Impact of GLP-1 Receptor Agonists on Cranial Nerve Palsies in Type 2 Diabetes: A Retrospective Cohort Study

Impact of GLP-1 Receptor Agonists on Cranial Nerve Palsies in Type 2 Diabetes: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of GLP-1 Receptor Agonists on Cranial Nerve Palsies in Type 2 Diabetes: A Retrospective Cohort Study Ronak Bhatia, Huda Al-Bana, Khalid Mohamed, Chimezie Amaefuna, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7497591/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as key agents in managing type 2 diabetes mellitus (T2DM), with proven benefits in glycemic control, weight loss, and cardiovascular risk reduction. However, their neurologic safety profile remains underexplored. Objective: To evaluate the association between GLP-1 receptor agonist use and the incidence of cranial nerve (CN) palsies in patients with T2DM. Methods: This retrospective cohort study utilized the TriNetX Global Collaborative Network, comprising de-identified records from 145 healthcare organizations. Patients with T2DM treated with GLP-1 receptor agonists were compared to matched T2DM controls who never received GLP-1 therapy. Exclusion criteria included prior CN palsy diagnoses, CNS malignancy, type 1 diabetes, and neurological comorbidities. Outcomes assessed over a 10-year period included third nerve palsy (H49.0), sixth nerve palsy (H49.2), and Bell’s palsy (G51.0). Propensity score matching was applied for age, sex, hypertension, obesity, and dyslipidemia. Results: After matching (n=765,345 per group), GLP-1 users had a significantly increased incidence of CN III palsy (RR: 1.63, 95% CI: 1.41–1.87), CN VI palsy (RR: 1.89, 95% CI: 1.68–2.12), and Bell’s palsy (RR: 1.37, 95% CI: 1.30–1.44), with p < 0.001 for all. Hazard ratios and Kaplan-Meier survival analysis corroborated these findings. Conclusion: While absolute risks remain low, GLP-1 receptor agonist use was associated with a statistically significant increase in cranial nerve palsies. These findings underscore the need for additional research into the neurophysiological effects of GLP-1 therapies, particularly in ophthalmological and neurological domains. Neurology Endocrinology & Metabolism Pharmacodynamics GLP-1 receptor agonists Cranial nerve palsy Bell’s palsy Type 2 diabetes mellitus Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder marked by hyperglycemia that arises primarily from insulin resistance and β-cell dysfunction [ 1 ]. Despite advancements in therapeutic strategies and public health initiatives, the global burden of T2DM continues to rise. Recent studies estimate that approximately 462 million individuals, which accounts for 6.28% of the global population, are affected by T2DM, emphasizing the urgent need for effective and sustainable treatment options [ 2 ]. Among emerging therapeutic agents, glucagon-like peptide-1 (GLP-1) receptor agonists have gained considerable attention for their dual utility in managing both T2DM and obesity [ 3 ]. These incretin-based therapies mimic endogenous GLP-1 and have shown efficacy in reducing hemoglobin A1c levels and promoting weight loss, making them highly attractive in the context of metabolic syndrome management [ 3 ]. Moreover, beyond glycemic control, GLP-1 receptor agonists have demonstrated significant cardiovascular benefits in large-scale clinical trials, with reductions in major adverse cardiovascular events in patients at high cardiovascular risk [ 4 ]. The therapeutic efficacy of GLP-1 receptor agonists extends across multiple domains. Not only do they improve glycemic control by enhancing insulin secretion and inhibiting glucagon release [ 5 ][ 6 ], but they also contribute to sustained weight loss through delayed gastric emptying and increased satiety [ 7 ]. These effects are particularly beneficial in obese individuals with T2DM, for whom weight management is often a key therapeutic target. Furthermore, cardiovascular outcome trials such as LEADER and SUSTAIN-6 have highlighted the cardioprotective potential of these agents, revealing statistically significant reductions in events such as myocardial infarction and stroke [ 4 ]. As the use of GLP-1 receptor agonists continues to grow, it is essential to carefully assess their safety profile. Gastrointestinal adverse effects, namely nausea, vomiting, and diarrhea, are the most frequently reported and may limit long-term adherence [ 8 ][ 9 ]. While early concerns were raised about a potential link between GLP-1 receptor agonists and pancreatitis, current evidence has not established a direct causal relationship [ 10 ]. Notably, despite widespread pharmacovigilance, the potential for central or peripheral neurologic adverse effects remains an underexplored area, warranting further investigation into the neurophysiological actions of GLP-1. At a mechanistic level, GLP-1 is an incretin hormone primarily secreted by L-cells in the distal ileum and colon in response to nutrient intake. Following meal ingestion, these L-cells detect luminal nutrients, such as amino acids, fatty acids, and carbohydrates, and release GLP-1 in a biphasic manner during the early and late postprandial phases [ 11 ][ 12 ]. Once secreted, GLP-1 exerts multiple physiological effects: it enhances glucose-dependent insulin secretion from pancreatic β-cells, inhibits glucagon release from α-cells under hyperglycemic conditions, delays gastric emptying via vagally mediated pathways, and promotes satiety [ 13 ][ 14 ][ 15 ]. Gut-derived GLP-1 interfaces with central neuroendocrine circuits involved in appetite regulation and energy balance, indicating its activity spans an extensive gut–brain axis [ 16 ][ 17 ]. Ophthalmologic complications are among the most common manifestations of diabetes mellitus [ 18 ]. Diabetic patients are at increased risk for third and sixth cranial nerve palsies. These palsies are typically attributed to ischemic injury of the cranial nerves resulting from chronic microvascular disease, a hallmark of long-standing diabetes. These neuro-ophthalmic complications can lead to acute diplopia, ptosis, and significant impairment in daily functioning [ 19 ]. As GLP-1 receptor agonists are increasingly used for glycemic control and weight management, it is essential to understand whether these agents influence the incidence of cranial nerve palsies in this population. These diverse and integrated actions raise questions regarding GLP-1’s influence on central nervous system function and the potential for neurologic effects. METHODS Study Design and Data Source We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, which aggregates de-identified