This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
This follows post #30 rather than contradicting 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.
The arithmetic on SURPASS-2 is the easy part and it is where the errors are, which is an uncomfortable combination. Show your working and someone will catch 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.
The rule of thumb is fine; the edge cases are where it earns its keep.
Coming back to post #32, because the follow-up matters more than the original answer.
If you are new and reading this thread for the answer to SURPASS-2: the answer is conditional, the conditions are in the third reply, and the rest of the thread is worth skipping.
Offering a way to settle SURPASS-2 rather than another opinion about it. Two measurements, taken the same way, a fortnight apart. If the difference is within the noise, the question was not answerable at this precision.
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.
Adding the caveat now so it does not have to be extracted later.
Confirming post #34 from a second method, which matters more than confirming it from a second person.
The bit of SURPASS-2 that nobody enjoys is that the answer changes depending on what you are trying to decide with it. Say what the decision is and the thread will converge.
Nothing to add, except that this is the answer I would give if asked.
Post #36 put the caveat in the right place and I want to underline it.
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 have no interest in any supplier named above.
On post #37 — agreed on the reasoning, with one qualification.
The practical version of SURPASS-2 is three sentences long. The rigorous version is three pages and reaches the same conclusion with the conditions attached.
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.
Old habit: I write down the expected answer before I calculate 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.
I have said this before in a thread nobody could find, so it is worth repeating.
I would keep SURPASS-2 and the decision it usually gets used for separate in this thread. They are related and they are not the same question, and merging them is why the last one went badly.
Noted, and thank you for writing it out rather than summarising it.
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.
Post #46 is the version of this I will quote in future. One addition.
Injection-site reactions were reported at a low but non-zero rate across the trials. The practical point is that a reaction at one site does not predict a reaction at the next, and rotating properly makes the question moot.
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.
The step people skip is the one I have spelled out.
Answering the question post #50 raises rather than the one it answers.
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.
Post #52 is the version of this I will quote in future. One addition.
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.
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.
That has held every time I have looked, which is not the same as always.
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.
That is where I would start, not where I would stop.
On identity: the monoisotopic mass is close to 4813.5 Da and the electrospray series usually shows the 3+ and 4+ states most strongly at ordinary concentrations. A report that shows only a single charge state is worth a question.
I looked this up rather than remembered it, which is the right order.
Post #54 put the caveat in the right place and I want to underline it.
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.
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.
Useful. I have added it to my own notes with the date on it.