What are the recommended CGRP (Calcitonin Gene-Related Peptide) inhibitors for migraine treatment?

CGRP Inhibitors for Migraine Treatment

Monoclonal Antibodies Targeting CGRP Peptide

The American College of Physicians and VA/DoD recommend fremanezumab, galcanezumab, and eptinezumab as humanized monoclonal antibodies that directly bind to the CGRP peptide itself for prevention of episodic or chronic migraine. 1

These agents work by neutralizing free CGRP, preventing it from activating its receptor and reducing bioavailable CGRP levels. 1 They are FDA-approved for preventive treatment of migraine in adults. 2

• Fremanezumab (Ajovy): Administered subcutaneously, typically monthly or quarterly, with demonstrated efficacy in reducing monthly migraine days by approximately 0.8-2.3 days compared to placebo 1
• Galcanezumab: Available in 120 mg and 240 mg doses, with network meta-analysis suggesting the 120 mg dose may be among the best clinical protocols after comprehensive assessment 3
• Eptinezumab: Intravenous administration, received strong recommendations from the American College of Physicians 1

Monoclonal Antibody Targeting CGRP Receptor

Erenumab (Aimovig) received a "strong for" recommendation but carries an important safety concern: it may increase risk for development or worsening of hypertension. 1, 4

• This agent works differently by blocking the CGRP receptor rather than neutralizing the peptide itself 1
• FDA-approved as a calcitonin gene-related peptide receptor antagonist for preventive treatment of migraine in adults 5
• Available in 70 mg and 140 mg doses, with the 140 mg dose showing superior efficacy in reducing average migraine days per month 3
• Post-marketing studies have confirmed hypertension risk, making fremanezumab a potentially safer option for patients with cardiovascular concerns 4

Oral CGRP Receptor Antagonists (Gepants)

For Prevention:

• Atogepant: Received a "weak for" recommendation from the American College of Physicians for episodic migraine prevention, taken daily as an oral CGRP receptor antagonist 1
• Rimegepant: Received a "neither for nor against" recommendation for episodic migraine prevention, though it has demonstrated efficacy in clinical trials 1

For Acute Treatment:

• Rimegepant, Ubrogepant, and Zavegepant: Oral CGRP receptor antagonists approved for acute episodic migraine treatment 1

Clinical Decision Algorithm

When selecting among CGRP inhibitors, prioritize based on the following hierarchy:

1. Route of administration preference: Patients generally prefer oral treatments over injectables (moderate-certainty evidence), making gepants attractive despite higher costs 1, 4

2. Cardiovascular risk: For patients with hypertension or cardiovascular concerns, avoid erenumab and consider fremanezumab, galcanezumab, or eptinezumab instead 4

3. Cost considerations: Annual costs range from $7,071 to $22,790, substantially higher than traditional preventive medications, with CGRP-mAbs potentially having intermediate value and gepants having low value compared to no preventive treatment 4

4. Treatment line positioning: CGRP monoclonal antibodies are recommended as third-line preventive treatments after first-line options (beta-blockers, valproate, venlafaxine, amitriptyline) and second-line options have been tried 6

Comparative Efficacy

No direct comparative evidence shows superiority of one CGRP-mAb over another in terms of efficacy. 4

• All CGRP-targeting therapies show similar efficacy in reducing monthly migraine days by approximately 0.8-2.3 days compared to placebo 1
• CGRP-mAbs may reduce migraine frequency by 0.80 fewer days per month compared to topiramate and 0.76 fewer days per month compared to valproate (low-certainty evidence) 1
• Network meta-analysis suggests fremanezumab 225 mg and galcanezumab 120 mg may be optimal protocols after comprehensive assessment 3
• About 27.6-61.4% of chronic migraine patients experience a 50% reduction in monthly migraine days with anti-CGRP mAbs 7

Safety Profile and Common Pitfalls

Adverse event profiles are generally mild across CGRP antagonists, with most common side effects including injection-site pain and upper respiratory tract infection. 4

• Discontinuation rates due to adverse events are significantly lower with CGRP-mAbs (162 fewer events per 1000 treated people) compared to topiramate (moderate-certainty evidence) 4
• Critical pitfall: Erenumab's hypertension risk requires blood pressure monitoring, particularly in patients with pre-existing cardiovascular disease 4
• Switching between anti-CGRP mAbs may be viable for patients with ineffectiveness, with modest improvements observed in real-world data, though switching due to side effects shows less consistent benefit 8
• Treatment efficacy should be assessed after 3-6 months of use for CGRP monoclonal antibodies 6
• Obesity appears to be the main negative predictor of response to anti-CGRP mAbs 7