I changed my mind about SURPASS-2 after someone here asked me for the source and I could not produce one. That is worth saying out loud because it is the ordinary way it happens.
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Evidence · Journal club · continued
Journal club: SURPASS-2 and the semaglutide 1 mg comparator posts 31–60
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1 · go to the accepted answer.
t.ibarra, post #28: Where I part company with post #26, and it is a narrow parting. What I want from this SURPASS-2 thread is the list of things that would need to be true for the claim to hold. If we can write that list, we can check it. Go to post
The most common failure mode is spending fifty minutes on the effect size and ten on the population. Reversing that ratio would improve most sessions.
Where I part company with post #29, and it is a narrow parting.
The useful distinction on SURPASS-2 is between what was measured and what was inferred from it. Both end up in the same sentence and only one of them has error bars.
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What would change my mind on SURPASS-2 is a second dataset collected by someone with no stake in the first. Until then I hold it loosely and I would rather say so than pretend to more.
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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 would want to see it done twice before believing it once.
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t.nardone, post #27: Adding a small correction to the SURPASS-2 summary above rather than a disagreement with it. The substance holds; one of the figures is out by a factor that matters. Go to post
Nothing to add on the substance. Thank you for taking the question at face value.
Post #33 put the caveat in the right place and I want to underline it.
Sessions on negative or null results are consistently the most instructive and the hardest to get anyone to attend.
This is the sort of thing the wiki should carry and currently does not.
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Collapsed as off-topic by two members at trust level 3 or above
On post #37 — agreed on the reasoning, with one qualification.
SURPASS-2 is one of those subjects where the general answer and the answer for a specific case diverge, and the thread will go in circles until someone says which one is being asked for.
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.
I have deliberately not rounded that, because the rounding is where the argument starts.
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Adding the measurement that post #38 says would settle it.
SURPASS-2 was covered in the wiki last year and the page has a review date on it, which is a better starting point than my memory of a thread.
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Collapsed as off-topic by two members at trust level 3 or above
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.
Adding a source would improve this post and I do not have one to hand.
j.vandermolen, post #32: The most common failure mode is spending fifty minutes on the effect size and ten on the population. Reversing that ratio would improve most sessions. Go to post
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.
Not the answer, but possibly the question that gets there.
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.
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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.
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ambient_review, post #40: 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. I have deliberately not rounded that, because the rounding is where the argument starts. Go to post
Saving this. It is the version I will quote when the question comes round again.
g.ekstrom, post #37: Post #33 put the caveat in the right place and I want to underline it. Sessions on negative or null results are consistently the most instructive and the hardest to get anyone to attend. This is the sort of thing the wiki should carry and currently does not. Go to post
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.
If that reads as pedantic, it is, and it has saved me twice.
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.
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Reading back through, this was answered upthread and I missed it. My fault.
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j.vandermolen, post #32: The most common failure mode is spending fifty minutes on the effect size and ten on the population. Reversing that ratio would improve most sessions. Go to post
What I can speak to on SURPASS-2 is narrow, so I will keep it narrow rather than generalising from it. Beyond that boundary I do not know.
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.
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Post #52 is right about the mechanism and I think understates the practical bit.
One more thing on SURPASS-2 that took me far too long to see: the two figures people quote are not measuring the same quantity. Once you notice that, the apparent contradiction disappears.
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ambient_review, post #40: 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. I have deliberately not rounded that, because the rounding is where the argument starts. Go to post
Post #52 and I disagree about the size of the effect, not about the direction.
Reporting rather than recommending, on SURPASS-2. What happened is above. Whether it should have is a different question and not one I am qualified to answer.
Isaksen, post #29: Where the group cannot agree, record the disagreement rather than resolving it by seniority. The recorded disagreement is more honest and more useful later. I would be interested in a counterexample if anyone has one. Go to post
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.
Filing this under things that are true until someone shows me otherwise.
Counterpoint on SURPASS-2, offered without confidence: the same observation is consistent with a much duller explanation, and nobody has ruled the dull one out.
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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.
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quiet_lurker, post #3: Seconded. It reads as careful rather than confident, which is the right register. Go to post
Post #55 put the caveat in the right place and I want to underline it.
Sessions on negative or null results are consistently the most instructive and the hardest to get anyone to attend.
The general case is well covered; this is the awkward specific one.