193 Safety considerations in the treatment with anti-CGRP antibodies 9 INTRODUCTION Over the past few years, monoclonal anti-Calcitonin Gene-Related Peptide-(Receptor-) monoclonal Antibodies (anti-CGRP(R)-mAbs) have emerged as a promising prophylactic treatment for migraine.1-3 These antibodies bind to either the CGRP ligand or its receptor, thereby blocking its actions. While the efficacy of anti-CGRP(R)-mAbs in preventing migraines has been established, it is crucial to consider the potential physiological implications associated with their prolonged usage. This necessity arises from the multifaceted role of CGRP in various biological processes within the human body.4 CGRP, a potent systemic vasodilator capable of reducing blood pressure (BP), and exerting both chronotropic and inotropic effects on the heart, plays a critical role in maintaining the cerebro- and cardiovascular (CV) homeostasis.5 In theory, anti-CGRP(R)-mAbs may diminish the protective effect of CGRP on CV-infarct size and increase the risk of heart failure.5-7 Notably, migraine itself is an independent CV risk factor, further emphasizing the need for a comprehensive understanding of the CV implications of anti-CGRP(R)-mAbs.8-10 Moreover, as CGRP can be found in the digestive tract, lungs, kidney, liver and adipose tissue as well, other regulatory systems may be affected by the neuropeptide, although less is known about the exact sites of action and underlying mechanisms.4, 11 In vitro studies demonstrated that erenumab inhibited CGRP-mediated vasodilation, while not interacting with other vasoactive compounds.12 Furthermore, work in mice demonstrated that treatment with a CGRP receptor antagonist worsened cerebral ischemic outcomes,6 and rat studies demonstrated that cardiac ischemic outcome is worsened by the blocking of the CGRP receptor.7 Thus, these animal studies indicate an important role of CGRP in preserving tissue during ischemic conditions. A handful of studies have evaluated the effect of erenumab in vivo and yielded mixed results, with one study that did not find any alterations in vasomotor reactivity or flow-mediated dilation in patients with migraine, while another demonstrated that it did affect trigeminovascular reactivity by a decrease in capsaicin-induced dermal blood flow.13, 14 Recent studies, including a meta-analysis of 19 randomized controlled trials and the analysis of the US FDA Adverse Event Reporting System (FAERS) database, aimed to evaluate the safety and tolerability of monoclonal antibodies and gepants targeting the CGRP pathway.15, 16 While these RCTs did not reveal differences in serious adverse events between active treatments and placebo, they were limited by their short-term nature of 3 to 6 months, their focus on solely SAEs, or lack of investigation into laboratory or ECG findings.16 Furthermore, the FAERS database, while reporting also low frequency
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