A recent population-based cohort study, conducted by a research team from McGill University and the Lady Davis Institute for Medical Research (LDI) at the Jewish General Hospital, shows that glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which include Ozempic®, Rybelsus® and other widely- prescribed drugs for type 2 diabetes and obesity management, may increase the risk of developing gastroesophageal reflux disease (GERD) and its complications compared to sodium–glucose cotransporter-2 (SGLT-2) inhibitors (such as Brenzavvy™, Invokana®, etc.). These findings, published in Annals of Internal Medicine, bring attention to a potential side effect associated with GLP-1 RAs, which have gained popularity due to their benefits in glycemic control and weight loss.
GLP-1 RAs work by stimulating insulin secretion, slowing gastric emptying, and reducing appetite, which contribute to their therapeutic effects. However, the delayed gastric emptying caused by these drugs may also lead to gastrointestinal side effects such as nausea, vomiting, gastroparesis, and as this study highlights, an increased risk of GERD. GERD is a condition characterized by acid reflux that can severely impact quality of life and lead to serious complications including Barrett esophagus and esophageal adenocarcinoma.
The study, led by Professor Laurent Azoulay, Senior investigator in the Centre for Clinical Epidemiology of the LDI, analyzed data from a large cohort of patients with type 2 diabetes, comparing those using GLP-1 RAs to those on SGLT-2 inhibitors. It was found that the incidence of GERD and related complications was significantly higher among GLP-1 RA users. This increased risk was especially notable in patients who were ever-smokers, obese, or had other comorbidities affecting gastric motility. The results were consistent across multiple sensitivity analyses, strengthening the validity of the findings.
In addition, the study utilized the UK Clinical Practice Research Datalink (CPRD) to conduct an active-comparator new-user cohort analysis, minimizing bias and increasing the clinical relevance of the results. The research focused on newly developed GERD cases among adults with type 2 diabetes and accounted for a broad range of lifestyle and clinical factors.
As Professor Laurent Azoulay noted, “Our study indicates a clear association between GLP-1 receptor agonists and an elevated risk of gastroesophageal reflux disease in patients with type 2 diabetes. While GLP-1 RAs offer important benefits, clinicians should carefully consider these potential risks, particularly in patients predisposed to GERD or gastroparesis.”
This research adds to a limited but growing body of evidence highlighting gastrointestinal adverse effects linked to GLP-1 RAs. Prior studies and clinical trials have suggested similar trends, but this is among the first to use a rigorous, population-based design to compare GLP-1 RAs with an active comparator, SGLT-2 inhibitors, which do not affect gastric emptying.
Key findings:
- The use of GLP-1 RAs is associated with an increased risk of GERD and its complications in patients with type 2 diabetes.
- Certain subgroups, including patients with a history of smoking, obesity, and certain comorbidities, are more vulnerable to these adverse effects.
- Healthcare providers should carefully consider the potential risks and benefits of GLP-1 RAs when prescribing them to patients with type 2 diabetes.
- Monitoring patients for signs of GERD and taking proactive steps to mitigate these risks is crucial.
Despite these findings, the researchers emphasize that the well-established benefits of GLP-1 RAs in managing type 2 diabetes and obesity remain significant. They recommend that healthcare providers balance these benefits against the potential for increased GERD risk and monitor patients accordingly. Further studies are needed to confirm these results and to explore the risks in populations without diabetes but using GLP-1 RAs for obesity management.
Yunha Noh, Hui Yin, Oriana H.Y. Yu, et al. Glucagon-Like Peptide-1 Receptor Agonists and Risk for Gastroesophageal Reflux Disease in Patients With Type 2 Diabetes: A Population-Based Cohort Study. Ann Intern Med. [Epub 15 July 2025]. doi:10.7326/ANNALS-24-03420.
