New-user, active-comparator cohort study across three paired cohorts comparing severe GI adverse event risk (hospitalization-level nausea, vomiting, diarrhea, gastroparesis) between dulaglutide, subcutaneous semaglutide, and tirzepatide in T2DM patients (January 2019–August 2024). Provides head-to-head comparative GI safety data in routine clinical practice. Delivers comparative real-world GI safety evidence across three leading GLP-1-based agents—enabling risk-stratified prescribing based on GI tolerability concerns and identifying whether tirzepatide's dual mechanism produces a different severe GI adverse event profile versus GLP-1-only semaglutide.
Abstract
BACKGROUND: The comparative gastrointestinal safety across glucagon-like peptide-1 receptor agonists and tirzepatide is still unclear.
OBJECTIVE: To compare the risk for severe gastrointestinal adverse events across dulaglutide, subcutaneous semaglutide, and tirzepatide in patients with type 2 diabetes (T2D) in routine clinical practice.
DESIGN: New-user, active-comparator cohort study.
SETTING: Population-based study.
PARTICIPANTS: Adults with T2D initiating dulaglutide, subcutaneous semaglutide, and tirzepatide between 1 January 2019 and 30 August 2024 in 3 cohorts corresponding to 3 pairwise comparisons.
MEASUREMENTS: The primary outcome was a composite of acute pancreatitis, biliary disease, bowel obstruction, gastroparesis, and severe constipation. Secondary outcomes of interest were the individual components of the primary outcome. Patients were 1:1 propensity score matched within each comparison. We calculated hazard ratios (HRs) with 95% CIs.
RESULTS: There were 65 238 matched pairs in the semaglutide versus dulaglutide cohort, 20 893 in the tirzepatide versus dulaglutide cohort, and 46 620 in the tirzepatide versus semaglutide cohort. The HR of gastrointestinal events was 0.96 (95% CI, 0.87 to 1.06) in the semaglutide versus dulaglutide cohort, 0.96 (CI, 0.77 to 1.20) in the tirzepatide versus dulaglutide cohort, and 1.07 (CI, 0.90 to 1.26) in the tirzepatide versus semaglutide cohort.
LIMITATION: Possible residual confounding by glycemic control and body mass index.
CONCLUSION: These findings suggest that dulaglutide, semaglutide, and tirzepatide have similar gastrointestinal safety profiles in adults with T2D. This study provides clinicians with evidence to weigh the benefits and risks of these medications.
PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases.