[2026 update] 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.
Post #29 answers the question as asked. The question underneath it is different.
Dual agonism is worth one more sentence than it usually gets, and the sentence is the one about how the number was arrived at.
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.
Small methodological point on dual agonism: repeating a measurement is cheap and resolves most of what is being argued about here at no cost to anyone.
Worth separating two things that post #33 runs together.
An honest declaration on dual agonism: I have a prior here and it is strong enough that you should weight what I say downward. Stating it rather than hiding it.
Adding a null result on dual agonism. I looked, carefully, and found nothing, and null results deserve posting precisely because they never are.
Everything in post #40 holds. The case it does not cover is the one I have.
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.
Building on post #42 rather than restating it.
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.
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.
On balance I think that is right, and I would not bet much on it.
The arithmetic in post #42 is right; the assumption feeding it is the part to check.
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.
Answering the question post #44 raises rather than the one it answers.
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.
Dual agonism: I would want to see the raw numbers rather than the summary before agreeing. Summaries lose exactly the information that would settle this.
Adding the measurement that post #46 says would settle it.
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.
Not a strong opinion, just a consistent one.
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.
That is the shape of it. The detail is where I would expect to be corrected.
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.
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.
Worth saying I have only my own numbers here, and n is small.
Where I part company with post #51, and it is a narrow parting.
The reason dual agonism keeps being re-asked is that the answer is conditional and people quote it without the condition. It is not that the answer is unknown.
Post #51 is the version of this I will quote in future. One addition.
Dual agonism is well covered in the tag pages, and the older discussions are better than the recent ones because they were argued out properly. Worth twenty minutes before adding to this one.
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.
Confirming post #55 from a second method, which matters more than confirming it from a second person.
If someone has run dual agonism properly I would rather read that than my own reconstruction of it. Posting mine only because the thread has gone quiet.
Worth separating two things that post #55 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.
Worth reading the earlier posts in this thread before acting on mine.
Practical answer on dual agonism, since the theoretical one is upthread: do the simplest check first, write down the result, and only then decide whether the complicated explanation is needed. It usually is not.