Written By: Vikas Londhe, Chief Editor
GLP-1 receptor agonists have become a cornerstone of modern diabetes and weight-loss treatment. Millions of patients now use these medicines for blood sugar control, weight reduction, and cardiovascular risk improvement. While their gastrointestinal side effects are well recognized, new research suggests another possible and less discussed issue: persistent cough.
A large real-world study published in JAMA Otolaryngology–Head & Neck Surgery raises important questions for both healthcare professionals and patients about a potential association between GLP-1 drugs and chronic cough.
About the Study
Researchers conducted a retrospective cohort study using data from 70 U.S. healthcare organizations, covering the period from April 2005 to April 2025. The analysis included 427,555 new users of GLP-1 receptor agonists (mean age 55.8 years; 58.9% female) and compared them with 1,614,495 patients receiving other second-line diabetes therapies.
The study focused on newly initiated treatments and evaluated outcomes occurring within the first five years after therapy initiation. Although the dataset spans two decades, most GLP-1 exposure occurred in more recent years following the widespread clinical adoption of these agents.
Key finding
GLP-1RA users showed higher chronic cough risk versus non-GLP-1RA medications, specifically with those receiving other diabetes therapies, including:
- DPP-4 inhibitors
- SGLT2 inhibitors
- Sulfonylureas
This was not about short-term throat irritation. The cough was persistent enough to result in repeated healthcare visits and clinical documentation.
How Was the Study Conducted?
The researchers used a large retrospective cohort design based on U.S. electronic health records and claims data, incorporating several methodological safeguards to strengthen the analysis. Only new users of diabetes medications were included to reduce bias from prior treatment exposure. Patients receiving GLP-1 receptor agonists were compared with active treatment groups using other glucose-lowering therapies rather than untreated controls.
Participants were followed for up to five years after treatment initiation, with follow-up ending at drug discontinuation, switching, death, or loss to follow-up. Persistent cough was identified using repeated diagnostic codes, cough-related clinical encounters, or ENT visits over time rather than isolated acute episodes.
To address confounding, the analysis adjusted for age, sex, obesity, smoking status, asthma, gastroesophageal reflux disease, ACE-inhibitor use, and baseline respiratory conditions using multivariable models and propensity score matching. While this approach strengthens the observed association, it does not establish a causal relationship.
Which GLP-1 Drugs Were Involved?
The analysis primarily evaluated GLP-1 receptor agonists as a drug class rather than singling out individual agents. Prescription data indicate that commonly used drugs contributed to the signal, including:
- Semaglutide (injectable and oral formulations)
- Liraglutide
- Dulaglutide
- Exenatide (immediate- and extended-release)
No single medication emerged as a dominant contributor. The risk appeared class-wide, suggesting a mechanism related to GLP-1 receptor activity itself rather than formulation-specific differences.
What Does the Cough Look Like Clinically?
Across patient records, the cough followed a recognizable pattern:
- Onset: Often developed weeks to months after starting GLP-1 therapy
- Duration: Frequently lasted longer than eight weeks, meeting criteria for chronic cough
- Clinical impact: Led to ENT referrals, reflux evaluations, asthma workups, and empiric treatments
- Clinical course: In some patients, cough-related visits decreased after stopping or switching therapy, although formal rechallenge data were limited
Why Might GLP-1 Drugs Affect the Airway?
As described by the investigators, the observed association may be explained by several biologically plausible mechanisms rather than a confirmed causal pathway. GLP-1 receptors are not confined to pancreatic tissue and are also expressed in airway epithelium and vagal sensory nerves involved in regulating the cough reflex. Activation of these pathways may increase airway sensitivity and lower the threshold for coughing through neurogenic mechanisms.
In addition, GLP-1 receptor agonists are known to delay gastric emptying and may exacerbate gastroesophageal or laryngopharyngeal reflux, which is a well-established trigger for chronic cough. Importantly, the investigators note that this potential mechanism differs from ACE inhibitor–associated cough, as it does not appear to involve bradykinin-mediated pathways
Supporting Case Evidence
Several case reports and perioperative case series provide supportive, hypothesis-generating evidence that may help explain the cohort signal. Published reports describe semaglutide-associated delayed gastric emptying with resultant regurgitation, silent micro-aspiration, and, in isolated cases, organizing pneumonia. These events can manifest clinically with a persistent cough or recurrent respiratory complaints.
Although anecdotal in nature and subject to reporting bias, these cases do not prove causation. However, they are consistent with the investigators’ proposed reflux, aspiration, and neurogenic-sensitivity mechanisms and strengthen the rationale for clinician awareness and targeted evaluation in selected patients.
Common Considerations for Patients and Physicians
As emphasized by the investigators, the findings should be interpreted as a safety signal that warrants awareness rather than immediate concern. GLP-1 receptor agonists continue to demonstrate substantial benefits in glycemic control, weight reduction, and cardiometabolic risk reduction, and the majority of patients in the dataset did not develop chronic cough.
However, a cough persisting for several weeks to months after GLP-1 initiation should prompt clinical attention rather than being dismissed as incidental. Such symptoms should be evaluated in the context of medication exposure alongside other common causes of chronic cough, including gastroesophageal reflux, asthma, allergic disease, and concomitant medications.
The study does not support unsupervised discontinuation of therapy. Instead, the investigators highlight the importance of physician-led assessment and individualized decision-making when persistent respiratory symptoms arise during GLP-1 treatment.
Conclusion
This large real-world analysis identifies persistent cough as a potential safety signal observed in association with GLP-1 receptor agonist use. The study does not establish a causal relationship, and no formal causality assessment has been confirmed by marketing authorization holders or regulatory agencies.
While the consistency of the association across comparator therapies and the scale of the dataset support the signal’s clinical relevance, biological plausibility remains hypothesis-generating and is based on investigator interpretation rather than validated mechanistic evidence. Further evaluation through MAH-led pharmacovigilance activities, targeted studies, and regulatory review will be required to determine whether a causal relationship exists.
As the use of GLP-1 therapies continues to expand, recognition of emerging safety signals in real-world data may support earlier clinical awareness, while formal causality determination remains the responsibility of marketing authorization holders and regulatory authorities.
References
Gallagher TJ, Razura DE, Li A, Kim I, Vukkadala N, Barbu AM. Glucagon-Like Peptide-1 Receptor Agonists and Chronic Cough. JAMA Otolaryngol Head Neck Surg. Published online November 26, 2025. doi:10.1001/jamaoto.2025.4181
Medical News in Brief, GLP-1 Drugs Linked with Chronic Cough, JAMA, Published Online: December 19, 2025 doi: 10.1001/jama.2025.20026
Kobina Essilfie-Quaye et al, Semaglutide-Induced Silent Aspiration: An Unrecognised Cause of Organising Pneumonia, Respiratory Case Reports, Volume 13, Issue 7, July 2025, e70249, https://doi.org/10.1002/rcr2.70249
Avraham SA et al, Pulmonary aspiration of gastric contents in two patients taking semaglutide for weight loss. Anaesth Rep. 2024 Jan 14;12(1):e12278. doi: 10.1002/anr3.12278. PMID: 38225986; PMCID: PMC10788311.
Semaglutide. Reactions Weekly 2070, 499 (2025). https://doi.org/10.1007/s40278-025-87567-y