Calcitonin gene-related peptide antagonists in Raynaud's phenomenon: a disproportionality study based on real data and drug-gene network analysis

Abstract

This study aims to investigate the potential risk and possible mechanisms of Raynaud's phenomenon (RP) associated with the use of calcitonin gene-related peptide (CGRP) antagonists through a comprehensive analysis of the FDA Adverse Event Reporting System (FAERS) database combined with drug-gene network analysis methods. In this disproportionality study, we evaluated the adverse event (AE) signal of RP associated with CGRP antagonists from the FAERS covering the quarter 2 of 2018 to quarter 1 of 2025, using four methods. The gene targets of CGRP antagonists and RP targets were predicted using multiple databases and protein-protein interactions (PPI) using the STRING database. Subsequently, Kyoto Encyclopedia of genes and genomes (KEGG) enrichment analysis was performed using R software to identify the potential mechanisms of CGRP antagonists related to RP. This study retrieved a total of 149 AE reports related to CGRP antagonists and RP reports from the FAERS database, involving 7 CGRP antagonists. Erenumab has the highest number of reports. The data mining results indicate that fremanezumab resulted in the strongest AE signals of the four methods. Protein-protein interaction (PPI) network analysis revealed key nodes of non-peptide small molecule CGRP antagonists in RP, such as the key nodes of rimegepant in RP is AKT1, EGFR, ERBB2, and others. The KEGG pathway enrichment analysis showed that the most possible mechanisms of rimegepant, atogepant, and ubrogepant induce RP is the PI3K signaling pathway. Using a novel approach, we systematically integrated the FAERS database with drug-gene network analysis. Our results not only suggest a potential risk of RP associated with CGRP antagonists but also reveal that the PI3K/AKT pathway is the underlying mechanism for non-peptide small molecules. We recommend that patients receiving these antagonists, particularly those with underlying vascular dysfunction, undergo regular monitoring for RP.

Keywords: Calcitonin gene-related peptide antagonists; Drug-gene network analysis; FAERS; Migraine; Raynaud’s phenomenon.