CGRP-CV
(2026)Objective
To examine whether CGRP inhibitor use is associated with an increased risk of cardiovascular events in patients with migraine
Study Summary
• MI, revascularization, peripheral arterial disease, and central retinal artery occlusion not significantly elevated; results considered hypothesis-generating (Class II evidence)
Intervention
CGRP inhibitor initiation vs non-use in Medicare migraine patients
Inclusion Criteria
Medicare beneficiaries with migraine diagnosis
Study Design
Arms: CGRP Inhibitor Initiators vs Non-Initiators
Patients per Arm: CGRP Initiators: 58,679, Non-Initiators: 841,691
Outcome
• Ischemic stroke: aHR 1.26 (95% CI 1.07-1.49)
• MI, revascularization, PAD: not significantly elevated
Bottom Line
In a large Medicare cohort of 900,370 beneficiaries, CGRP inhibitor initiation was associated with a modest 26% increase in composite cardiovascular events (aHR 1.26), driven primarily by ischemic stroke. The absolute risk increase remains small (8.77 vs 6.76 per 1,000 person-years), and results are hypothesis-generating rather than practice-changing.
Major Points
- Meta-analysis of cardiovascular safety of CGRP-targeting therapies (mAbs + gepants) in migraine.
- No increased cardiovascular risk: composite CV events not elevated vs placebo across all trials.
- CGRP is a potent vasodilator — theoretical concern about CV events with CGRP blockade.
- Included data from erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, ubrogepant, atogepant.
- BP changes: small but clinically insignificant increases (1-2 mmHg) with some agents.
- Raynaud's phenomenon: numerically higher in some trials but no clinically significant signal.
- Patients with significant CV disease were excluded from pivotal trials — limits generalizability.
- Supports CV safety of CGRP therapies in migraine patients without established CV disease.
- Long-term registry data still accumulating for post-market surveillance.
- Addresses key clinical concern for prescribers of CGRP-targeting preventive migraine therapies.
Study Design
- Study Type
- Retrospective, observational cohort study
- Randomization
- No
- Blinding
- N/A (observational)
- Sample Size
- 900370
Primary Outcome
Definition: Composite cardiovascular events (MI, ischemic stroke, revascularization, PAD, CRAO)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | 1.26 (1.10-1.45) | - |
Limitations & Criticisms
- Observational design cannot establish causation
- Confounding by indication: CGRP users may have more severe migraine with inherently higher CV risk
- Medicare population may not generalize to younger migraine patients
- Absolute risk increase is small despite statistical significance
Citation
Lusk JB et al. Neurology. 2026;106(3):e214479. DOI: 10.1212/WNL.0000000000214479