Journal club: SURPASS-2 and the semaglutide 1 mg comparator posts 61–77

I keep a log for SURPASS-2 specifically because my memory of it turned out to be systematically wrong in one direction. Six weeks of notes cost nothing and settled it.

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.

Building on post #61 rather than restating it.

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 short answer was in the first line; everything after is the working.

For anyone finding this later: the short answer on SURPASS-2 is that it depends on one thing, and the rest of the thread is people identifying which thing.

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.

Everything in post #62 holds. The case it does not cover is the one I have.

Practical note on SURPASS-2: write down what you expect before you look. The number of times I have found what I went looking for is higher than chance would allow.

A request rather than an answer: could whoever has the primary source for SURPASS-2 post it? I have seen the claim three times this month and each version had lost a qualifier.

This settles it for me, at least until somebody posts a reason it should not.

Picking up post #67: that is the part I would want checked first.

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.

I would put moderate confidence on the mainstream reading of SURPASS-2 and no more. That is not scepticism for its own sake; it is where the sourcing actually stops.

Where the group cannot agree, record the disagreement rather than resolving it by seniority. The recorded disagreement is more honest and more useful later.

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.

Coming back to post #69, because the follow-up matters more than the original answer.

SURPASS-2 looks different depending on whether you are reading the primary literature or the summaries of it, and the difference is not in our favour.

Post #73 is right about the mechanism and I think understates the practical bit.

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.