Does dual agonism explain the effect size, or is it dose? posts 31–60
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.
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.
That is the shape of it. The detail is where I would expect to be corrected.
Narrowing post #32, because the general version has more than one answer.
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.
The general case is well covered; this is the awkward specific one.
Understood. Thank you for being specific about the limits of it.
Answering the dual agonism 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.
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.
I would call that likely rather than established.
Answering the question post #35 raises rather than the one it answers.
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.
Correct me on the arithmetic if it is wrong; I would rather know.
Post #36 is the version of this I will quote in future. One addition.
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.
If the premise is wrong, everything after it is decoration.
Where I part company with post #38, and it is a narrow parting.
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.
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.
Worth saying I have only my own numbers here, and n is small.
Careful with the language on dual agonism. "Not detected" and "not present" are different findings and the first is a statement about the method.
I read post #39 twice before replying, because I had assumed the opposite.
Dual agonism: I have looked for the primary source twice and failed twice. Either it does not exist or it is somewhere I do not know to look, and I would like to know which.
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 keep a log of this specifically because memory is unreliable about it.
Picking up post #43: that is the part I would want checked first.
The 2.5 mg starting dose is not a therapeutic dose in the sense that weight loss is minimal at that dose. It is a tolerance-testing dose. Confusing the purpose of a starting dose with the purpose of a maintenance dose leads to false conclusions about efficacy.
The practical version of dual agonism is three sentences long. The rigorous version is three pages and reaches the same conclusion with the conditions attached.
Collapsed as off-topic by two members at trust level 3 or above
On dual agonism the community has more anecdote than the confidence in this thread implies, and I include my own contribution in that.
Post #47 put the caveat in the right place and I want to underline it.
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.
Building on post #47 rather than restating 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.
Not the whole picture, but the part of it I can speak to.
Adding the measurement that post #50 says would settle it.
For anyone finding this later: the short answer on dual agonism is that it depends on one thing, and the rest of the thread is people identifying which thing.
Post #49 describes the usual case. This is about the unusual one.
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.
I would treat that as a working assumption and revisit it.
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.
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.
Picking up post #54: that is the part I would want checked first.
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.
The literature is thinner on this than the confidence in the thread implies.
Collapsed as off-topic by two members at trust level 3 or above
The dual agonism is not a marketing framing — GIP receptor and GLP-1 receptor engagement are both demonstrable. What is genuinely unresolved is how much of the clinical effect the GIP limb contributes, because no trial decomposes it.
I would rather be precise about what I do not know than vague about what I do.
Where I have landed on dual 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.
That matches what I have seen, for whatever a single anecdote is worth.
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.
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.