For reference: semaglutide · liraglutide.
These are treated as interchangeable and I do not think they are.
If both are acceptable I would like to know that, so I can stop thinking about it.
What is the actual trade-off, and does it matter at the scale I am working at?
This is answerable from the published record, but only if you take the placebo arm seriously rather than reading the active arm alone.
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 |
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.
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.
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.
Analytical standards and reagents with traceable certificates. Every quantitative result you read inherits the accuracy of the standard behind it.
Shop standardsBefore comparing two trials, check whether they share an endpoint definition. Frequently they do not, and the numbers then are not comparable in any sense.
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.
On the detail: 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.
Answer 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.
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.
Concretely, 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.
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.
The short version: check the endpoint, check the comparator, check who was excluded, then look at the number.
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.
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.
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.
When two sources disagree, the answer is almost always in the methods section of the one you have not read.
edited 14 Jun 2024 by Dr_Colm_Fitzhenry — tightened the wording; no substantive change
The part that matters: the trial answers a narrower question than the headline suggests, and the narrowing is where the useful information is.
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.
SELECT reported a hazard ratio of 0.80 (95% CI 0.72–0.90) for the primary composite major adverse cardiovascular event endpoint with semaglutide 2.4 mg in overweight or obese adults with established cardiovascular disease and without diabetes[1].
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.
If a claim cannot be traced to a named trial with a named endpoint, treat it as a claim rather than as evidence.
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.