This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Adding a reference point for SURPASS-2. Mine is a single case, collected without controls, and I am posting the method alongside it so it can be discounted appropriately.
Answering the question post #30 raises rather than the one it answers.
The failure mode on SURPASS-2 is boring rather than dramatic. It is almost always the step everyone assumes was done correctly because it is too simple to get wrong.
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.
The claim is narrower than it sounds, and deliberately so.
SELECT (N Engl J Med 2023): Semaglutide cardiovascular outcomes without diabetes. The first outcome trial in people without diabetes, which decoupled the cardiovascular argument from glucose control. Read the absolute numbers, not just the relative reduction.
Adding it because I spent an afternoon working it out and nobody should have to twice.
Summarising the SURPASS-2 thread so far, since it is long and the answer is buried: the first reply has the method, the fourth has the correction to it, and the rest is people agreeing at length.
I had written a reply contradicting post #34 and deleted it. Here is what survived.
Sessions on negative or null results are consistently the most instructive and the hardest to get anyone to attend.
I would not lead a decision with this, but I would not ignore it either.
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.
Happy to be corrected if someone holds better data than mine.
Worth stating the null on SURPASS-2 before we explain it: the observation may be nothing. That possibility deserves a sentence and usually does not get one.
I had read the opposite somewhere and cannot now find where, which tells me something.
Building on post #42 rather than restating it.
I read the earlier replies on SURPASS-2 twice before writing this, because I had assumed the opposite and wanted to be sure I was disagreeing with what was said rather than what I expected.
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.
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.
Two sources, same conclusion, and I could not rule out that one copied the other.
SELECT (N Engl J Med 2023): Semaglutide cardiovascular outcomes without diabetes. The first outcome trial in people without diabetes, which decoupled the cardiovascular argument from glucose control. Read the absolute numbers, not just the relative reduction.
Adding the measurement that post #47 says would settle it.
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.
Post #50 is right about the mechanism and I think understates the practical bit.
On SURPASS-2, I would rather understate and be corrected upward than overstate and be quoted. That is a house style here and it is a good one.
Coming back to post #48, because the follow-up matters more than the original answer.
Where the group cannot agree, record the disagreement rather than resolving it by seniority. The recorded disagreement is more honest and more useful later.
If that is already documented somewhere, ignore me and link it.
The version of SURPASS-2 that I was taught turned out to be a teaching simplification. Useful, and not true in the way I had assumed it was.
Post #54 answers the question as asked. The question underneath it is different.
I have been on both sides of the SURPASS-2 argument in this category within eighteen months, which should tell you how strong the evidence for either side is.
SURPASS-2 is a good example of a question where the honest answer is boring and the interesting answers are unsupported. I would go with boring.
This is the sort of exchange that makes the archive worth searching.
Worth separating two things that post #56 runs together.
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.
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.