SUSTAIN-6 results, in plain terms: among 3,297 adults with type 2 diabetes and a high chance of heart trouble, weekly semaglutide injections came with fewer major heart events than placebo over about two years. A heart attack, stroke or cardiovascular death, counted together, happened to 6.6% of people versus 8.9%. The trial was built to check that the drug was safe for the heart, and it came out better than safe. It also found more diabetic eye complications, 3.0% versus 1.8%, and that finding is still on the label.
Semaglutide, later sold as Ozempic, is a GLP-1 drug that copies a gut hormone involved in blood sugar and appetite. The results appeared in the New England Journal of Medicine in 2016 (Marso et al., NEJM 2016).
What question did SUSTAIN-6 ask?
A safety question. Regulators wanted makers of new diabetes drugs to rule out extra heart risk, so SUSTAIN-6 was a non-inferiority trial: its job was to show semaglutide was not meaningfully worse than placebo for the heart, not to prove it was better. The top of the trial's statistical range for heart risk had to land below 1.8, which rules out a rise of 80% or more (registry record, NCT01720446).
The main outcome was MACE, short for major adverse cardiovascular events: a cardiovascular death, nonfatal heart attack or nonfatal stroke, counted once per person at the first event.
Who was in the SUSTAIN-6 trial
Everyone had type 2 diabetes with an HbA1c, the roughly three-month blood-sugar average, of 7.0% or higher. They were 50 or older with established heart, blood-vessel or kidney disease, or 60 or older with other heart risk factors. The average participant was 65 and had lived with diabetes for about 14 years; 83% already had cardiovascular disease, chronic kidney disease, or both.
People were left out if they'd had a heart attack or stroke in the previous 90 days, had the most severe heart failure, or had a personal or family history of medullary thyroid cancer.
Participants were assigned by chance to weekly semaglutide 0.5 mg or 1 mg, or a look-alike placebo shot, on top of usual care for 104 weeks, with a median observation time of 2.1 years (Ozempic prescribing information).
SUSTAIN-6 results: the heart numbers
| First event during the trial | Semaglutide (1,648 people) | Placebo (1,649 people) | Hazard ratio |
|---|---|---|---|
| Heart attack, stroke or cardiovascular death | 108 (6.6%) | 146 (8.9%) | 0.74 |
| Nonfatal heart attack | 47 (2.9%) | 64 (3.9%) | 0.74 |
| Nonfatal stroke | 27 (1.6%) | 44 (2.7%) | 0.61 |
| Cardiovascular death | 44 (2.7%) | 46 (2.8%) | 0.98 |
A hazard ratio compares how quickly events happened in each group; 0.74 is where the "26% lower risk" headline comes from. In plain counts, about 23 fewer people per 1,000 had a major event over roughly two years.
Read the rows, though. Stroke was the only single piece that cleared the statistical threshold on its own, and deaths from heart causes were essentially the same.
The SUSTAIN-6 retinopathy signal
The surprise was in the eyes. Retinopathy is damage to the light-sensing layer at the back of the eye, and the trial counted its complications: needing laser treatment or eye injections, bleeding inside the eye, or diabetes-related blindness. These happened to 50 people on semaglutide (3.0%) and 29 on placebo (1.8%), a hazard ratio of 1.76.
Who they happened to matters most. Of the 79 people with a complication, 66 already had retinopathy when they joined (Vilsbøll et al., Diabetes Obes Metab 2018). With existing retinopathy, the rates were 8.2% on semaglutide and 5.2% on placebo; without it, 0.7% and 0.4%. All five semaglutide patients who met the trial's blindness definition had advanced retinopathy treated before they enrolled.
That is the origin of the retinopathy warning on today's Ozempic and Wegovy labels. The Ozempic label, revised 5/2026, adds that fast blood-sugar improvement has been linked to temporary worsening and that the long-term effect has not been studied; semaglutide and vision covers the wider eye picture.
