I read the opening post twice before replying, because I had assumed the opposite. 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. Take the…
The question in the title: Triple agonism: additive, synergistic, or neither? I will give what I have already checked below so nobody repeats it.
Asking about triple agonism on behalf of the question I keep seeing asked badly, including by me.
Framed properly it is answerable. Framed the usual way it is not, and that is most of why the previous threads went nowhere.
This follows the opening post rather than contradicting it.
Agreed on triple agonism, with one qualification that I think matters. The reasoning holds for the case as described. Change the starting assumption and it does not, and the starting assumption is the part nobody states.
I read the opening post twice before replying, because I had assumed the opposite.
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.
Take the reasoning and check the arithmetic; I do not always get it right.
On post #3 — agreed on the reasoning, with one qualification.
Taking triple agonism 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.
Picking up post #3: that is the part I would want checked first.
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.
That is what I would do. It may not be what is correct.
Triple agonism is well covered in the tag pages, and the older discussions are better than the recent ones because they were argued out properly. Worth twenty minutes before adding to this one.
Reading back through the triple agonism threads from last year, the same three questions come up every time and only one of them has ever been answered properly. That seems like a documentation gap rather than a knowledge gap.
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.
That is one dataset and I would not build a rule on it.
The failure mode on triple agonism is boring rather than dramatic. It is almost always the step everyone assumes was done correctly because it is too simple to get wrong.
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.
Small point, but it is the one that usually catches people.
Worth stating the null on triple agonism before we explain it: the observation may be nothing. That possibility deserves a sentence and usually does not get one.
That reframing is the whole thing. The facts I already had.
Narrowing post #12, because the general version has more than one answer.
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.
The bit of triple agonism that nobody enjoys is that the answer changes depending on what you are trying to decide with it. Say what the decision is and the thread will converge.
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.
I have kept the units in throughout, for the obvious reason.
Offering a way to settle triple agonism rather than another opinion about it. Two measurements, taken the same way, a fortnight apart. If the difference is within the noise, the question was not answerable at this precision.
Post #16 answers the question as asked. The question underneath it is different.
Reframing triple agonism slightly, because I think the disagreement is about the question rather than the answer. If the question is "does it happen", yes. If it is "how often", nobody here knows.
I read post #18 twice before replying, because I had assumed the opposite.
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.
Worth separating two things that post #19 runs together.
Speaking only to triple agonism as I have actually seen it, rather than as it is usually described: the effect is real, it is smaller than the thread suggests, and the variance between people is larger than the effect.
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.
Take it as a starting point and not as a specification.
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.
Post #23 answers the question as asked. The question underneath it is different.
I changed my mind about triple agonism after someone here asked me for the source and I could not produce one. That is worth saying out loud because it is the ordinary way it happens.
On post #23 — agreed on the reasoning, with one qualification.
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.
Reading rather than answering, but this is the post I would point somebody at.
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 seen it go both ways, which is why I hedge.
Building on post #28 rather than restating it.
A note on scope: what I am saying about triple agonism applies to the case in the first post and I would not extend it further without checking.