S786 Comparative Gastrointestinal Safety of Tirzepatide vs Semaglutide: A Real-World Multicenter Analysis

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists and dual gastric inhibitory peptide (GIP)/GLP-1 agonists are integral to obesity treatment, but gastrointestinal (GI) adverse effects—such as gastroparesis, pancreatitis, gastroesophageal reflux disease (GERD), and small intestinal bacterial overgrowth (SIBO)—remain a concern. Comparative real-world data on the GI safety of semaglutide and tirzepatide are limited. Methods: We conducted a retrospective cohort study using TriNetX, a global federated network of de-identified electronic health records. Adults (≥18 years) prescribed semaglutide or tirzepatide were assigned to mutually exclusive cohorts, excluding those exposed to both drugs. The index date was the first prescription, with follow-up starting one day later. Patients with a prior diagnosis of any outcome were excluded from that outcome’s analysis. Propensity score matching (1:1, nearest-neighbor) was used to balance demographics and comorbidities. Primary outcomes were gastroparesis, pancreatitis, GERD, and SIBO. Risk ratios (RRs) and Kaplan-Meier analyses with hazard ratios (HRs) were used to assess incidence and time-to-event outcomes. Results: Post-matching, each group included 280,094 patients. Gastroparesis incidence was lower with tirzepatide (0.2%) vs semaglutide (0.5%; RR: 0.41; 95% confidence interval [CI]: 0.37–0.45; P < 0.001; HR: 0.78; 95% CI: 0.70–0.86; P < 0.001). Pancreatitis occurred in 2.1% (tirzepatide) vs 4.2% (semaglutide; RR: 0.51; 95% CI: 0.49–0.53; P < 0.001), but time-to-event difference was not significant (HR: 0.97; 95% CI: 0.93–1.00; P = 0.07). GERD was less common with 4.4% (tirzepatide)vs 8.0% (semaglutide; RR: 0.55; 95% CI: 0.53–0.56; P < 0.001; HR: 0.93; 95% CI: 0.90–0.95; P < 0.001). SIBO incidence was 0.1% (tirzepatide) vs 0.3% (semaglutide; RR: 0.46; 95% CI: 0.40–0.52; P < 0.001), with no significant survival difference (HR: 0.96; 95% CI: 0.84–1.10; P = 0.53). Conclusion: Tirzepatide was associated with a lower incidence of GI adverse events compared to semaglutide. While event rates were consistently lower, time-to-event differences were modest or non-significant for pancreatitis and SIBO. These findings suggest a potentially favorable GI safety profile for tirzepatide, supporting its use in clinical practice. Prospective studies are warranted for confirmation.