Posting this under the heading it deserves: Journal club: semaglutide in MASH, and surrogate endpoints Everything below is what sits behind that.
Working notes on semaglutide in MASH rather than a conclusion. I would rather post the reasoning while it can still be corrected than post the answer once I am committed to it.
Everything below is checkable. Where I have taken a figure from somewhere else I have said where; where I have estimated, I have said that too.
Coming back to the opening post, because the follow-up matters more than the original answer.
The question underneath semaglutide in MASH is usually "how would I tell?" rather than "what is true?", and that one has a method attached to it.
Write down what you would expect to see under each hypothesis before you collect anything. If they predict the same observation, collecting it will not help.
Where I have landed on semaglutide in MASH, having got it wrong once in public: the direction is clear, the magnitude is not, and anyone quoting a precise magnitude has borrowed it from somewhere that did not measure it.
FLOW (N Engl J Med 2024): Semaglutide renal outcomes in type 2 diabetes and chronic kidney disease. Stopped early for efficacy. Component-by-component analysis is essential because the components differ in how patient-important they are.
The reasoning is more useful than the number, which is why I have shown it.
Confirming post #4 from a second method, which matters more than confirming it from a second person.
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.
Where I would look next, rather than where I would stop.
The confident answers on semaglutide in MASH and the well-sourced answers are not the same answers, which is the most useful thing I have learned reading this category.
Two things can be true about semaglutide in MASH at once: the mechanism is plausible and the evidence for the size of the effect is thin. Most of the argument here is people defending the first against attacks on the second.
Sessions on negative or null results are consistently the most instructive and the hardest to get anyone to attend.
Reading back through the semaglutide in MASH threads from last year, the same three questions come up every time and only one of them has ever been answered properly. That seems like a documentation gap rather than a knowledge gap.
Staff rationale: Hidden by community flags. The substance was fine; the framing attributed motive rather than error, which is R1.
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.
The confident version of this sentence would be wrong, so here is the hedged one.
The corresponding entry is in the public moderation log. Hidden posts are never deleted.
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.
I am confident about the direction and much less about the magnitude.
Reframing semaglutide in MASH slightly, because I think the disagreement is about the question rather than the answer. If the question is "does it happen", yes. If it is "how often", nobody here knows.
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.
The disagreement above is smaller than it looks once the terms are fixed.
The bit of semaglutide in MASH that nobody enjoys is that the answer changes depending on what you are trying to decide with it. Say what the decision is and the thread will converge.
Adding the measurement that post #13 says would settle it.
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.
Something worth flagging about semaglutide in MASH: the strongest-sounding claims in this thread are the ones with no source attached, which is the usual pattern and not a coincidence.
That is the distinction I keep failing to hold on to. Written down now.
Taking post #17 at face value and following it one step further.
The reason semaglutide in MASH is hard to answer is that the obvious measurement and the relevant quantity are not the same thing, and substituting one for the other is silent.
Adding the boring version of semaglutide in MASH, because the interesting version keeps getting posted and the boring one is usually right.
Check the ordinary explanations, in order, and stop when one of them accounts for what you are seeing. Most of the time the second one does.
Answering the question post #20 raises rather than the one it answers.
The baseline characteristics table is the single most useful page for the questions that get asked here, because it tells you who the result applies to.
Post #22 is the version of this I will quote in future. One addition.
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.
That holds for the case as described. Change the assumptions and it may not.
Everything in post #24 holds. The case it does not cover is the one I have.
Where the group cannot agree, record the disagreement rather than resolving it by seniority. The recorded disagreement is more honest and more useful later.
One case, stated as one case.
Before the thread moves on from semaglutide in MASH — what is the sample size behind the claim? I am not being difficult; I have seen the same figure quoted from an n of four and from an n of four hundred.
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.
That is one dataset and I would not build a rule on it.
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 holds under the stated conditions and I have stated them.
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