The published pharmacokinetics show dose proportionality across the studied range, which means dose arithmetic behaves the way you would naively expect. That is not true of every compound and it is worth knowing which ones it is true of. If it helps: the failure mode here is usually boring rather than dramatic.
Asking directly, because I could not find a straight answer: Does dual agonism explain the effect size, or is it dose?
A question about dual agonism that I think has a definite answer, unlike most of what I ask here.
I have the reasoning below and I am fairly confident about the direction. I am not confident about the size, and the size is what the decision turns on.
Worth separating two things that the opening post runs together.
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.
Take the reasoning and check the arithmetic; I do not always get it right.
Acknowledging rather than arguing. The reasoning holds as far as I can follow it.
The published pharmacokinetics show dose proportionality across the studied range, which means dose arithmetic behaves the way you would naively expect. That is not true of every compound and it is worth knowing which ones it is true of.
If it helps: the failure mode here is usually boring rather than dramatic.
Titration schedules for tirzepatide have more dose steps than semaglutide partly because the compound is more potent and partly because the clinical programme used a finer gradation. That does not mean you cannot escalate on a coarser schedule if that suits you — the published schedule is not a lower bound.
I looked this up rather than remembered it, which is the right order.
Building on post #6 rather than restating 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.
On dual agonism the community has more anecdote than the confidence in this thread implies, and I include my own contribution in that.
Post #11 answers the question as asked. The question underneath it is different.
Worth separating dual agonism as a question about the compound from dual agonism as a question about the documentation. They get answered by different people and only one of them is answerable here.
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.
I would treat that as a working assumption and revisit it.
Coming back to post #11, because the follow-up matters more than the original answer.
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.
Before the thread moves on from dual agonism — what is the sample size behind the claim? I am not being difficult; I have seen the same figure quoted from an n of four and from an n of four hundred.
SURPASS-2 compared tirzepatide with semaglutide 1.0 mg, the licensed diabetes dose at that time. It did not compare with semaglutide 2.4 mg, the highest approved dose. That is the central and legitimate criticism of the head-to-head evidence and it is worth remembering when people quote the trial.
I have written this out at length because the short version keeps being misread.
The apnoea-hypopnoea index used in SURMOUNT-OSA is an objective measurement rather than a symptom scale, which is why that trial carries more weight than its size suggests. Two parallel trials with and without positive airway pressure addressed the obvious confounder directly.
Written quickly, so the reasoning may be tighter than the wording.
Useful. I had the fact and not the reason, which turns out to be the important half.
Post #19 answers the question as asked. The question underneath it is different.
An observation about dual agonism that I cannot explain and am posting anyway, on the principle that unexplained observations are more useful public than private.
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.
I keep a log of this specifically because memory is unreliable about it.
Worth separating two things that post #22 runs together.
On the mechanism question specifically: the honest position is that GIP agonism plausibly contributes and that the trial design cannot separate its contribution from simply achieving greater receptor engagement overall.
Stating my assumptions rather than smuggling them in.
Narrowing post #24, because the general version has more than one answer.
Practical experience of dual agonism, offered as one case with the conditions stated, not as a general finding. Conditions first, because they are what make it interpretable.
Everything in post #22 holds. The case it does not cover is the one I have.
I would be cautious about generalising from the dual agonism example above. It is a good example. It is one example.
The GIP component: GIP receptor agonism is thought to amplify the GLP-1 effect on satiety and energy expenditure, but how much of tirzepatide's effect is that and how much is simply achieving higher receptor occupancy remains genuinely open. The mechanistic literature is active.
Dual agonism versus dose: how much of tirzepatide's effect is the GIP component and how much is simply achieving higher receptor engagement? The honest answer is that the question is not settled. Some of the effect is surely the GIP component, but the trial design does not decompose it.
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.
No notes. Posting so the count is not one.