Second pass at: Triple agonism: additive, synergistic, or neither? posts 61–90

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.

Thank you for the correction. I would rather find out here than later.

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 a description of practice, not a recommendation of it.

The arithmetic in post #75 is right; the assumption feeding it is the part to check.

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 #75 put the caveat in the right place and I want to underline it.

Worth separating Triple agonism as a question about the compound from Triple agonism as a question about the documentation. They get answered by different people and only one of them is answerable here.

Where I have landed on Triple agonism, having got it wrong once in public: the direction is clear, the magnitude is not, and anyone quoting a precise magnitude has borrowed it from somewhere that did not measure it.

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 variance between people here is larger than the effect being discussed.

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.

Written in the hope of being told what I have missed.

Confirming post #80 from a second method, which matters more than confirming it from a second person.

The claim about Triple agonism upthread is stronger than its source supports. I have read the source. The source says "associated with" and the post says "causes".

My understanding of Triple agonism is a few years old and may have been superseded. If it has been, I would genuinely like to know rather than keep repeating it.

Reading rather than contributing, but this is the most useful thread I have found on it.

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.

That matches what I was told, which is not the same as knowing it.

Post #84 is the version of this I will quote in future. One addition.

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.

Where I part company with post #86, and it is a narrow parting.

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.

The arithmetic in post #88 is right; the assumption feeding it is the part to check.

What I would check first on Triple agonism is whether the thing being measured moved or whether the way of measuring it moved. Those look identical in a graph.

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.