electronic medical records from 145 healthcare organizations. Data are standardized using ICD-10-CM codes for diagnoses and RXNORM for medications. As the data are de-identified and analyzed retrospectively, the study was exempt from IRB oversight under HIPAA regulations. Cohort Definition Two cohorts were created. Cohort 1 included patients with T2DM (ICD-10: E11) who received a GLP-1 receptor agonist (e.g., exenatide, liraglutide, semaglutide). Cohort 2 included patients with T2DM who were never treated with GLP-1 receptor agonists. The index event was defined as the first GLP-1 prescription for Cohort 1 and the T2DM diagnosis date for Cohort 2. Exclusion Criteria Patients were excluded if they had a prior diagnosis of cranial nerve palsies of interest—Bell’s palsy (G51.0), third nerve palsy (H49.0), or sixth nerve palsy (H49.2)—type 1 diabetes (E10), or underlying neurologic conditions (e.g., multiple sclerosis, myasthenia gravis, CNS malignancy). Propensity Score Matching To adjust for baseline differences, 1:1 propensity score matching was performed on age, sex, hypertension (I10), obesity (E66), and dyslipidemia (E78) using TriNetX’s nearest-neighbor algorithm. Outcomes and Follow-up The primary outcomes were the incidence of third cranial nerve palsy (H49.0), sixth cranial nerve palsy (H49.2), and Bell’s palsy (G51.0). Events were tracked over a 10-year follow-up, beginning one day after the index event to mitigate immortal time bias. Statistical Analysis Risk differences (RD), risk ratios (RR), and odds ratios (OR) were calculated. Kaplan-Meier survival analysis and log-rank tests were used to compare time-to-event outcomes. A hazard ratio (HR) with 95% confidence intervals was reported for each outcome. Analyses were conducted within the TriNetX platform. RESULTS Patient Characteristics After propensity score matching, each cohort contained 765,345 patients. Demographics were well balanced: mean age 62.2 ± 13.2 years in Cohort 1 and 62.0 ± 13.7 years in Cohort 2; sex distribution 52.6 percent female vs 52.0 percent female; comorbidities were comparable for essential hypertension, obesity, and dyslipidemia. Baseline proportion counts were not available in the platform export and are therefore not shown. Outcome 1: Third Cranial Nerve Palsy (CN III) CN III palsy (ICD-10: H49.0) occurred in 0.07 percent (515/764,833) of GLP-1 users versus 0.04 percent (317/765,345) of non-users. The risk difference was 0.03 percent, p < 0.001; risk ratio 1.626 (95 percent CI, 1.413 to 1.870); odds ratio 1.626 (95 percent CI, 1.414 to 1.870). Kaplan–Meier log-rank χ² = 25.88, p < 0.001; hazard ratio 1.44 (95 percent CI, 1.25 to 1.65). KM-estimated CN III palsy-free survival at end of follow-up was 99.75 percent in GLP-1 users and 99.84 percent in non-users (KM estimates; counts not applicable due to censoring). See Table 1 and Figure 1. Table 1. The risk of developing CN III palsy among patients with type 2 diabetes who were treated with or without GLP-1 agonists. CN III Palsy Risk analysis excluding patients with outcome prior to the time window Cohort Patients in cohort after matching Patients with outcome Risk 1) Type 2 Diabetes with GLP 1 agonists 764,833 515 0.0007 2) Type 2 Diabetes without GLP 1 agonists 765,345 317 0.0004 Risk Difference 0.0003 p < 0.001 Risk Ratio 1.626 95% CI: (1.413, 1.870) Odds Ratio 1.626 95% CI: (1.414, 1.870) Outcome 2: Sixth Cranial Nerve Palsy (CN VI) CN VI palsy (ICD-10: H49.2) occurred in 0.11 percent (843/764,570) of GLP-1 users versus 0.06 percent (447/765,345) of non-users. The risk difference was 0.05 percent, p < 0.001; risk ratio 1.888 (95 percent CI, 1.683 to 2.117); odds ratio 1.889 (95 percent CI, 1.684 to 2.118). Kaplan–Meier log-rank χ² = 77.51, p < 0.001; hazard ratio 1.67 (95 percent CI, 1.48 to 1.87). KM-estimated CN VI palsy-free survival at end of follow-up was 98.25 percent in GLP-1 users and 99.72 percent in non-users (KM estimates; counts not applicable due to censoring). See Table 2 and Figure 2. Table 2. The risk of developing sixth cranial nerve (CN VI) palsy among patients with type 2 diabetes, comparing those treated with GLP-1 agonists versus those not treated with GLP-1 agonists. CN VI Palsy Risk analysis excluding patients with outcome prior to the time window Cohort Patients in cohort after matching Patients with outcome Risk 1) Type 2 Diabetes with GLP 1 agonists 764,570 843 0.0011 2) Type 2 Diabetes without GLP 1 agonists 765,345 447 0.0006 Risk Difference 0.0005 p < 0.001 Risk Ratio 1.888 95% CI: (1.683, 2.117) Odds Ratio 1.889 95% CI: (1.684, 2.118) Outcome 3: Bell’s Palsy (CN VII) Bell’s palsy (ICD-10: G51.0) occurred in 0.43 percent (3,284/761,576) of GLP-1 users versus 0.31 percent (2,412/765,345) of non-users. The risk difference was 0.12 percent, p < 0.001; risk ratio 1.368 (95 percent CI, 1.298 to 1.442); odds ratio 1.370 (95 percent CI, 1.300 to 1.444). See Table 3 and Figure 3. Pooled risk ratios across outcomes are shown in Figure 4. Table 3. The risk of developing Bell’s palsy (cranial nerve VII palsy) in patients with type 2 diabetes, comparing those who were treated with GLP-1 agonists versus those not treated with GLP-1 agonists. Bell’s Palsy Risk analysis excluding patients with outcome prior to the time window Cohort Patients in cohort after matching Patients with outcome Risk 1) Type 2 Diabetes with GLP 1 agonists 761,576 3,284 0.0043 2) Type 2 Diabetes without GLP 1 agonists 765,345 2,412 0.0031 Risk Difference 0.0012 p < 0.001 Risk Ratio 1.368 95% CI: (1.298, 1.442) Odds Ratio 1.370 95% CI: (1.300, 1.444) DISCUSSION The findings from this retrospective cohort study suggest that treatment with GLP-1 receptor agonists in patients with T2DM is associated with a significantly increased risk of developing cranial nerve palsies, specifically third (CN III), sixth (CN VI), and seventh (CN VII, Bell’s palsy), compared to diabetic patients not treated with GLP-1 agonists. While the absolute risk in both groups remained low, the consistently elevated risk ratios, odds ratios, and hazard ratios across all outcomes indicate a statistically significant and potentially clinically relevant association. The pathophysiologic mechanisms linking GLP-1 agonist therapy to cranial nerve dysfunction remain unclear. GLP-1 receptors are widely expressed throughout the central and peripheral nervous systems, including the brainstem, hypothalamus, and cranial nerve nuclei. Preclinical studies have shown that GLP-1 analogs can cross the blood-brain barrier and modulate neuronal signaling, neuroinflammation, and oxidative stress [ 20 ]. Although these actions may confer neuroprotection in some