Short-acting GLP-1 receptor agonists may increase risk of GERD in patients with type 2 diabetes: Study

Using data from more than 1.5 million patients with type 2 diabetes mellitus (T2DM), the researchers found that patients on short-acting GLP-1 RAs were more likely to experience oesophageal strictures (HR, 1.28), erosive reflux (HR, 1.22), and Barrett's without and with dysplasia (HR, 1.37 and 1.51, respectively). Interestingly, these associations were not seen while using long-acting GLP-1 RAs.

"Given their increasing use, clinicians caring for patients on GLP-1 receptor agonists, particularly short-acting formulations, should be aware of possible complications," the researchers wrote.

Shorter half-life GLP-1 receptor agonists delay gastric emptying (DGE) more than GLP-1 RAs with longer half-lives. Delayed gastric emptying is a known risk factor for gastro-oesophageal reflux disease and its complications. Benjamin Douglas Liu, Case Western Reserve University, Cleveland, Ohio, USA, and colleagues aimed to investigate whether short-acting or long-acting GLP-1 RAs are associated with an increased risk of new GERD or GERD-related complications.

For this purpose, the researchers used the TriNetX global database to identify adult patients with T2DM and generated two cohorts comprising 1 543 351 patients on (1) GLP-1 RA or (2) other second-line diabetes medication. They analyzed outcomes and separately examined outcomes in patients starting short-acting (≤1 day) and long-acting (≥5 days) GLP-1 RAs using propensity-score matching, Kaplan-Meier Analysis and Cox-proportional hazards ratio (HR).

The study led to the following findings:

• 177 666 patients were in each propensity-matched cohort. GLP-1 RA exposure was associated with an increased risk (HR 1.15) of erosive reflux disease (ERD). However, this was solely due to short-acting (HR 1.215), but not long-acting (HR 0.994) GLP-1 RA exposure.
• Short-acting GLP-1 RAs were also associated with an increased risk of oesophageal stricture (HR 1.284), Barrett’s with dysplasia (HR 1.505), and Barrett’s without dysplasia (HR 1.372), 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.

The findings showed that starting shorter-acting GLP-1 receptor agonists is associated with increased risks of GERD and its complications. Therefore, clinicians caring for patients on GLP-1 RAs, specifically short-acting formulations, should be aware of possible complications given their increasing use.

"There is a need for further monitoring and studies to understand the gastrointestinal side effects of these medications," the researchers concluded.

Reference:

Liu BD, Udemba SC, Liang K, et alShorter-acting glucagon-like peptide-1 receptor agonists are associated with increased development of gastro-oesophageal reflux disease and its complications in patients with type 2 diabetes mellitus: a population-level retrospective matched cohort studyGut 2024;73:246-254.