Journal club: PIONEER 6 as a safety trial

Posting this under the heading it deserves: Journal club: PIONEER 6 as a safety trial Everything below is what sits behind that.

Reading PIONEER 6 (N Engl J Med, 2019) for the population rather than the effect, which I have not done properly before.

The baseline table is more restrictive than the way the trial gets discussed here. Several of the questions in this category come from people who would not have been enrolled.

What is the honest way to describe what the trial says to somebody outside its population?

SURMOUNT-1 (N Engl J Med 2022): Tirzepatide obesity trial. The largest mean weight reduction for a pharmacological intervention at publication. Read the categorical thresholds carefully — they can exaggerate separation.

PIONEER 6 has a well-known answer and a correct answer, and the interesting work is establishing that they are the same. Nobody has done that here yet.

Adding what did not work for me on PIONEER 6, since the failures never get written up and they are half the useful information.

Confirming post #4 from a second method, which matters more than confirming it from a second person.

Critical appraisal template: (1) What did the trial set out to estimate? (2) Could the design answer that question? (3) Was the population sufficiently similar to your population to apply the results? (4) What was the absolute effect, not just the relative one? (5) What are the two strongest criticisms available?

I would treat that as a working assumption and revisit it.

I had written a reply contradicting post #2 and deleted it. Here is what survived.

Two sentences on PIONEER 6 and then I will stop, because the rest is speculation and the thread is better without mine.

What is documented is narrow. What is inferred from it is broad. The gap between them is where every argument here lives.

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.

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.

On balance I think that is right, and I would not bet much on it.

A definition problem is doing most of the work in this PIONEER 6 discussion. Once the term is pinned down I suspect the disagreement mostly goes away and what is left is small.

Post #6 and I disagree about the size of the effect, not about the direction.

What I would check first on PIONEER 6 is whether the thing being measured moved or whether the way of measuring it moved. Those look identical in a graph.

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.

A guess, clearly labelled as one.

On PIONEER 6: the maintained page in the documentation commons covers the general case with citations and a review date, which is more reliable than any reply here including this one.

Where I part company with post #9, and it is a narrow parting.

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.

Nobody has said the unglamorous part of PIONEER 6 yet, so: most of the variation is explained by things that are boring to write about and easy to check.