Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used in the management of Type 2 diabetes (T2D), offering not only improved glycaemic control but also cardiovascular benefits. While their effects on gastrointestinal motility are well recognised, the potential link between GLP-1 RAs and peptic ulcer disease (PUD) has not been thoroughly investigated. A recent study, using data from over 66,000 individuals, offers the first large-scale evidence that GLP-1 RAs may reduce the risk of developing PUD.
Researchers carried out a nationwide retrospective cohort study using the US-based NIH “All of Us” database, examining adults with T2D. The primary analysis included 66,102 participants, and a sub-group analysis focused on 3,313 individuals who were newly initiated on either GLP-1 RAs or insulin as second-line treatment. The primary outcome was the diagnosis of PUD, assessed in a time-dependent manner. Statistical adjustments accounted for a range of confounders including concurrent use of insulin, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, proton pump inhibitors (PPIs), and demographic variables. A time-varying Cox proportional hazards model was applied in the sub-group analysis, considering death and gastrectomy as competing risks.
In the primary analysis, GLP-1 RA use was associated with a 44% lower odds of PUD diagnosis compared with non-use (adjusted Odds Ratio [aOR]: 0.56; 95% CI: 0.45–0.71; p<0.001). In the sub-group of new users, switching to a GLP-1 RA was associated with a 56% lower hazard of developing PUD compared with those who switched to insulin (adjusted Hazard Ratio [aHR]: 0.44; 95% CI: 0.30–0.63; p<0.001). As expected, NSAID use (HR: 2.39) and steroid use (HR: 1.84) were associated with an increased risk of PUD.
These findings suggest that GLP-1 RAs may offer an added protective effect against peptic ulcer disease in patients with T2DM. However, as a retrospective observational study, causality cannot be confirmed. Residual confounding and limitations in diagnostic coding may also influence results. Nonetheless, this research provides clinically relevant evidence to support the preferential use of GLP-1 RAs over insulin in eligible patients, particularly those at elevated risk for gastrointestinal complications.
Reference
Seika P et al. Glucagon-like peptide-1 receptor agonists are associated with a lower risk of peptic ulcer disease: a nationwide cohort study. Clin Gastroenterol Hepatol. 2025;DOI: 10.1016/j.cgh.2025.08.015.
