Writing this once so I can stop repeating it across threads. It is about the glucagon co-agonists, and it is deliberately narrow — everything I am not confident about is marked as such.
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.
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 after 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. Tell me what I have not thought of.
gary_naperville said:The glucagon co-agonists — survodutide, mazdutide, ecnoglutide — are all chasing the same idea: add energy expenditure to appetite suppression.
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.
gary_naperville 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].
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Browse GL BiochemThis one has a reasonably settled answer, so here it is. The pharmacokinetics explain nearly every practical question asked here. Albumin binding above 99% slows clearance enough to make weekly dosing possible; a terminal half-life near a week means four to five weeks to steady state and therefore a four-week titration interval; subcutaneous bioavailability around 89% means injection site barely matters. Those three facts answer most timing questions before they are asked.
PurityPaulOR 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…
Can confirm. Same sequence, different timescale.