Side effects in SUSTAIN-6
Stomach symptoms were the main difference, and they led more people to stop.
| During the trial | Semaglutide 0.5 mg | Semaglutide 1 mg | Placebo |
|---|---|---|---|
| Nausea | 17.3% | 21.8% | 7.5–8.0% |
| Vomiting | 10.5% | 14.8% | 4.0–5.1% |
| Diarrhea | 17.9% | 18.0% | 10.5–11.8% |
| Decreased appetite | 10.4% | 9.1% | 1.1–2.3% |
| Stopped treatment because of a side effect | 11.5% | 14.5% | 6.7% |
| Any serious adverse event | 32.1% | 29.2% | 34.9% |
Symptom rates come from the registry results, where placebo shows as a range because the trial ran two placebo groups, one matched to each dose. The stopping and serious-event rates come from the FDA's 2017 clinical review. Serious events, such as ones that put someone in hospital, were slightly less common with semaglutide.
What critics and later studies said
The trial was small for its question. It logged 254 first major events, according to the FDA's 2017 summary review, and the registry record labels the test showing semaglutide was better than placebo, not merely no worse, as post hoc: run after the fact rather than planned.
The eye finding drew sharper scrutiny. At an FDA advisory committee meeting on October 18, 2017, the panel's ophthalmologists said the way eye events were identified was not adequate. The trial team later reported that most of the excess traced to large, fast drops in blood sugar in the first 16 weeks among people with existing retinopathy; adjusting for that drop shrank the hazard ratio to 1.22, no longer statistically clear. The FDA's statistical reviewer called that analysis hypothesis-generating, not a conclusive explanation.
As of September 23, 2026, the day this article was written, a systematic review of the eye question covering 31 studies, published August 1, 2026, found that apart from SUSTAIN-6 no randomized trial had shown faster retinopathy progression, and no convincing evidence that these drugs damage the retina directly (Francisco et al., Graefes Arch Clin Exp Ophthalmol 2026). On the heart side, a 2026 analysis by Novo Nordisk-linked researchers found no link between weight lost by week 56 and later heart events (Navas et al., Diabetes Ther 2026).
What came next: SELECT, SOUL, FLOW and FOCUS
Ozempic's approval letter is dated December 5, 2017. On January 16, 2020, the agency added a heart indication, a use written into the label, based on SUSTAIN-6 (approval letter). Bigger trials followed:
- SELECT tested semaglutide 2.4 mg, the Wegovy dose, in 17,604 adults with heart disease and overweight or obesity but no diabetes; see SELECT trial results.
- SOUL tested the daily tablet in 9,650 adults with type 2 diabetes, designed from the start to show benefit; see SOUL trial results.
- FLOW tested 1 mg in 3,533 adults with diabetes and kidney disease and found fewer serious kidney events, a hazard ratio of 0.76 (Perkovic et al., NEJM 2024).
The eye question got its own five-year trial, FOCUS, in about 1,500 people. As of September 23, 2026, the day this article was written, it has not reported: its registry record, last updated September 9, 2026, lists primary completion for November 2027.
What SUSTAIN-6 can and cannot tell you
It describes older adults with long-standing type 2 diabetes and high heart risk, on 0.5 or 1 mg. It says nothing direct about people without diabetes; our semaglutide and heart health guide pulls that wider evidence together.
Its lasting legacy is the eye-history question. Because the extra complications clustered in people who already had retinopathy and saw big early blood-sugar drops, existing eye disease and the last dilated eye exam are things a prescriber weighs before semaglutide starts.
How the trial fits a prescribing conversation
SUSTAIN-6 tested Novo Nordisk's own product. Through Promise, semaglutide is dispensed as a compounded medication, which is different from an FDA-approved product: the formulation offered here is not FDA-approved. The trial's numbers belong to the product it tested and cannot simply be carried over. A licensed provider may still prescribe a compounded formulation; that decision is between you and your doctor.
Diabetes, eye disease, insulin use, recent heart events and kidney function all change how SUSTAIN-6 applies to one person. The prescriber sets any dose and how quickly it rises. At Promise, a licensed provider reviews every request, and not everyone qualifies.
