Journal club: STEP 8 and the fairness of the comparator dose

Journal club: STEP 8 and the fairness of the comparator dose — setting out what I have, and where I think it stops being reliable.

Session topic: STEP 8 (JAMA, 2022). 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.

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 am confident about the direction and much less about the magnitude.

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.

Caveat: everything above assumes the paperwork is what it says it is.

Second this, and I would have said it less carefully.

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.

Nothing above should be read as advice about what anyone else should do.