Dulaglutide, semaglutide, and tirzepatide exhibit comparable gastrointestinal adverse event risk

1. In this cohort study, dulaglutide, semaglutide, and tirzepatide demonstrated similar risks of gastrointestinal adverse events (AEs) in adults with type 2 diabetes (T2DM).

2. All three agents were associated with an increased risk of gastrointestinal AEs, particularly motility-related events, compared with sodium-glucose cotransporter-2 inhibitors (SGLT-2is).

Evidence Rating Level: 2 (Good)

Study Rundown: GLP-1 receptor agonists (GLP-1 RAs) and tirzepatide have transformed the management of type 2 diabetes and obesity, but their use has been linked to gastrointestinal adverse events (AEs), including nausea, vomiting, and constipation. This study directly compared gastrointestinal AEs associated with dulaglutide, subcutaneous semaglutide, and tirzepatide in adults with type 2 diabetes mellitus (T2DM). Across all comparisons including dulaglutide versus semaglutide, tirzepatide versus dulaglutide, and tirzepatide versus semaglutide, the risk of gastrointestinal AEs was similar. No differences were observed for pancreaticobiliary events or gastrointestinal motility-related outcomes. Subgroup analyses, including patients using insulin or with recent opioid use, were consistent, despite higher overall AE rates in these populations. Sensitivity analyses using SGLT-2 inhibitors as a comparator showed increased gastrointestinal AE risk for all three agents, driven primarily by motility-related events, while pancreaticobiliary risk remained unchanged. Limitations include potential outcome misclassification, underreporting of AEs, residual confounding, and the inability to assess risk by specific doses. Overall, these findings indicate that dulaglutide, semaglutide, and tirzepatide carry comparable gastrointestinal AE risks in real-world settings, offering clinicians evidence to weigh benefits and risks when selecting therapy.

Click to read this study in AIM

Relevant Reading: Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases

In-Depth [prospective cohort]: This cohort study evaluated gastrointestinal AEs associated with dulaglutide, semaglutide, and tirzepatide in adults with type 2 diabetes mellitus. Patients were grouped into three cohorts: semaglutide versus dulaglutide (January 2019-August 2024), tirzepatide versus dulaglutide (May 2022-August 2024), and tirzepatide versus semaglutide (May 2022-August 2024). Inclusion criteria were age ≥18 years, T2DM diagnosis, ≥365 days enrollment before treatment initiation, and no prior GLP-1 RA use. Exclusions included pre-existing biliary disease, bowel obstruction, pancreatitis, gastroparesis, severe constipation, autonomic neuropathy, type 1 or secondary diabetes, organ transplant, multiple endocrine neoplasia type 2, or end-stage renal disease. The primary outcome was a composite of severe gastrointestinal AEs requiring inpatient or emergency care, including pancreatitis, biliary disease, bowel obstruction, gastroparesis, and severe constipation. Secondary outcomes were the individual components, grouped as pancreaticobiliary outcomes (pancreatitis, biliary disease) and gastrointestinal motility-related outcomes (obstruction, gastroparesis, constipation). Cohort sizes were 143,085 semaglutide versus 76,213 dulaglutide, 46,762 tirzepatide versus 29,431 dulaglutide, and 46,676 tirzepatide versus 102,366 semaglutide. Patients on dulaglutide were slightly older in the semaglutide and tirzepatide comparisons, while semaglutide patients were older in the tirzepatide comparison. Propensity matching generated 65,238 semaglutide-dulaglutide pairs, 20,893 tirzepatide-dulaglutide pairs, and 46,620 tirzepatide-semaglutide pairs. Median follow-up ranged from 163 to 183 days across cohorts. Primary outcomes occurred at similar rates across medications: semaglutide 12.07 versus dulaglutide 12.49 per 1000 person-years (PY; HR 0.96), tirzepatide 12.01 versus dulaglutide 12.66 per 1000 PY (HR 0.96), and tirzepatide 10.56 versus semaglutide 9.96 per 1000 PY (HR 1.07). No differences were observed for pancreaticobiliary or gastrointestinal motility-related outcomes. Subgroup analyses, including insulin users and recent opioid users, showed consistent results despite higher overall AE rates. Sensitivity analyses using SGLT-2 inhibitors as a comparator indicated increased risk of gastrointestinal AEs for all three drugs (HR 1.22-1.53), driven by motility-related outcomes, with no differences in pancreaticobiliary risk. Overall, semaglutide, dulaglutide, and tirzepatide exhibit similar gastrointestinal AE risk in real-world settings, informing clinicians’ benefit-risk considerations when selecting therapy.

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