EU Empagliflozin Indication to Be Expanded for CVD Prevention?

Liam Davenport and Lisa Nainggolan

December 16, 2016

(updated 12/19/16) The indication for empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for the treatment of type 2 diabetes should be expanded beyond glycemic control to encompass prevention of cardiovascular events, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended.

The CHMP adopted the positive opinion this week recommending a change to the marketing authorization for empagliflozin in the European Union. This was done using cryptic wording, which appears to suggest a similar additional indication to that which was approved recently by the US Food and Drug Administration (ie, the prevention of cardiovascular disease [CVD] death in adults with both type 2 diabetes and existing CVD).

However, it is not totally clear.

Boehringer Ingelheim has issued a press release entitled: "CHMP adopts a positive opinion acknowledging that Jardiance reduces the risk of CV death."

It contains the following statement: "The CHMP recommends to update the label for Jardiance for the treatment of adults with insufficiently controlled type 2 diabetes. This is the first time the CHMP supports the use of a diabetes treatment for its effect on both glycemic control and cardiovascular events."

The FDA approval for the additional indication was based on results from the Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, conducted in more than 7000 patients in 42 countries.

This landmark study, reported in September 2015, was the first to show a type 2 diabetes drug that confers benefits beyond glucose lowering, with empagliflozin resulting in a 38% relative risk reduction in cardiovascular mortality compared with placebo in type 2 diabetes patients with existing CVD.

The adoption of this positive opinion by the CHMP sees the recommended wording move away from emphasizing the role of empagliflozin in glycemic control to underlining its utility in the treatment of diabetes, adds Boehringer Ingelheim.

This recommendation to update the product information means it will now include "data on the reduction of risk of cardiovascular death in patients with type 2 diabetes and established CV disease, in addition to data on the improvements of blood sugar control," the company notes.

Normally, a positive opinion in the European Union automatically becomes a marketing authorization within 67 days.

Hans-Juergen Woerle, MD, global vice president medicine, therapeutic area metabolism, Boehringer Ingelheim, commented in the press release that CVD is the "number-one cause of death" in people with type 2 diabetes, shortening their life expectancy by up to 12 years.

He added: "There is a significant need for therapies that add to and go beyond the current standard of care. Therefore, this recommendation by the CHMP is an important step toward addressing and reducing the burden of cardiovascular mortality for people with type 2 diabetes."

What Does It Mean? EMA Takes Different Stance From FDA

Asked for his thoughts on this European decision, cardiologist Darren McGuire, MD, University of Texas Southwestern, Dallas, who has been involved in a number of the cardiovascular-outcomes trials for type 2 diabetes drugs, told Medscape Medical News: "The changes are quite different between the FDA and EMA."

For the FDA, an indication was added for empagliflozin to "reduce the risk of CV death in patients with diabetes," but the original/primary indication remains as an adjunct to diet and exercise to lower blood glucose, Dr McGuire observed.

But the EMA is recommending completely altering the indication and has "implicitly woven all into one, such that the medication will be indicated to treat patients with diabetes as opposed to treating hyperglycemia in patients with diabetes (ie, indication for the patient instead of indication for the biomarker)," he said.

This is "a key and novel distinction/indication in the field of diabetes," stressed Dr McGuire.

By doing this, the EMA indication "appropriately partitions the effects of empagliflozin on biomarkers from the effects on patient experience/outcomes. And the EMA does not limit the indication to CV death reduction but apparently leaves that to the interpretation of the provider," by saying see CV effects summarized in sections 4.4, 4.5, and 5.1, he concluded.

Dr McGuire reported receiving personal fees from Boehringer Ingelheim, Lilly, Janssen, Sanofi,, Merck Sharp & Dohme, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon, and Pfizer.

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