Exenatide Study of Cardiovascular Event Lowering - EXSCEL

Contribution To Literature:

The EXSCEL trial showed that exenatide was noninferior to placebo at preventing adverse events.


The goal of the trial was to evaluate extended-release exenatide (glucagon-like peptide-1 [GLP-1] receptor agonist) compared with placebo among patients with type 2 diabetes.

Study Design

  • Randomized
  • Parallel
  • Blinded
  • Placebo

Patients with type 2 diabetes with or without cardiovascular disease (73.1% had previous cardiovascular disease) were randomized to subcutaneous exenatide 2 mg once weekly (n = 7,356) versus subcutaneous placebo once weekly (n = 7,396).

  • Total number of enrollees: 14,752
  • Duration of follow-up: median 3.2 years
  • Percentage female: 38%

Inclusion criteria:

  • Patient has type 2 diabetes
  • Patient is able to see a usual care provider at least twice a year
  • Patient has a hemoglobin A1c of ≥6.5% and ≤10.0% and is currently on a stable diabetes treatment regimen
  • Patients with any level of cardiovascular risk
  • Patients ≥18 years

Exclusion criteria:

  • Two or more episodes of severe hypoglycemia
  • End-stage renal disease
  • Family history of medullary thyroid cancer or multiple endocrine neoplasia type 2
  • Calcitonin level >40 ng/L
  • Previous treatment with a GLP-1 receptor agonist

Principal Findings:

The primary outcome, incidence of cardiovascular death, myocardial infarction, or stroke, occurred in 11.4% of the exenatide group vs. 12.2% of the placebo group (p < 0.001 for noninferiority; p = 0.06 for superiority). There was no evidence of enhanced benefit for exenatide vs. placebo according to baseline risk.

Secondary outcomes:

  • All-cause death: 6.9% for exenatide vs. 7.9% for placebo (hazard ratio 0.86, 95% confidence interval 0.77-0.98)
  • Any serious adverse event: 16.8% for exenatide vs. 16.6% for placebo
  • Among the 10,782 patients with cardiovascular disease at baseline, exenatide vs. placebo was associated with a marginal reduction in the primary outcome (HR 0.90, 95% CI 0.82-1.0); however, there was no evidence for treatment interaction compared with the group without cardiovascular disease (p for interaction = 0.50).


Among patients with type 2 diabetes, extended-release exenatide was noninferior to placebo at preventing adverse cardiovascular events. Exenatide failed to demonstrate superiority at preventing adverse cardiovascular events. The authors were unable to claim a reduction in all-cause mortality due to the prespecified hierarchical testing plan. Results were the same in tested subgroups, including those with versus without a history of cardiovascular disease.


Mentz RJ, Thompson VP, Aguilar D, et al. Effects of Once-Weekly Exenatide on Clinical Outcomes in Patients With Preexisting Cardiovascular Disease: A Prespecified Analysis From EXSCEL. Circulation 2018;Aug 28:[Epub ahead of print].

Presented by Dr. Robert J. Mentz at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 13, 2017.

Holman RR, Bethel MA, Mentz RJ, et al., on behalf of the EXSCEL Study Group. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228-39.

Keywords: AHA17, AHA Annual Scientific Sessions, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Glucagon-Like Peptide 1, Glycated Hemoglobin A, Myocardial Infarction, Metabolic Syndrome, Peptides, Primary Prevention, Risk Factors, Stroke, Treatment Outcome

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