STEP 4 — trial digest
STEP 4 (JAMA 2021): What happens if you stop after reaching the maintenance dose?
Citation and design
| Field | Value |
|---|---|
| Trial | STEP 4 |
| Intervention | Semaglutide 2.4 mg weekly, continuation versus withdrawal |
| Publication | JAMA, 2021 (first author Rubino) |
| Design | Randomised withdrawal after a 20-week run-in, then 48 weeks |
| Population | Adults with overweight or obesity who had completed titration |
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 happens if you stop after reaching the maintenance dose?
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
A randomised withdrawal design: everyone titrated, then those still on treatment were randomised to continue or to switch to placebo.
Continuation was followed by further reduction; withdrawal was followed by regain. The direction of both findings is unambiguous.
This is the most cited evidence for the proposition that the treatment effect depends on continued treatment.
Criticisms the journal club considered material
- The run-in selects for people who tolerated the drug and responded, which limits generalisation of the withdrawal result to everyone who starts.
- The trial does not identify a lowest effective maintenance dose, because it did not study one. That is the question most members here actually want answered.
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
| 2026-06-17 | aliquot_line | Plain-language pass on the opening section after feedback from a newcomer. |
| 2026-02-27 | q.zhao_qa | Reverted an unsourced change and asked the editor to re-apply it with a citation. |
| 2025-10-11 | unit_conversion | Removed a paragraph that duplicated a linked page, and linked it instead. |
| 2025-09-14 | ms_holloway | Corrected a unit label in the second table — it read mg where it should have read mg/mL. |
| 2025-07-21 | sourced_claims | Updated a dated claim and added the date explicitly, per the maintenance convention. |
| 2025-04-15 | j.delacroix | 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 3 — trial digestSTEP 3 (JAMA 2021): What does semaglutide add on top of intensive behavioural therapy?
- 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?