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.
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.
That reframing is the whole thing. The facts I already had.
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.
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.
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.
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.
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.
Saving this. It is the version I will quote when the question comes round again.
Read the full topic (81 posts)
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Why retatrutide discussion here is more cautious than elsewhere
Why retatrutide discussion here is more cautious than elsewhere I have a specific reason for asking rather than idle curiosity, and the context is below. A question about retatrutide discussion that I think…
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+7 | 12 | 7.7k | 2mo |
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How to read a phase 2 result without treating it as a phase 3 result — what changed since
Asking directly, because I could not find a straight answer: How to read a phase 2 result without treating it as a phase 3 result — what changed since Putting the numbers in the first post, because a question…
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+25 | 35 | 568 | 6mo |
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Follow-up: The retatrutide phase 2 obesity paper, read closely
The retatrutide phase 2 obesity paper, read closely — setting out what I have, and where I think it stops being reliable. A follow-up question about retatrutide phase 2 obesity paper that I did not know to…
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+19 | 23 | 16k | 2d |
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Why a glucagon receptor agonist in a weight-loss compound is not a contradiction
The question in the title: Why a glucagon receptor agonist in a weight-loss compound is not a contradiction I will give what I have already checked below so nobody repeats it. I would like to disagree…
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+43 | 47 | 19k | 2d |
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Hepatic effects of glucagon receptor agonism: the mechanistic worry
Posting this under the heading it deserves: Hepatic effects of glucagon receptor agonism: the mechanistic worry Everything below is what sits behind that. Something about hepatic effects of glucagon receptor…
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+51 | 56 | 700 | 22mo |
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What a confidence interval means, from scratch — the long version
The question in the title: What a confidence interval means, from scratch — the long version I will give what I have already checked below so nobody repeats it. Asking about confidence interval directly,…
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+16 | 20 | 2.3k | 8mo |
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Citing a preprint in a maintained document: our rule and its reasoning
On the subject in the title: Citing a preprint in a maintained document: our rule and its reasoning Working notes rather than a conclusion. A preprint question rather than a question about the finding in it.…
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2 | 467 | 4mo | |
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Glucagon receptor agonism in a weight-loss compound
On the subject in the title: Glucagon receptor agonism in a weight-loss compound Working notes rather than a conclusion. Glucagon receptor agonism: setting out the arithmetic in full, because I have had to do…
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2 | 5.1k | 20mo | |
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A pooled estimate that changed when one trial was added
A pooled estimate that changed when one trial was added — setting out what I have, and where I think it stops being reliable. I was wrong about pooled estimate in a thread last spring and I would like to…
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+24 | 28 | 3.5k | 2d |
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Journal club: SELECT, absolute risk, and how it was reported — a second dataset
On the subject in the title: Journal club: SELECT, absolute risk, and how it was reported — a second dataset Working notes rather than a conclusion. Posting a small dataset on SELECT. It is mine, it is…
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4 | 1.3k | 1mo |