Concretely: SUSTAIN-6 · semaglutide.
The figures are clear enough; the question is what they mean and what they do not.
I can supply the numbers if the specifics change the answer.
How should I read this, and where are the traps?
Check the SUSTAIN-6 inclusion criteria against yourself in that order: entry BMI band, diabetes status, prior weight-loss attempts, and what the run-in excluded. Registration programmes recruit a population selected to show an effect if one exists, which is the right design and a poor basis for generalising. The run-in is the part that is easiest to miss: a programme that drops people during a placebo lead-in has already removed those least likely to tolerate or comply, and the published arms describe the survivors. External validity is not a property of the trial; it is a property of the distance between its population and yours, and that distance is yours to measure.
The trial answers a narrower question than the headline suggests, and the narrowing is where the useful information is.
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.
| 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 |
It helps to be literal here: 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.
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.
Analytical standards and reagents with traceable certificates. Every quantitative result you read inherits the accuracy of the standard behind it.
Shop standardsAnswer 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.
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.
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.
Meta-analyses in this area are dominated by whichever trial contributed the most participants, so read the forest plot rather than the summary estimate.
Read the protocol and the statistical analysis plan if the result matters to you. Both are usually published alongside.
The part that matters: a trial establishes what happened to a defined group under a defined protocol. Extending it beyond that group is inference, and inference is allowed as long as it is labelled.
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.
It helps to be literal here: 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.
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.
Quote the interval alongside the estimate and half the disagreements on this site would not start.
The honest answer here is that the published evidence supports part of the claim and is silent on the rest, and it is worth being precise about which part is which.
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.
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.
Look at the discontinuation rate alongside the efficacy figure. A large effect in the two thirds who stayed is a different result from a large effect in everyone.
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.
Registry entries at ClinicalTrials.gov carry the pre-specified primary endpoint with a timestamp, which is the cheapest available check on whether an endpoint was changed after the data were seen.
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.
When two sources disagree, the answer is almost always in the methods section of the one you have not read.
edited 15 Apr 2026 by pk_curve — added the citation requested in comments
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.