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 ask the first time.
The earlier thread answered what I asked. What I should have asked is below, and I think it is the one that matters.
Why this subcategory is more cautious than elsewhere: retatrutide is investigational, phase 3 is ongoing, and the heart-rate signal in phase 2 is not negligible. Caution is proportionate to the evidence status.
I would be interested in a counterexample if anyone has one.
TRIUMPH is phase 3 and it is ongoing. No phase 3 results exist. Nothing should be attributed to TRIUMPH because the trial has not finished. When it does, this page will update.
That has held every time I have looked, which is not the same as always.
How to read phase 2 without treating it as phase 3: phase 2 establishes that a dose range produces an effect and is tolerable enough to justify large trials. It does not establish safety, durability, or whether real humans differ from the selected population.
The honest answer is that it depends, and here is what it depends on.
The phase 2 obesity data is genuinely striking and it is phase 2 data. Sample sizes at that stage characterise a dose-response relationship; they do not characterise a safety profile, and treating them as though they did is the error to avoid here.
Take the reasoning and check the arithmetic; I do not always get it right.
Narrowing post #7, because the general version has more than one answer.
The evidence status here should be stated in the first line of any post about it rather than the last. Everything is phase 2 or earlier, and a reader arriving from a search will not know that unless somebody says so.
That holds under the stated conditions and I have stated them.
Mass and identity: a report on retatrutide should state the mass detected by LC-MS, not assume a theoretical mass. The theoretical mass is not published in peer-reviewed literature for retatrutide at present.
A single observation, in a thread that deserves better than single observations.
Confirming post #7 from a second method, which matters more than confirming it from a second person.
Retatrutide is investigational. Material obtained outside a clinical trial is research-use-only by definition, is not approved for human use, and carries no assurance about its identity or content beyond whatever independent testing you commission yourself.
I would be glad to be shown a cleaner way of putting this.
Anyone deciding on the basis of what is published should know that what is published is a phase 2 programme and some pharmacokinetics. That is a genuinely early evidence base and this page will say so until it changes.
Coming back to post #10, because the follow-up matters more than the original answer.
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.
The mechanism is plausible, which is not the same as established.
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.
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.
Discontinuation for adverse effects in phase 2 was not negligible at the higher doses. That figure belongs next to the efficacy figure whenever the efficacy figure is quoted.
Picking up post #16: that is the part I would want checked first.
A theoretical mass for retatrutide is not published in the peer-reviewed literature in a form worth quoting. A report should state the mass observed on the instrument rather than assert agreement with a figure nobody can check.
That holds for the case as described. Change the assumptions and it may not.
On post #14 — agreed on the reasoning, with one qualification.
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 the version I use. It may not be the version that is correct.
No phase 3 results exist for retatrutide. Anything attributed to a completed phase 3 trial of this compound is either a misreading or an invention, and the honest answer to most questions here is that the data is not in yet.
I would put the burden of proof on the interesting explanation, not the dull one.
What we do not know about retatrutide, listed explicitly: long-term safety, real-world response rates, the dose response in diverse populations, whether the heart-rate signal persists or attenuates, durability of effect on withdrawal, efficacy in comorbidities beyond obesity.
Same experience here, different supplier, so it is at least not unique to one of them.
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.
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.
Not the whole picture, but the part of it I can speak to.
Post #23 is the version of this I will quote in future. One addition.
Dose-response in the phase 2 obesity work was clear across the studied range, with no obvious plateau within it. Extrapolating beyond the highest studied dose from that is exactly the reasoning trials are designed to prevent.
That matches what I was told, which is not the same as knowing it.
| Topic | Participants | Replies | Views | Activity |
|---|---|---|---|---|
|
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…
|
+43 | 47 | 19k | 2d |
|
Triple agonism: additive, synergistic, or neither?
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…
|
+71 | 80 | 38k | 11mo |
|
Revisiting: Hepatic effects of glucagon receptor agonism: the mechanistic worry
Revisiting: Hepatic effects of glucagon receptor agonism: the mechanistic worry Writing it up because I had to work it out twice and would rather nobody else did. A methods question rather than a substantive…
|
+10 | 14 | 8.4k | 16h |
|
The retatrutide phase 2 obesity paper, read closely
Posting this under the heading it deserves: The retatrutide phase 2 obesity paper, read closely Everything below is what sits behind that. Retatrutide phase 2 obesity paper, from the point of view of someone…
|
2 | 65k | 10mo | |
|
Retatrutide's phase 2 heart-rate signal and how to think about it
On the subject in the title: Retatrutide's phase 2 heart-rate signal and how to think about it Working notes rather than a conclusion. Putting the numbers in the first post, because a question about a…
|
+19 | 23 | 20k | 7mo |
| Topic | Participants | Replies | Views | Activity |
|---|---|---|---|---|
|
Criticising the method without criticising the authors
Criticising the method without criticising the authors Writing it up because I had to work it out twice and would rather nobody else did. I was wrong about criticising the method without criticising in a…
|
+55 | 61 | 60k | 15mo |
|
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…
|
+24 | 28 | 3.5k | 2d |
|
A preprint whose numbers changed substantially at publication — what changed since
On the subject in the title: A preprint whose numbers changed substantially at publication — what changed since Working notes rather than a conclusion. A preprint question rather than a question about the…
|
+3 | 7 | 125 | 8mo |
|
TB-500 and thymosin beta-4: the fragment versus the protein
TB-500 and thymosin beta-4: the fragment versus the protein Writing it up because I had to work it out twice and would rather nobody else did. TB-500 and thymosin beta-4: what I expected, what I found, and…
|
+107 | 118 | 22k | 11mo |
|
Journal club: STEP 8 and the fairness of the comparator dose — a second dataset
Posting this under the heading it deserves: Journal club: STEP 8 and the fairness of the comparator dose — a second dataset Everything below is what sits behind that. Posting a small dataset on STEP 8. It is…
|
+18 | 22 | 656 | 13h |