Deep Dive: CGRP Therapies: First-Line Status, New Safety Signal

A practicing clinician’s guide to all 8 FDA-approved CGRP-targeted agents: mechanism, agent selection, safety, and monitoring

For most of their history, CGRP-targeted therapies were treatments of last resort. As of March 2024, that is no longer true, and a lot of practicing clinicians have not caught up. The American Headache Society’s updated position statement now designates CGRP-targeting therapies a first-line option for migraine prevention, explicitly stating that initiation should not require trial and failure of non-specific migraine preventive medication approaches. Headache That single sentence rewrites the referral and prior-authorization logic that has governed this class since erenumab’s 2018 approval, and it means a patient sitting in front of you today with four migraine days a month has a legitimate claim to a CGRP agent before anyone tries topiramate, a beta-blocker, or an SNRI.

That expansion is colliding with a safety story that is still being written, and two signals in particular deserve tracking. The first is vascular: a 2025 analysis of the FDA Adverse Event Reporting System found a significant disproportionality signal for Raynaud phenomenon across the CGRP class as a whole (reporting odds ratio 19.12; 95% CI, 15.44–23.69), with individual-agent signals ranging widely and fremanezumab, galcanezumab, and ubrogepant among the highest. SciRep The second is hypertension, which prompted an FDA label update after postmarketing reports, though the real-world data are more reassuring than those case reports alone would suggest: a 2025 systematic review encompassing 75,065 patients across five studies found no significant hypertension signal in normotensive patients, with only a small annual increase in antihypertensive medication use among those with pre-existing hypertension. Cureus Both signals were characterized while CGRP therapies were still reserved largely for patients who had already failed other preventives; the population now eligible under first-line criteria is broader than the one those studies captured. Headache As Shaheen Lakhan, MD, PhD, put it to Medscape, these agents “have not been a universal or magical fix, but they have meaningfully improved outcomes for many patients who previously cycled through nonspecific preventives with poor tolerability.” Medscape

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