Semaglutide trial finds lower heart risk and more eye complications over two years

The New England Journal of Medicine has published SUSTAIN-6, a randomized trial that gave semaglutide its first two-year safety record in people with type 2 diabetes at high cardiovascular risk. The study assigned 3,297 adults to weekly semaglutide or placebo, and the combined rate of cardiovascular death, nonfatal heart attack or nonfatal stroke was 6.6% on semaglutide versus 8.9% on placebo ^[1][2].

How the trial was run

Patients were randomized 1:1:1:1 to once-weekly semaglutide at 0.5 mg or 1.0 mg, or to a matching placebo, at 230 sites in 20 countries ^[1]. Enrollment ran from February through December 2013, and the last patient visit was March 15, 2016 ^[1].

The treatment period was 104 weeks, followed by a five-week follow-up period, for a planned observation period of 109 weeks; the median observation time was 2.1 years ^[1]. Everyone in the trial had type 2 diabetes, and 2,735 people, or 83.0%, already had established cardiovascular disease, chronic kidney disease, or both ^[1][2]. About 20% of participants stopped treatment early, at similar rates in the semaglutide and placebo groups ^[1].

The trial was built to show semaglutide was not worse than placebo for cardiovascular risk. The noninferiority margin was a hazard ratio of 1.80 at the upper end of the 95% confidence interval ^[1][2].

What the trial found

The primary outcome — the first cardiovascular death, nonfatal heart attack or nonfatal stroke — occurred in 108 of 1,648 people on semaglutide (6.6%) and 146 of 1,649 on placebo (8.9%). That is a hazard ratio of 0.74, with a 95% confidence interval of 0.58 to 0.95 (P<0.001 for noninferiority) ^[1][2].

Nonfatal heart attack occurred in 2.9% of the semaglutide group and 3.9% of the placebo group (hazard ratio 0.74; 95% CI 0.51 to 1.08; P=0.12). Nonfatal stroke occurred in 1.6% versus 2.7% (hazard ratio 0.61; 95% CI 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups ^[1][2].

Retinopathy complications — vitreous hemorrhage, blindness, or eye conditions requiring treatment with an intravitreal agent or photocoagulation — were significantly more frequent with semaglutide, with a hazard ratio of 1.76 (95% CI 1.11 to 2.78; P=0.02) ^[1][2]. New or worsening nephropathy was less common in the semaglutide group ^[1][2]. Fewer serious adverse events occurred with semaglutide, but more patients discontinued treatment because of adverse events, mainly gastrointestinal ^[1][2].

The authors describe the trial's formal goal as confirming noninferiority. Testing for superiority on the primary outcome was not prespecified and was not adjusted for multiple comparisons ^[1]. The trial was funded by Novo Nordisk, the drug's manufacturer ^[1][2]. At the time of publication, semaglutide was in development and had not been approved for type 2 diabetes ^[1].

Why it matters for patients

This is the longest randomized dataset people still cite when asking whether staying on semaglutide for years is safe, and its design — placebo-controlled, double-blind, with cardiovascular events checked by an independent committee — gives it more weight than observational reports ^[1]. Over roughly two years, the composite cardiovascular outcome was about 2 percentage points less common on semaglutide, or about 2 fewer events per 100 people treated ^[1][2].

The retinopathy finding runs the other way and is the main safety signal in the trial. The study reported that eye complications were more common on semaglutide but does not explain why, and it did not establish whether the risk changes with longer use ^[1][2].

The results also come with limits. Everyone enrolled had type 2 diabetes and high cardiovascular risk, so the numbers do not describe people without diabetes or people taking semaglutide for weight loss alone. The doses studied were 0.5 mg and 1.0 mg weekly, and the trial followed patients for 109 weeks, not longer ^[1][2]. Cardiovascular effects beyond that window have not been reported from this trial.

What happens next

Longer-term safety data beyond the 109-week observation period have not been disclosed from SUSTAIN-6 ^[1]. Later semaglutide trials in other populations have since been published, including a 2023 study in adults with obesity without diabetes and a 2024 study in chronic kidney disease with type 2 diabetes ^[2], but their results are separate from the two-year record reported here.