A reference post rather than a discussion. Corrections are the point; I would rather this be right than mine. It is about the glucagon co-agonists, and it is deliberately narrow — everything I am not confident about is marked as such.
What is actually established
The glucagon co-agonists — survodutide, mazdutide, ecnoglutide — are all chasing the same idea: add energy expenditure to appetite suppression. The liver signal is where they look strongest, because hepatic fatty-acid oxidation responds to glucagon directly rather than as a consequence of weight loss.
The condition it depends on
Worth remembering these are at different regulatory stages in different regions, and a phase 2 result in one jurisdiction is being quoted here as if it were a global standard of care.
What I am not sure about
The question I want answered is whether the liver signal is independent of weight loss or downstream of it, because that determines whether any of this is interesting for someone whose weight is already where they want it. I have searched first, so if this is covered somewhere point me at it and I will read it.
sarah.morrison said:The glucagon co-agonists — survodutide, mazdutide, ecnoglutide — are all chasing the same idea: add energy expenditure to appetite suppression.
Glucagon receptor pharmacology in triple agonists (retatrutide), relevant to the glucagon co-agonists: the glucagon component is the most controversial because glucagon traditionally raises blood glucose. So why include it in an anti-obesity drug?
Key insight: glucagon increases energy expenditure (thermogenesis), promotes hepatic lipid oxidation, and reduces appetite through distinct CNS mechanisms. The hyperglycemic effect is counterbalanced by the GLP-1 component's insulin secretagogue action.
Net result: more weight loss through increased expenditure (glucagon) + decreased intake (GLP-1/GIP), with neutral or improved glycemia. An elegant pharmacological balancing act[1].
[1] Day JW, et al. Nat Rev Drug Discov. 2022;21:37-54.
sarah.morrison said:The glucagon co-agonists — survodutide, mazdutide, ecnoglutide — are all chasing the same idea: add energy expenditure to appetite suppression.
This is where I part company with the consensus forming above. The counter-case has not been addressed. Somebody upthread described the situation that does not fit, and the thread moved on rather than engaging with it, which is the failure mode this board is supposed to avoid.
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Shop Reference StandardsShort answer first, then the reasoning. It is worth asking what the claim would look like if it were false. If nothing would look different, it is not a claim about the world and no amount of discussion will settle it.
Happy to go further on any of that.
FDA_TrackerJim said:Glucagon receptor pharmacology in triple agonists (retatrutide), relevant to the glucagon co-agonists: the glucagon component is the most…
Same pattern here, and in the same order. Nothing to add that would improve it.