Posting this because the summary going around does not say what the paper says, and the difference matters for how people here are using it.
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.
Where I think it is weakest: the population was selected and supported in ways a real cohort is not, so I would read the effect size as a ceiling rather than an expectation.
So the question, as narrowly as I can put it: 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. Not looking for reassurance. Looking for the part I have got wrong.
Figures above are from the primary publication rather than the press summary. If a number here disagrees with one you have, post yours and we will work out which of us is reading a secondary source.
stefan_berlin 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.
stefan_berlin said:The glucagon co-agonists — survodutide, mazdutide, ecnoglutide — are all chasing the same idea: add energy expenditure to appetite suppression.
I do not accept the framing. The question has been narrowed to the version that has a tidy answer, and the part that was dropped is the part the OP actually asked about.
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Shop Reference StandardsAnswering the narrow version, because the broad one does not have a single answer. There is a difference between no evidence and evidence of no effect, and this subject is one where the two get swapped freely in both directions.
Happy to go further on any of that.
JennaRN said:Glucagon receptor pharmacology in triple agonists (retatrutide), relevant to the glucagon co-agonists: the glucagon component is the most…
This is my experience too, for whatever a second data point is worth. Posting only so the count is not one.