 Receptor Agonists Used for Weight Loss: A Real-World Cohort Study

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and naltrexone-bupropion are commonly prescribed for weight management. While GLP-1 RAs offer superior weight loss, emerging evidence links them to serious gastrointestinal (GI) complications. Existing safety data are limited by small trials and short follow-up. We aimed to compare the incidence of GI adverse events in patients with obesity treated with GLP-1 RAs versus naltrexone-bupropion. Methods: We conducted a retrospective cohort study using the TriNetX database to identify adults (≥18 years) with obesity. We then identified patients who were treated with GLP-1 RA for weight loss. Patients in the GLP-1 RA cohort were matched to patients used naltrexone-bupropion for weight loss using 1:1 propensity score matching for demographics, comorbidities, and geographical location. Primary outcome was the incidence of GI adverse events including biliary disease, pancreatitis, bowel obstruction, and gastroparesis. Kaplan-Meier analysis with Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models. Results: Among 8,903 patients treated with GLP-1RAs, the mean age was 46.4 ± 13.2 years, and 74.3% were women. Compared to bupropion-naltrexone, GLP-1RA use was associated with an increased risk of gastroparesis (aHR: 3.13, 95% CI: 1.82–5.38; P < 0.001) and gallbladder disease (aHR: 1.18, 95% CI: 1.02–1.37; P = 0.027). No significant association was observed for acute pancreatitis (aHR: 1.42, 95% CI: 0.88–2.29; P = 0.153) or intestinal obstruction (aHR: 0.98, 95% CI: 0.71–1.35; P = 0.891). Subgroup analyses revealed that the highest risk of gastroparesis was in patients aged >50 years (aHR: 2.21, 95% CI: 1.21–4.04; P = 0.008). The association with gallbladder disease was strongest in women (aHR: 1.36, 95% CI: 1.15–1.60; P = < 0.001) and adults under 50 (aHR: 1.27, 95% CI: 1.05–1.53; P = 0.014). Conclusion: Our results provide real-world evidence that GLP-1RAs were associated with higher risks of gastroparesis and gallbladder disease compared to naltrexone-bupropion in patients with obesity. Although these adverse events are relatively uncommon, their potential clinical impact warrants attention. This is particularly important for individuals using GLP-1RAs exclusively for weight loss, where the therapeutic risk-benefit profile may differ from those with type 2 diabetes. Clinicians should communicate these risks to support individualized decisions in obesity pharmacotherapy.