contexts, they may paradoxically contribute to adverse neural outcomes in others, depending on receptor density, individual metabolic milieu, and cumulative exposure. In particular, the oculomotor and abducens nerves, due to their long intracranial course and vulnerability to ischemia or inflammation, may be more susceptible to microvascular injury or immune-mediated dysfunction induced by GLP-1 agonists. An emerging body of evidence also suggests that GLP-1 analogs may alter immune cell trafficking and cytokine release, potentially triggering autoimmune or inflammatory responses in susceptible individuals [ 21 ]. This is consistent with rare reports of cranial neuropathies and central nervous system adverse events in post marketing surveillance data and pharmacovigilance studies, although these have not been systematically studied. Additionally, metabolic changes associated with GLP-1 therapy, such as altered gut brain signaling, changes in cerebrovascular reactivity, or dysregulation of the vagus nerve, could also contribute to transient or chronic neuropathic effects [ 20 ]. Although these findings are novel, they must be interpreted with caution. To date, most major clinical trials involving GLP-1 receptor agonists, such as LEADER, SUSTAIN, and REWIND, have focused on metabolic and cardiovascular outcomes, with little attention paid to neurologic safety endpoints. These trials are typically underpowered to detect rare but clinically important adverse events such as cranial nerve palsies. By contrast, our study leveraged real world data from over 1.5 million matched patients, enabling the detection of low frequency outcomes with statistical confidence. Importantly, while our results suggest a potential safety signal, they do not establish causality. The relatively small absolute risk increases (for example, 0.03% for CN III palsy and 0.05% for CN VI palsy) must be balanced against the well documented benefits of GLP-1 agonists in glycemic control, weight loss, and cardiovascular event reduction. Nevertheless, clinicians should be aware of these potential risks, particularly in patients presenting with new onset diplopia, facial weakness, or other focal neurologic symptoms during GLP-1 therapy. Enhanced post treatment monitoring and patient counseling may be warranted. This study has several strengths, including its large sample size, use of propensity score matching to reduce confounding, and standardized diagnostic coding. However, limitations include reliance on ICD-10 coding without access to clinical severity or imaging data, inability to differentiate among individual GLP-1 agents (for example, semaglutide vs liraglutide), and lack of dosage or duration data. This study has similar limitations inherent to any retrospective study and reliance on electronic health records. Additionally, unmeasured confounding from socioeconomic, genetic, or healthcare access factors cannot be excluded. Future directions should include mechanistic studies to elucidate the biologic basis for these observations, as well as prospective pharmacovigilance and subgroup analyses stratified by age, sex, ancestry, and comorbid autoimmune or neurological disease. Given the expanding use of GLP-1 receptor agonists in non diabetic populations, such as for obesity and cardiovascular risk reduction, the potential neurologic effects merit careful monitoring [ 22 ]. To our knowledge, this study represents the first large scale, U.S.-based investigation to report a significant association between GLP-1 receptor agonist use and cranial nerve palsies. These findings contribute to a growing dialogue on the neurologic safety of incretin-based therapies and underscore the need for vigilance in both clinical and research settings. CONCLUSION In conclusion, this study identified a statistically significant association between GLP-1 receptor agonist use and increased risk of cranial nerve palsies, specifically CN III, CN VI, and CN VII (Bell’s palsy), in patients with type 2 diabetes. Although the absolute risk remains low, the consistently elevated risk ratios across all outcomes highlight a potential neurologic safety signal that has been underexplored in prior clinical trials. These findings underscore the importance of continued post-marketing surveillance and mechanistic studies to better understand the neurologic effects of GLP-1 therapies, especially as their use expands beyond glycemic control to broader metabolic and cardiovascular indications. While the clinical benefits of GLP-1 agonists remain substantial, awareness of rare but meaningful neurologic adverse events may inform patient counseling and risk-benefit discussions in clinical practice. Declarations This study was determined to be exempt from Howard University Hospitals Institutional Review Board (IRB) review as it involved the retrospective analysis of de-identified patient data obtained from a national research network. No identifiable private information was collected or recorded, and there was no direct interaction with patients. As such, the research qualifies for exemption under 45 CFR 46.104(d)(4). Ethics approval and consent to participate This retrospective analysis used only de-identified data from the TriNetX Global Collaborative Network. Because no identifiable private information was accessed, this work did not constitute human subjects research and institutional review board approval and informed consent were not required. Competing interests The authors declare that they have no competing interests (financial or non-financial) relevant to this work. Funding/Support No external funding or specific grant from public, commercial, or not-for-profit sectors was received for this study. Availability of data and materials The underlying data are held by TriNetX and participating healthcare organizations and are not publicly shareable. Aggregated, de-identified outputs and detailed cohort definitions, code lists, and query parameters used in this study are available from the corresponding author upon reasonable request and subject to TriNetX data use policies. Author contributions All authors contributed to study conception and design, data curation within the TriNetX environment, interpretation of results, and drafting or critical revision of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Acknowledgments None. Prior presentations None. Use of generative AI Generative artificial intelligence (OpenAI ChatGPT) was used only for language editing and formatting. No AI tool was used to generate data, perform analyses, or draw scientific conclusions. All content was reviewed and approved by the authors. References Basu A, Dalla Man C, Basu R, Toffolo G, Cobelli C, Rizza RA. 