The Risk of Vestibular Disorders with Semaglutide and Tirzepatide: Findings from a Large Real-World Cohort

Abstract

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of type 2 diabetes and obesity. While their metabolic benefits are well-established, their potential effects on vestibular function remain unexplored. This study investigated the association between GLP-1RA use and the risk of vestibular disorders. Methods: Using the TriNetX research network (accessed 3 November 2024), we conducted a retrospective cohort study of adults prescribed semaglutide (n = 419,497) or tirzepatide (n = 77,259) between January 2018 and October 2024. Cases were matched 1:1 with controls using propensity scores based on demographics and comorbidities. The primary outcome was new-onset vestibular disorders, analyzed at 6 months, 1 year, and 3 years after treatment initiation. Results: Both medications were associated with an increased risk of vestibular disorders. Semaglutide users showed a higher cumulative incidence (0.12% at 6 months to 0.41% at 3 years) compared to controls (0.03% to 0.16%, p < 0.001), with hazard ratios ranging from 4.02 (95% CI: 3.33-4.86) at 6 months to 4.95 (95% CI: 4.51-5.43) at 3 years. Tirzepatide users demonstrated similar patterns but lower absolute rates (0.10% at 6 months to 0.19% at 3 years vs. controls 0.04% to 0.15%), with hazard ratios from 3.19 (95% CI: 2.11-4.81) to 4.55 (95% CI: 3.43-6.03). The direct comparison showed a higher risk with semaglutide versus tirzepatide (RR 1.53-2.04, p < 0.001). Conclusions: GLP-1RA therapy is associated with an increased risk of vestibular disorders, with a higher risk observed with semaglutide compared to tirzepatide. These findings suggest the need for vestibular symptom monitoring in patients receiving these medications and warrant further investigation into underlying mechanisms.

Keywords: GLP-1 receptor agonists; adverse effects; dizziness; obesity; pharmacovigilance; semaglutide; tirzepatide; type 2 diabetes; vertigo; vestibular disorders.

Figure 1

The chemical structure of Glucagon-like peptide-1 receptor agonists (GLP-1RA) and their key features. (A) Semaglutide and (B) tirzepatide. Both proteins have a long hydrocarbon chain (ellipse shape) attached to the main polypeptides, which facilitates passing through the blood–brain barrier (BBB). The chemical structure and data were obtained from the free source PubChem (Available online: https://pubchem.ncbi.nlm.nih.gov) (accessed on 15 April 2025).

Figure 2

Cumulative incidence of vestibular disorders in GLP-1 receptor agonist users and matched controls over time. (A) Semaglutide users (n = 419,497) versus matched controls. *** p < 0.001 for all semaglutide comparisons. (B) Tirzepatide users (n = 77,932) versus matched controls. The cumulative incidence is presented as percentages at 6 months, 1 year, and 3 years after treatment initiation. *** p < 0.001 for 6-month and 1-year tirzepatide comparisons, * p = 0.042 for 3-year tirzepatide comparison.

Figure 3

Hazard ratios for vestibular disorders in GLP-1 receptor agonist users compared to matched controls. (A) Semaglutide users (n = 419,497) versus matched controls. (B) Tirzepatide users (n = 77,932) versus matched controls. Hazard ratios with 95% confidence intervals are presented at 6 months, 1 year, and 3 years after treatment initiation.

Figure 4

The comparative relative risk of vestibular disorders between semaglutide and tirzepatide users across different time points. The risk ratios with 95% confidence intervals show the relative risk of vestibular disorders in semaglutide users compared to tirzepatide users at 6 months (RR: 1.53, 95% CI: 1.08–2.17, p = 0.018), 1 year (RR: 1.36, 95% CI: 1.02–1.82, p = 0.038), and 3 years (RR: 2.04, 95% CI: 1.69–2.46, p < 0.0001) after treatment initiation.

Figure 5

Proposed mechanisms of GLP-1RA-associated vestibular dysfunction. Multiple interconnected pathways potentially contribute to vestibular symptoms: (1) direct central vestibular modulation via GLP-1R in brainstem nuclei; (2) inner ear fluid homeostasis disruption; (3) mitochondrial stress in vestibular hair cells; (4) autonomic dysregulation affecting postural control; and (5) systematic effect due to rapid weight loss. Created with BioRender.com (E.A.T.) (accessed 13 April 2025).

Figure 6

Putative molecular interactions link GLP-1 receptor agonists (GLP-1Ras) to vestibular disorders. GLP1R, located in the plasma membrane, serves as the central hub connecting downstream proteins involved in cellular signaling, metabolism, and inflammation. Key pathways include autophagy regulation via Sequestosome-1 (SQSTM1), glucose transport mediated by Solute Carrier Family 2 Member 5 (SLC2A5), endocytic trafficking through “Neural precursor cell-expressed developmentally down-regulated protein 4; (NEDD4) and Ras-related protein Rab-8A (RAB8A), pyrimidine synthesis involving Carbamoyl-phosphate synthetase 2 (CAD), and nuclear signaling via “Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A (RELA; NF-κB pathway). Source: https://digitalinsights.qiagen.com/IPA (accessed 4 April 2025).