S736 Gastrointestinal Tolerability of Tirzepatide Compared With GLP-1 Receptor Agonists, Insulin and Placebo in Obesity: A Meta-Analysis of 11,000+ Subjects

Introduction: Dual glucagon-like peptide-1 (GLP1)/ glucose-dependent insulinotropic polypeptide (GIP) and GLP1 receptor agonists (GLP1 RA) are cornerstone therapies for obesity and Type 2 diabetes (T2DM). Gastrointestinal adverse events (GI AEs) are a major limiting factor for utility, often leading to treatment discontinuation, reduced adherence, hospitalizations, and gastroenterology referrals. The frequency and severity of GI AEs remain under-characterized, prompting this meta-analysis to clarify their profiles for clinicians navigating GI tolerability challenges. Methods: PubMed, Embase and clinicaltrials.gov databases were searched through March 2025 for randomized controlled trials (RCTs) and observational studies evaluating once-weekly subcutaneous tirzepatide (5–15 mg) vs GLP1 RA, basal insulin and placebo in adults with body mass index (BMI) ≥25 kg m⁻² and T2DM. Primary outcomes included nausea, vomiting, diarrhea, and constipation; secondary outcomes were abdominal pain and elevated lipase. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using Random-effects models; I² assessed heterogeneity. Results: Fourteen trials (N = 11,502) were included. Mean age: 58.1 years; BMI: 32.7 kg/m²; weight: 90.5 kg; 54% men; baseline HbA1c: 8.4%. Tirzepatide was associated with higher GI AEs compared to insulin (nausea OR: 13.51, vomiting OR: 8.06, diarrhea OR: 4.77, constipation OR: 7.64) and placebo (nausea OR: 3.34, vomiting OR: 3.86, diarrhea OR: 2.30, constipation OR: 2.96). For secondary outcomes, tirzepatide increased abdominal pain (OR: 3.20) and lipase (OR: 4.00) vs insulin. Compared to placebo, only lipase was elevated (OR: 1.99); abdominal pain showed no difference. No significant differences in primary and secondary outcomes were observed when compared to GLP1 RAs. Conclusion: In our meta-analysis, we found that the GI AE profile of tirzepatide closely mirrors that of GLP1 RAs. Confirming that dual-agonist medications do not amplify GLP1-related GI intolerance and support tirzepatide as a well-tolerated, weight-centric treatment for obesity-driven T2DM. However, the odds ratio remained notably higher with insulin compared to placebo. This elevated ratio likely reflects lower GI AEs with insulin, rather than intrinsic toxicity from tirzepatide. Future patient-level analyses would help identify predictors of intolerance to optimize dosing and maximize therapeutic benefit. Furthermore, these AEs were dose-dependent, with higher doses correlating with increased frequency and severity. Hence, careful titration of medication in high-risk populations may enhance therapeutic outcomes.