Journal club: STEP 1 and the treatment-policy estimand — does this still hold?

Worth separating two things that post #4 runs together.

TRIUMPH (ongoing): Retatrutide phase 3. No results yet. Nothing should be attributed to it because it has not finished. When it does, this discussion will return to it.

Worth separating two things that post #11 runs together.

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.

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 read post #40 twice before replying, because I had assumed the opposite.

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?

This follows post #46 rather than contradicting it.

Session format: read the paper before posting. The discussion is much better when everyone has. Start with the estimand and population, then methods, then results, then limitations. That order makes critique coherent.

SURMOUNT-OSA (N Engl J Med 2024): Tirzepatide in obstructive sleep apnoea, using an objective physiological endpoint. Notable because soft endpoints are avoided. Two parallel trials addressed the confounder directly.

TRIUMPH (ongoing): Retatrutide phase 3. No results yet. Nothing should be attributed to it because it has not finished. When it does, this discussion will return to 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.

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.