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Elkomi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYBADGQkgceADkGBjJ1ILD0jLwRkgLcykaGHmATEJaTFvP2P4uYDBhkeyvTvxsM2vbfJ8zAyMHz7m4NYicybHWHoGQxqPNM/ZDYdz+24btjEzMEvO3IZbiwRD7gZpHobDPHISuUAtPbcZgVrYmHnxaeF/u/k3D8N/iBbLntv2hLVI5G4D2nKARxqkheHH7UQitLz/Zs1jkMwj2XN2w8HehtvJbcyMzfj9wp+WfJunwk5O4njv5g8//ty2nd/efPDDRzxaIMAASjO2gckGQuqRwR9SFI+CUTAKRsFIAQBhvEnkCV/2DAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-3707-544X","institution":"Howard University Department of Internal Medicine","correspondingAuthor":true,"prefix":"","firstName":"Rawan","middleName":"","lastName":"Elkomi","suffix":""},{"id":507924199,"identity":"f9bc93f2-c765-414e-ae83-c53ae18a09a7","order_by":7,"name":"Syed Fahad Gillani","email":"","orcid":"","institution":"Howard University Department of Internal 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Miriam","middleName":"","lastName":"Michael","suffix":""}],"badges":[],"createdAt":"2025-08-30 22:59:32","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7497591/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7497591/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90884705,"identity":"f3494e04-00f1-4471-bd92-7eef7937ecc4","added_by":"auto","created_at":"2025-09-09 10:00:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45208,"visible":true,"origin":"","legend":"\u003cp\u003eThe proportion of patients with type 2 diabetes (T2D) who developed third cranial nerve (CN III) palsy, comparing those treated with GLP-1 agonists versus those not treated with GLP-1 agonists.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7497591/v1/a735e9dac2e9c39b2297a0e8.png"},{"id":90882631,"identity":"9589194f-f999-42f0-98da-f6d79ee86f26","added_by":"auto","created_at":"2025-09-09 09:52:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57692,"visible":true,"origin":"","legend":"\u003cp\u003eThe proportion of sixth cranial nerve (CN VI) palsy cases among patients with type 2 diabetes (T2D) treated with GLP-1 agonists versus those not treated with GLP-1 agonists.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7497591/v1/5594936875e814d8c1cf5bbf.png"},{"id":90886236,"identity":"f6ae2e39-b6a4-4bb8-992e-860c1346e36f","added_by":"auto","created_at":"2025-09-09 10:08:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":54313,"visible":true,"origin":"","legend":"\u003cp\u003eThe proportion of Bell’s palsy (CN VII palsy) cases among patients with type 2 diabetes, comparing those treated with GLP-1 agonists versus those not treated with GLP-1 agonists.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7497591/v1/bbf838c8e5eeb77c83689e22.png"},{"id":90882634,"identity":"766b82d3-e41a-4a8c-b52e-5f6867910825","added_by":"auto","created_at":"2025-09-09 09:52:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":67822,"visible":true,"origin":"","legend":"\u003cp\u003eThe risk ratios for three neurological outcomes: third cranial nerve (CN III) palsy, sixth cranial nerve (CN VI) palsy, and Bell’s palsy (CN VII palsy) between type 2 diabetes patients treated with GLP-1 agonists versus those not treated with GLP-1 agonists.\u003c/p\u003e","description":"","filename":"figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7497591/v1/fd8d6359b58a7b4275a81bf3.png"},{"id":90886965,"identity":"992bd442-def2-444b-82f7-edfd510071bf","added_by":"auto","created_at":"2025-09-09 10:16:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":949149,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7497591/v1/84773069-f32e-4899-aeae-1fc9d6d90667.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eImpact of GLP-1 Receptor Agonists on Cranial Nerve Palsies in Type 2 Diabetes: A Retrospective Cohort Study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eType 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder marked by hyperglycemia that arises primarily from insulin resistance and β-cell dysfunction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite advancements in therapeutic strategies and public health initiatives, the global burden of T2DM continues to rise. Recent studies estimate that approximately 462\u0026nbsp;million individuals, which accounts for 6.28% of the global population, are affected by T2DM, emphasizing the urgent need for effective and sustainable treatment options [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong emerging therapeutic agents, glucagon-like peptide-1 (GLP-1) receptor agonists have gained considerable attention for their dual utility in managing both T2DM and obesity [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These incretin-based therapies mimic endogenous GLP-1 and have shown efficacy in reducing hemoglobin A1c levels and promoting weight loss, making them highly attractive in the context of metabolic syndrome management [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Moreover, beyond glycemic control, GLP-1 receptor agonists have demonstrated significant cardiovascular benefits in large-scale clinical trials, with reductions in major adverse cardiovascular events in patients at high cardiovascular risk [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe therapeutic efficacy of GLP-1 receptor agonists extends across multiple domains. Not only do they improve glycemic control by enhancing insulin secretion and inhibiting glucagon release [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e][\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], but they also contribute to sustained weight loss through delayed gastric emptying and increased satiety [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These effects are particularly beneficial in obese individuals with T2DM, for whom weight management is often a key therapeutic target. Furthermore, cardiovascular outcome trials such as LEADER and SUSTAIN-6 have highlighted the cardioprotective potential of these agents, revealing statistically significant reductions in events such as myocardial infarction and stroke [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAs the use of GLP-1 receptor agonists continues to grow, it is essential to carefully assess their safety profile. Gastrointestinal adverse effects, namely nausea, vomiting, and diarrhea, are the most frequently reported and may limit long-term adherence [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. While early concerns were raised about a potential link between GLP-1 receptor agonists and pancreatitis, current evidence has not established a direct causal relationship [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Notably, despite widespread pharmacovigilance, the potential for central or peripheral neurologic adverse effects remains an underexplored area, warranting further investigation into the neurophysiological actions of GLP-1.