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FDA advisory committee splits on CV benefit claim for Jardiance
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An FDA advisory panel on Tuesday voted 12 to 11 in favor of an expanded indication for the SGLT2 inhibitor Jardiance, supporting language in the prescribing information that the drug can reduce the incidence of cardiovascular death in patients with type 2 diabetes and a history of cardiovascular disease.
The decision follows an in-depth analysis of primary and secondary endpoints in the EMPA-REG Outcome trial, a randomized, double blind, placebo-controlled study that revealed a surprise CV benefit in patients with type 2 diabetes at high CV risk. The FDA requires that all diabetes drugs undergo testing for CV outcomes. Jardiance (empagliflozin, Boehringer Ingelheim/Lilly) was the first to demonstrate a CV benefit.
In a split decision, the panel voted that the EMPA-REG trial results provided “substantial evidence” that empagliflozin reduces the risk for CV death in the population studied.
The panel also voted 23-0 in support of claims that the drug fulfilled recommendations laid out in the 2008 Guidance for Industry by demonstrating that the use of the drug does not result in unacceptable increase in CV risk.
In its supplemental new drug applications, Boehringer Ingelheim sought a new indication that both empagliflozin and empagliflozin plus metformin (Synjardy) reduced the risk for all-cause mortality by decreasing the incidence of CV death, and reduced the risk for CV death or hospitalization for heart failure in patients with type 2 diabetes who are also at high risk for CVD.
“Today’s vote is a critical step as we look to gain approval of a new indication for the first type 2 diabetes treatment to provide a cardiovascular benefit,” Thomas Seck, MD, vice president of clinical development and medical affairs – metabolism, Boehringer Ingelheim Pharmaceuticals, Inc., told Endocrine Today. “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.”
EMPA-REG results
In announcing the findings in September from EMPA-REG, researchers said that empagliflozin, when combined with standard care, reduced the risk for CV death by 38% compared with placebo, with no significant difference in the risk for nonfatal myocardial infarction or stroke. Patients treated with empagliflozin also experienced a 32% reduction in all-cause mortality risk and a 35% reduction in risk for hospitalization for heart failure, according to researchers.
The trial included 7,020 adults with type 2 diabetes and an established history of CVD (mean age, 63 years; 72% men; mean HbA1c, 8%; mean BMI, 30.6 kg/m²) randomly assigned 10 mg empagliflozin (n = 2,345), 25 mg empagliflozin (n = 2,342) or placebo (n = 2,333). Within the cohort, 76% of participants had an established history of coronary artery disease; 46% of participants had a history of MI; between 9.5% and 10.5% of participants had a history of cardiac failure. Between 80% and 81% of participants were using ACE inhibitors; between 75% and 78% of participants were using statins.
Clinical trial concerns
In an FDA analysis of the trial’s CV findings related to major adverse cardiac events, reviewers noted that the primary endpoint — time to first occurrence of CV death, nonfatal MI and nonfatal stroke — excluded silent MIs. In addition, the trial used an algorithm for silent MIs that likely did not identify all potential events, and reviewers found that data on time-to-event for silent MIs was “not reliable” because in some cases, silent MI changes were also present on earlier electrocardiogram.
“When silent MIs are included in the analysis, the pooled empaglifozin doses are no longer superior to placebo for the composite primary endpoint,” the reviewers wrote in a letter to the Division of Metabolism and Endocrinology Products (DMEP), adding, “the discrepancy merits further consideration.”
Missing data was another issue of concern, according to reviewers; 211 participants discontinued the trial prematurely, so follow-up information for primary endpoint is not available for the entire cohort.
“Considering the totality of the data, including the stroke findings, the silent MI findings, and the missing data, we do not believe that the trial provides substantial evidence that empagliflozin lowers the risk for MACE, and, specifically, strokes and MIs,” the reviewers wrote. “We do, however, believe that the trial provides substantial evidence that empagliflozin reduces the risk for CV death.”
In analysis of the trial findings related to CV death and all-cause mortality, the reviewers cautioned that there were many undetermined causes of death; of the 463 deaths in the trial, 124 (71 empagliflozin; 53 placebo) were defined as “fatal events not assessable” and were presumed to be CV deaths.
“Thus, these deaths, which may or may not have been CV deaths, comprise 40.1% of all CV deaths and 26.8% of all deaths in the trial,” the reviewers wrote. However, sensitivity analysis excluding the 124 cases still demonstrated a reduction in risk for CV death in pooled empagliflozin doses vs. placebo, reviewers noted (HR = 0.59; 95% CI, 0.44-0.79).
“It is important to note that the empagliflozin finding on CV death was driven by treatment effects on three components, including undetermined deaths, worsening heart failure and sudden death,” the reviewers wrote. “As a result, we do not have a good understanding of the mechanism by which empagliflozin is improving mortality.”
The reviewers did not support the applicant’s claim related to hospitalization for HF and a composite of CV death (excluding fatal stroke) or hospitalization for HF. Due to empagliflozin’s diuretic effect, FDA reviewers agreed it is “certainly plausible” the drug could reduce risk for hospitalization for HF; however, the hypothesis should be confirmed in a trial in patients with HF, they wrote.
“In general, we rarely give indications for reducing the risk for all-cause mortality in CV outcome trials, because this endpoint is typically driven by CV death,” they wrote.
The panel’s recommendations are nonbinding, although the FDA often follows its suggestions. – by Regina Schaffer
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Robert H. Eckel, MD
The FDA advisory committee voted to approve an additional indication for empaglifozin for adult patients with type 2 diabetes mellitus and high cardiovascular risk to reduce the risk for all-cause mortality by reducing the incidence of cardiovascular death and the risk for cardiovascular death or hospitalization for heart failure. This is a milestone indication for type 2 diabetes patients at high cardiovascular disease (CVD) risk and needs serious consideration by practicing endocrinologists and by cardiologists and primary care providers as well. A note of caution, however; like any other first-in-class drug effect, this benefit of empaglifozin requires confirmation for benefits in reducing similar outcomes for other members of the SGTLT2 inhibitor class.
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