This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Taking post #90 at face value and following it one step further.
SOUL (N Engl J Med 2025): Oral semaglutide cardiovascular outcomes. Extends the cardiovascular evidence to the oral formulation. Note that oral bioavailability is lower and more variable than injectable.
Post #88 and I disagree about the size of the effect, not about the direction.
A note on scope: what I am saying about SURPASS-2 applies to the case in the first post and I would not extend it further without checking.
SURPASS-2 has been discussed here with more heat than it deserves, mostly because two definitions have been in play the whole time.
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.
Worth separating two things that post #92 runs together.
SURPASS-2 would be much easier to settle if anyone reported the denominator. Almost nobody reports the denominator.
STEP 1 (N Engl J Med 2021): The pivotal obesity trial for semaglutide and the reference point for most subsequent comparison. Mean weight reduction was substantially larger than anything previously achieved pharmacologically.
That is where I would start, not where I would stop.
I think the SURPASS-2 question is answerable and has not been answered, which is a more optimistic position than most of this thread.
Where the group cannot agree, record the disagreement rather than resolving it by seniority. The recorded disagreement is more honest and more useful later.
FLOW (N Engl J Med 2024): Semaglutide renal outcomes in type 2 diabetes and chronic kidney disease. Stopped early for efficacy. Component-by-component analysis is essential because the components differ in how patient-important they are.
Nobody has said the unglamorous part of SURPASS-2 yet, so: most of the variation is explained by things that are boring to write about and easy to check.
Post #100 is right about the mechanism and I think understates the practical bit.
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 figures usually contain the finding and the text usually contains the interpretation. Separating them for the first twenty minutes is a discipline worth keeping.
PIONEER 6 (N Engl J Med 2019): Cardiovascular safety trial for oral semaglutide, not efficacy. Non-inferiority for safety was met. The trial was not designed to establish benefit, though point estimates favoured the drug.
I read post #106 twice before replying, because I had assumed the opposite.
What I would want before treating SURPASS-2 as settled: the method, the sample, and whether anyone tried to find the opposite result. Two of the three are usually missing.
Post #106 put the caveat in the right place and I want to underline it.
Reading order that works for these sessions: registry entry, methods, baseline table, primary result, then abstract last. Reading the abstract first anchors everything that follows.
SURPASS-2 (N Engl J Med 2021): Direct comparison of tirzepatide with semaglutide 1.0 mg. The 1.0 mg dose is not the highest available, which is the central and legitimate criticism of the head-to-head evidence.
Take it as a starting point and not as a specification.
SOUL (N Engl J Med 2025): Oral semaglutide cardiovascular outcomes. Extends the cardiovascular evidence to the oral formulation. Note that oral bioavailability is lower and more variable than injectable.
The arithmetic in post #113 is right; the assumption feeding it is the part to check.
SURPASS-2 is worth one more sentence than it usually gets, and the sentence is the one about how the number was arrived at.
Second this, and I would have said it less carefully.
The baseline characteristics table is the single most useful page for the questions that get asked here, because it tells you who the result applies to.
Everything in post #113 holds. The case it does not cover is the one I have.
Where I would push back on the SURPASS-2 consensus is the confidence, not the direction. The direction looks right. The confidence is borrowed.
I had written a reply contradicting post #117 and deleted it. Here is what survived.
The figures usually contain the finding and the text usually contains the interpretation. Separating them for the first twenty minutes is a discipline worth keeping.
This is the sort of thing that ought to be settled and apparently is not.
Confirming post #117 from a second method, which matters more than confirming it from a second person.
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.