\u003c/p\u003e\u003cp\u003eAt a mechanistic level, GLP-1 is an incretin hormone primarily secreted by L-cells in the distal ileum and colon in response to nutrient intake. Following meal ingestion, these L-cells detect luminal nutrients, such as amino acids, fatty acids, and carbohydrates, and release GLP-1 in a biphasic manner during the early and late postprandial phases [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e][\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Once secreted, GLP-1 exerts multiple physiological effects: it enhances glucose-dependent insulin secretion from pancreatic β-cells, inhibits glucagon release from α-cells under hyperglycemic conditions, delays gastric emptying via vagally mediated pathways, and promotes satiety [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e][\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e][\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Gut-derived GLP-1 interfaces with central neuroendocrine circuits involved in appetite regulation and energy balance, indicating its activity spans an extensive gut\u0026ndash;brain axis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e][\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOphthalmologic complications are among the most common manifestations of diabetes mellitus [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Diabetic patients are at increased risk for third and sixth cranial nerve palsies. These palsies are typically attributed to ischemic injury of the cranial nerves resulting from chronic microvascular disease, a hallmark of long-standing diabetes. These neuro-ophthalmic complications can lead to acute diplopia, ptosis, and significant impairment in daily functioning [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. As GLP-1 receptor agonists are increasingly used for glycemic control and weight management, it is essential to understand whether these agents influence the incidence of cranial nerve palsies in this population.\u003c/p\u003e\u003cp\u003eThese diverse and integrated actions raise questions regarding GLP-1\u0026rsquo;s influence on central nervous system function and the potential for neurologic effects.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Data Source\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a retrospective cohort study using the TriNetX Global Collaborative Network, which aggregates de-identified electronic medical records from 145 healthcare organizations. Data are standardized using ICD-10-CM codes for diagnoses and RXNORM for medications. As the data are de-identified and analyzed retrospectively, the study was exempt from IRB oversight under HIPAA regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCohort Definition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo cohorts were created. Cohort 1 included patients with T2DM (ICD-10: E11) who received a GLP-1 receptor agonist (e.g., exenatide, liraglutide, semaglutide). Cohort 2 included patients with T2DM who were never treated with GLP-1 receptor agonists. The index event was defined as the first GLP-1 prescription for Cohort 1 and the T2DM diagnosis date for Cohort 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were excluded if they had a prior diagnosis of cranial nerve palsies of interest\u0026mdash;Bell\u0026rsquo;s palsy (G51.0), third nerve palsy (H49.0), or sixth nerve palsy (H49.2)\u0026mdash;type 1 diabetes (E10), or underlying neurologic conditions (e.g., multiple sclerosis, myasthenia gravis, CNS malignancy).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePropensity Score Matching\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo adjust for baseline differences, 1:1 propensity score matching was performed on age, sex, hypertension (I10), obesity (E66), and dyslipidemia (E78) using TriNetX\u0026rsquo;s nearest-neighbor algorithm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes and Follow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcomes were the incidence of third cranial nerve palsy (H49.0), sixth cranial nerve palsy (H49.2), and Bell\u0026rsquo;s palsy (G51.0). Events were tracked over a 10-year follow-up, beginning one day after the index event to mitigate immortal time bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRisk differences (RD), risk ratios (RR), and odds ratios (OR) were calculated. Kaplan-Meier survival analysis and log-rank tests were used to compare time-to-event outcomes. A hazard ratio (HR) with 95% confidence intervals was reported for each outcome. Analyses were conducted within the TriNetX platform.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003ePatient Characteristics\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter propensity score matching, each cohort contained 765,345 patients. Demographics were well balanced: mean age 62.2 \u0026plusmn; 13.2 years in Cohort 1 and 62.0 \u0026plusmn; 13.7 years in Cohort 2; sex distribution 52.6 percent female vs 52.0 percent female; comorbidities were comparable for essential hypertension, obesity, and dyslipidemia. Baseline proportion counts were not available in the platform export and are therefore not shown.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome 1: Third Cranial Nerve Palsy (CN III)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCN III palsy (ICD-10: H49.0) occurred in 0.07 percent (515/764,833) of GLP-1 users versus 0.04 percent (317/765,345) of non-users. The risk difference was 0.03 percent, p \u0026lt; 0.001; risk ratio 1.626 (95 percent CI, 1.413 to 1.870); odds ratio 1.626 (95 percent CI, 1.414 to 1.870). Kaplan\u0026ndash;Meier log-rank \u0026chi;\u0026sup2; = 25.88, p \u0026lt; 0.001; hazard ratio 1.44 (95 percent CI, 1.25 to 1.65). KM-estimated CN III palsy-free survival at end of follow-up was 99.75 percent in GLP-1 users and 99.84 percent in non-users (KM estimates; counts not applicable due to censoring). See Table 1 and Figure 1.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e The risk of developing CN III palsy among patients with type 2 diabetes who were treated with or without GLP-1 agonists.