Tirzepatide molecular mass and the charge states you would expect on ESI — does this still hold?

Asking directly, because I could not find a straight answer: Tirzepatide molecular mass and the charge states you would expect on ESI — does this still hold?

Comparing STEP 2 (Lancet, 2021) with SURMOUNT-OSA (N Engl J Med, 2024) and finding the comparison harder than it looks.

Different populations, different durations, different endpoints defined slightly differently, and in one case a different estimand. People compare the headline percentages anyway, including me until recently.

Is there a defensible way to put these side by side, or is the honest answer that there is not and we should stop?

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.

I disagree with the reply above, and I think the disagreement is substantive rather than terminological.

The distinction being drawn does not survive when you look at the published data for this specific question. I would be glad to be shown wrong on this, because the version I am arguing against is more convenient.

On post #3 — agreed on the reasoning, with one qualification.

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.

Half-life difference: tirzepatide is about 5 days versus semaglutide's week-long. Practically, that means steady state is reached slightly faster and the post-dose swing is slightly larger. Most people do not report noticing the difference in practical terms.

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.

post #6 is right about the mechanism and I think understates the practical bit.

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.

Worth separating two things that post #4 runs together.

Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive.

Nausea profile: some people report tirzepatide as less nausea-prone than semaglutide, others report it as more. The trial reported gastrointestinal effects broadly comparable in character. Individual variation is the largest factor.

Coming back to post #8, because the follow-up matters more than the original answer.

Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive.

Mass and charge states: tirzepatide is about 4813.5 Da and on an electrospray instrument you would expect to see charge states mostly in the 2+ to 4+ range, the same as semaglutide. A doubly charged species would appear at about (4813.5 + 2 × 1.008) / 2 ≈ 2408.

SURMOUNT-OSA is notable because it used an objective physiological endpoint, the apnoea-hypopnoea index, rather than a symptom scale. Two parallel trials, with and without positive airway pressure, addressed the confounder directly. The reduction was substantial in both.