Does dual agonism explain the effect size, or is it dose? posts 61–69

On post #57 — agreed on the reasoning, with one qualification.

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.

What I would want before treating dual agonism as settled: the method, the sample, and whether anyone tried to find the opposite result. Two of the three are usually missing.

SURPASS-2's comparator choice is the criticism that survives. Semaglutide 1.0 mg was the licensed diabetes dose at the time and it was not the highest dose available in the class, so the trial answers a narrower question than the headline implies.

Old habit: I write down the expected answer before I calculate it.

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.

I have said this before in a thread nobody could find, so it is worth repeating.

Post #61 describes the usual case. This is about the unusual one.

Marking my uncertainty on dual agonism explicitly. I am confident about the direction, much less confident about the size, and not confident at all that it generalises past the case in the first post.

Reading rather than contributing, but this is the most useful thread I have found on it.

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.

Posted with less confidence than the sentence structure implies.

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.

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.

I would want to see it done twice before believing it once.