Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes - SUSTAIN-6


The goal of the trial was to assess the cardiovascular (CV) safety of semaglutide in patients with type 2 diabetes mellitus (DM2) at high risk for CV events. Semaglutide is a once-a-week injectable glucagon-like peptide 1 (GLP-1) agonist.

Contribution to the Literature: The SUSTAIN-6 trial showed that semaglutide is superior to placebo in improving glycemic control and reducing CV events in patients with DM2 and high CV risk.

Study Design

Patients were randomized in a 1:1:1:1 fashion to either semaglutide 0.5 mg (n = 826), semaglutide 1 mg (n = 822), or matching placebo (n = 824, 825, respectively). Both medications were administered as a subcutaneous injection once a week.

  • Total number screened: 4,346
  • Total number of enrollees: 3,297
  • Duration of follow-up: 2.1 years
  • Mean patient age: 64.6 years
  • Percentage female: 39%

Other salient features/characteristics:

  • Established coronary artery disease: 60.5%
  • Body weight: 92.1 kg
  • Mean glycated hemoglobin (HbA1c): 8.7%
  • Mean duration of DM2: 13.9 years

Inclusion criteria:

  • DM2
  • Age ≥50 years and concomitant CV, cerebrovascular, or peripheral vascular disease or chronic renal failure or chronic heart failure OR age ≥60 years and other specified risk factors of vascular disease (microalbuminuria/proteinuria, hypertension, left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, ankle-brachial index <0.9)
  • HbA1c ≥7.0%
  • Antidiabetic drug-naive or treated with no more than two oral antidiabetic drugs, with or without basal or premixed insulin

Exclusion criteria:

  • Type 1 diabetes
  • Use of a GLP-1 receptor agonist within 90 days or any dipeptidyl peptidase 4 (DPP-4) inhibitor within the 1 month prior
  • Use of insulin other than human NPH insulin or long-acting insulin analogue or premixed insulin within 3 months prior
  • Acute coronary syndrome or cerebrovascular accident within 90 days
  • Planned coronary, carotid, or peripheral revascularization
  • Long-term dialysis

Principal Findings:

The primary outcome, CV death, nonfatal myocardial infarction (MI), or stroke for semaglutide vs. placebo, was 6.6% vs. 8.9% (hazard ratio 0.74, 95% confidence interval 0.58-0.95, p < 0.001 for noninferiority; p = 0.02 for superiority).

  • CV death: 2.7% vs. 2.8%, p = 0.92
  • All MI: 2.9% vs. 3.9%, p = 0.12
  • All stroke: 1.6% vs. 2.7%, p = 0.04
  • Effect was similar across both doses of semaglutide.

Secondary outcomes:

  • HbA1c at week 104 for 0.5 mg vs. 1 mg vs. placebo: 7.6% vs. 7.3% vs. 8.3%
  • Change in body weight at week 104 for 0.5 mg vs. 1 mg vs. placebo: -3.6% vs. -4.9% vs. -0.6 kg (p < 0.001 for both comparisons vs. placebo)
  • Change in heart rate at week 104 for 0.5 mg vs. 1 mg vs. placebo: 2.1 vs. 2.4 vs. 0.1 (p < 0.001)
  • Diabetic retinopathy for semaglutide vs. placebo: 3% vs. 1.8%, p = 0.02
  • All-cause mortality for semaglutide vs. placebo: 3.8% vs. 3.6%, p = 0.79
  • Chronic heart failure hospitalization for semaglutide vs. placebo: 3.6% vs. 3.3%, p = 0.57
  • New or worsening nephropathy for semaglutide vs. placebo: 3.8% vs. 6.1%, p = 0.005
  • Gallbladder disease for 0.5 mg vs. 1 mg vs. placebo: 3.9% vs. 3.2 vs. 3.7%, p < 0.001
  • Acute pancreatitis for 0.5 mg vs. 1 mg vs. placebo: 0.7% vs. 0.4% vs. 0.7%; pancreatic carcinoma: 0% vs. 0.1% vs. 0.2%
  • Severe or symptomatic hypoglycemic event: 23.1% vs. 21.7% vs. 21.3%


The results of this trial indicate that injectable once a week semaglutide is superior to placebo in improving glycemic control and reducing CV events in patients with DM2 and high CV risk. There was also a significant reduction in stroke and new or worsening nephropathy with semaglutide, perhaps related to a concomitant reduction in blood pressure, and also a reduction in body weight. These are really important findings and suggest that GLP-1 agonists may need to be considered as first-line therapy in similar high-risk patients going forward. Semaglutide is a novel drug for the treatment of DM2 and functions as a GLP-1 agonist. These drugs reduce hyperglycemia in patients with DM2 and are also known to cause slight reductions in weight and blood pressure. However, pulse increases with the use of these agents, but in this trial, suggests no adverse CV consequences. The higher incidence of diabetic retinopathy in this trial will need to be further investigated.

Following the much publicized CV safety concerns with rosiglitazone, the Food and Drug Administration mandated that all new diabetes drugs conduct studies demonstrating CV safety. The upper limit of the 95% confidence interval for the hazard ratio had to be <1.8 for premarketing studies and <1.3 for postmarketing studies. This trial thus establishes the CV safety profile of semaglutide for use in patients with DM2, and is in fact, one of the few large-scale DM2 trials to show an improvement in hard CV outcomes with simultaneous improvements in glycemic control in a high-risk population. The mechanisms for this benefit will need to be established in future trials. The overall results are similar to the liraglutide trial in LEADER (suggesting that it may be a class effect), although event rates are overall lower in this trial, suggesting enrollment of a slightly lower risk population in this trial compared with the LEADER trial.


Marso SP, Bain SC, Consoli A, et al., on behalf of the SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes. N Engl J Med 2016;375:1834-44.

Presented at the European Association for the Study of Diabetes Annual Meeting, Munich, Germany, September 16, 2016.

Keywords: Blood Glucose, Blood Pressure, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Glucagon-Like Peptide 1, Heart Failure, Glycated Hemoglobin A, Hyperglycemia, Hypertrophy, Left Ventricular, Hypoglycemic Agents, Kidney Failure, Chronic, Metabolic Syndrome, Myocardial Infarction, Pancreatic Neoplasms, Peripheral Vascular Diseases, Primary Prevention, Risk Factors, Stroke

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