The case in front of me: STEP 5 · semaglutide.
I would like to know the limits of what can be inferred from this.
What I am trying to avoid is over-reading a single result, which I have done before.
What can I legitimately conclude from this figure?
Whatever its primary endpoint was, at the power it was designed for, in the population it recruited — and nothing else. STEP 5 was sized to answer one question. Every other result in it is a secondary or exploratory endpoint, powered incidentally if at all, and a nominally significant secondary in a programme with twenty of them is what you would expect from chance alone. So the reading order is: primary endpoint, then whether the secondaries were pre-specified and hierarchically tested, then everything else as hypothesis-generating. A trial establishes one thing well and suggests several things badly, and the press coverage inverts that ranking reliably.
Before comparing two trials, check whether they share an endpoint definition. Frequently they do not, and the numbers then are not comparable in any sense.
Open-label extensions are not the same evidence as the randomised phase. Once everyone knows what they are taking, the reported outcomes acquire a bias that no analysis fully removes.
| Trial | Agent | n | Duration | Primary result |
|---|---|---|---|---|
| STEP 1 | Semaglutide 2.4 mg | 1,961 | 68 wk | −14.9 % vs −2.4 % weight |
| STEP 2 | Semaglutide 2.4 mg, T2DM | 1,210 | 68 wk | −9.6 % vs −3.4 % weight |
| SURMOUNT-1 | Tirzepatide 5/10/15 mg | 2,539 | 72 wk | −15 / −19 / −21 % weight |
| SURMOUNT-4 | Tirzepatide, withdrawal | 670 | 88 wk | Continued loss vs substantial regain |
| SELECT | Semaglutide 2.4 mg | 17,604 | ~40 mo | MACE HR 0.80 (0.72–0.90) |
| FLOW | Semaglutide 1.0 mg, CKD | 3,533 | ~3.4 yr | Renal composite reduced; stopped early |
| SURMOUNT-OSA | Tirzepatide, OSA | 469 | 52 wk | AHI reduced with and without PAP |
Concretely, a composite endpoint is only as informative as its least serious component. Where a cardiovascular composite combines death, infarction and stroke, ask which component moved, because they are not interchangeable outcomes.
Where a result is quoted from a conference abstract rather than a peer-reviewed publication, the numbers routinely move between the two. It is worth checking which one you are reading.
The short version: check the endpoint, check the comparator, check who was excluded, then look at the number.
Aggregated, published test results and vendor ratings built from submitted batches. Methodology stated, dataset browsable, no listing fees.
Browse resultsAnswer first: read the primary endpoint, the comparator and the population before you read the effect size. Almost every argument on this site about a trial is really an argument about one of those three.
Placebo arms in this class are not nothing. Lifestyle-intervention placebo arms in the major obesity trials commonly lose two to three per cent of body weight, so an active-arm figure quoted without its comparator overstates the drug effect by roughly that much.
The part that matters: intention-to-treat and per-protocol analyses answer different questions. ITT asks what happens if you offer the treatment; per-protocol asks what happens if it is taken as directed. The gap between the two is a measure of how tolerable the protocol was.
Meta-analyses in this area are dominated by whichever trial contributed the most participants, so read the forest plot rather than the summary estimate.
I am not a clinician and this is not medical advice; it is a reading of a published protocol.
Quote the interval alongside the estimate and half the disagreements on this site would not start.
Stated carefully, the trial answers a narrower question than the headline suggests, and the narrowing is where the useful information is.
Non-inferiority and superiority designs are not interchangeable. A non-inferiority result says the new agent is not meaningfully worse against a pre-specified margin — it does not say it is as good, and it certainly does not say it is better.
Mechanically, duration decides what can be seen. A 68-week trial can measure weight and glycaemia; it cannot measure anything whose event rate is one per cent per year without enrolling tens of thousands.
One qualification: absence of a signal in a trial of this size is not evidence of absence for a rare event. It is evidence that the event is rarer than the trial could detect.
Read the protocol and the statistical analysis plan if the result matters to you. Both are usually published alongside.
Concretely, this is answerable from the published record, but only if you take the placebo arm seriously rather than reading the active arm alone.
Confidence intervals matter more than point estimates when two trials disagree. Two studies reporting fifteen and twenty per cent whose intervals overlap heavily have not disagreed about anything.
The cardiovascular outcome programme in this class runs to several large randomised trials — LEADER for liraglutide, SUSTAIN-6 and SELECT for semaglutide, REWIND for dulaglutide — and they are the reason the class is discussed as more than a weight intervention.
Be careful about generalising from a trial population to yourself. The exclusion criteria are usually the most informative page in the supplement.
If a claim cannot be traced to a named trial with a named endpoint, treat it as a claim rather than as evidence.
The short version: the effect is real, the magnitude depends on the population, and the population is usually the part that gets dropped when a result is quoted second-hand.
Trial populations are selected. Exclusion criteria in this class routinely remove people with significant renal impairment, prior pancreatitis and unstable psychiatric illness, which is exactly the population the results are then quoted for.
The caveat is that trial evidence is about licensed product administered under supervision. None of it transfers automatically to research-grade material of unverified content.
When two sources disagree, the answer is almost always in the methods section of the one you have not read.
Ask PeptideStack is a static archive. Posting is closed, but the norms are worth stating: answer the question that was asked, show your working, cite the trial or the certificate, and say plainly where the evidence runs out.