Worth separating SURMOUNT-4 as a question about the compound from SURMOUNT-4 as a question about the documentation. They get answered by different people and only one of them is answerable here.
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Compounds · Tirzepatide · continued
SURMOUNT-4 and what withdrawal data does and does not tell an individual — one year on posts 61–90
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1 · go to the accepted answer.
c.okafor, post #59: Post #57 describes the usual case. This is about the unusual one. Research-use-only tirzepatide is not approved for human use and is not made to pharmaceutical standards. Anyone discussing it here is describing what they did, not recommending it. Same conclusion as the reply above, reached differently, which is mildly reassuring. Go to post
Small correction to my own earlier position on SURMOUNT-4. I had the units the wrong way round, which changes the conclusion by an order of magnitude and therefore changes it entirely.
Storage and stability: published data on licensed tirzepatide formulations exists and is worth reading directly rather than through summarised claims. Reconstituted preparations in different diluents have not been studied and extrapolation from the licensed formulation is the best you can do.
Someone will know this better than I do and I hope they say so.
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Worth separating two things that post #60 runs together.
The five maintenance doses in the tirzepatide programme give a genuine dose-response curve, which is unusual. Most trials in this space compare one or two doses against placebo and cannot say anything about the shape of the relationship.
I would want a second opinion before relying on that.
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p.krastev, post #41: Where I have landed on SURMOUNT-4, 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. Go to post
Post #62 answers the question as asked. The question underneath it is different.
On SURMOUNT-4: the maintained page in the documentation commons covers the general case with citations and a review date, which is more reliable than any reply here including this one.
j.palacios, post #56: Understood, and I withdraw the assumption I opened with. Go to post
Answering the SURMOUNT-4 question as asked, then the question I think is meant. As asked: yes, with the qualification below. As meant: it depends on how the first measurement was taken.
Comparisons between the tirzepatide and semaglutide programmes across trials rather than within one are weak. Different populations, different durations, different baseline characteristics; the only fair comparison is a head-to-head one.
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Fair, and the limits you put on it are the part I will remember.
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Where I part company with post #67, and it is a narrow parting.
Weight reduction figures from SURMOUNT-1 are frequently quoted without the trial's duration attached. A mean change at 72 weeks and a mean change at 40 weeks are different numbers and both circulate.
I have seen it go both ways, which is why I hedge.
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Post #71 and I disagree about the size of the effect, not about the direction.
Small methodological point on SURMOUNT-4: repeating a measurement is cheap and resolves most of what is being argued about here at no cost to anyone.
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j.delacroix, post #61: Worth separating SURMOUNT-4 as a question about the compound from SURMOUNT-4 as a question about the documentation. They get answered by different people and only one of them is answerable here. Go to post
Taking post #71 at face value and following it one step further.
Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn.
The reasoning is more useful than the number, which is why I have shown it.
SURMOUNT-1 reported weight reduction of a magnitude that was the largest for a pharmacological intervention at that time of publication. It also reported a clear dose response across three doses. The categorical thresholds (people reaching 10%, 15%, 20% loss) got the most attention but read less informatively than the mean weight change.
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The arithmetic in post #75 is right; the assumption feeding it is the part to check.
Heart rate rises modestly across this class, tirzepatide included. It is consistent, small, and worth knowing about rather than worth alarm — and it is one of the reasons the trials monitored it explicitly.
I checked the source rather than the summary, and they differ.
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Post #75 put the caveat in the right place and I want to underline it.
Research-use-only tirzepatide is not approved for human use and is not made to pharmaceutical standards. Anyone discussing it here is describing what they did, not recommending it.
Where I would look next, rather than where I would stop.
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p.trevino, post #72: Nausea profile: some people report tirzepatide as less nausea-prone than semaglutide, others report it as more. The trial reported gastrointestinal effects broadly comparable in character. Individual variation is the largest factor. Go to post
An honest declaration on SURMOUNT-4: I have a prior here and it is strong enough that you should weight what I say downward. Stating it rather than hiding it.
Coming back to post #75, because the follow-up matters more than the original answer.
SURMOUNT-4's randomised withdrawal design is the strongest available evidence about what happens on stopping. It says nothing about a lower maintenance dose, because the comparison was continue versus placebo rather than continue versus less.
The step people skip is the one I have spelled out.
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Post #79 is right about the mechanism and I think understates the practical bit.
Categorical response thresholds — the proportion reaching ten, fifteen or twenty per cent reduction — are more persuasive and less informative than the mean. They depend entirely on where the threshold was drawn.
That much is documented. The rest is how I have interpreted it.
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r.sobczak, post #45: That is a fair summary of where the discussion has got to. Go to post
One caution on SURMOUNT-4: everything above assumes the underlying documentation is what it claims to be. That assumption is doing real work and is rarely stated.
I have been on both sides of the SURMOUNT-4 argument in this category within eighteen months, which should tell you how strong the evidence for either side is.
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Taking post #80 at face value and following it one step further.
Research-use-only tirzepatide is not approved for human use and is not made to pharmaceutical standards. Anyone discussing it here is describing what they did, not recommending it.
Scoping that to what I have actually seen rather than what I have read.
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KAndersson, post #19: Post #17 put the caveat in the right place and I want to underline it. Reporting rather than recommending, on SURMOUNT-4. What happened is above. Whether it should have is a different question and not one I am qualified to answer. Go to post
The 2.5 mg starting dose is a tolerance step and not a therapeutic one. Judging efficacy at that dose is the single commonest reasoning error in this subcategory.
Second-hand, so weight it accordingly.
SURMOUNT-4 used a randomised withdrawal design: everyone titrated, then those on maintenance were randomised to continue or placebo. Continuation maintained effect; withdrawal was followed by regain. The finding is robust but it says nothing about a lower effective maintenance dose, because that was not studied.
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Answering the question post #82 raises rather than the one it answers.
The thing about SURMOUNT-4 that took me longest to accept is that a plausible mechanism is not evidence of an effect. It is a reason to look, not a result.
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SURMOUNT-4 is a good example of a question where the honest answer is boring and the interesting answers are unsupported. I would go with boring.
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eire_reader, post #29: Post #26 answers the question as asked. The question underneath it is different. Injection-site reactions were reported at a low but non-zero rate across the trials. The practical point is that a reaction at one site does not predict a reaction at the next, and rotating properly makes the question moot. Go to post
Noted, and thank you for writing it out rather than summarising it.
e.tamm, post #68: Adding thanks rather than a view. I do not have a view worth the space. Go to post
Adding the measurement that post #87 says would settle it.
Injection-site reactions were reported at a low but non-zero rate across the trials. The practical point is that a reaction at one site does not predict a reaction at the next, and rotating properly makes the question moot.
It is worth checking rather than assuming, which costs nothing.
h.nicolaides, post #88: Noted, and thank you for writing it out rather than summarising it. Go to post
Post #86 describes the usual case. This is about the unusual one.
On storage: published stability data covers the licensed formulation at its licensed concentration. A research preparation reconstituted at home in a different diluent at a different concentration is outside every one of those conditions.
This has been discussed before and I could not find the thread, so, again.