CGRP and metabolism: another factor to consider when blocking CGRP?

We should not forget the potential off-target metabolic effects of CGRP inhibitors, say Christopher S Walker and Debbie L Hay of the School of Biological Sciences, The University of Auckland, New Zealand

The major concern when considering the possible off-target effects of blocking CGRP activity in migraine with small molecule antagonists or antibodies, appears to be possible cardiovascular effects.1 It is important to remember that CGRP has a long history and is reported to have pharmacological effects in numerous experimental paradigms, which extend beyond the cardiovascular system.2

A recent report by Liu et al highlights an element of CGRP biology that is worth discussing in the context of chronic CGRP blockade that would likely occur with the current suite of investigational drugs.3 The authors reported positive metabolic benefit of CGRP depletion, in the context of a mouse model that lacks CGRP: a CGRP knockout mouse.

Interestingly this study mirrors an earlier report published in 2010, which drew very similar conclusions.4 Both studies report that, when challenged with a high-fat diet, the CGRP knockout mice had lower body weight, adiposity and resistance to hepatic lipid accumulation. These are the only CGRP knockout studies reporting metabolic effects, but other work supports the conclusion that CGRP does have activity on the metabolic axis.

For example, there are studies showing a variety of metabolic effects, including that the CGRP antagonist CGRP8-37 affects metabolic health, that CGRP affects fat metabolism and that CGRP affects feeding behaviour.5-12 It is not clear which CGRP receptor(s) mediate these effects, nor if there is any metabolic effect of CGRP in humans. However, as clinical studies of CGRP blocking agents in migraine proceed, these other reported effects of the CGRP system should be kept in mind.

Professor Debbie Hay (University of Auckland, New Zealand)
Dr Christopher S Walker (University of Auckland, Auckland, New Zealand)

Contact: Debbie L Hay


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