Comparison of Injectable CGRP Inhibitors for Migraine Prevention
All four injectable CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) demonstrate comparable efficacy in reducing monthly migraine days, with no evidence that one is superior to another, though they differ mechanistically and in specific safety considerations—particularly erenumab's unique association with hypertension risk. 1, 2
Mechanism of Action Differences
The injectable CGRP inhibitors fall into two mechanistic categories:
CGRP ligand-binding antibodies: Fremanezumab, galcanezumab, and eptinezumab directly bind to the CGRP peptide itself, preventing it from activating its receptor and reducing free, bioavailable CGRP 1
CGRP receptor antagonist: Erenumab uniquely binds to the CGRP receptor rather than the peptide, blocking receptor activation without affecting CGRP levels 1, 3
This mechanistic distinction has clinical implications, particularly regarding cardiovascular safety profiles discussed below.
Efficacy Comparison
Overall Effectiveness
No significant differences exist between the three main antibodies in reducing mean monthly headache days or disability scores in head-to-head real-world comparisons 2
All CGRP-mAbs reduce migraine frequency by approximately 0.76-0.80 fewer days per month compared to traditional preventives like valproate and topiramate 4, 1
Responder rates (≥50% reduction in monthly headache days) reach approximately 80% at 3 months and 78.8% at 6 months across all three agents 5
Specific Efficacy Data by Agent
Galcanezumab: Mean reduction of 12.0 monthly migraine days from baseline (p < 0.001) 2
Fremanezumab: Mean reduction of 12.3 monthly migraine days from baseline (p < 0.001) 2
Erenumab: Mean reduction of 10.8 monthly migraine days from baseline (p < 0.001) 2
Medication Overuse Headache
Galcanezumab and erenumab demonstrate more rapid effect in medication overuse headache patients after 3 months compared to fremanezumab (-10.8 and -11.1 vs. -4.0 days; p = 0.029) 2
All three agents effectively reduce medication overuse without requiring drug withdrawal, with 80% achieving ≥50% reduction in both headache days and analgesic intake 5
Safety and Tolerability Profile
Common Adverse Events
Mild adverse events include injection-site pain, upper respiratory tract infection, nausea, constipation, and fatigue across all agents 1, 6
Discontinuation rates due to adverse events are generally low, with CGRP-mAbs showing 162 fewer discontinuations per 1000 treated people compared to topiramate 1
Critical Safety Distinction: Erenumab and Hypertension
Erenumab carries unique risk for development or worsening of hypertension in post-marketing surveillance, which has not been observed with the CGRP ligand-binding antibodies 1, 3
Fremanezumab may be considered the safer cardiovascular option for patients with hypertension concerns, as it has not been associated with blood pressure changes and theoretical vasoconstriction concerns have not materialized clinically 1
Administration Characteristics
Dosing Schedules
Monthly subcutaneous injections: Standard for erenumab and galcanezumab 4
Monthly or quarterly options: Fremanezumab offers flexibility with both dosing intervals 4
Quarterly intravenous infusion: Eptinezumab requires outpatient infusion every 3 months, adding associated care costs 4
Patient Preference Considerations
Patients generally prefer oral treatments over injectables with moderate-certainty evidence, though route of administration is as important as effect on migraine frequency 4, 1
The injectable route may limit adherence compared to oral alternatives, though simplified dosing schedules (monthly or less frequent) improve compliance 4
Cost Analysis
Pricing Structure
Annual costs for all injectable CGRP-mAbs range from $7,071 to $22,790, substantially higher than traditional preventives 4, 1
Traditional first-line agents cost dramatically less: metoprolol ($123), propranolol ($393), valproate ($274), venlafaxine ($378), and amitriptyline ($67) annually 4
Value Assessment
Erenumab and fremanezumab may have intermediate value compared to no preventive treatment in patients with prior treatment failures (low-certainty evidence) 4
Cost considerations heavily influence guideline recommendations, with CGRP-mAbs relegated to second or third-line status primarily due to expense rather than efficacy or safety concerns 4
Clinical Positioning in Treatment Algorithms
Current Guideline Recommendations
The 2025 American College of Physicians guideline positions CGRP-mAbs as second-line therapy, recommending initial trials of β-blockers (metoprolol or propranolol), valproate, venlafaxine, or amitriptyline before CGRP-mAbs, driven primarily by cost differences rather than efficacy 4
The 2021 Nature Reviews Neurology guideline classifies CGRP-mAbs as third-line medications in Europe, with regulatory restrictions limiting use to patients in whom other preventives have failed or are contraindicated 4
Contrasting Position: American Headache Society
The 2024 American Headache Society position statement argues CGRP-targeting therapies should be considered first-line options without requiring prior failure of other preventive classes, based on superior evidence for efficacy, tolerability, and safety compared to traditional preventives 7
This represents a significant divergence in expert opinion, with the American Headache Society prioritizing the strength of evidence and migraine-specific mechanism over cost considerations 7
Assessment Timeline
Efficacy should be assessed after 3-6 months for CGRP monoclonal antibodies, as therapeutic benefits may not be immediately apparent 4
Treatment can be paused after 6-12 months of success to determine if preventive therapy can be discontinued, minimizing unnecessary drug exposure 4
Key Clinical Pitfalls
Do not assume failure of one CGRP-mAb predicts failure of another, as individual patient responses may vary despite similar class efficacy 4
Do not overlook erenumab's hypertension risk in patients with cardiovascular concerns; fremanezumab may be preferable in this population 1
Do not prematurely discontinue therapy before the 3-6 month assessment window, as efficacy develops gradually 4
Do not ignore medication overuse headache as a barrier to preventive efficacy; CGRP-mAbs effectively address this without requiring withdrawal 5