Following the glucagon co-agonists mostly for the liver endpoints rather than the weight ones, which seems to be the opposite of how they get discussed here.
The bit I cannot resolve on my own 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.
Practical detail welcome, however dull — the duller the better.
This one has a reasonably settled answer, so here it is. Read four things before the headline number. The population, because trial populations are selected and supported in ways that real cohorts are not. The comparator, because "better than placebo" and "better than the current standard" are different claims and get reported identically. The primary endpoint as pre-registered, because a secondary endpoint promoted after the fact is a hypothesis rather than a finding. And the completion rate, because a large effect in the half of participants who finished is a different result from a large effect in everybody enrolled.
That is the short version; the long version is somebody else's post.
Dr.AddMedPHL said:Read four things before the headline number.
Agreed, and subgroup analyses deserve particular suspicion. With enough subgroups something is significant by chance, and pre-registered subgroups are a different animal from ones found afterwards.
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Shop Reference StandardsZaraB_AL said:Following the glucagon co-agonists mostly for the liver endpoints rather than the weight ones, which seems to be the opposite of how they get…
Second this.
Clinical perspective, offered as context rather than as advice.
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.