EXSCEL: No CV Benefit, but No Harm With Bydureon in Diabetes

May 25, 2017

Top-line results from the large cardiovascular safety outcomes trial for AstraZeneca's once-weekly version of the glucagonlike peptide-1 (GLP-1) receptor agonist drug for type 2 diabetes, exenatide (Bydureon), show the agent met the goal of cardiovascular safety but failed to show any cardiovascular benefit.

The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial involved 14,000 people with type 2 diabetes at a wide range of cardiovascular risk, from 35 countries, and randomized them to once-weekly exenatide (2 mg subcutaneously) or placebo on top of usual care.

"Fewer cardiovascular events were observed in the Bydureon arm of the trial; however, the efficacy objective of a superior reduction in major adverse cardiovascular events did not reach statistical significance," the company notes in a statement.

It adds that the full results of EXSCEL will be reported on September 14, at the European Association for the Study of Diabetes meeting in Lisbon, Portugal.

Showing CV Benefit Is the New Norm in Type 2 Diabetes

Trials such as EXSCEL were designed to demonstrate cardiovascular safety of type 2 diabetes drugs in the wake of the rosiglitazone (Avandia, GlaxoSmithKline) scandal.

But surprisingly, some of these trials have also demonstrated cardiovascular benefit, rather than simply lack of harm, and so this has now become the expectation as more and more of these studies are reported.

These include two with other GLP-1 agonists, the LEADER trial with liraglutide (Victoza, Novo Nordisk), a once-daily subcutaneous injection product that has been on the market for some time, and the SUSTAIN-6 trial with another Novo Nordisk GLP-1 agonist, semaglutide.

Semaglutide is a once-weekly subcutaneous injectable product that has not yet been approved; the company is also trying to develop an oral version.

In addition, the landmark EMPA-REG trial — with a different class of type 2 diabetes drug, the sodium glucose cotransporter-2 (SGLT-2) inhibitors — was the first to show a reduction in cardiovascular deaths with a diabetes drug, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) and last December, the FDA allowed a label to be added to that product indicating that it can improve survival.

Therefore, the fact that EXSCEL has failed to show any cardiovascular benefit with once-weekly exenatide when other trials of GLP-1 agonists have shown this to be the case will be viewed as somewhat disappointing.

In the meantime, two more large cardiovascular safety outcomes trials are due to be reported at the American Diabetes Association Scientific Sessions next month.

Those from two trials with the SGLT-2 inhibitor canagliflozin (Invokana, Johnson & Johnson), the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS-R — the latter looking at renal outcomes — in more than 10,000 patients with type 2 diabetes and a history of or at high risk for cardiovascular events will be eagerly anticipated.

And the data from the DEVOTE study will examine the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) compared with insulin glargine.

Follow Lisa Nainggolan on Twitter: @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

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