This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1 · go to the accepted answer.
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.
I have no financial interest in anything named in this thread and I want to say so before I comment on Triple agonism, because it is the sort of subject where it matters.
On post #89 — agreed on the reasoning, with one qualification.
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.
The answer changed when I changed how I was measuring, which was informative.
Coming back to post #93, because the follow-up matters more than the original answer.
Counterpoint on Triple agonism, offered without confidence: the same observation is consistent with a much duller explanation, and nobody has ruled the dull one out.
On Triple agonism I would separate what is worth knowing from what is worth acting on. The first list is long and the second is short, and conflating them is how threads get heated.
This follows post #97 rather than contradicting it.
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.
I would be interested in a counterexample if anyone has one.
This is the first time the answer has come with its own limits attached. Appreciated.
I think the Triple agonism question is answerable and has not been answered, which is a more optimistic position than most of this thread.
Worth separating two things that post #102 runs together.
Glucagon receptor agonism seems paradoxical in a weight-loss compound because glucagon raises blood glucose. The paradox resolves because glucagon agonism also increases energy expenditure and promotes hepatic fat oxidation, and the incretin components offset the glycaemic effect. In diabetes trials, HbA1c improved rather than worsened.
If anyone can point at the primary source I would be grateful.
This follows post #102 rather than contradicting it.
Triple agonism would be much easier to settle if anyone reported the denominator. Almost nobody reports the denominator.
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.
That is the shape of it. The detail is where I would expect to be corrected.
Post #105 and I disagree about the size of the effect, not about the direction.
Triple agonism has been discussed here with more heat than it deserves, mostly because two definitions have been in play the whole time.
Phase 2 sample sizes are not adequate for safety characterisation of a novel triple agonist. Phase 3 is where that question gets answered. Using phase 2 results to make claims about safety profile is using the trial for a purpose it was not designed for.
I had written a reply contradicting post #105 and deleted it. Here is what survived.
What would change my mind on Triple agonism is a second dataset collected by someone with no stake in the first. Until then I hold it loosely and I would rather say so than pretend to more.
Confirming post #108 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 have written this out at length because the short version keeps being misread.
If someone has run Triple agonism properly I would rather read that than my own reconstruction of it. Posting mine only because the thread has gone quiet.
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.
I looked this up rather than remembered it, which is the right order.
Two people in this thread mean different things by Triple agonism and are disagreeing about the definition while believing they are disagreeing about the facts. Worth pausing to define it.
Coming back to post #114, because the follow-up matters more than the original answer.
Practical answer on Triple agonism, since the theoretical one is upthread: do the simplest check first, write down the result, and only then decide whether the complicated explanation is needed. It usually is not.
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.
A qualification I should have led with rather than closed on.
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.
Building on post #116 rather than restating it.
Genuine question rather than a rhetorical one: has anyone here actually observed Triple agonism, as opposed to read about it? The thread is long and I cannot tell.
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.
The interesting part of this is the exception, and I do not understand the exception.