SUSTAIN 6 — trial digest
SUSTAIN 6 (N Engl J Med 2016): Is semaglutide cardiovascular-safe in high-risk type 2 diabetes, and is there benefit?
Citation and design
| Field | Value |
|---|---|
| Trial | SUSTAIN 6 |
| Intervention | Semaglutide 0.5 mg and 1.0 mg weekly |
| Publication | N Engl J Med, 2016 (first author Marso) |
| Design | Double-blind, placebo-controlled cardiovascular safety trial, 104 weeks |
| Population | Adults with type 2 diabetes at high cardiovascular risk |
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
Is semaglutide cardiovascular-safe in high-risk type 2 diabetes, and is there benefit?
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
Designed as a non-inferiority safety trial; the composite cardiovascular outcome favoured semaglutide.
A signal for diabetic retinopathy complications was observed and has been discussed extensively since, with rapid glycaemic improvement as the leading proposed explanation.
The trial predates the obesity programme and is the origin of much of the cardiovascular discussion in this class.
Criticisms the journal club considered material
- Event numbers for individual components were small, and the retinopathy finding in particular rests on few events.
- A safety trial powered for non-inferiority is not the ideal instrument for establishing benefit, even when the result is favourable.
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
| 2026-02-15 | NLoughran | Recorded a dissent from one maintainer rather than resolving it silently. |
| 2025-10-29 | dietitian_hollis | Plain-language pass on the opening section after feedback from a newcomer. |
| 2025-08-10 | outline_first | Updated a dated claim and added the date explicitly, per the maintenance convention. |
| 2025-06-19 | mira.patel | 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 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?