Semaglutide trial cut heart attacks and strokes in type 2 diabetes but raised retinopathy risk

The cardiovascular safety trial known as SUSTAIN 6 found that adults with type 2 diabetes at high cardiovascular risk who took once-weekly semaglutide had fewer heart attacks, strokes and cardiovascular deaths than those who took a placebo. The trial also found a higher rate of diabetic retinopathy complications, a finding that still appears as a warning in the U.S. prescribing information for Ozempic, the injectable semaglutide brand approved for type 2 diabetes ^[1][2].

SUSTAIN 6 randomly assigned 3,297 patients with type 2 diabetes who were already on standard care to once-weekly semaglutide at 0.5 mg or 1.0 mg, or to placebo, for 104 weeks ^[1]. At the start, 2,735 of them, or 83.0%, already had established cardiovascular disease, chronic kidney disease, or both ^[1]. The main outcome measured was the first occurrence of cardiovascular death, nonfatal heart attack or nonfatal stroke ^[1].

That outcome occurred in 108 of 1,648 patients (6.6%) taking semaglutide and in 146 of 1,649 patients (8.9%) taking placebo, for a hazard ratio of 0.74 and a 95% confidence interval of 0.58 to 0.95 ^[1]. In absolute terms, the gap was 2.3 percentage points. The trial's stated purpose was to show semaglutide was not worse than placebo for cardiovascular risk, a standard called noninferiority, and it met that goal with a P value below 0.001 ^[1]. The lower rate in the semaglutide group suggested an advantage rather than simply an equal result.

Looking at the pieces of that combined outcome separately, nonfatal heart attack occurred in 2.9% of patients on semaglutide and 3.9% on placebo (hazard ratio 0.74; 95% CI, 0.51 to 1.08; P=0.12), and nonfatal stroke occurred in 1.6% and 2.7% respectively (hazard ratio 0.61; 95% CI, 0.38 to 0.99; P=0.04) ^[1]. Rates of death from cardiovascular causes were similar in the two groups ^[1]. New or worsening kidney disease was less common with semaglutide ^[1].

On the other side of the ledger, retinopathy complications defined as vitreous hemorrhage, blindness, or conditions needing treatment with an intravitreal agent or photocoagulation were significantly more common with semaglutide, with a hazard ratio of 1.76 (95% CI, 1.11 to 2.78; P=0.02) ^[1]. Ozempic's prescribing information lists diabetic retinopathy complications among its warnings and precautions and says patients with a history of diabetic retinopathy should be monitored ^[2]. The trial report does not explain why those complications were more frequent.

Fewer serious adverse events occurred overall in the semaglutide group, but more patients stopped treatment because of adverse events, mainly gastrointestinal ones ^[1]. The label lists nausea, vomiting, diarrhea, abdominal pain and constipation as the most common adverse reactions, reported in at least 5% of patients ^[2].

The trial was funded by Novo Nordisk, which makes semaglutide, and registered as NCT01720446 ^[1]. Such cardiovascular trials are required by regulators to rule out excess heart risk in new diabetes therapies ^[1]. Ozempic received its initial U.S. approval in 2017 ^[2].

Why it matters for patients

For adults who have type 2 diabetes along with established cardiovascular disease, reducing the risk of major cardiovascular events is an approved use of Ozempic, alongside improving blood sugar as an addition to diet and exercise ^[2]. For people with type 2 diabetes who do not have established cardiovascular disease, that cardiovascular indication does not apply, and the sources do not establish whether the same benefit would appear. The trial enrolled a high-risk group in which most patients already had cardiovascular disease, kidney disease, or both ^[1].

The retinopathy finding is the main counterweight. It means a history of diabetic eye disease is relevant information for a prescribing clinician, because the label calls for monitoring in those patients ^[2]. The trial ran for 104 weeks, so what happens over longer periods is not addressed in these sources. The gastrointestinal side effects were the most common reason patients stopped treatment in the trial ^[1], and they remain the most frequently reported adverse reactions on the label ^[2].

Whether these results extend to other semaglutide products, such as the oral form or the weight-management brand, is not established by this trial, which studied the injectable form in type 2 diabetes only ^[1][2].