STEP 3 — trial digest
STEP 3 (JAMA 2021): What does semaglutide add on top of intensive behavioural therapy?
Citation and design
| Field | Value |
|---|---|
| Trial | STEP 3 |
| Intervention | Semaglutide 2.4 mg weekly with intensive behavioural therapy |
| Publication | JAMA, 2021 (first author Wadden) |
| Design | Double-blind, placebo-controlled, 68 weeks, with intensive behavioural therapy in both arms |
| Population | Adults with overweight or obesity without diabetes |
This digest summarises the trial and the criticisms our journal club considered material. It is not a substitute for the paper, and where the two differ the paper is right.
The question it set out to answer
What does semaglutide add on top of intensive behavioural therapy?
Stating the question before the result is a house convention. A great many arguments about this trial are actually arguments about what it was for.
What it found
Both arms received intensive behavioural therapy including a low-calorie diet period, which raised the placebo-arm result substantially compared with STEP 1.
The drug-placebo difference was therefore smaller than in STEP 1 while the absolute result in the active arm was comparable.
This is the trial to cite when someone claims lifestyle intervention is ineffective; the placebo arm here says otherwise.
Criticisms the journal club considered material
- Intensive behavioural therapy as delivered in a trial is not what is available in routine care, which limits the practical read-across in both directions.
- The design answers "what does the drug add to a strong programme", not "what does the drug do", and the two are frequently conflated.
These are criticisms of the design and of how the result is used, not of the investigators. Sessions that lose that distinction get moderated.
How it is misused
The two recurring misuses of this trial in general discussion are quoting the relative effect without the absolute one, and extending the result to a population the trial did not enrol. Both are easy to correct and both keep happening.
Where a number appears in secondary coverage without an estimand attached, assume it is whichever version is larger and check the paper.
Maintenance
Digests are reviewed when new analyses of the same trial are published, and at the review date shown above regardless. If a secondary publication changes the picture, raise it in journal club rather than editing the digest directly, so the change is discussed before it lands.
Revision history
| 2026-04-09 | j.delacroix | Added the table of acceptance criteria requested in doc review. |
| 2026-03-04 | aliquot_line | Removed a paragraph that duplicated a linked page, and linked it instead. |
| 2025-10-07 | ms_holloway | Recorded a dissent from one maintainer rather than resolving it silently. |
| 2025-06-10 | mira.patel | Added the worked example that the review thread asked for. |
| 2025-03-25 | q.zhao_qa | Initial promotion from the source topic. Structure taken from the marked solution. |
Every edit to a maintained document records its author and a note explaining the change. An edit without a note may be reverted by any wiki editor under R9, and the revert is logged. Disagreements about content belong on the source topic rather than in the revision history (R10).
Related documents
- STEP 1 — trial digestSTEP 1 (N Engl J Med 2021): Does semaglutide 2.4 mg weekly reduce body weight in adults with obesity and no diabetes?
- STEP 2 — trial digestSTEP 2 (Lancet 2021): What weight reduction does semaglutide 2.4 mg achieve in people who also have type 2 diabetes?
- STEP 4 — trial digestSTEP 4 (JAMA 2021): What happens if you stop after reaching the maintenance dose?
- STEP 8 — trial digestSTEP 8 (JAMA 2022): How does weekly semaglutide compare directly with daily liraglutide?
- SUSTAIN 6 — trial digestSUSTAIN 6 (N Engl J Med 2016): Is semaglutide cardiovascular-safe in high-risk type 2 diabetes, and is there benefit?