–FDA reviewers have raised no major questions ahead of Tuesday’s advisory panel meeting.
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will likely lend its support to an important new expanded indication for empagliflozin (Jardiance, Boehringer Ingelheim). The new indication is to reduce the risk of all-cause mortality by reducing the incidence of cardiovascular death, and to reduce the risk of cardiovascular death or hospitalization for heart failure in patients with type 2 diabetes who are also at high risk for cardiovascular disease.
The advisory panel will base its recommendation on a detailed FDA staff analysis of last year’s Empa-Reg Outcome trial. This was the first trial with any of the new diabetes drugs to demonstrate a significant benefit on cardiovascular outcomes, and the new indication would be the first for any diabetes drug to claim a cardiovascular benefit.
The FDA reviewers did not raise any major objections to the proposed indication, though their painstaking analysis will provide plenty of chewy meat for the panelists’ intellectual meal. But the reviewers accepted the main finding of the trial, which found that empagliflozin demonstrated that it was both noninferior and superior to placebo in the reduction of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke (HR 0.86; 95% CI 0.74, 0.99; P=0.04 for superiority). “We believe that the data demonstrate that empagliflozin reduces the risk of CV [cardiovascular] death in adult patients with type 2 diabetes mellitus who are at high CV risk,” the FDA’s cardiology consultants wrote.
The FDA reviewers raised several questions about the manner in which the trial examined hospitalization for heart failure and other heart failure endpoints. The need for rigorous review of heart failure endpoints in diabetes trials has been the subject of considerable recent discussion. The reviewers said they did not recommend approval of the drug for the reduction of heart failure hospitalization or the composite of cardiovascular death (excluding fatal stroke) or hospitalization for heart failure.
Another issue will be the size of the trial, since it was not prospectively sized “with the expressed intent of demonstrating a cardiovascular benefit,” the reviewers noted. But the highly significant results and the large number of endpoint events will likely provide the panel with a level of comfort. For similar reasons, the panel will likely be able to comfortably dismiss concerns about the use of a single trial to support the proposed indication.
The panel will also discuss the precise wording of the mortality benefit. “We rarely give indications for reducing the risk of all-cause mortality in CV outcome trials because this endpoint is typically driven by CV death,” a reviewer wrote.
No new safety concerns were identified in the FDA review.