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCN III Palsy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk analysis excluding patients with outcome prior to the time window\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePatients in cohort after matching\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePatients with outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eRisk\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1) Type 2 Diabetes with GLP 1 agonists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e764,833\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e515\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2) Type 2 Diabetes without GLP 1 agonists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e765,345\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e317\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Difference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ep \u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.626\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e95% CI: (1.413, 1.870)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOdds Ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.626\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e95% CI: (1.414, 1.870)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome 2: Sixth Cranial Nerve Palsy (CN VI)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCN VI palsy (ICD-10: H49.2) occurred in 0.11 percent (843/764,570) of GLP-1 users versus 0.06 percent (447/765,345) of non-users. The risk difference was 0.05 percent, p \u0026lt; 0.001; risk ratio 1.888 (95 percent CI, 1.683 to 2.117); odds ratio 1.889 (95 percent CI, 1.684 to 2.118). Kaplan\u0026ndash;Meier log-rank \u0026chi;\u0026sup2; = 77.51, p \u0026lt; 0.001; hazard ratio 1.67 (95 percent CI, 1.48 to 1.87). KM-estimated CN VI palsy-free survival at end of follow-up was 98.25 percent in GLP-1 users and 99.72 percent in non-users (KM estimates; counts not applicable due to censoring). See Table 2 and Figure 2.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e The risk of developing sixth cranial nerve (CN VI) palsy among patients with type 2 diabetes, comparing those treated with GLP-1 agonists versus those not treated with GLP-1 agonists.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCN VI Palsy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk analysis excluding patients with outcome prior to the time window\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePatients in cohort after matching\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePatients with outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eRisk\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1) Type 2 Diabetes with GLP 1 agonists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e764,570\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e843\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2) Type 2 Diabetes without GLP 1 agonists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e765,345\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Difference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ep \u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e95% CI: (1.683, 2.117)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOdds Ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.889\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e95% CI: (1.684, 2.118)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome 3: Bell\u0026rsquo;s Palsy (CN VII)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBell\u0026rsquo;s palsy (ICD-10: G51.0) occurred in 0.43 percent (3,284/761,576) of GLP-1 users versus 0.31 percent (2,412/765,345) of non-users. The risk difference was 0.12 percent, p \u0026lt; 0.001; risk ratio 1.368 (95 percent CI, 1.298 to 1.442); odds ratio 1.370 (95 percent CI, 1.300 to 1.444). See Table 3 and Figure 3. Pooled risk ratios across outcomes are shown in Figure 4.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e The risk of developing Bell\u0026rsquo;s palsy (cranial nerve VII palsy) in patients with type 2 diabetes, comparing those who were treated with GLP-1 agonists versus those not treated with GLP-1 agonists.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBell\u0026rsquo;s Palsy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 624px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk analysis excluding patients with outcome prior to the time window\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePatients in cohort after matching\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ePatients with outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eRisk\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1) Type 2 Diabetes with GLP 1 agonists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e761,576\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e3,284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2) Type 2 Diabetes without GLP 1 agonists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e765,345\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e2,412\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0031\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Difference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.0012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ep \u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.368\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e95% CI: (1.298, 1.442)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOdds Ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e1.370\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e95% CI: (1.300, 1.444)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe findings from this retrospective cohort study suggest that treatment with GLP-1 receptor agonists in patients with T2DM is associated with a significantly increased risk of developing cranial nerve palsies, specifically third (CN III), sixth (CN VI), and seventh (CN VII, Bell\u0026rsquo;s palsy), compared to diabetic patients not treated with GLP-1 agonists. While the absolute risk in both groups remained low, the consistently elevated risk ratios, odds ratios, and hazard ratios across all outcomes indicate a statistically significant and potentially clinically relevant association.\u003c/p\u003e\u003cp\u003eThe pathophysiologic mechanisms linking GLP-1 agonist therapy to cranial nerve dysfunction remain unclear. GLP-1 receptors are widely expressed throughout the central and peripheral nervous systems, including the brainstem, hypothalamus, and cranial nerve nuclei. Preclinical studies have shown that GLP-1 analogs can cross the blood-brain barrier and modulate neuronal signaling, neuroinflammation, and oxidative stress [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Although these actions may confer neuroprotection in some contexts, they may paradoxically contribute to adverse neural outcomes in others, depending on receptor density, individual metabolic milieu, and cumulative exposure. In particular, the oculomotor and abducens nerves, due to their long intracranial course and vulnerability to ischemia or inflammation, may be more susceptible to microvascular injury or immune-mediated dysfunction induced by GLP-1 agonists.