A new observational study compared the risk for severe gastrointestinal adverse events across dulaglutide, semaglutide, and tirzepatide in patients with type 2 diabetes (T2D). The study found that the medications have similar gastrointestinal safety profiles among those with T2D, providing clinicians with evidence to weigh the risks and benefits of these medications for their patients. The findings are published in Annals of Internal Medicine.
Prior placebo-controlled randomized controlled trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and tirzepatide have shown that these medications are associated with an increased risk for gastrointestinal-related adverse events; however, whether individual GLP-1 RAs and tirzepatide have different gastrointestinal safety among patients with type 2 diabetes in clinical practice remains unclear.
Researchers from Brigham and Women's Hospital and Harvard Medical School and colleagues used data from Optum’s deidentified Clinformatics Data Mart database to emulate three clinic trials of adults with T2D initiating dulaglutide, subcutaneous semaglutide, or tirzepatide between 1 January 2019 and 30 August 2024.
They assessed 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 primary outcome was a composite of severe gastrointestinal AEs resulting in an inpatient and/or emergency department encounter. The hazard ratio 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.
These findings were consistent across subgroups and sensitivity analyses. The results align with those seen in head-to-head randomized clinical trials and may help physicians when determining the benefits and risks of prescribing these popular medications.
Reference: Salvatore Crisafulli, Wajd Alkabbani, Julie M. Paik, et al. Comparative Gastrointestinal Safety of Dulaglutide, Semaglutide, and Tirzepatide in Adults With Type 2 Diabetes. Ann Intern Med. [Epub 4 November 2025]. doi:10.7326/ANNALS-25-01724
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