Synergistic Effect of GLP-1 Receptor Agonists and Opioids on Gastric Emptying and Symptom Burden: A Propensity-Matched Multicenter Analysis

Introduction and Objective: GLP-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for diabetes and obesity but carry risks of delayed gastric emptying. Opioids similarly impair gastric motility through μ-receptor mechanisms. The synergistic impact of concurrent use on gastroparesis risk and gastrointestinal symptom burden remains inadequately characterized. Methods: Retrospective cohort study with the TriNetX Research Network. Adults initiating GLP-1 RA therapy were categorized by exposure to opioids within one month of GLP-1 initiation. Propensity score matching (1:1) on demographics, comorbidities, baseline medications generated 304,716 matched individuals (152,358 per group). Outcomes over 180 days included gastroparesis diagnoses, gastric emptying studies, composite symptom cluster (nausea, vomiting, early satiety, abdominal distension, dyspepsia), and antiemetic use. Risk ratios and Kaplan-Meier analyses assessed relative and time-dependent risk. Results: Concurrent opioid-GLP-1 therapy produced significantly higher risks across all evaluated outcomes compared with GLP-1 monotherapy: gastroparesis diagnosis (0.27% vs 0.08%; RR 3.31, 95% CI 2.70-4.03), gastric emptying studies (0.20% vs 0.06%; RR 3.13, 95% CI 2.49-3.94), composite GI symptoms (3.7% vs 1.6%; RR 2.31, 95% CI 2.21-2.43) and antiemetic use (17.9% vs 3.2%; RR 5.61, 95% CI 5.42-5.81). These findings represent 2 to 6 fold increases in symptomatic and diagnostic burdens. Kaplan-Meier curves demonstrated early and sustained divergence in event-free survival (log-rank p<0.001). Number needed to harm was 7 for antiemetics and 48 for symptomatic GI events, indicating substantial clinical consequences even with modest absolute risks. Conclusion: Concurrent opioid-GLP-1 RA therapy confers 3-6-fold increased risks of gastroparesis, diagnostic testing, and symptomatic GI complications. Clinicians should exercise heightened vigilance when co-prescribing these agents. Disclosure: A. Vanaparti: None. T. Ikpeze: None. J. Koyi: None. H.M. Baloch: None.