\u003c/p\u003e\u003cp\u003eAn emerging body of evidence also suggests that GLP-1 analogs may alter immune cell trafficking and cytokine release, potentially triggering autoimmune or inflammatory responses in susceptible individuals [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This is consistent with rare reports of cranial neuropathies and central nervous system adverse events in post marketing surveillance data and pharmacovigilance studies, although these have not been systematically studied. Additionally, metabolic changes associated with GLP-1 therapy, such as altered gut brain signaling, changes in cerebrovascular reactivity, or dysregulation of the vagus nerve, could also contribute to transient or chronic neuropathic effects [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough these findings are novel, they must be interpreted with caution. To date, most major clinical trials involving GLP-1 receptor agonists, such as LEADER, SUSTAIN, and REWIND, have focused on metabolic and cardiovascular outcomes, with little attention paid to neurologic safety endpoints. These trials are typically underpowered to detect rare but clinically important adverse events such as cranial nerve palsies. By contrast, our study leveraged real world data from over 1.5\u0026nbsp;million matched patients, enabling the detection of low frequency outcomes with statistical confidence.\u003c/p\u003e\u003cp\u003eImportantly, while our results suggest a potential safety signal, they do not establish causality. The relatively small absolute risk increases (for example, 0.03% for CN III palsy and 0.05% for CN VI palsy) must be balanced against the well documented benefits of GLP-1 agonists in glycemic control, weight loss, and cardiovascular event reduction. Nevertheless, clinicians should be aware of these potential risks, particularly in patients presenting with new onset diplopia, facial weakness, or other focal neurologic symptoms during GLP-1 therapy. Enhanced post treatment monitoring and patient counseling may be warranted.\u003c/p\u003e\u003cp\u003eThis study has several strengths, including its large sample size, use of propensity score matching to reduce confounding, and standardized diagnostic coding. However, limitations include reliance on ICD-10 coding without access to clinical severity or imaging data, inability to differentiate among individual GLP-1 agents (for example, semaglutide vs liraglutide), and lack of dosage or duration data. This study has similar limitations inherent to any retrospective study and reliance on electronic health records. Additionally, unmeasured confounding from socioeconomic, genetic, or healthcare access factors cannot be excluded.\u003c/p\u003e\u003cp\u003eFuture directions should include mechanistic studies to elucidate the biologic basis for these observations, as well as prospective pharmacovigilance and subgroup analyses stratified by age, sex, ancestry, and comorbid autoimmune or neurological disease. Given the expanding use of GLP-1 receptor agonists in non diabetic populations, such as for obesity and cardiovascular risk reduction, the potential neurologic effects merit careful monitoring [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo our knowledge, this study represents the first large scale, U.S.-based investigation to report a significant association between GLP-1 receptor agonist use and cranial nerve palsies. These findings contribute to a growing dialogue on the neurologic safety of incretin-based therapies and underscore the need for vigilance in both clinical and research settings.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, this study identified a statistically significant association between GLP-1 receptor agonist use and increased risk of cranial nerve palsies, specifically CN III, CN VI, and CN VII (Bell\u0026rsquo;s palsy), in patients with type 2 diabetes. Although the absolute risk remains low, the consistently elevated risk ratios across all outcomes highlight a potential neurologic safety signal that has been underexplored in prior clinical trials. These findings underscore the importance of continued post-marketing surveillance and mechanistic studies to better understand the neurologic effects of GLP-1 therapies, especially as their use expands beyond glycemic control to broader metabolic and cardiovascular indications. While the clinical benefits of GLP-1 agonists remain substantial, awareness of rare but meaningful neurologic adverse events may inform patient counseling and risk-benefit discussions in clinical practice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cspan\u003eThis study was determined to be exempt from Howard University Hospitals Institutional Review Board (IRB) review as it involved the retrospective analysis of de-identified patient data obtained from a national research network. No identifiable private information was collected or recorded, and there was no direct interaction with patients. As such, the research qualifies for exemption under 45 CFR 46.104(d)(4).\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective analysis used only de-identified data from the TriNetX Global Collaborative Network. Because no identifiable private information was accessed, this work did not constitute human subjects research and institutional review board approval and informed consent were not required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests (financial or non-financial) relevant to this work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo external funding or specific grant from public, commercial, or not-for-profit sectors was received for this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe underlying data are held by TriNetX and participating healthcare organizations and are not publicly shareable. Aggregated, de-identified outputs and detailed cohort definitions, code lists, and query parameters used in this study are available from the corresponding author upon reasonable request and subject to TriNetX data use policies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to study conception and design, data curation within the TriNetX environment, interpretation of results, and drafting or critical revision of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrior presentations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUse of generative AI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenerative artificial intelligence (OpenAI ChatGPT) was used only for language editing and formatting. No AI tool was used to generate data, perform analyses, or draw scientific conclusions. All content was reviewed and approved by the authors.