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At Stake: The Possible Long-Term Side Effects of CGRP Antagonists

As AHS holds its annual meeting, very specific questions are arising about the use of CGRPs in migraine prevention. The author poses key considerations and sample cases for prescribing this new class of monoclonal antibodies.
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A commentary for clinicians involved in the treatment of chronic headache and migraine

The novel class of monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) are a valuable addition to our preventives for migraine. However, there are significant conceivable long-term adverse effects that need to be considered as these new products gain approval and enter the market. We will have a better feel for the true risk in 10 years. For each patient, we have to decide whether the benefits outweigh the possible risks. With luck, it may come to pass that the biologics targeting CGRP carry very few long-term risks. Certainly, these have been safe compounds for the short-term. Three-year safety data has recently been presented (see also “A New Frontier in Migraine Management: Inside CGRP Inhibitors & Migraine Prevention”). Herein, I  discuss some of the possible long-term issues with these long-awaiting medications.

The following are presented as a series of questions related to core systems (eg, cardiovascular, central nervous, gastrointestinal, reproductive, and more) that need to be addressed before CGRP antagonists are used widely. Most of these questions do not have answers at this time. Much of the CGRP research to date has been conducted in animal models, which, as we know, does not always correlate with effects in humans. Hopefully, over time, the community will be able to determine which of our patients may be at increased risk for long-term adverse effects. 


Cardiovascular and Pulmonary System

1. CGRP plays an important role in resisting the onset of hypertension (HTN); how relevant is this when prescribing to young patients, particularly those at higher risk for HTN? How much does vascular dilation redundancy matter (with other vasodilator mediators, such as PGs and NO, compensating for the loss of CGRP)?

2. With the onset of HTN, there is a compensatory release of CGRP: how relevant is this, and what effects do the antagonists have? In the face of HTN, CGRP release may become attenuated over time. There have been conflicting studies as to the amount of plasma CGRP present in those with HTN. To date, the antagonists have not appeared to affect blood pressure. Will CGRP antagonists be studied in those with HTN? Will these be evaluated in the face of poorly controlled HTN? Deletion of RAMP 1, for example, has been associated with cytokine production (proinflammatory) and HTN. Is this clinically relevant?

3. CGRP may delay or protect against the development of cardiovascular disease. For which patients is this relevant? CGRP is the most potent of all the vasodilators, so how might this influence prescribing for higher risk patients?

4. The effect of CGRP on the expression of endothelial nitric oxide synthase (eNOS): depleting CGRP may lead to enhanced loss of eNOS; what is the clinical relevance?

5. CGRP depletion may produce oxidative stress in the aorta; how clinically relevant is this?

6. If CGRP is knocked out, and the vasodilator effects are diminished, do other compounds (eg, nitrous oxide, substance P, prostaglandins) help to compensate (primarily at the resistance vessel level)? One study indicated that both substance P and CGRP had to be blocked for there to be a loss of vasodilatation.

7. There is polymorphism with the CALC 1 gene (this gene encodes CGRP and calcitonin, linked to essential HTN); is this clinically relevant in light of mAb use?

8. Evidence from KO mice indicates that reduction of CGRP on the cardiovasvular system may become pathologically relevant primarily in conjunction with compromised vasculature. Infusions of CGRP improve the circulation in the presence of heart disease. We need angiographic (and other) studies in patients with cardiovascular disease (CAD), ideally prior to and after treatment with the antagonist. Are further studies planned?

9. Could smaller cardiac or cerebral infarcts become more dangerous resulting from the protective effects of CGRP being blocked? CGRP protects against ischemia, cell death, and vascular inflammation in various organs (heart, brain, GI, kidney). When CGRP is seriously depleted, there is an increased susceptibility to injury via ischemia. How clinically relevant is blocking CGRP? This will need more research.

10. CGRP plays a role in heart failure. Infusion of CGRP improves circulation in the face of heart disease. Regarding microvascular growth, CGRP is an angiogenic facilitator. Should patients at high risk for failure, or with actual heart failure, not be prescribed these medications?

11. There is evidence that CGRP helps to protect the heart, and this effect is lessened in the presence of diabetes. For patients with both diabetes and CAD, should CGRP inhibitors be withheld?

12. CGRP levels decline with age (although there may be a bimodal effect) and CGRP helps to protect the myocardium; should CGRP inhibitors be withheld in older patients, particularly for those with heart disease?

13. Do the Amylin 1 receptors (or other calcitonin-group receptors) help to “cover” for the loss of beneficial effects, particularly vasodilatory, after the blocking of CGRP?

14. With regards to the cardiovascular system, is there a difference between antagonizing the ligand of CGRP, and blocking the receptor?

15. Regarding advanced CAD, how important is CGRP as a vasodilator? CGRP levels are increased during myocardial infarction. Could antagonizing CGRP lead to a more severe infarct? There was an erenumab-aooe (Aimovig, Amgen/Novartis - the first FDA approved CGRP mAb for migraine prevention) study of 90 patients with stable angina, who were given 140 mg IV as a one-time dose. There were no problems found in the 3 months post-infusion. Are further studies planned?

16. How clinically relevant is CGRP in the cerebral vasculature? CGRP is an inhibitor of platelet aggregation, through cAMP activity. Inhibiting CGRP could lead to embolic cardiac or cerebral events.

17. Is CGRP a vasodilator in both smaller and larger cerebral arteries?

18. CGRP and pulmonary HTN: CGRP is abundant in the lung; for high- risk individuals, would blocking CGRP increase the chance of developing pulmonary HTN? There is evidence that CGRP is beneficial in those with pulmonary HTN. Should patients with pulmonary HTN be excluded from receiving CGRP antagonists?

Central Nervous System (within the Blood-Brain Barrier)

1. There is slight penetration of these large-molecule mAbs into the CNS, from 0.1% to 1%; is this clinically relevant as to the mechanism of action of the mAbs? Probably not, but certainly it is possible.

2. Botox undergoes transcytosis (tracking along the axon from the trigeminal ganglion, into the brainstem): does this also occur with mAbs? Most likely it does not, but it may happen to a small degree. Radioisotope studies to identify elements of the mAb in the brainstem would be helpful.

Last updated on: July 18, 2018
Continue Reading:
A New Frontier in Migraine Management: Inside CGRP Inhibitors & Migraine Prevention