GLP-1 Receptor Agonists Linked to 12% Higher Risk of Chronic Cough in Large-Scale Study
核心洞察
A large-scale study of over 2 million patients found that GLP-1 receptor (搜索) agonists increase chronic cough (搜索) risk by 12% compared to other diabetes medications.
The elevated risk persisted even in patients without gastroesophageal reflux disease (搜索) (GERD (搜索)), suggesting mechanisms beyond acid reflux may be involved.
Long-acting GLP-1 receptor (搜索) agonists showed significantly higher cough risk, while short-acting formulations did not demonstrate increased risk.
A comprehensive analysis of over 2 million patients has revealed that GLP-1 receptor (搜索) agonists are associated with a 12% increased risk of developing chronic cough (搜索) compared to other second-line diabetes medications. The findings, published in JAMA Otolaryngology-Head & Neck Surgery, represent one of the largest studies to examine this potential side effect of the popular diabetes and weight-loss medications.
Study Design and Patient Population
Researchers from Cedars Sinai (搜索) and other institutions analyzed data from the TriNetX research network, examining electronic medical records from 70 tertiary care organizations between April 2005 and April 2025. The study compared 427,555 adults with type 2 diabetes (搜索) prescribed GLP-1 receptor (搜索) agonists (including liraglutide, semaglutide, exenatide, dulaglutide, and lixisenatide) to 1,614,495 patients receiving other second-line diabetes medications.
Using propensity score matching, researchers balanced the groups based on multiple factors including age, sex, race, medical history, and concurrent medications. The GLP-1 receptor (搜索) agonist group had a mean age of 55.8 years with 58.9% women, while the comparison group had a mean age of 63.7 years with 44.4% women.
Key Findings on Chronic Cough Risk
The analysis revealed significantly elevated chronic cough (搜索) risk among GLP-1 receptor (搜索) agonist users compared to several control groups. Patients prescribed GLP-1 receptor agonists showed an adjusted hazard ratio of 1.12 (95% CI, 1.08-1.16) for developing chronic cough compared to any non-GLP-1 second-line medication.
When compared to specific medication classes, the risk was even more pronounced. GLP-1 receptor (搜索) agonist users had an 18% higher risk compared to DPP-4 inhibitor users (aHR = 1.18; 95% CI, 1.11-1.26) and a 32% higher risk compared to sulfonylurea users (aHR = 1.32; 95% CI, 1.24-1.4). Notably, no significant difference was observed when compared specifically to SGLT2 inhibitor users.
Risk Persists Beyond GERD
A particularly significant finding emerged when researchers excluded patients with previous GERD (搜索) diagnoses. The elevated chronic cough (搜索) risk persisted across all comparison groups, with hazard ratios ranging from 1.14 to 1.36. This suggests that mechanisms beyond gastroesophageal reflux may contribute to the increased cough risk.
"The largest impact we hope to have with this study is to bring awareness about the relationship between these medications and chronic cough (搜索), even in the absence of GERD (搜索)," said Dr. Anca M. Barbu, associate professor of surgery at Cedars Sinai (搜索) and lead author of the study.
Formulation-Specific Effects
The research revealed important differences between GLP-1 receptor (搜索) agonist formulations. Long-acting preparations showed a significantly elevated risk for chronic cough (搜索) (aHR = 1.11; 95% CI, 1.07-1.16) compared to non-GLP-1 medications, while short-acting formulations did not demonstrate increased risk. However, researchers noted that the short-acting analysis was limited by lack of statistical power.
Proposed Mechanisms
The study provides insights into potential mechanisms underlying the cough association. GLP-1 receptor (搜索) agonists slow gastric emptying, causing food and stomach acid to remain in the stomach longer than usual. This increases pressure on the lower esophageal sphincter and can worsen gastroesophageal reflux disease (搜索).
When stomach acid reaches the esophagus and potentially the throat or voice box, it irritates tissue linings and triggers reflexive coughing. Even without upper airway involvement, lower esophageal irritation can stimulate nerves connected to the airways. In some cases, tiny amounts of refluxed material may enter the airways, causing inflammation and worsening pre-existing conditions like asthma (搜索).
Clinical Implications
The findings have important implications for healthcare providers prescribing GLP-1 receptor (搜索) agonists. Unlike typical coughs that resolve quickly, chronic cough (搜索) can present as a dry, irritating cough or one producing mucus, often accompanied by throat sensations, hoarseness, chest discomfort, sleep disruption, and fatigue.
Dr. Barbu noted that as otolaryngologists, "we see patients who suffer from throat-related symptoms, such as chronic cough (搜索), and we noticed a correlation beyond laryngopharyngeal reflux with more of our patients utilizing the benefit of GLP-1 agonists."
The research also found that GLP-1 receptor (搜索) agonist users had elevated risk for new GERD (搜索) diagnoses compared to DPP-4 inhibitor users (aHR = 1.03), SGLT2 inhibitor users (aHR = 1.13), and sulfonylurea users (aHR = 1.12).
Future Research Directions
The study authors emphasize that their findings should raise awareness among both healthcare providers and patients about potential respiratory side effects of GLP-1 receptor (搜索) agonists. "There are more areas of interface between these new medications and otolaryngology that merit further exploration," Dr. Barbu noted.
The research represents an important step in understanding the full safety profile of GLP-1 receptor (搜索) agonists as their use continues to expand for both diabetes management and obesity (搜索) treatment.