What difference would an empagliflozin CVD indication make?

When a Food and Drug Administration advisory committee met on June 28 to consider a new indication for the type 2 diabetes drug empagliflozin – reduction of cardiovascular mortality in patients with type 2 diabetes with existing cardiovascular disease or at high risk for cardiovascular disease – an inevitable question was, How will this matter to empagliflozin?

Empagliflozin (Jardiance) received FDA approval in 2014 for treating patients with type 2 diabetes. In 2015, an unexpected result from the EMPA-REG OUTCOME trial showed that treatment of such high-risk diabetes patients with empagliflozin led to a dramatic and still unexplained 38% relative risk reduction in cardiovascular disease (CVD) death, compared with placebo (a 2.2% absolute risk reduction) during a median 2.6 years of treatment and 3.1 years of total follow-up. This surprising result from a trial designed to test empagliflozin’s CVD safety but not its preventive efficacy first went public in a report at the European Association for the Study of Diabetes annual meeting in Stockholm in September 2015 and in a simultaneously published article (N Engl J Med. 2015;373:2117-28).

Dr. Gregg C. Fonarow

So the drug is already on the U.S. market, and its remarkable effect on CVD mortality in a selected population is already on record. Will translating this into a FDA-approved indication mean anything more?

The short answer is it probably will, especially for persuading health insurance payers to cover the substantial cost for prescribing empagliflozin. The other end an added FDA indication achieves is objective confirmation that the CVD mortality benefit seen in the EMPA-REG OUTCOME trial was real and could be anticipated in routine practice.

Some clinicians have already concluded this was a believable result, and that it gives empagliflozin an edge above other oral hypoglycemic drugs for patients who match the study’s enrollment criteria.

“Based on available evidence, the sodium-glucose cotransporter-2 inhibitors [the class that includes empagliflozin] are the preferred therapy for patients with type 2 diabetes and CVD or at high risk for CVD in patients treated with metformin or where metformin is not tolerated. It also should be given preference in patients with or at risk for heart failure,” Gregg C. Fonarow, MD, professor and associate chief of cardiology at the University of California, Los Angeles, said in an interview.

“I am using [empagliflozin] in addition to metformin and aggressive lifestyle changes in patients with established CVD and uncontrolled type 2 diabetes,” said another cardiologist, Alison L. Bailey, MD.

But Dr. Bailey also highlighted her concern about the extra cost to patients for empagliflozin, especially if their insurer wouldn’t pay for it.

Dr. Prakash Deedwania

“Metformin should be the first step based on it’s documented efficacy and cost. I would then add empagliflozin to most of my patients who can get the drug without financial burden,” she told me in an interview.

If an insurer balks at paying for empagliflozin, or if the patient has little or no drug insurance, the financial burden could be substantial. The cost of a month on empagliflozin at the dosage used in the EMPA-REG OUTCOME study is about $415 from one web-based drug supplier, compared with a monthly price of about $6 for a typical monthly regimen of generic metformin. Over the course of a year, that’s about $5,000, compared with $72.

Empagliflozin is “an expensive drug with limited experience,” commented Prakash Deedwania, MD, a cardiologist at the University of California, San Francisco, in Fresno. Metformin, the current linchpin oral agent for treating most patients with type 2 diabetes, has the advantages of low cost and a large, worldwide track record of efficacy and safety, he added.

An FDA indication for reducing cardiovascular disease mortality in selected patients with type 2 diabetes would set empagliflozin apart as the only oral hypoglycemic drug recognized to have this activity and might help grease the wheels for reimbursement.

“Patients can only get the medications their insurance covers. I have a feeling that this indication might help drive coverage,” commented Abraham Thomas, MD, an endocrinologist at New York University, when explaining his vote in favor of the new indication as a member of the FDA advisory committee.

^{Mitchel L. Zoler/Frontline Medical News}

Dr. Abraham Thomas

The other consequence from a positive FDA decision would be a strong statement of confidence that the EMPA-REG OUTCOME result is real. Clearly not everyone on the advisory panel was convinced. The panel’s vote split 12 in favor of the FDA granting the indication and 11 votes against, and many panelists said they found it very hard to balance the powerful result on the one hand against the inexplicable mechanism of the effect and the fact that the mortality benefit came from left field, without prespecification in the study’s design. Now it’s on the FDA’s shoulders to make a decision after parsing the vote, the panelists’ comments, the data, and concerns.