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Glucagon-like peptide-1 receptor agonists may increase risk of reflux in patients with type 2 diabetes
1. In this population-based cohort study, patients with type 2 diabetes who received glucagon-like peptide-1 receptor agonists had a higher risk of developing gastroesophageal reflux disease and associated complications compared with those who received sodium-glucose cotransporter-2 inhibitors.
2. The risk of gastroesophageal reflux disease was increased for all agents in the class except lixisenatide, while the risk of complications was particularly high among ever smokers, patients with obesity, and patients with gastric comorbidities.
Evidence Rating Level: 2 (Good)
Study Rundown: Concerns have arisen that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may be associated with gastroesophageal reflux disease (GERD) due to potent effects on the rate of gastric emptying, but evidence surrounding this topic is limited. Considering the increasing use of GLP-1 RAs and the already high prevalence of GERD, this study aimed to evaluate the effect of GLP-1 RAs compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors on the risk of GERD among people with type 2 diabetes. It was found that GLP-1 RA use was associated with a persistently increased risk of GERD and of GERD complications compared with SGLT-2 inhibitor use up to three years of follow-up. Secondary analyses showed increased risk of GERD for each GLP-1 RA agent except lixisenatide. The risk of GERD complications was also elevated among people who had ever smoked, patients with obesity, and patients with gastric comorbidities. The generalizability of this study was limited by potential outcome and exposure misclassification, as well as analysis limited to those with type 2 diabetes. In summary, this study suggested that GLP-1 RAs may increase the risk of GERD and GERD complications among patients with type 2 diabetes.
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In-Depth [retrospective cohort]: This population-based cohort study aimed to evaluate the effect of GLP-1 RAs on the risk of GERD or GERD complications compared with SGLT-2 inhibitors among patients with type 2 diabetes. Patients were eligible if they were aged 18 or older, were previously diagnosed with type 2 diabetes; had at least 1 year of medical history available; and did not have recorded history of esophageal or gastric diseases, among others. The GLP-1 RAs studied were exenatide, lixisenatide, liraglutide, dulaglutide, and semaglutide; the SGLT-2 inhibitors studied were canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. The primary outcome was diagnosis of GERD, while the secondary outcome was complications of GERD, including Barrett’s esophagus, esophageal stricture, and erosion or ulceration of esophagitis. The study included 24,708 new users of GLP-1 RAs and 89,096 new users of SGLT-2 inhibitors; GLP-1 RA users were younger and more likely to be female or have obesity, longer diabetes duration, or microvascular complications of diabetes. Median follow-up was 3.0 years (interquartile range [IQR], 1.5 to 3.0 years) for GLP-1 RA users and 2.7 years (IQR, 1.2 to 3.0 years) for SGLT-2 inhibitor users. During follow-up, 1954 GERD events, or 7.9 events (95% CI, 7.5 to 8.2) per 1000 person-years, were observed along with 138 events corresponding to GERD complications. After 3 years of follow-up, the risk ratio [RR] of GERD was 1.27 (95% CI, 1.14 to 1.42) among GLP-1 RA users compared with SGLT-2 inhibitor users (risk difference [RD], 0.7 per 100 patients). The RR for GERD complications was 1.55 (95% CI, 1.12 to 2.29) among GLP-1 RA users compared with SGLT-2 inhibitor users (RD, 0.8 per 1000 patients). Risk of GERD complications was also higher among ever-smokers (RR, 1.83 [95% CI, 1.25 to 2.81]) and in patients with gastric comorbidities (RR, 2.01 [95% CI, 1.05 to 4.66]). Overall, this study suggested that GLP-1 RA use may be associated with increased risk of GERD and GERD complications among individuals with type 2 diabetes.
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