Esophagus to Small Intestine

Gut. 2024;73(2):246–54

Liu BD, Udemba SC, Liang K, Tarabichi Y, Hill H, Fass R, Song G

Shorter-acting glucagon-like peptide-1 receptor agonists are associated with increased development of gastroesophageal reflux disease and its complications in patients with type 2 diabetes mellitus: A population-level retrospective matched cohort study

Background: Shorter half-life glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying (DGE) more than GLP-1 RAs with longer half-lives. DGE is a known risk factor for gastroesophageal reflux disease (GERD) and its complications.
Aim: To determine whether short-acting or long-acting GLP-1 RAs are associated with an increased risk of new GERD or GERD-related complications
Design: The authors used the TriNetX global database to identify adult patients with type 2 diabetes mellitus and generated 2 cohorts totaling 1,543,351 patients on (1) GLP-1 RA or (2) other second-line diabetes medication. Using propensity-score matching, Kaplan-Meier analysis and Cox-proportional hazards ratio (HR), they analyzed outcomes and separately examined outcomes in patients starting short-acting (≤ 1 day) and long-acting (≥ 5 days) GLP-1 RAs.
Results: 177,666 patients were in each propensity-matched cohort. GLP-1 RA exposure was associated with an in-creased risk (HR = 1.15; 95% confidence interval [CI]: 1.09–1.22) of erosive reflux disease (ERD). However, this was solely due to short-acting (HR = 1.215; 95% CI: 1.111–1.328), but not long-acting (HR = 0.994; 95% CI: 0.924–1.069) GLP-1 RA exposure. Short-acting GLP-1 RAs were also associated with increased risk of esophageal stricture (HR = 1.284; 95% CI: 1.135–1.453), Barrett’s without dysplasia (HR = 1.372; 95% CI: 1.217–1.546) and Barrett’s with dysplasia (HR = 1.505; 95% CI: 1.164–1.946) whereas long-acting GLP-1 RAs were not. This association persisted in sensitivity analyses, and when individually examining the short-acting GLP-1 RAs liraglutide, lixisenatide and exenatide.

Conclusion: Starting shorter-acting glucagon-like peptide-1 receptor agonists is associated with increased risks of gastroesophageal reflux disease and its complications.

G. Song, M.D., Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA, E-Mail:

DOI: 10.1136/gutjnl-2023-329651

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