Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, +8 more
New England Journal of Medicine (2016) · n=3297
In 3,297 high-cardiovascular-risk type 2 diabetes patients, weekly semaglutide reduced the composite primary cardiovascular endpoint by 26% over a median 2.1 years — the trial that established cardiovascular benefit for the GLP-1 class and presaged the 2023 SELECT result in obesity.
SUSTAIN-6 is the cardiovascular safety / cardiovascular outcomes trial that established semaglutide's cardiovascular benefit in type 2 diabetes years before the 2023 SELECT trial extended that benefit to the obesity-without-diabetes population. The trial randomized 3,297 patients with type 2 diabetes who were on standard-care diabetes regimens — 83% of whom had established cardiovascular disease, chronic kidney disease, or both — in a 1:1 ratio to once-weekly subcutaneous semaglutide (0.5 mg or 1.0 mg pooled across two arms) or placebo for a median follow-up of 2.1 years. The primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke occurred in 108 of 1,648 patients (6.6%) on semaglutide versus 146 of 1,649 (8.9%) on placebo, a hazard ratio of 0.74 (95% CI 0.58–0.95, P<0.001 for noninferiority and significantly favoring semaglutide on superiority). Nonfatal stroke specifically dropped from 2.7% to 1.6% (HR 0.61, 95% CI 0.38–0.99, P=0.04). New or worsening nephropathy rates were lower on semaglutide. The result satisfied the FDA's cardiovascular safety requirement for diabetes drugs and established positive cardiovascular benefit beyond noninferiority — a finding that supported expanded use within the diabetes indication and helped justify the larger SELECT trial in cardiovascular obesity.
A consistent concerning finding from SUSTAIN-6 was an increase in retinopathy complications on semaglutide (3.0% vs 1.8%, HR 1.76, 95% CI 1.11–2.78, P=0.02). The mechanism is debated: some commentators attribute it to the rapid glycemic improvement on semaglutide unmasking pre-existing retinopathy (a known phenomenon with any rapid glycemic correction), others to a more direct semaglutide-specific effect. Subsequent trials and pooled analyses have produced mixed signals; the FOCUS retinopathy outcomes trial (ongoing as of early 2026) is designed to clarify. The trial population was largely Western, middle-aged-to-older adults with substantial cardiovascular comorbidity; generalizability to younger or earlier-stage diabetes patients is partial. Industry sponsorship by Novo Nordisk is disclosed. The 2.1-year median follow-up is substantial for a CVOT but short relative to the chronic-therapy timeline most patients will use the drug across.