Identifying cardiac safety signals of disproportionate reporting for CGRP antagonists: evidence from the FDA Adverse...

The objective of this study was to investigate the potential association between the use of calcitonin gene-related peptide (CGRP) antagonists and the reporting of cardiac adverse events (cAEs) by analyzing data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). CGRP antagonists are a novel class of effective treatments for migraine. However, given CGRP's crucial role as a potent vasodilator, concerns about the cardiac safety of its long-term blockade persist. This study aimed to assess real-world post-marketing safety signals for this drug class. FAERS data from Q1 2018 to Q2 2025 were analyzed. CGRP antagonists included monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) and small-molecule receptor antagonists (rimegepant, ubrogepant, atogepant). Disproportionality analyses were conducted using the reporting odds ratio (ROR) and information component (IC). The impact of age, sex, and weight on cAE was assessed. Time-to-onset analyses were also carried out. A total of 1806 cAE reports associated with CGRP antagonists were identified. Palpitations emerged as a consistent signal across all seven agents, suggesting a class effect. Monoclonal antibodies, particularly erenumab and fremanezumab, exhibited a broader spectrum of cAE signals, including coronary artery dissection, Prinzmetal angina, and postural orthostatic tachycardia syndrome. The results showed higher body weight was significantly associated with the cAE signal of disproportionate reporting (SDR) of erenumab (odds ratio [OR] 1.48, 95% CI 1.02-2.11, P = 0.034). Meanwhile, male sex was significantly associated with the cAE SDR of galcanezumab (OR 2.41, 95% CI 1.25-4.40, P = 0.006). Time-to-onset analyses indicated that most cAEs followed an early failure pattern, with the highest reporting intensity shortly after treatment initiation. Using FAERS, this pharmacovigilance study detected signals of disproportionate reporting of cardiac adverse events for most CGRP antagonists. These results are hypothesis-generating and reflect reporting patterns rather than incidence or relative risk; therefore, they should not be interpreted as evidence of causality or as patient-level cAE risk factors. Continued post-marketing surveillance and confirmatory pharmacoepidemiologic studies in well-defined populations are warranted.  CLINICAL TRIAL NUMBER: Not applicable.