FDA Advisory Panel Narrowly Recommends CVD Mortality Indication for Diabetes Drug Empagliflozin

(UPDATED) A US Food and Drug Administration (FDA) advisory committee voted narrowly today in favor of recommending an expanded indication for empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) that would state the diabetes drug reduces the risk of cardiovascular mortality.

The Endocrinologic and Metabolic Drugs Advisory Committee was almost equally split on the voting question about the quality of evidence supporting the cardiovascular mortality indication for empagliflozin. In total, 12 panel members felt the data provided substantial evidence in establishing that empagliflozin significantly decreases the risk of cardiovascular mortality, while 11 committee members did not. The panel was unanimous in their belief that the drug does not result in an unacceptable increase in cardiovascular risk.

With the split vote, Marvin Konstam, MD (Tufts Medical Center, Boston, MA), wished the FDA luck in figuring out what to do regarding the label. “I think the vote, actually, is very representative of what’s been going on in my mind all day long, of going back and forth about what the right thing to do is,” said Konstam, one of the 12 yes votes. “I will say that every member voted no, I agree with what they said. I agree with everybody. It’s tough.”

The agency is not required to follow the advice of the advisory panel, although it typically does.

Empagliflozin Impresses in EMPA-REG

During the daylong meeting, the advisory committee sifted through data from the EMPA-REG OUTCOME trial, a large-scale cardiovascular outcomes study designed to meet the safety requirements for diabetic medications set out by the FDA. In 2008, the FDA issued guidance for industry requiring companies to show that their drugs do not result in an unacceptable increase in cardiovascular risk.

Empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, is currently approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes.

Presented in 2015 at the European Association for the Study of Diabetes meeting and published simultaneously in the New England Journal of Medicine, the trial showed that treatment with empagliflozin reduced the risk of cardiovascular death, nonfatal stroke, and nonfatal MI by 14% compared with placebo-treated patients receiving standard therapy for glycemic control. In addition, empagliflozin significantly lowered the risks of all-cause and cardiovascular mortality by 32% and 38%, respectively, compared with placebo.

Despite the reductions in all-cause and cardiovascular mortality observed in the trial, panel members grappled with understanding the mechanism of benefit. In the study, empagliflozin failed to reduce the risk of nonfatal MI and nonfatal stroke, the two other components of the three-part primary endpoint. Treatment with empagliflozin also had no significant impact on unstable angina and the need for coronary revascularization. There was a significant 35% reduction in the risk of heart-failure hospitalizations, but the panel members, as well as the FDA reviewers, questioned the adjudication of those events and the reliability of the outcome.

Melissa Li-Ng, MD (Cleveland Clinic Abu Dhabi, United Arab Emirates), who voted no, said the lack of clear mechanism behind the reduction in cardiovascular mortality was a sticking point. “Clinically, I practice in a region where SGLT-2 inhibitors were approved before the US FDA approved them—they’ve been in use for 3 or 4 years already—and for me to tell a patient that now [the drugs] have been shown to decrease your risk of dying based on one study, despite the robust evidence, that’s very hard for me to say that without a second study to confirm these findings,” she commented.

While some panel members, like Li-Ng, desired a second trial to confirm the mortality reduction, others had a hard time reconciling an expanded indication based on a secondary endpoint. As another no vote, Susan Heckbert, MD (University of Washington, Seattle), said the clinical trial did provide evidence of a reduction in cardiovascular mortality, but given that committee members were asked whether or not that evidence was “substantial” enough to recommend an expanded claim, she said it was not. She struggled with aspects of the trial, including some of the nonassessable causes of death, as well as the fact that cardiovascular mortality was not the primary endpoint.

“Also, the FDA usually requires two well-designed and conducted trials to add this type of indication,” said Heckbert. “Taking all those things together, my opinion is that although these data are intriguing and promising, a second study is needed before this indication would be added.”

Peter Wilson, MD (Emory University, Atlanta, GA), also voted no, pointing out that empagliflozin is the first drug in its class seeking a cardiovascular mortality claim. “I think we should have a higher bar for the quality of the evidence,” he said. “Given the importance of the findings, they should really be substantiated.”

Some Committee Members See a Glass Half Full  

In explaining his vote, Konstam noted that in EMPA-REG OUTCOME, the P value for superiority in the primary composite endpoint was 0.04—if the P value was 0.07, he wondered, would the panel even have convened to discuss the cardiovascular mortality reduction indication? Still, Konstam voted to recommend the expanded claim, saying he was impressed by the number of clinical events in the trial. In total, 172 of 4,687 patients died from cardiovascular causes in the empagliflozin arm (3.7%) compared with 137 of 2,333 patients in the placebo arm (5.9%).

Commenting on his yes recommendation, Abraham Thomas, MD (NYU Lutheran Medical Center, Brooklyn, NY), admitted he also struggled with the statistical strength of the primary endpoint.

“However, the mortality is very convincing,” said Thomas. “Fortunately, the all-cause mortality is consistent. This isn’t the case like previous trials where there was an improvement in cardiovascular mortality but all-cause mortality goes the wrong way. What’s important though, and what I was wrestling with, is whether you require a second trial or not? I voted yes, thinking you probably don’t, but there are a lot of unanswered questions—the mechanism, heart failure—that could be studied in additional trials.”

Numerous cardiologists on the panel voted yes, including James de Lemos, MD (UT Southwestern Medical Center, Dallas, TX), and Brendan Everett, MD (Brigham and Women’s Hospital, Boston, MA). For de Lemos, he questioned how clinical events were classified in EMPA-REG, noting that some events were likely misclassified in the trial. He also said the cardiovascular mortality reduction is probably “dramatically overestimated” and unlikely to be replicated to the same degree in future trials. “But the robustness of the finding, the large number of endpoint events, and most importantly, the fact that it buttressed by all-cause mortality, the ultimate endpoint, that to me drove a narrow decision to recommend approval,” said de Lemos.

For Everett, the positive primary endpoint, even though it was a composite, allowed him “to get through the door” to examine the individual components, such as cardiovascular mortality. “The effect on cardiovascular mortality is clear and substantial, and as others have mentioned, survives multiple sensitivity analyses,” he said. However, he acknowledged the lack of replication, either with empagliflozin or another SGLT-2 inhibitor, making him hesitant in voting yes.

“As the FDA is turning [over] these comments over the course of the next several months, I would not object to waiting to give the label until there is a second or third endpoint trial that includes cardiovascular death as one of its key components,” said Everett.

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