\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003eBasu A, Dalla Man C, Basu R, Toffolo G, Cobelli C, Rizza RA. 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A systematic review of acute pancreatitis as an adverse event of type 2 diabetes drugs: from hard facts to a balanced position. \u003cem\u003eDiabetes, Obesity \u0026amp; Metabolism\u003c/em\u003e. 2014;16(11):1041-1047. doi:https://doi.org/10.1111/dom.12297\u003c/li\u003e\n \u003cli\u003eM\u0026uuml;ller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). \u003cem\u003eMolecular Metabolism\u003c/em\u003e. 2019;30:72-130. doi:https://doi.org/10.1016/j.molmet.2019.09.010\u003c/li\u003e\n \u003cli\u003eNalini Sodum, Mattila O, Sharma R, et al. Nutrient Combinations Sensed by L-Cell Receptors Potentiate GLP-1 Secretion. \u003cem\u003eInternational Journal of Molecular Sciences\u003c/em\u003e. 2024;25(2):1087-1087. doi:https://doi.org/10.3390/ijms25021087\u003c/li\u003e\n \u003cli\u003eQiyuan Keith Liu. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. \u003cem\u003eFrontiers in Endocrinology\u003c/em\u003e. 2024;15. doi:https://doi.org/10.3389/fendo.2024.1431292\u003c/li\u003e\n \u003cli\u003eLim GE, Brubaker PL. Glucagon-Like Peptide 1 Secretion by the L-Cell: The View From Within. \u003cem\u003eDiabetes\u003c/em\u003e. 2006;55(Supplement 2):S70-S77. doi:https://doi.org/10.2337/db06-s020\u003c/li\u003e\n \u003cli\u003eZheng Z, Zong Y, Ma Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. \u003cem\u003eSignal Transduction and Targeted Therapy\u003c/em\u003e. 2024;9(1):1-29. doi:https://doi.org/10.1038/s41392-024-01931-z\u003c/li\u003e\n \u003cli\u003eHolst JJ. Incretin hormones and the satiation signal. \u003cem\u003eInternational Journal of Obesity\u003c/em\u003e. 2013;37(9):1161-1168. doi:https://doi.org/10.1038/ijo.2012.208\u003c/li\u003e\n \u003cli\u003eWilliams DL. Minireview: Finding the Sweet Spot: Peripheral Versus Central Glucagon-Like Peptide 1 Action in Feeding and Glucose Homeostasis. \u003cem\u003eEndocrinology\u003c/em\u003e. 2009;150(7):2997-3001. doi:https://doi.org/10.1210/en.2009-0220\u003c/li\u003e\n \u003cli\u003eChung SM. Ocular complications of diabetes mellitus. \u003cem\u003eWorld J Diabetes\u003c/em\u003e. 2015 Feb 15;6(1):92-108. doi: 10.4239/wjd.v6.i1.92\u003c/li\u003e\n \u003cli\u003eJeganathan VS, Wang JJ, Wong TY. Ocular associations of diabetes other than diabetic retinopathy. \u003cem\u003eDiabetes Care\u003c/em\u003e. 2008 Sep;31(9):1905-12. doi: 10.2337/dc08-0342. PMID: 18753669; PMCID: PMC2518369.\u003c/li\u003e\n \u003cli\u003eH\u0026ouml;lscher C. Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. \u003cem\u003eJournal of Endocrinology\u003c/em\u003e. 2013;221(1):T31-T41. doi:https://doi.org/10.1530/joe-13-0221\u003c/li\u003e\n \u003cli\u003eHarkavyi A, Whitton PS. Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. \u003cem\u003eBritish Journal of Pharmacology\u003c/em\u003e. 2010;159(3):495-501. doi:https://doi.org/10.1111/j.1476-5381.2009.00486.x\u003c/li\u003e\n \u003cli\u003eChen J, Mei A, Wei Y, et al. GLP-1 receptor agonist as a modulator of innate immunity. \u003cem\u003eFrontiers in Immunology\u003c/em\u003e. 2022;13. doi:https://doi.org/10.3389/fimmu.2022.997578\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Howard University Hospital","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"GLP-1 receptor agonists, Cranial nerve palsy, Bell’s palsy, Type 2 diabetes mellitus","lastPublishedDoi":"10.21203/rs.3.rs-7497591/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7497591/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as key agents in managing type 2 diabetes mellitus (T2DM), with proven benefits in glycemic control, weight loss, and cardiovascular risk reduction. However, their neurologic safety profile remains underexplored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To evaluate the association between GLP-1 receptor agonist use and the incidence of cranial nerve (CN) palsies in patients with T2DM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This retrospective cohort study utilized the TriNetX Global Collaborative Network, comprising de-identified records from 145 healthcare organizations. Patients with T2DM treated with GLP-1 receptor agonists were compared to matched T2DM controls who never received GLP-1 therapy. Exclusion criteria included prior CN palsy diagnoses, CNS malignancy, type 1 diabetes, and neurological comorbidities. Outcomes assessed over a 10-year period included third nerve palsy (H49.0), sixth nerve palsy (H49.2), and Bell’s palsy (G51.0). Propensity score matching was applied for age, sex, hypertension, obesity, and dyslipidemia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After matching (n=765,345 per group), GLP-1 users had a significantly increased incidence of CN III palsy (RR: 1.63, 95% CI: 1.41–1.87), CN VI palsy (RR: 1.89, 95% CI: 1.68–2.12), and Bell’s palsy (RR: 1.37, 95% CI: 1.30–1.44), with p \u0026lt; 0.001 for all. Hazard ratios and Kaplan-Meier survival analysis corroborated these findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e While absolute risks remain low, GLP-1 receptor agonist use was associated with a statistically significant increase in cranial nerve palsies. These findings underscore the need for additional research into the neurophysiological effects of GLP-1 therapies, particularly in ophthalmological and neurological domains.\u003c/p\u003e","manuscriptTitle":"Impact of GLP-1 Receptor Agonists on Cranial Nerve Palsies in Type 2 Diabetes: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 09:52:49","doi":"10.21203/rs.3.rs-7497591/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cdd9f3b0-b213-4f0f-8683-463f081937c0","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53947770,"name":"Neurology"},{"id":53947771,"name":"Endocrinology \u0026 Metabolism"},{"id":53947772,"name":"Pharmacodynamics"}],"tags":[],"updatedAt":"2025-09-09T09:52:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-09 09:52:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7497591","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7497591","identity":"rs-7497591","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}