CGRP Inhibitors Reduce Glaucoma Risk Compared to Traditional Migraine Preventives

Ocular Vascular Health and Migraine Prophylaxis

Migraine is increasingly understood as a systemic disorder with microvascular consequences, including an elevated risk for retinal vascular events and various maculopathies [1]. While traditional oral preventive medications like topiramate and divalproex are widely used, their clinical utility can be limited by tolerability issues and inconsistent evidence on long-term systemic safety [2]. The development of therapies targeting the calcitonin gene-related peptide (CGRP) pathway has significantly altered the management of both episodic and chronic migraine, offering high specificity and a favorable safety profile [3, 4]. Given that CGRP is a potent vasodilator active in both nociceptive and vascular pathways, its long-term inhibition raises important questions about ocular hemodynamics and the risk of comorbid conditions like glaucoma [5]. A recent multinational cohort study provides new data clarifying the association between these targeted inhibitors and the risk of incident glaucoma.

Comparative Analysis of Incident Glaucoma Risk

This Class II multinational retrospective cohort study analyzed data from 73,644 adults with migraine who were prescribed preventive therapies between 2018 and 2024. To create a fair comparison between treatment strategies, the researchers employed propensity score matching in a 1:1 ratio. This statistical technique balances baseline patient characteristics between groups to minimize confounding variables and isolate the effect of the medication itself. The study population was divided into two cohorts: the first received calcitonin gene-related peptide inhibitors, including the monoclonal antibodies erenumab, fremanezumab, galcanezumab, and eptinezumab, or the small-molecule receptor antagonists atogepant and rimegepant. The second cohort, serving as the comparator group, received traditional preventive medications, including valproate, topiramate, flunarizine, candesartan, lisinopril, metoprolol, propranolol, nadolol, amitriptyline, or venlafaxine. To ensure the analysis captured drug-specific effects, the study design prohibited crossovers between the groups, and the non-CGRPi cohort included only patients who had never used a CGRP inhibitor. This rigorous design allowed for a direct comparison of long-term ocular outcomes between modern and traditional migraine prophylaxis.

Quantifying the Protective Association

Participants were followed for up to three years to track new-onset cases of glaucoma. The investigators used a Cox proportional hazards model, a statistical method for analyzing the time until an event occurs, to compare glaucoma risk between the two treatment groups. The results, reported as hazard ratios (HRs), revealed that CGRPi users had a significantly lower risk of developing glaucoma within three years of their first prescription compared with users of non-CGRPi medications (HR 0.75; 95% CI 0.61 to 0.92). This association held when CGRPi use was compared directly against several specific traditional agents. For instance, a reduced risk was observed relative to the anticonvulsants topiramate (HR 0.73; 95% CI 0.59 to 0.90) and valproate (HR 0.54; 95% CI 0.35 to 0.83). This finding is particularly relevant for topiramate, which carries a known risk of inducing secondary angle-closure glaucoma. The risk reduction was also evident when compared with beta-blockers like propranolol (HR 0.76; 95% CI 0.59 to 0.98) and metoprolol (HR 0.76; 95% CI 0.59 to 0.98), as well as antidepressants such as amitriptyline (HR 0.69; 95% CI 0.54 to 0.89) and venlafaxine (HR 0.68; 95% CI 0.50 to 0.91). The most substantial risk difference was seen in comparison to the angiotensin-converting enzyme inhibitor lisinopril (HR 0.49; 95% CI 0.38 to 0.62), suggesting the choice of migraine prophylaxis may influence long-term ocular health.

Subgroup Vulnerability and Class-Specific Effects

A deeper analysis into the CGRPi class revealed that this protective association was not uniform. The data showed that only users of monoclonal antibody CGRP inhibitors (erenumab, fremanezumab, galcanezumab, eptinezumab) had a reduced risk of glaucoma compared with non-CGRPi users (HR 0.77; 95% CI 0.61 to 0.98). This distinction suggests the mechanism of action, whether a large injectable protein or a small-molecule oral gepant, may be a key factor in the observed ocular effects, a critical consideration for clinicians selecting therapies for patients with pre-existing glaucoma risk. The study also confirmed that the reduced glaucoma risk associated with CGRPi use was consistent across key patient populations. The association was present in older adults and in women, groups with a higher baseline prevalence of both migraine and glaucoma. Furthermore, the benefit extended across different migraine phenotypes, which are the clinical presentations of the disorder, as the reduced risk was observed in patients with chronic migraine as well as those with migraine without aura. This consistency suggests the potential ocular benefit of monoclonal antibody CGRPi is broadly applicable to many patients requiring long-term migraine prevention.

References

1. Mohamed MI, Halwag MI, Mahmoud NH, Salib M, Nada MA. Migraine as a risk factor for retinal vascular events and maculopathies: a systematic review and meta-analysis of 47 million individuals. The Journal of Headache and Pain. 2026. doi:10.1186/s10194-026-02353-8

2. Robblee J, Hakim SM, Reynolds JM, Monteith TS, Zhang N, Barad M. Nonspecific oral medications versus anti-calcitonin gene-related peptide monoclonal antibodies for migraine: A systematic review and meta-analysis of randomized controlled trials.. Headache. 2024. doi:10.1111/head.14693

3. Szulewski M, Bajor G, Gniadek Z, et al. BEYOND TRIPTANS: SYSTEMATIC REVIEW FOCUSING ON THE EFFICACY AND SAFETY PROFILE OF CGRP RECEPTOR ANTAGONISTS IN MIGRAINE MANAGEMENT. International Journal of Innovative Technologies in Social Science. 2026. doi:10.31435/ijitss.1(49).2026.5037

4. Wang X, Chen Y, Song J, You C. Efficacy and Safety of Monoclonal Antibody Against Calcitonin Gene-Related Peptide or Its Receptor for Migraine: A Systematic Review and Network Meta-analysis.. Frontiers in pharmacology. 2021. doi:10.3389/fphar.2021.649143

5. Schou WS, Ashina S, Amin FM, Goadsby PJ, Ashina M. Calcitonin gene-related peptide and pain: a systematic review. The Journal of Headache and Pain. 2017. doi:10.1186/s10194-017-0741-2