FDA approves empagliflozin for broader types of heart failure_Cortex

Introduction: The FDA approved Jardiance (empagliflozin) for the treatment of a wider range of heart failure types, including patients with heart failure with preserved ejection fraction.

On February 25, 2022, the FDA approved empagliflozin, jointly developed by Eli Lilly and Germany's Boehringer Ingelheim, to treat a wider range of heart failure types, including patients with heart failure with preserved ejection fraction (HFpEF), who have poor prognosis and very limited treatment options.

The FDA announced the approval in a press release but did not specify the left ventricular ejection fraction (LVEF) threshold required to expand the drug's indications.

However, a press release from Germany's Boehringer Ingelheim stated that the drug is indicated for all patients with heart failure, regardless of the patient's ejection fraction (EF), and can be started in patients with estimated glomerular filtration rates as low as 20 mL/min/1.73. With the expanded indications for the drug, an estimated 3 million Americans will now be able to receive empagliflozin.

"This indication specifically mentions improving cardiovascular death and hospitalization in adults with heart failure. So, in fact, it's not related to ejection fraction," Dr. Mohamed Eid, vice president of cardiometabolic and respiratory medicine, clinical development and medical affairs, told AJMC®.

In January 2022, the European Medicines Agency's Committee for Medicinal Products for Human Use issued a positive opinion on empagliflozin, citing data showing that the drug is effective in patients with heart failure whose left ventricular ejection fraction exceeds 40%.

Entresto (sacubitril and valsartan), developed by Novartis, is the only other drug approved to treat heart failure with preserved ejection fraction, although it showed modest benefit in a pivotal Phase 3 trial. Regulators reviewed evidence from multiple studies and found that the drug showed better efficacy in subgroups of patients, including those with left ventricular ejection fraction ≥45%.

It is worth noting that the results of a phase 3 study released last year showed that empagliflozin is effective in patients with an ejection fraction as high as 65%, which accounts for 90% of heart failure patients. In addition, the researchers provided data showing that the drug was more effective in patients with left ventricular ejection fractions of 41%-49%, 50%-59%, and 60% and above.

That's why experts are considering whether better outcomes might be achieved in patients who have what the European Society of Cardiology (ESC) defines as a "mildly reduced" left ventricular ejection fraction. The ESC updated the guidelines in 2021, changing "heart failure with intermediate ejection fraction" to "heart failure with mildly reduced ejection fraction" (HFmrEF) to describe patients with a left ventricular ejection fraction of 41%-49%.

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that was first approved for use in patients with type 2 diabetes (T2D) in 2014. Results from a 2015 trial showed the drug also had cardiovascular benefits. In July 2021, results from the EMPEROR-Preserved trial marked the first successful clinical trial of empagliflozin, which reduces the risk of hospitalization and cardiovascular death in patients with heart failure with preserved ejection fraction.

Eid explained that the EMPEROR-Preserved trial builds on data published from earlier studies, which together paint a spectrum of heart failure from reduced to preserved ejection fraction.

Data released at the 2021 ESC Annual Meeting showed that empagliflozin reduced patients' risk of hospitalization and death by 21%, including a 27% reduction in first-time and recurrence hospitalization rates, and a non-significant reduction in cardiovascular mortality (9%). Previous studies have also shown that the drug is effective in both acute and chronic heart failure.

A total of 5988 patients were enrolled in the EMPEROR-Preserved trial, with a mean age of 72 years and a mean ejection fraction of 54%. Participants were randomly divided into 2 groups at a ratio of 1:1, one group received empagliflozin treatment, and the other group received placebo. After a median of 26.2 months, 407 patients were hospitalized (first time and relapsed) in the empagliflozin group compared with 541 patients in the placebo group (HR, 0.73; 95% CI, 0.61-0.88, p < .001).

"We actually do have a prespecified pooled analysis to look at the entire heart failure spectrum," Eid said.

The prevalence of heart failure with normal ejection fraction is increasing at a rate of about 1% per year, and rising hospitalization rates are driving up medical costs. Data from 2014 show that the average cost of hospitalization for heart failure is about $11,500, with the total cost of treating patients nationwide being $11 billion.

"I think empagliflozin is the first therapy to really improve outcomes in heart failure with preserved ejection fraction," Nihar R. Desai, MD, MPH, told AJMC®.

Desai is a cardiologist, associate professor of medicine and associate chief of the Division of Cardiovascular Medicine at Yale University School of Medicine.

"We are very excited about this because we know what this means for the patients we serve," he said. "Overall, EMPEROR shows that the SGLT2 inhibitor empagliflozin can benefit patients with heart failure regardless of ejection fraction." "

Prior to this, this therapy received breakthrough therapy designation in September 2021 for heart failure with preserved ejection fraction. As of August 2021, empagliflozin is also approved for heart failure with reduced ejection fraction, regardless of whether these patients also have type 2 diabetes.

Approximately 6 million people in the United States have heart failure with preserved ejection fraction, and approximately 30 million patients worldwide. The incidence increases with the age of the population, and the condition is very common in older women. About half of people with heart failure will die within 5 years of diagnosis, and each heart failure hospitalization increases the risk of death.

Preserved ejection fraction heart failure occurs when the left ventricle fills abnormally, resulting in insufficient blood being delivered throughout the body, resulting in a lack of oxygen to the body and organs.

Empagliflozin and other SGLT2 inhibitors have not been widely adopted among heart failure patients in the United States, in part because third-party agencies are reluctant to cover the drugs in insurance. But because of its positive effects on diabetes, kidney function and heart failure, the value of empagliflozin extends far beyond its price tag.

"Value-based care is a very important component of overall care," Eid said. The company is actively working to increase access to the drug and integrate empagliflozin into a value-based system.

"Many organizations and institutions have also made positive decisions in favor of empagliflozin as a treatment option for patients with heart failure, regardless of whether they also have diabetes," he said.

“We work with these organizations on a customized basis, tailoring the approach after really understanding their thinking, the characteristics of their groups, the collaborative approach we should be leveraging, and understanding how to represent that impact in their own systems.”

Whether these drugs have some efficacy in heart failure with preserved ejection fraction remains to be seen. Another study called DELIVER is underway to study dapagliflozin in heart failure.

Although meta-analyses of the SGLT1/2 inhibitor sogliflozin have demonstrated benefit in the treatment of heart failure with preserved ejection fraction, dedicated research programs in heart failure currently lack funding.