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
| Component | Semaglutide | Placebo | HR (95% CI) |
|---|---|---|---|
| Nonfatal myocardial infarction | 2.9% | 3.9% | 0.74 (0.51 to 1.08); P=0.12 |
| Nonfatal stroke | 1.6% | 2.7% | 0.61 (0.38 to 0.99); P=0.04 |
| Cardiovascular death | similar 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
- 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.
- 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.