FDA's Fast Track Designation for Empagliflozin in Heart Failure Points to New Paradigm

On Wednesday, Boehringer Ingelheim and Eli Lilly announced that FDA had granted Fast Track status for empagliflozin (Jardiance), for reduction of the risk of cardiovascular death and hospitalization for heart failure for patients with chronic heart failure.

The designation is for the EMPEROR Reduced and EMPEROR Preserved clinical trials, which began in February 2017 and are scheduled to run through June 2020. It allows for an expedited review to treat a serious or life-threatening condition for which there is an unmet medical need.

“This is very exciting news, not just for Boehringer Ingelheim and Eli Lilly, but also for heart failure patients that we serve,” said Mohamed Eid, MD, MPH, MHA, vice president for Clinical Development & Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. In addition to its approval for type 2 diabetes (T2D), empagliflozin received an indication to reduce the risk of cardiovascular death in patients with T2D. However, the EMPEROR trials are studying the drug’s effects in patients with heart failure with and without diabetes, so the new indications could move the drug’s use into new territory.

The Fast Track designation “will help facilitate the new indications,” Eid said, by allowing for more regular interactions and dialogue with regulators.

First approved in 2014, empagliflozin and other sodium glucose cotransporter 2 (SGLT2) inhibitors have reshaped care for T2D, along with another new drug class, glucagon-like peptide-1 (GLP-1) receptor agonists. The unique mechanism of the SGLT2 inhibitors targets a protein in the renal system and causes glucose to be excreted through the urine; these drugs are poised to be all-purpose workhorses to treat the cardiorenal system, based on results that were presented earlier this month at the American Diabetes Association (ADA) Scientific Sessions in San Francisco, California.

In a statement, Boehringer Ingelheim and Eli Lilly said that heart failure affects more than 6.5 million people in the United States and contributes to 1 in 9 deaths. A leading cause of hospitalization, heart failure is such a huge cost driver that it was one of the first conditions targeted by CMS in the Hospital Readmission Reduction Program starting in 2012.

Empagliflozin surged ahead of competitors, after investigators shocked the diabetes world nearly 4 years ago with trial results that showed the drug substantially reduced the risks of cardiovascular death (38%) and hospitalization for heart failure (35%). Canagliflozin (Invokana, Janssen) and dapagliflozin (Farxiga, AstraZeneca) have since been shown to have benefits in heart failure, but last fall empagliflozin earned a favorable position on the American College of Cardiology’s Expert Consensus Decision Pathway.

Empagliflozin’s benefits in heart failure were revealed after the condition was initially passed over as a focus of the first cardiovascular outcomes trials (CVOTs). In a 2017 interview, heart failure specialist Eldrin F. Lewis, MD, MPH, told The American Journal of Managed Care^® that specialists in the field had encouraged designers of the first CVOTs to make heart failure a primary end point. Although they did not succeed, Lewis said heart failure belatedly gained notice after EMPA-REG OUTCOME and other studies showed the potential for SGLT2 inhibitors to prevent this debilitating condition. About 25% of patients with heart failure have diabetes.

(After EMPA-REG OUTCOME investigators reported their findings, the leaders of the DECLARE-TIMI trial for dapagliflozin added cardiovascular death and hospitalization for heart failure as a second co-primary end point, which produced a significant positive result.)

Eid noted the wave of CVOTs presented earlier this month at ADA, many of which focused on the potential for SGLT2 inhibitors to prevent renal decline. The first dedicated renal outcomes trial, CREDENCE, just reported results showing that canagliflozin reduced renal failure and death 30% in patients with T2D and chronic kidney disease.

“This is a paradigm shift in how we understand diabetes and how we treat diabetes,” Eid said. “Previously, it was about blood sugar and sugar control. Now, we have a different view of diabetes, kidney complications, heart complications, and the cardiometabolic-renal milieu, and that brings about the medication we want to develop that should be able to address the facets of this syndrome.”

Empagliflozin, he said, has the potential to address the “overlapping, unmet need of diabetes, heart failure, and chronic kidney disease,” although he noted that the EMPEROR trials would also be studying the drug in patients with heart failure without diabetes.

Coverage. A 2018 late-breaking study at the ADA Sessions found 28% of patients did not start new diabetes medications, notably SGLT2 inhibitors, due to cost reasons. Patients younger than 65 had more difficulty than those eligible for Medicare.

Ask if coverage remained a challenge, Eid said, “We are always in constant dialogue with payers and other stakeholders” to share information on which patients would benefit from having access to therapy. “It’s our role to provide evidence to support the decision,” he said, noting that in addition to the clinical trial evidence, real-world evidence from the EMPRISE study has supported access to SGLT2 inhibitors.

Potential in Type 1 Diabetes. Eid discussed recent positive results from phase 3 trials for the use of empagliflozin as an adjunct to insulin in type 1 diabetes (T1D). Other manufacturers have studied SGLT2 inhibitors in T1D; the class appears to reduce the “roller coaster” effect and help these patients achieve better time in range, which is emerging as a more important indicator of long-term health than glycated hemoglobin alone. Trials showed increased incidence of diabetic ketoacidosis (DKA); however, the EASE-3 study tested a lower dose of empagliflozin, 2.5 mg, with less increase in DKA than placebo.