Semaglutide or Tirzepatide and Optic Nerve and Visual Pathway Disorders in Type 2 Diabetes

Abstract

Importance: Semaglutide and tirzepatide, the new generation of glucagon-like peptide-1 receptor agonist used to treat type 2 diabetes and obesity, were recently reported to be associated with increased risk of nonarteritic anterior ischemic optic neuropathy (NAION). However, reported associations were inconsistent, and it remains unknown if semaglutide or tirzepatide is associated with other disorders of the optic nerve and visual pathways.

Objective: To examine associations of treatment with either semaglutide or tirzepatide with first-time diagnoses of optic nerve and visual pathway disorders in patients with type 2 diabetes.

Design, setting, and participants: This cohort study emulated target trials based on a nationwide, population-based database of US patient electronic health records from December 2017 to January 2023. Models were adjusted by propensity score matching. Eligible patients had type 2 diabetes and no prior diagnosis of eye disorders and were prescribed semaglutide, tirzepatide, or other antidiabetic medications.

Exposures: Prescription of semaglutide or tirzepatide vs other antidiabetic medications (insulins, metformin, dipeptidyl-peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, thiazolidinediones, and other glucagon-like peptide 1 receptor agonists).

Main outcomes and measures: First-time diagnoses of NAION and other optic nerve disorders during a 2-year follow-up were examined using Cox proportional hazards and Kaplan-Meier survival analyses.

Results: After propensity score matching among 1 511 637 eligible patients, the study population comprised 159 398 matched patients with type 2 diabetes (mean [SD] age, 56.5 [13.3] years; 83 123 women [52.15%]), including 79 699 patients in the semaglutide or tirzepatide group and 79 699 patients in the comparison group. During the 2-year follow-up, there were 35 patients (0.04%) with NAION in the semaglutide or tirzepatide group and 19 patients (0.02%) with NAION in the matched comparison group (hazard ratio, 1.76 [95% CI, 1.01-3.07]). There were 93 patients (0.12%) with other optic nerve disorders in the semaglutide or tirzepatide group and 54 patients (0.07%) with other optic nerve disorders in the matched comparison group (hazard ratio, 1.65 [95% CI, 1.18-2.31]). No association was found with other disorders of the optic nerve or visual pathways.

Conclusions and relevance: In this study of patients with type 2 diabetes who had no prior eye disorders, patients prescribed semaglutide or tirzepatide had an increased risk of NAION and other optic nerve disorders, although the overall risk was low. These findings highlight the need for close monitoring of these conditions.

Figure 1.. Study Flowchart

DPP-4i indicates dipeptidyl-peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium-glucose cotransporter-2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. ^aThe combined total of 1 428 665 patients in the comparison arm is not a sum of patients from each antidiabetic medication group because a patient could be prescribed more than 1 antidiabetic medication during the study period. However, there was no overlap between the semaglutide or tirzepatide group and comparison medication groups. ^bOther GLP-1RAs included albiglutide (1108 patients [0.89%]), dulaglutide (83 501 patients [66.85%]), exenatide (17 046 patients [13.65%]), liraglutide (53 189 patients [42.59%]), and lixisenatide (2465 patients [1.97%]).

Figure 2.. Risk of Optic Nerve and Visual Pathway Disorders for Semaglutide or Tirzepatide vs Other Antidiabetic Medications

Exposure and comparison groups were propensity score matched for variables listed in Table 1, and the status of variables was based on the presence of related clinical codes any time up to 1 day before the index event (first prescription of semaglutide or tirzepatide vs comparison medication classes during December 2017 to January 2023). Individuals in matched groups were followed up after the index event until the occurrence of the outcome, death, loss to follow-up, or 2 years after the index event, whichever occurred first. Hazard rates were calculated using a Cox proportional hazards model with censoring applied. Overall risk was the number of patients with outcomes during the follow-up time window divided by the number of patients in the cohort at the beginning of the time window. HR indicates hazard ratio; NAION, nonarteritic anterior ischemic optic neuropathy.

Figure 3.. Cumulative Incidence of Optic Nerve and Visual Pathway Disorders

The 2-year cumulative incidence curves are shown for A, optic nerve disorders, B, nonarteritic anterior ischemic optic neuropathy (NAION), and C, other optic nerve disorders for the propensity score matched semaglutide or tirzepatide group and other antidiabetic medication groups in patients with type 2 diabetes who had no prior diagnosis of eye disorders.

Figure 4.. Risk of Optic Nerve and Visual Pathway Disorders for Semaglutide or Tirzepatide vs Other Glucagon-Like Peptide 1 Agonists (GLP-1RAs)

Exposure and comparison groups were propensity score matched. HR indicates hazard ratio; NAION, nonarteritic anterior ischemic optic neuropathy.