FDA Advisers Narrowly Okay Empagliflozin CV Mortality Claim

Alicia Ault

June 29, 2016

A US Food and Drug Administration advisory committee has hesitantly given its backing to a new labeling claim, that of reduced cardiovascular mortality for the sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), a drug used to treat type 2 diabetes.

The Endocrinologic and Metabolic Drugs Advisory Committee voted 12-11 on June 28 that the data in the EMPA-REG OUTCOME study provided substantial evidence to establish that empagliflozin reduced cardiovascular mortality in the population studied, those with type 2 diabetes and established CV disease.

Empagliflozin would be the first diabetes drug to claim that it can cut death — if the FDA follows the panel's advice. But the advice wasn't exactly clear-cut.

"Good luck on figuring out what to do," committee member Marvin A Konstam, MD, professor of medicine, Tufts University, Boston, Massachusetts, told agency officials.

Most panelists said they were impressed with the reduction in cardiovascular and all-cause mortality, but a majority also 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.

"I don't think we have to understand a mechanism to accept a benefit," said David W Cooke, MD, interim director of pediatric endocrinology at Johns Hopkins University School of Medicine, Baltimore, Maryland. But it is necessary to have an understanding of which patients might receive the greatest benefit from empagliflozin, said Dr Cooke, who voted against approving the new claim.

Just how empagliflozin is reducing mortality was a widely discussed topic at the recent American Diabetes Association Scientific Sessions in New Orleans, as reported by Medscape Medical News. Answers are still unclear.

"We haven't been presented with a plausible mechanism for the effects of this drug on cardiovascular mortality," said FDA panel chair Robert J Smith, MD, professor of medicine and an endocrinologist at the Warren Alpert School of Medicine, Brown University, Providence, Rhode Island.

Dr Smith voted against allowing a new labeling claim. "As one trial goes, this is a convincing set of data," he said, referring to EMPA-REG. But he added that he was uncertain whether a second trial could produce the same results.

Nonassessable Deaths Questioned

EMPA-REG was first reported at the EASD meeting last September and simultaneously published in the New England Journal of Medicine. This was the first time that a diabetes drug had been shown to offer cardiovascular benefits in addition to lowering blood glucose.

EMPA-REG was initially designed to answer safety concerns, but, with early data indicating a mortality benefit, it underwent multiple modifications in consultation with the FDA. The prespecified primary end point was the time to first occurrence of an adjudicated major adverse CV event (MACE), defined as CV death, nonfatal myocardial infarction (MI), or nonfatal stroke (three-point MACE). The trial was to stop after 691 participants had experienced an adjudicated MACE event.

The prespecified secondary end point was the time to first occurrence of adjudicated CV death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina (MACE+, or four-point MACE). The company was to conduct four analyses comparing pooled results of two different doses of empagliflozin with placebo with appropriate control of type-1 error.

According to the FDA, empagliflozin was found to be both noninferior and superior to placebo on MACE (hazard ratio [HR], 0.86; 95% CI, 0.74–0.99; P = .04 for superiority). The drug was also found to be noninferior but not superior to placebo on MACE+ (HR, 0.89; 95% CI 0.78–1.01; P = .08 for superiority).

The risk of MACE appeared to diverge early — about 3 months in — and was almost exclusively accounted for by the CV-death component (HR, 0.62; 95% CI, 0.49–0.77). Empagliflozin did not reduce nonfatal stroke (HR 1.24; 95% CI, 0.92–1.67) or nonfatal MI (HR 0.87; 95% CI, 0.70–1.09).

Seventy-one empagliflozin deaths and 53 placebo deaths were categorized as "nonassessable" and adjudicated as presumed CV deaths. Those presumed CV deaths made up 40% of the total CV deaths and 27% of overall deaths.

In a sensitivity analysis that removed all "nonassessable" deaths, empagliflozin was no longer superior to placebo (HR 0.90; 95% CI, 0.77–1.06).

Some panelists therefore questioned whether the mortality reduction was a true finding.

But Michael Proschan, PhD, a statistician in the biostatistics research branch at the National Institute of Allergy and Infectious Diseases, said the mortality benefit was real. "I think that's substantiated," he told his colleagues on the panel.

Boehringer Ingelheim also reported a reduction in hospitalization for heart failure, but most committee members said the company had not given enough proof. This finding is "not nearly as compelling" as the mortality data, said Dr Proschan, who voted for the mortality claim.

"I'm not impressed with the heart-failure data," agreed panelist Paul Palevsky, MD, professor of medicine at the University of Pittsburgh School of Medicine, Pennsylvania.

EMPA-REG also showed that empagliflozin was renoprotective, reducing the incidence of worsening nephropathy by 39%, according to Boehringer, which recently unveiled that data at the ADA meeting.

Dr Palevsky, who voted against the new labeling claim, said the renal data were not rigorously collected or adjudicated. "There are very intriguing data here, but it's far from the level that would establish a specific renal benefit," he said.

Decision Coming Soon?

The FDA accepted the Lilly/Boehringer Ingelheim application for a new claim for empagliflozin in January.

At the time, the company said it expected a decision "within the standard review time frame."

In a statement, Thomas Seck, MD, Boehringer vice president of clinical development and medical affairs, called the panel vote a "critical step" toward securing approval. "We look forward to continuing to work with the FDA in our ongoing efforts to provide options that help reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease," he said.

The company told Medscape Medical News it expects a decision on this additional labeling claim for empagliflozin in the second half of 2016.

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