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LITERATURE REVIEW · CARDIOVASCULAR OUTCOMES TRIAL

SUSTAIN-6

Semaglutide and cardiovascular outcomes in patients with type 2 diabetes — Marso et al., New England Journal of Medicine, 2016.

QUICK ANSWER
TL;DR

Quick answer

SUSTAIN-6 was a 3,297-patient randomised double-blind trial of once-weekly subcutaneous Semaglutide versus placebo in adults with type 2 diabetes at high cardiovascular risk. The primary three-point MACE composite (cardiovascular death, non-fatal MI, non-fatal stroke) was reduced with Semaglutide over a median follow-up of 2.1 years.
EXTENDED ANSWER
AI-ready

Extended answer

What was SUSTAIN-6?

SUSTAIN-6 was a randomised, double-blind, placebo-controlled cardiovascular outcomes trial designed to evaluate the cardiovascular safety of once-weekly subcutaneous Semaglutide in adults with type 2 diabetes at high cardiovascular risk. Published in the New England Journal of Medicine in 2016, it enrolled 3,297 participants and followed them for a median of 2.1 years. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (three-point MACE). Semaglutide met the pre-specified non-inferiority criterion versus placebo and showed a statistically significant reduction in the primary composite outcome. SUSTAIN-6 was pivotal in establishing the cardiovascular safety profile of Semaglutide and shaped subsequent GLP-1 receptor agonist clinical development. Oxford Research Peptides describes this trial for educational purposes only; research-grade Semaglutide is supplied strictly as an in-vitro reference standard.
KEY FACTS

Key facts

Compound
Semaglutide (0.5 mg, 1.0 mg SC weekly)
Design
Randomised, double-blind, placebo-controlled
Population
3,297 adults with T2D at high CV risk
Follow-up (median)
2.1 years
Primary outcome
3-point MACE (CV death, non-fatal MI, non-fatal stroke)
Journal
New England Journal of Medicine (2016)
PMID
27633186
DOI
10.1056/NEJMoa1607141

Background

GLP-1 receptor agonists had established glycaemic efficacy in type 2 diabetes by the mid-2010s. Regulators required cardiovascular safety trials for new glucose-lowering agents. SUSTAIN-6 was Semaglutide's dedicated cardiovascular outcomes trial.[1]

Study design

Randomised, double-blind, placebo-controlled, event-driven trial. Participants were randomised 1:1:1:1 to Semaglutide 0.5 mg weekly, Semaglutide 1.0 mg weekly, or matching placebo for each dose. All participants received standard-of-care glucose-lowering therapy.

Population

3,297 adults aged ≥ 50 years with type 2 diabetes and either established cardiovascular disease, chronic kidney disease, or both, or aged ≥ 60 years with cardiovascular risk factors.

Primary outcomes

The primary composite was cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (three-point MACE). Semaglutide reduced the primary composite versus placebo, with reductions in non-fatal stroke and non-fatal MI as leading components. Rates of retinopathy complications were higher with Semaglutide — a signal that has been discussed extensively in subsequent literature.[1]

Scientific significance

  • Established Semaglutide's cardiovascular safety profile.
  • Contributed to the class-consistent view of GLP-1 receptor agonists as cardiovascular-neutral-to-beneficial.
  • Framed subsequent Semaglutide trials in obesity (STEP), obesity without diabetes (SELECT) and CKD (FLOW).

Limitations

Research limitations

  • SUSTAIN-6 was primarily designed as a non-inferiority CV safety trial rather than a superiority trial for efficacy.
  • Median follow-up (2.1 years) is relatively short for cardiovascular endpoints.
  • The retinopathy signal remains debated and may reflect rapid glycaemic reduction rather than a direct drug effect.
  • Population was high-risk; results may not extrapolate to lower-risk populations.

Research-use framing

This is an educational literature summary of a published clinical trial. Oxford Research Peptides supplies Semaglutide as a lyophilised reference standard for in-vitro laboratory research only.

Related reading: Semaglutide monograph, Semaglutide mechanism of action, Semaglutide research applications, SELECT trial and FLOW trial.

References5

  1. 1.

    Marso SP, Bain SC, Consoli A, et al.. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6).. New England Journal of Medicine. 2016;375(19):1834-1844.

    DOI: 10.1056/NEJMoa1607141PMID: 27633186
  2. 2.

    Wilding JPH, Batterham RL, Calanna S, et al.. Once-weekly semaglutide in adults with overweight or obesity (STEP 1).. New England Journal of Medicine. 2021;384(11):989-1002.

    DOI: 10.1056/NEJMoa2032183PMID: 33567185
  3. 3.

    Davies M, Færch L, Jeppesen OK, et al.. Semaglutide 2·4 mg once a week in adults with overweight or obesity and type 2 diabetes (STEP 2).. Lancet. 2021;397(10278):971-984.

    DOI: 10.1016/S0140-6736(21)00213-0PMID: 33667417
  4. 4.

    Lincoff AM, Brown-Frandsen K, Colhoun HM, et al.. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT).. New England Journal of Medicine. 2023;389(24):2221-2232.

    DOI: 10.1056/NEJMoa2307563PMID: 37952131
  5. 5.

    Perkovic V, Tuttle KR, Rossing P, et al.. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW).. New England Journal of Medicine. 2024;391(2):109-121.

    DOI: 10.1056/NEJMoa2403347PMID: 38785209
EVIDENCE SUMMARY
Evidence

Evidence summary

Strong evidence
Research confidenceHigh confidence
Landmark peer-reviewed cardiovascular outcomes trial published in the New England Journal of Medicine (Marso et al. 2016). Findings are widely cited across the GLP-1 receptor agonist literature.
RELATED GUIDES
COMPOUND REFERENCE
EDITORIAL NOTICE

Research use only

All materials referenced are supplied strictly for in-vitro laboratory research. Not for human or animal consumption, diagnosis, or therapeutic use.
VERSION HISTORY
Editorial Team
Oxford Research Peptides Editorial Team
In-house editorial staff
Oxford Research Peptides
Scientific Reviewer
Scientific Review Panel
Independent scientific review
Oxford Research Peptides

Publication information

Published
2026-10-15
Updated
2026-10-15
Reviewed
2026-10-15
Version
1.0

Revision history

  1. v1.02026-10-15· Editorial Team

    Authority Sprint 2D — initial publication of GLP-1 foundation study summaries.

Editorial standards

Content is reviewed against our editorial process for scientific accuracy, sourcing, and clarity. Read our editorial standards.

Conflict of interest

Oxford Research Peptides supplies research-grade reference peptides commercially. Editorial pages are drafted and reviewed to describe published scientific literature accurately and do not recommend, promote or endorse any specific commercial product. Product mentions on educational pages are strictly for cross-referencing catalogue entries.

Next scheduled review: 2028-04-15. Our research methodology describes how the review is conducted.

Research use only

All materials referenced are supplied strictly for in-vitro laboratory research. Not for human or animal consumption, diagnosis, or therapeutic use.
Published: 2026-10-15Updated: 2026-10-15