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SUSTAIN-6: semaglutide and cardiovascular outcomes in type 2 diabetes

The 2016 heart safety trial of semaglutide in 3297 people with type 2 diabetes, 104 weeks. Heart events 6.6 vs 8.9 percent, plus a diabetic eye signal.

2 min readUpdated September 4, 2026By FormBlends editorial team2 sourcesEducational, not medical advice

SUSTAIN-6: the trial at a glance

From the data
SUSTAIN-6 at a glance: 3,297 randomised, 104 weeks, primary endpoint major adverse cardiovascular events.Four facts about SUSTAIN-6 and its primary result: Primary outcome in 108 of 1648 (6.6%) on semaglutide versus 146 of 1649 (8.9%) on placebo; hazard ratio 0.74 (95% CI 0.58 to 0.95; P<0.001 for noninferiority).Randomised3,297Duration104 weeksPhase3ComparatorplaceboPrimary resultPrimary outcome in 108 of 1648 (6.6%) on semaglutide versus 146 of 1649 (8.9%)on placebo; hazard ratio 0.74 (95% CI 0.58 to 0.95; P<0.001 fornoninferiority).
Figures as stated in the PubMed abstract. Primary endpoint: First occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. Source: PubMed 27633186. Source: N Engl J Med 2016;375(19):1834-1844, PubMed 27633186.

Watch, with the fact-check

Semaglutide and Cardiovascular Outcomes in Obesity | NEJM

NEJM Group · 2:17 · uploaded 2023

What it gets right. NEJM's two-minute summary of SELECT: 17,604 adults with cardiovascular disease and overweight or obesity but no diabetes, semaglutide 2.4 mg versus placebo, primary composite of cardiovascular death, non-fatal MI or non-fatal stroke in 6.5 versus 8.0 percent over a mean 39.8 months.

What it leaves out. It does not state the hazard ratio, the absolute risk reduction or the number needed to treat, and it says nothing about how much of the effect tracked weight loss.

Watch on YouTube

Embedded from YouTube (privacy-enhanced player, loads on click); verified against YouTube's oEmbed record on 2026-09-04. Nothing is rehosted. The fact-check is the FormBlends editorial team's reading, not the channel's endorsement.

SUSTAIN-6 predates Ozempic's approval. It was designed to rule out cardiovascular harm, as regulators required of new diabetes drugs, and instead found fewer events. It also produced the retinopathy signal that still appears in the semaglutide labels.

What the trial asked

Whether semaglutide is noninferior to placebo for major cardiovascular events in people with type 2 diabetes at high cardiovascular risk. The prespecified hypothesis was noninferiority, with a margin of 1.8 for the upper bound of the 95% confidence interval of the hazard ratio.

Design

Randomised, placebo-controlled. Once-weekly semaglutide 0.5 mg or 1.0 mg versus placebo for 104 weeks, on top of standard care. Primary composite: first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke.

Who was enrolled

3297 patients with type 2 diabetes on a standard-care regimen. At baseline, 2735 (83.0 percent) had established cardiovascular disease, chronic kidney disease or both.

Primary endpoint and result

Primary outcome in 108 of 1648 (6.6 percent) on semaglutide and 146 of 1649 (8.9 percent) on placebo. Hazard ratio 0.74 (95% CI 0.58 to 0.95; P less than 0.001 for noninferiority). The upper bound of 0.95 is below 1.0, so the result also happened to exclude harm and suggest benefit, but the trial was designed and powered for noninferiority.

Key secondary results

ComponentSemaglutidePlaceboHR (95% CI)
Nonfatal myocardial infarction2.9%3.9%0.74 (0.51 to 1.08); P=0.12
Nonfatal stroke1.6%2.7%0.61 (0.38 to 0.99); P=0.04
Cardiovascular deathsimilar in both groups

New or worsening nephropathy was less frequent with semaglutide. Retinopathy complications (vitreous haemorrhage, blindness, or conditions needing an intravitreal agent or photocoagulation) were significantly more frequent: hazard ratio 1.76 (95% CI 1.11 to 2.78; P=0.02).

Adverse events and discontinuation

Fewer serious adverse events occurred with semaglutide, but more patients discontinued because of adverse events, mainly gastrointestinal. The abstract does not give percentages.

Funding and registration

Novo Nordisk. ClinicalTrials.gov NCT01720446.

What this trial does not show

  • It was a noninferiority safety trial. The apparent benefit was not what it was powered to prove, and later trials (SELECT, FLOW) were needed to test benefit prospectively.
  • Doses were 0.5 and 1.0 mg. No weight-management dose.
  • The retinopathy finding is a signal, not a mechanism. The trial did not establish whether it reflects rapid glucose lowering in people with existing retinopathy or a direct drug effect.
  • Weight change is not in the abstract.

Where the numbers come from

PubMed abstract of the primary paper (PubMed 27633186), fetched 4 September 2026. The oral-semaglutide counterpart is PIONEER 6.

Sources (2)

  1. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6). N Engl J Med 2016;375(19):1834-1844. PubMed 27633186 Accessed September 4, 2026.
  2. ClinicalTrials.gov NCT01720446 Accessed September 4, 2026.

Canonical URL: https://formblendsresearch.com/trials/sustain-6. Written by the FormBlends editorial team. This page is educational and is not medical advice; see the medical disclaimer.