Gepants for Migraine: An Update on Long-Term Outcomes and Safety Profiles

Calcitonin gene-related peptide receptor antagonists, also referred to as gepants, represent a transformative advancement in migraine pharmacotherapy, providing both acute and preventive treatment options without the vasoconstrictive limitations of triptans. Since their initial approval in 2019, gepants have gained widespread clinical adoption, necessitating comprehensive evaluation of their long-term safety and efficacy. This review synthesizes current evidence on four calcitonin gene-related peptide receptor antagonists (rimegepant, atogepant, ubrogepant, and zavegepant) derived from pivotal trials, open-label extension studies, and real-world observational data. Rimegepant demonstrates sustained efficacy and minimal adverse events over 52 weeks, with no evidence of medication-overuse headaches or hepatotoxicity. Atogepant maintains progressive clinical benefits and favorable tolerability for up to 1 year, exhibiting low rates of treatment-emergent adverse events and discontinuation. Ubrogepant remains effective and well-tolerated during long-term intermittent use, with no clinically significant safety signals over extended exposure. Zavegepant, the first intranasal gepant, shows promising long-term tolerability, with the most frequently reported localized adverse event being transient dysgeusia. No consistent hepatic, cardiovascular, or serious systemic toxicity has emerged for any of the agents, and discontinuation rates due to adverse events remain consistently low. Current evidence supports gepants as safe and effective therapies for long-term migraine management, although ongoing surveillance and extended-duration studies remain essential to fully characterize their safety profile, particularly in high-risk populations and combination therapy scenarios. In conclusion, gepants offer a well-tolerated, non-vasoconstrictive alternative for migraine patients who require sustained treatment, representing a significant therapeutic advancement in migraine.