Bydureon EXSCEL trial shows favorable cardiovascular safety profile in patients with type-2 diabetes

Exenatide once-weekly did not increase the incidence of major adverse cardiovascular events (MACE), a composite endpoint of CV death, non-fatal heart attack (myocardial infarction) or non-fatal stroke, compared to placebo (Hazard Ratio [HR]: 0.91; 95% Confidence Interval [CI]: 0.83-1.00; p<0.001 for non-inferiority).

There were also fewer CV events observed in the exenatide arm of the trial (839 [11.4%] versus 905 [12.2%]), although the primary efficacy objective of a superior reduction in MACE narrowly missed statistical significance (p=0.061).

The direction of the cardiovascular outcomes results in EXSCEL was consistent with those seen in recently completed outcomes trials within the GLP-1 receptor agonist class. Additionally, in a prespecified secondary analysis, patients on exenatide had a 14% lower incidence of death from all causes (HR: 0.86; 95% CI: 0.77-0.97).

The full results of EXSCEL, including important secondary endpoints, sensitivity analyses and regional data, were presented at the 53rd annual meeting of EASD and simultaneously published today online in the New England Journal of Medicine.

Investigator Rury Holman, Professor of Diabetic Medicine and Diabetes Trials Unit Director, University of Oxford, UK, said: “People with type-2 diabetes have up to a two-times increased risk for all-cause mortality and four-times increased risk for cardiovascular death compared to the general population, making it imperative that their type-2 medication does not further increase their risk for cardiovascular disease and related complications.

“The EXSCEL study results demonstrated that exenatide could be used safely in patients with type-2 diabetes with a wide range of cardiovascular risk and suggested potential benefit with respect to all-cause mortality.”

Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic Diseases, Global Medicines Development, said: “The results from the EXSCEL trial provide important evidence supporting the use of once-weekly Bydureon in a broad population of patients with type-2 diabetes at a wide range of cardiovascular risk.

This comprehensive trial is representative of our commitment to address multiple risk factors or co-morbidities associated with cardiovascular and metabolic diseases and helps to inform clinical practice for the benefit of millions of patients with type-2 diabetes.”

Multiple sensitivity analyses for MACE, recalculating the outcome under alternative assumptions to determine the potential impact of different variables, were consistent with primary analyses. No safety issues were identified during the EXSCEL trial and data were consistent with the known safety profile of exenatide. Specifically, there was no imbalance in retinopathy, a microvascular complication that commonly occurs from type-2 diabetes and can lead to serious visual disability and blindness.

The EXSCEL trial enrolled the largest and most inclusive patient population of any CV outcomes trial of the glucagon-like peptide-1 (GLP-1) receptor agonist class conducted to date, having included more than 14,500 patients at 687 trial sites across 35 countries, incorporating usual care and wide-ranging eligibility criteria.

BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. BYDUREON is not indicated to reduce the risk of MACE or all-cause mortality, and there are no clinical trials establishing conclusive evidence of macrovascular risk reduction with BYDUREON. AstraZeneca is working with regulatory authorities to incorporate these data into the Bydureon label.

EXSCEL is a Phase IIIb/IV, double-blind, placebo-controlled, global CV outcomes trial conducted in 35 countries and enrolled more than 14,500 patients with type-2 diabetes with or without additional CV risk factors or prior CV events.

 Participants were randomized to receive exenatide once-weekly 2mg or matching placebo by subcutaneous injections. EXSCEL was run jointly by two academic research organizations – the Duke Clinical Research Institute (Durham, NC, US) and the University of Oxford Diabetes Trials Unit (Oxford, UK).