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.
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.
This is the sort of thing the wiki should carry and currently does not.
Post #28 describes the usual case. This is about the unusual one.
Triple agonism is a question about a distribution, not about a value, and treating it as a value is what produces the confident wrong answers.
I would call the community position on triple agonism likely rather than established, and I would be comfortable defending that hedge.
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 that ought to be settled and apparently is not.
Appreciated. The plain phrasing does more work here than a longer post would.
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.
Two sources, same conclusion, and I could not rule out that one copied the other.
Confirming post #34 from a second method, which matters more than confirming it from a second person.
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.
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.
This follows post #38 rather than contradicting 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.
I would not lead a decision with this, but I would not ignore it either.
Where I part company with post #38, and it is a narrow parting.
A request rather than an answer: could whoever has the primary source for triple agonism post it? I have seen the claim three times this month and each version had lost a qualifier.
Post #41 is the version of this I will quote in future. One addition.
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 am not the right person to answer the follow-up to this.
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.
That is the version I use. It may not be the version that is correct.
Source for the triple agonism figure, since it was asked for. It is in the discussion rather than the abstract, which is why the version circulating is stronger than the paper is.
Reading the surrounding paragraph is worth the two minutes. The authors are more careful than their summarisers.
Post #45 describes the usual case. This is about the unusual one.
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.
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.
The answer changed when I changed how I was measuring, which was informative.
On triple agonism, the part that usually goes wrong is that the question is asked as though it has one answer. It has a range, and the width of the range is the interesting bit.
If you can post the two or three numbers you are working from, several people here will check the arithmetic rather than argue about the conclusion.
Triple agonism has been discussed here with more heat than it deserves, mostly because two definitions have been in play the whole time.
Taking post #48 at face value and following it one step further.
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.
Post #51 and I disagree about the size of the effect, not about the direction.
One more thing on triple agonism that took me far too long to see: the two figures people quote are not measuring the same quantity. Once you notice that, the apparent contradiction disappears.
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.
The general answer and the answer for your case may diverge here.
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 have no interest in any supplier named above.
Adding a reference point for triple agonism. Mine is a single case, collected without controls, and I am posting the method alongside it so it can be discounted appropriately.
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 separated what I observed from what I concluded, which does not always happen.
I will take the caveat as seriously as the claim, which is the point of putting it there.
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.
I would want to see it done twice before believing it once.