GLP1 analogue with extended half-life is non-inferior to placebo

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Literature - Marso SP, et al, NEJM, 2016

Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators.
N Engl J Med. 2016 Sep 15. [Epub ahead of print]


Recent trials evaluating a sodium-glucose cotransporter 2 inhibitor (empagliflozin) and a glucagon-like peptide 1 (GLP-1) analogue (liraglutide) have shown a clinical CV benefit in patients with type 2 diabetes (T2DM) who were at high risk of CV events [1,2].
Semaglutide is a GLP-1 analogue with an extended half-life of approximately 1 week, allowing once-weekly subcutaneous administration [3]. Regulatory guidance demands the need to establish the CV safety of new therapies for T2DM, in order to rule out excess CV risk.

The preapproval Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) therefore aims to assess the noninferiority of semaglutide as compared with placebo in terms of CV safety in patients with T2DM. The SUSTAIN-6 study was a randomised, double-blind, placebo-controlled, parallel-group trial at 230 sites in 20 countries. 3297 patients with T2DM and HbA1c of ≥7% and of ≥50 years old with established CV disease, chronic heart failure, or chronic kidney disease were randomised, or of 60 years old with at least one CV risk factor were randomised. Included patients had not been treated a dipeptidyl-peptidase 4 (DPP4) inhibitor, with a GLP1 receptor agonist or insulin other than basal or premixed within 30/90 days before screening. Patients were treated with 0.5 or 1.0 mg once-weekly subcutaneous semaglutide or volume-matched placebo.

Main results

  • At baseline, 2735 (83%) of patients had established CV disease (including chronic kidney disease of stage 3 or higher), 1940 patients (58.8%) established CV disease without chronic kidney disease, 353 (10.7%) had chronic kidney disease only and 442 (13.4%) had both CV disease as well as kidney disease.
  • During a 104-week treatment period and a consequent 5-week follow-up period, the composite primary outcome ‘first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal stroke’ occurred in 108 of 1648 (6.6%) in the semaglutide group and in 146 of 1649 (8.9%) patients in the placebo group (HR 0.74; 95% CI: 0.58-0.95, P<0.001 for noninferiority, P=0.02 for superiority).
  • MI occurred in 2.9% of the semaglutide group and 3.9% of the placebo group (HR 0.74, 95% CI: 0.51-1.08, P=0.12), non-fatal stroke in 1.6% vs. 2.7% of semaglutide vs. placebo-treated patients respectively (HR 0.61, 95% CI: 0.39-0.99, P=0.04) and the risk of death was 2.7% vs. 2.8% in the semaglutide vs. placebo group respectively (HR 0.98, 95% CI: 0.65-1.48, P=0.92).
  • For both doses of semaglutide, similar risk reductions for the primary outcome and its components were observed.
  • At week 104, glycated haemoglobin level decreased with 1.1% and 1.4% for patients receiving 0.5 mg and 1.0 mg semaglutide respectively. In the placebo group, the mean level decreased 0.4% in both group (P<0.001 for both doses comparisons semaglutide vs. placebo).
  • Body weight decreased with 3.6 kg and 4.9 kg for 0.5 mg and 1.0 mg semaglutide-treated patients respectively. This was -0.7 and -0.5 kg in the placebo groups (P<0.001 for both comparisons).
  • Diabetic retinopathy complications occurred in 3.0% in the semaglutide group and 1.8% in the placebo group (HR 1.76, 95% CI: 1.11-2.78, P=0.002). New or worsening nephropathy occurred in 3.8% of the semaglutide group and 6.1% of the placebo groups.
  • The mean systolic blood pressure (SBP) was, compared to the placebo group, 1.3 mmHg (P=0.10) and 2.6 mmHg (P<0.001) lower in patients receiving 0.5 and 1.0 mg semaglutide respectively.
  • The mean pulse rate was, compared to the placebo group, 2.0 bpm and 2.5 bpm higher in patients receiving 0.5 and 1.0 mg semaglutide, respectively (P<0.001 for both comparisons).
  • Gastrointestinal events were more frequent in the semaglutide group than in the placebo group (50.7 and 52.3% for 0.5 and 1.0 mg semaglutide respectively and 35.7 and 35.2% for both placebo groups). Most events were mild or moderate in the first 30 weeks
  • Discontinuation because of adverse events was more frequent in the semaglutide group. The frequency of serious events was lower in the semaglutide group.


Semaglutide is noninferior to placebo. Semaglutide-treated patients had a significant lower risk of the primary composite outcome ‘death from CV causes, nonfatal MI or nonfatal stroke’. This was driven by a significant decrease in the rate of nonfatal stroke and a nonsignificant decrease in nonfatal MI. Doses of semaglutide resulted in similar risk reductions.

Except for complications of retinopathy, semaglutide had a safety profile similar to that of other GLP1-receptor agonists.

Find this publication online at NEJM


1.  Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-28.
2.  Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-22
3.  Lau J, Bloch P, Schäffer L, et al. Discovery of the once-weekly  glucagon-like  peptide-1  (GLP-1)  analogue  semaglutide.  J Med Chem 2015;58:7370-80.

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