Triple agonism: additive, synergistic, or neither? posts 61–81

Worth separating two things that post #59 runs together.

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.

That is what the documentation says. What happens in practice is usually close.

The reason triple agonism is hard to answer is that the obvious measurement and the relevant quantity are not the same thing, and substituting one for the other is silent.

Triple agonism: I would want to see the raw numbers rather than the summary before agreeing. Summaries lose exactly the information that would settle this.

Post #63 answers the question as asked. The question underneath it is different.

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.

Helpful, and short, which on this subject is harder than long.

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.

The confident version of this sentence would be wrong, so here is the hedged one.

Everything in post #63 holds. The case it does not cover is the one I have.

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.

Narrowing post #67, because the general version has more than one answer.

Practical experience of triple agonism, offered as one case with the conditions stated, not as a general finding. Conditions first, because they are what make it interpretable.

Reading this triple agonism thread as someone who came in with a fixed view: the third and seventh replies moved me and the confident ones did not.

Adding the measurement that post #67 says would settle 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.

The strongest argument against my own position on triple agonism, stated as well as I can state it, since nobody else has yet.

Worth separating two things that post #68 runs together.

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.

Worth saying I have only my own numbers here, and n is small.

Triple agonism would be much easier to settle if anyone reported the denominator. Almost nobody reports the denominator.