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FDA Approves Drug for Reducing CVD Death

Dec 15, 2016

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

The sodium glucose cotransporter-2 inhibitor (SGLT-2) 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.

The new indication sets Jardiance apart from its competitors among sodium glucose cotransporter-2 (SGLT2) inhibitors more than a year after the CV benefits of the drug were found in the EMPA-REG OUTCOME study. In that trial, which involved 7000 patients, Jardiance was found to reduce the risk of CV death, compared to a placebo, when added to standard of care therapies for diabetes and atherosclerotic CV disease.

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.

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.

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. 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.

Thus, Jardiance is the first diabetes drug to show a CV benefit in high-risk patients, which researchers considered a “holy grail” The safety trial that uncovered the benefit, in fact, was the result of findings a decade prior in which an earlier blockbuster class of diabetes drugs were found to have potential risks, which caused the FDA to change its approval process to require post marketing cardiovascular outcomes trials.

For the first time, the FDA approved the claim that a diabetes drug empagliflozin (Jardiance) reduces cardiovascular death risk for people with type 2 diabetes and co-existing cardiovascular disease. This is truly important information as most people with diabetes die from cardiovascular disease, strokes and heart attacks. It’s the first such claim ever allowed for a diabetes drug.  Its benefit for cardiovascular risk reduction was demonstrated in the so-called EMPA-REG trial, results of which were reported in 2015.
The CDC reports that death from CV disease is 70% higher among those with diabetes than those without, and reported in the journal of the American College of Cardiology that, among the 3 main risk factors—the other 2 being hypertension and obesity—those who have diabetes by age 45 face the greatest increase in risk of dying from heart failure.

SGLT2 inhibitors work through a distinct mechanism of action in which excess glucose is expelled from the body through the urinary tract. The drug class is known to have positive effects on hypertension and may produce modest weight loss. SGLT2 inhibitors are only approved for use in T2D, but they are being studied in patients with type 1 diabetes.

Practice Pearls

  • On December 2, 2016, the FDA approved empagliflozin for a new indication: to reduce the risk for CV death in adults with T2D and established CVD.
  • Decision was based on a post-marketing clinical trial, EMPA-REG OUTCOME, involving more than 7000 patients with T2D who had CVD, showing that empagliflozin reduced CV deaths significantly compared with placebo.
  • Not intended for patients with type 1 diabetes or for treating DKA. Contraindicated in patients with history of serious hypersensitivity reactions to the drug, severe renal impairment, end-stage renal disease, or dialysis.

N Engl J Med. Published September 17, 2015. Article