Whether triple agonism is additive or synergistic is an open question and the published work does not answer it. A phase 2 trial without a dual-agonist comparator arm cannot distinguish the two. The claim is narrower than it sounds, and deliberately so.
Posting this under the heading it deserves: Hepatic effects of glucagon receptor agonism: the mechanistic worry Everything below is what sits behind that.
Something about hepatic effects of glucagon receptor does not reconcile and I would like a second pair of eyes before I decide which half is wrong.
Two sources, both reputable, giving figures that cannot both be right unless they are measuring different quantities. My suspicion is that they are, and I cannot see how.
Triple agonism at GLP-1, GIP and glucagon receptors is the defining feature and the glucagon limb is the one people find counter-intuitive. It raises energy expenditure and promotes hepatic fat oxidation, and the incretin limbs offset the glycaemic consequence.
Happy to be corrected if someone holds better data than mine.
Heart rate increased in a dose-dependent way in the phase 2 work. That is not a footnote — it is one of the specific things phase 3 exists to characterise, and it is why this subcategory is written more cautiously than the others.
Adding it in case it saves somebody the afternoon it cost me.
Everything in post #2 holds. The case it does not cover is the one I have.
I would put moderate confidence on the mainstream reading of hepatic effects of glucagon receptor and no more. That is not scepticism for its own sake; it is where the sourcing actually stops.
Post #4 is the version of this I will quote in future. One addition.
What I would want before treating hepatic effects of glucagon receptor as settled: the method, the sample, and whether anyone tried to find the opposite result. Two of the three are usually missing.
Nausea and vomiting were dose-related in the phase 2 work, as they are throughout this class. What is not established is whether the tolerability profile differs from the dual agonists at equipotent effect, because equipotence has not been established either.
This is the sort of exchange that makes the archive worth searching.
Whether triple agonism is additive or synergistic is an open question and the published work does not answer it. A phase 2 trial without a dual-agonist comparator arm cannot distinguish the two.
The claim is narrower than it sounds, and deliberately so.
This follows post #8 rather than contradicting it.
Taking hepatic effects of glucagon receptor seriously for a moment rather than deflecting: the honest position is that the community has observations and no controlled comparison, and those two things support very different sentences.
Worth separating two things that post #6 runs together.
Marking my uncertainty on hepatic effects of glucagon receptor explicitly. I am confident about the direction, much less confident about the size, and not confident at all that it generalises past the case in the first post.
Retatrutide is investigational. Anything obtained outside a trial is by definition research-use-only material with no human-use authorisation. This site will state that plainly rather than winking at it.
Not a strong opinion, just a consistent one.
I read post #9 twice before replying, because I had assumed the opposite.
An observation about hepatic effects of glucagon receptor that I cannot explain and am posting anyway, on the principle that unexplained observations are more useful public than private.
Heart rate increased in a dose-dependent way in the phase 2 work. That is not a footnote — it is one of the specific things phase 3 exists to characterise, and it is why this subcategory is written more cautiously than the others.
I have written this out at length because the short version keeps being misread.
Glycaemic effects improved rather than worsened in the diabetes work despite the glucagon component, which is the observation that resolves the apparent paradox. It is worth understanding that mechanism before repeating either half of it.
Written quickly, so the reasoning may be tighter than the wording.
Hepatic effects: glucagon receptor agonism promotes hepatic fat oxidation, which is mechanistically plausible for benefit in metabolic liver disease. Whether that translates to improved clinical outcomes is being tested in phase 2 work.
Noting that the question and the thing people usually mean by it are different.
Narrowing post #16, because the general version has more than one answer.
Two sentences on hepatic effects of glucagon receptor and then I will stop, because the rest is speculation and the thread is better without mine.
What is documented is narrow. What is inferred from it is broad. The gap between them is where every argument here lives.
Post #18 put the caveat in the right place and I want to underline it.
Second-hand on hepatic effects of glucagon receptor, so weight it accordingly — someone whose method I trust told me this and I have not verified it myself.
Building on post #18 rather than restating it.
Nausea and vomiting were dose-related in the phase 2 work, as they are throughout this class. What is not established is whether the tolerability profile differs from the dual agonists at equipotent effect, because equipotence has not been established either.
Trying to state the hepatic effects of glucagon receptor position in a way that someone who disagrees would recognise as fair, because I do not think the version in this thread passes that test.
Post #21 describes the usual case. This is about the unusual one.
Hepatic effects of glucagon receptor sits at the boundary between what this community can usefully discuss and what it cannot, and I think it falls on the discussable side, narrowly.
Confirming post #22 from a second method, which matters more than confirming it from a second person.
Retatrutide is investigational. Anything obtained outside a trial is by definition research-use-only material with no human-use authorisation. This site will state that plainly rather than winking at it.
I would want to see it done twice before believing it once.
Heart rate increased in a dose-dependent way in the phase 2 work. That is not a footnote — it is one of the specific things phase 3 exists to characterise, and it is why this subcategory is written more cautiously than the others.
This is the sort of thing the wiki should carry and currently does not.
Post #26 is right about the mechanism and I think understates the practical bit.
Triple agonism: is the effect additive, synergistic, or neither? A phase 2 comparison of tirzepatide (dual) to retatrutide (triple) would answer that question. The published data does not include such a direct comparison.
Narrowing post #26, because the general version has more than one answer.
I think the hepatic effects of glucagon receptor question is answerable and has not been answered, which is a more optimistic position than most of this thread.
The hepatic-steatosis rationale follows directly from glucagon receptor agonism promoting fat oxidation in the liver. Mechanistic plausibility in this field has a poor record of predicting clinical outcomes, which is why the trials matter more than the mechanism.
Two sources, same conclusion, and I could not rule out that one copied the other.