5E-06 - Comparative Gastrointestinal Safety of Dulaglutide, Semaglutide, and Tirzepatide in patients with Type 2 Diabetes

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and tirzepatide are associated with an increased risk of serious gastrointestinal adverse events. Despite their increasing popularity, the comparative gastrointestinal safety among these drugs remains unclear.

Objectives: To compare the risk of severe gastrointestinal (GI) adverse events among dulaglutide, subcutaneous (SQ) semaglutide, and tirzepatide in patients with type 2 diabetes (T2D) in routine clinical practice.

Methods: We conducted a new-user, active comparator cohort study of commercially insured adults with T2D who initiated dulaglutide, SQ semaglutide, and tirzepatide between January 1, 2019, and August 30, 2024, in three cohorts corresponding to three pairwise comparisons: semaglutide vs. dulaglutide, tirzepatide vs. dulaglutide, and tirzepatide vs. SQ semaglutide. 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 pairwise comparison. We calculated incidence rates, hazard ratios (HR) and rate differences (RD) per 1,000 person-years with 95% confidence intervals (CIs). In secondary analyses, individual GLP-1RA and tirzepatide were compared head-to-head with sodium-glucose cotransporter-2 inhibitors (SGLT-2i), an external comparator with distinct mechanism of action and safety profile.

Results: After propensity score matching, there were 65,238 matched pairs in the SQ semaglutide vs. dulaglutide cohort, 20,893 matched pairs in the tirzepatide vs. dulaglutide cohort, and 46,620 matched pairs in the tirzepatide vs. SQ semaglutide cohort. Across the three cohorts, mean age ranged between 60.2 and 62.8 years. Over a median follow-up ranging from 5.3 to 5.7 months, we observed similar risk of severe GI adverse events across the three study cohorts: HR, 0.96 [95% CI, 0.87 to 1.06] and RD, -0.42 [95% CI, -1.69 to 0.85] in the SQ semaglutide vs. dulaglutide cohort; HR, 0.96 [95% CI, 0.77 to 1.20 and RD, -0.65 [95% CI, -3.34 to 2.04] in the tirzepatide vs dulaglutide cohort; and HR, 1.07 [95% CI, 0.90 to 1.26] and RD, 0.60 [95% CI, -1.10 to 2.30] in the tirzepatide vs. SQ semaglutide cohort. Similar risk was also observed for the individual components of the primary outcome. We confirmed a 22%-53% increased risk of severe GI adverse events associated with individual GLP-1RA or tirzepatide compared with SGLT-2i.

Conclusions: This study suggests that dulaglutide, SQ semaglutide, and tirzepatide have comparable GI safety profiles in adults with T2D.