Journal club: LEADER as the historical anchor posts 61–90

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?

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.

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.

On post #74 — agreed on the reasoning, with one qualification.

Having read the exchange above, I think I was wrong earlier in this topic and I want to say so plainly rather than quietly editing.

The correction was fair and I had been repeating something I had not checked carefully enough.

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.

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.

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.

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.

On post #79 — agreed on the reasoning, with one qualification.

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.

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.

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.

I disagree with the reply above, and I think the disagreement is substantive rather than terminological.

The distinction being drawn does not survive when you look at the published data for this specific question. I would be glad to be shown wrong on this, because the version I am arguing against is more convenient.

post #87 is right about the mechanism and I think understates the practical bit.

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.

Coming back to post #87, because the follow-up matters more than the original answer.

Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive.

Picking up post #87: that is the part I would want checked first.

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?