The 2.5 mg starting dose is not a therapeutic dose — why that matters — a second dataset

Posting this under the heading it deserves: The 2.5 mg starting dose is not a therapeutic dose — why that matters — a second dataset Everything below is what sits behind that.

Posting a small dataset on 2.5 mg starting dose. It is mine, it is uncontrolled, and the method is stated so it can be discounted appropriately.

What I would like is not agreement but a second dataset collected by someone with no stake in mine. If one exists I would rather read it than argue for this one.

The opening post and I disagree about the size of the effect, not about the direction.

Practical answer on 2.5 mg starting dose, 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.

The opening post answers the question as asked. The question underneath it is different.

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.

A modest claim, modestly supported.

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 this contradicts something upthread, the upthread version may well be the better one.

The failure mode on 2.5 mg starting dose is boring rather than dramatic. It is almost always the step everyone assumes was done correctly because it is too simple to get wrong.

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.

Narrowing post #4, because the general version has more than one answer.

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.

Small point, but it is the one that usually catches people.

Useful. I have added it to my own notes with the date on it.

Agreed on all of that, and I have nothing to add to 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.

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 rather be precise about what I do not know than vague about what I do.

Confirming post #10 from a second method, which matters more than confirming it from a second person.

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 literature is thinner on this than the confidence in the thread implies.

Nobody has said the unglamorous part of 2.5 mg starting dose yet, so: most of the variation is explained by things that are boring to write about and easy to check.

Answering the 2.5 mg starting dose 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.