Amylin co-agonism: CagriSema REDEFINE results and implications

Dr.KarenChen said:

Amylin analogues act on a different satiety circuit — area postrema and dorsal raphe — rather than the arcuate pathway GLP-1 agonists use.

Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were relying on physical fullness feel the effect fade while the appetite effect is still working.

If somebody has the primary source to hand I would rather cite it than paraphrase it.

Dr.KarenChen said:

Amylin analogues act on a different satiety circuit — area postrema and dorsal raphe — rather than the arcuate pathway GLP-1 agonists use.

This is where I part company with the consensus forming above. Two drugs, two side-effect profiles, one price. The efficiency argument only works if the tolerability really is better than dose-escalating a single agent, and I have not seen that demonstrated head to head.

Happy to go further on any of that.

Taking the question as asked, rather than the general version of it. The mechanism is more central than most summaries suggest. Receptor agonism in the arcuate nucleus activates POMC neurons and inhibits AgRP/NPY signalling, and the downstream MC4R pathway is the same one disrupted in monogenic obesity — convergent genetic evidence that the target is the right one. Peripherally there is glucose-dependent insulin secretion, glucagon suppression and delayed gastric emptying, but the gastric component largely adapts over months while the central effect persists, which is why the durable effect is appetite rather than fullness.

pete_manc_UK said:

Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were…

Same pattern here, and in the same order. Posting only so the count is not one.