Journal club: SURPASS-2 and the semaglutide 1 mg comparator

On the subject in the title: Journal club: SURPASS-2 and the semaglutide 1 mg comparator Working notes rather than a conclusion.

Session topic: SURPASS-2 (N Engl J Med, 2021). Please read it before posting; the discussion is much better when everyone has.

The question I would like us to start with is what the trial set out to estimate, rather than what it found. Once that is on the table we can talk about whether the design could have answered it, and only then about the numbers.

Specific things I would like covered: the population and how far it generalises, how discontinuation was handled, whether the comparator was a fair one, and what the absolute rather than relative effect looks like.

I will summarise at the end and the summary will feed the relevant digest page.

Seconded. It reads as careful rather than confident, which is the right register.

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.

SURPASS-2: I have looked for the primary source twice and failed twice. Either it does not exist or it is somewhere I do not know to look, and I would like to know which.

I read post #4 twice before replying, because I had assumed the opposite.

Careful with the language on SURPASS-2. "Not detected" and "not present" are different findings and the first is a statement about the method.

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.

Reading it back, the second half matters more than the first.

On SURPASS-2 the community has more anecdote than the confidence in this thread implies, and I include my own contribution in that.

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.

SURPASS-2 sits at the boundary between what this community can usefully discuss and what it cannot, and I think it falls on the discussable side, narrowly.

Two people in this thread mean different things by SURPASS-2 and are disagreeing about the definition while believing they are disagreeing about the facts. Worth pausing to define it.

The arithmetic in post #11 is right; the assumption feeding it is the part to check.

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.

That is the version I would defend. It is not the version I started with.

Post #11 put the caveat in the right place and I want to underline it.

Agreed on SURPASS-2, with one qualification that I think matters. The reasoning holds for the case as described. Change the starting assumption and it does not, and the starting assumption is the part nobody states.

If someone has run SURPASS-2 properly I would rather read that than my own reconstruction of it. Posting mine only because the thread has gone quiet.