FDA Approves Empagliflozin for Reducing CVD Death

Miriam E. Tucker

December 02, 2016

The US Food and Drug Administration (FDA) has approved empagliflozin (Jardiance, Boehringer Ingelheim Pharmaceuticals Inc) for the new indication of improving survival in adults with type 2 diabetes and cardiovascular disease (CVD).

The sodium glucose cotransporter-2 inhibitor empagliflozin was first approved by the FDA in August 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is also available in Europe. The new US indication labels it for prevention of death due to CVD in adults with both type 2 diabetes and existing CVD.

"Cardiovascular disease is a leading cause of death in adults with type 2 diabetes mellitus," Jean-Marc Guettier, MD, CM, director of the Division of Metabolism and Endocrinology Products in FDA's Center for Drug Evaluation and Research, said in a statement. "Availability of antidiabetes therapies that can help people live longer by reducing the risk of cardiovascular death is an important advance for adults with type 2 diabetes."

The FDA's decision is based on a postmarketing study required by the agency at the time it approved empagliflozin for treating type 2 diabetes.

Findings from that study, the landmark (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving more than 7000 patients, were first reported in September 2015 at the European Association for the Study of Diabetes (EASD) meeting in Stockholm, Sweden, and simultaneously published in The New England Journal of Medicine. The results were the first (others also have since) to show that a diabetes drug offered cardiovascular benefit beyond mere glucose lowering.

Empagliflozin produced a 38% relative risk reduction in cardiovascular mortality and a 32% risk reduction in all-cause mortality compared with placebo among the patients with type 2 diabetes, all of whom had established cardiovascular disease and were already being treated with statins, angiotensin-converting inhibitors, and aspirin.

"Empagliflozin is reducing death, the ultimate outcome," senior author of the study, Silvio Inzucchi, MD, from Yale Diabetes Center, New Haven, Connecticut, told Medscape Medical News at the 2015 EASD meeting. "This is a first in my lifetime — a diabetes drug trial that has shown improved outcomes in high-risk cardiovascular patients."

However, although an FDA advisory panel endorsed the indication at a June 2016 meeting, the vote was close (12-11). Panel members who voted against it said they had reservations about using a single study to support a new labeling claim, especially for the first drug in a relatively new class of agents. A few expressed concern that the mechanism for the mortality reduction has not been determined.

The FDA cautions that empagliflozin can cause dehydration and hypotension and may also lead to ketoacidosis, serious urinary tract infection (UTI), acute kidney injury and impairment in renal function, hypoglycemia (when used with insulin or insulin secretagogues), vaginal yeast infections, genital mycotic infections, and dyslipidemia. Of these, the most common are UTIs and genital infections in females.

Empagliflozin is not intended for patients with type 1 diabetes mellitus or for treating diabetic ketoacidosis. It is contraindicated in patients with a history of serious hypersensitivity reactions to the drug, severe renal impairment, end-stage renal disease, or dialysis.

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