Abstract

This study examines the cerebrovascular safety of calcitonin gene-related peptide (CGRP)–targeted therapies in patients with migraine, a group where vascular risk differs by migraine subtype. Migraine with aura (MWA) is a well-established risk factor for ischemic stroke, while the association with migraine without aura (MWoA) is less clear. Although CGRP inhibitors are highly effective for preventing migraines, their long-term effects on stroke risk are still unclear due to CGRP’s vasodilatory and neuroprotective roles. Using real-world data from over 186,000 adults in the TriNetX Global Collaborative Network, this retrospective cohort study looked at ischemic stroke rates in patients with MWA and MWoA who received CGRP-targeted treatments compared to matched controls who did not. After excluding patients with a prior myocardial infarction or peripheral vascular disease, rigorous 1:1 propensity score matching was applied to control for demographics and vascular comorbidities. The analysis revealed a modest but statistically significant increase in ischemic stroke risk in both migraine subtypes. In MWA, CGRP use was linked to a 36% higher hazard of stroke (HR 1.36; 95% CI 1.20–1.54), while in MWoA, the hazard was elevated by 51% (HR 1.51; 95% CI 1.32–1.73). Absolute risk, however, remained very low (<0.3%). Notably, specific agents such as galcanezumab and rimegepant were linked to higher stroke hazards. The study highlights the need to balance the benefits of CGRP therapies with potential vascular risks, especially in patients with MWA or existing vascular risk factors. Healthcare providers should include vascular risk assessments and close monitoring as part of routine care. Future prospective research is necessary to determine investigate agent-specific risks and better understand the role of CGRP in cerebrovascular health.