SURPASS-2 and the comparator dose question that will not go away — setting out what I have, and where I think it stops being reliable.
A methods question rather than a substantive one, about SURPASS-2.
Everyone quotes the same figure and I cannot find anyone who says how it was arrived at. That is not an accusation; it usually means the derivation is somewhere obvious and I have missed it.
What I would tell a new member reading about SURPASS-2 for the first time: the confident posts are not the reliable ones, and the reliable ones are longer.
Adding the measurement that post #3 says would settle 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.
I had written a reply contradicting post #3 and deleted it. Here is what survived.
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.
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.
Where I would look next, rather than where I would stop.
Where the SURPASS-2 reasoning breaks down for me is the step from the group result to the individual case. That step is almost never argued for.
I think the SURPASS-2 question is answerable and has not been answered, which is a more optimistic position than most of this thread.
This is the first time the answer has come with its own limits attached. Appreciated.
Post #7 is right about the mechanism and I think understates the practical bit.
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.
Taking post #8 at face value and following it one step further.
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.
The strength of my opinion here exceeds the strength of my evidence.
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 number is defensible. The precision I gave it is not.
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.
Flagging that the sources on this are thinner than the confidence in the thread suggests.
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.
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.
The part I am sure of is shorter than the part I have written.
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.
If this contradicts something upthread, the upthread version may well be the better one.
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.
Thank you — that answers what I came here to find out.
Small methodological point on SURPASS-2: repeating a measurement is cheap and resolves most of what is being argued about here at no cost to anyone.
Answering the SURPASS-2 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 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.
If anyone has run this properly I would rather read that than my own guess.
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.
Not a conclusion. A place to stand while looking for one.
Post #23 is the version of this I will quote in future. One addition.
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.
If it helps: the failure mode here is usually boring rather than dramatic.
My experience of SURPASS-2 contradicts the reply above. I am posting it as a data point rather than as a refutation, because one person's experience is exactly that.
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.
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.
It is the sort of thing that seems obvious in retrospect and was not at the time.
On purity: the trailing-edge features people report on tirzepatide chromatograms are frequently deamidation products, which elute close to the main peak and are easy to integrate into it. That is a method question rather than a quality question.
The evidence for this is thinner than the way I have phrased it suggests.