Research Square · Oct 19, 2026

Gastrointestinal Adverse Events Associated With GLP-1 Receptor Agonists Versus DPP-4 Inhibitors in Patients with Type 2 Diabetes: A Multicenter Retrospective Cohort Study

By Yan Y, Xu M, Lu S et al.

Objective To estimate the causal effect of initiating glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus dipeptidyl peptidase-4 inhibitors (DPP-4is) on the risk of gastrointestinal adverse events among adults with type 2 diabetes mellitus (T2DM) in China, using the target trial emulation framework. Methods: This multicenter retrospective cohort study included adults with T2DM who newly initiated a GLP-1RA or DPP-4i at three tertiary hospitals in Shanghai, China, between January 2015 and December 2023. An active-comparator, new-user design with a 12-month washout period was used. After 1:10 propensity score matching, 29,216 patients were included, comprising 2,656 GLP-1RA initiators and 26,560 DPP-4i initiators. The primary outcome was a composite of biliary disease, pancreatitis, intestinal obstruction, or gastroparesis. Intention-to-treat analyses used Cox proportional hazards models, while per-protocol analyses incorporated inverse probability of censoring weighting. Sensitivity and subgroup analyses were performed. Results Over a median follow-up of 913 days (73,295 total person-years), the composite gastrointestinal outcome occurred in 958 patients. GLP-1RA initiation was associated with a higher risk of the composite outcome compared with DPP-4i initiation in the ITT analysis (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.08 to 1.61; P=0.006). Gastroparesis showed the strongest signal (HR 1.99, 95% CI 1.40 to 2.81; P<0.001). Biliary disease (HR 1.11, 95% CI 0.82 to 1.51), pancreatitis (HR 1.31, 95% CI 0.74 to 2.34), and intestinal obstruction (HR 1.02, 95% CI 0.60 to 1.74) were not significantly elevated. Per-protocol estimates were consistently larger (composite HR 1.65; gastroparesis HR 2.45). The gastroparesis E-value of 3.4 indicated robustness to unmeasured confounding. Results were stable across sensitivity analyses and 21 prespecified subgroups. Conclusions Among adults with T2DM in Shanghai, GLP-1RA initiation was associated with a higher risk of composite gastrointestinal adverse events compared with DPP-4i initiation, driven primarily by a twofold increase in gastroparesis risk. Biliary disease risk was elevated under sustained use. These findings support heightened clinical vigilance for gastroparesis symptoms among GLP-1RA initiators, particularly those with long-standing diabetes.

doi.org/10.21203/rs.3.rs-11029518/v1Open accessInterventions