Which calcitonin gene-related peptide (CGRP) inhibitors reduce CGRP levels?

Which CGRP Inhibitors Reduce CGRP Levels

Only the small molecule CGRP receptor antagonists (gepants)—atogepant, rimegepant, and ubrogepant—do NOT reduce CGRP levels; they block CGRP receptors instead. In contrast, the CGRP monoclonal antibodies (fremanezumab, galcanezumab, and eptinezumab) bind to and neutralize CGRP itself, thereby reducing available CGRP levels, while erenumab blocks the CGRP receptor without reducing CGRP levels. 1

Mechanism-Based Classification

CGRP Ligand-Binding Antibodies (Reduce CGRP Levels)

• Fremanezumab, galcanezumab, and eptinezumab are humanized monoclonal antibodies that directly bind to the CGRP peptide itself, preventing it from activating its receptor and effectively reducing the amount of free, bioavailable CGRP 2, 1
• Fremanezumab has been shown in preclinical studies to reduce CGRP release from trigeminal tissues and decrease the fraction of trigeminal ganglion neurons immunoreactive to CGRP 3, 4
• These three agents received "strong for" recommendations from the VA/DoD for prevention of episodic or chronic migraine based on their ability to reduce mean monthly migraine days through CGRP neutralization 2

CGRP Receptor Antagonists (Do NOT Reduce CGRP Levels)

• Erenumab is a monoclonal antibody that binds to the CGRP receptor (specifically the calcitonin receptor-like receptor/RAMP1 complex) rather than to CGRP itself, so it does not reduce CGRP levels 2, 5, 1
• Erenumab also received a "strong for" recommendation but works by blocking receptor activation, not by reducing the peptide 2
• Post-marketing surveillance has identified that erenumab may increase risk for development or worsening of hypertension, which has been added to prescribing information 2, 6

Small Molecule CGRP Receptor Antagonists (Do NOT Reduce CGRP Levels)

• Atogepant and rimegepant (gepants) are oral CGRP receptor antagonists that competitively block the CGRP receptor without affecting CGRP levels 2, 7
• Atogepant is described as "a calcitonin gene-related peptide (CGRP) receptor antagonist" in its FDA labeling, confirming it blocks receptors rather than reducing CGRP 7
• The American College of Physicians gives atogepant a "weak for" recommendation and rimegepant a "neither for nor against" recommendation for episodic migraine prevention 2, 8

Clinical Implications

Why This Distinction Matters

• The theoretical concern about blocking CGRP signaling relates to CGRP's vasodilatory and cardioprotective effects, but this has not translated into significant clinical cardiovascular complications across either mechanism 6, 9
• Fremanezumab may be considered safer for patients with cardiovascular concerns as it has not been associated with hypertension development, unlike erenumab 6
• The redundancy of peptides within the CGRP family and potential compensation by a second CGRP receptor may explain the favorable safety profile of all CGRP-targeting drugs regardless of mechanism 9

Practical Considerations

• All CGRP-targeting therapies—whether they reduce CGRP levels or block receptors—show similar efficacy in reducing monthly migraine days by approximately 0.8-2.3 days compared to placebo 2
• No direct comparative evidence demonstrates superiority of CGRP ligand-binding antibodies over receptor antagonists in terms of clinical outcomes 6
• The choice between agents should be guided by route of administration preference (oral gepants vs. injectable monoclonal antibodies), cost considerations, and specific safety concerns like hypertension risk with erenumab 2, 6