FDA Approves Empagliflozin for Broader Type of Heart Failure

This story has been updated.

The FDA today approved the use of Eli Lilly and Boehringer Ingelheim’s Jardiance (empagliflozin) for a broader range of patients with heart failure, including those with preserved ejection fraction (HFpEF)—a condition with a poor prognosis and very limited treatment options.

Approval was announced in an FDA press release, which did not specify the left ventribular ejection fraction (LVEF) percentage thresholds for which the medicine received the expanded indication.

However, a press release from Boehringer Ingelheim states the indication includes all patients with HF, regardless of EF, and can be started in patients with an estimated glomerular filtration rate as low as 20 mL/min/1.73. An estimated 3 million Americans will now be able to take empagliflozin under the wider indication.

"The indication specifically references improving cardiovascular death and hospitalization in adults with heart failure. So in fact, it is regardless of ejection fraction," said Mohamed Eid, MD, vice president of Clinical Development & Medical Affairs, Cardio-Metabolism & Respiratory Medicine, at Boehringer Ingelheim in an interview with The American Journal of Managed Care® (AJMC®) .

In January 2022, the Committee for Medicinal Products for Human Use of the European Medicines Agency issued a positive opinion for empagliflozin citing data that showed the treatment was effective in patients with heart failure with LVEF over 40%.

Novartis’ Entresto (sacubitril and valsartan) is the only other therapy approved for HFpEF, despite the fact it narrowly missed achieving superiority in a critical phase 3 trial. Regulators evaluated a body of evidence across several studies including patients with LVEF of ≥45% and found that subsets of patients had superior outcomes.

Notably, a phase 3 study presented last year found that empagliflozin is effective in patients with an EF up to 65%—which encompasses all but 10% of the HF population—and investigators have produced data showing benefits in those with LVEF of 41% to 49%, 50% to 59%, and 60% and higher.

Because of this, experts have deliberated whether most of the benefit is accrued in patients who now fit a definition of "mildly reduced" LVEF under European Society of Cardiology Guidelines. Releseased in 2021, the ESC updates include a change from “heart failure with mid-range ejection fraction” to the term “heart failure with mildly reduced ejection fraction” (HFmrEF) to describe patients with LVEF of 41% to 49%.

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that was first approved for patients with type 2 diabetes (T2D) in 2014. However, in 2015, trial findings indicated the drug yielded cardiovascular benefits, while in July of 2021, results from EMPEROR-Preserved marked the first time a clinical trial had successfully demonstrated a therapy can cut the risk of hospitalization and cardiovascular death for those with HFpEF.

EMPEROR-Preserved built upon previously published data that together represent the spectrum of HF from reduced ejection fraction to preserved ejection fraction, Eid explained.

Data, which were presented at the 2021 ESC Annual Meeting, revealed empagliflozin resulted in a 21% reduced risk of hospitalization and death in patients, with those results driven by a 27% reduction in first and recurrent HF hospitalization. Reduction in cardiovascular mortality did not reach significance (9%). Previous research has also shown the treatment is effective for both acute and chronic HF.

A total of 5988 patients were enrolled in EMPEROR-Preserved, with an average EF of 54% and average age of 72 years. Participants were randomized 1:1 to empagliflozin or placebo. After a median of 26.2 months, the number of hospitalizations (first and recurrent) for heart failure in the empagliflozin group was 407; the number in the placebo group was 541 (HR, 0.73; 95% CI, 0.61-0.88, P < .001).

"We actually did have a pre-specified pooled analysis to look across that spectrum [of HF]," in EMPEROR-preserved, Eid said.

Prevalence of HFpEF is growing at about 1% per year while higher rates of hospitalizations are driving up medical costs. Figures from 2014 show the mean cost of an HF hospitalization is around $11,500, accounting for a total nationwide cost of $11 billion.

"[Empagliflozin] is the first therapy, I think, that really clearly demonstrates an improvement in outcomes for patients with HFpEF," said Nihar R. Desai, MD, MPH, in an interview with AJMC®.

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

"We're incredibly excited about what it means for the patients that we serve," he noted, adding the EMPEROR program as a whole provides "a sense of the benefit of SGLT2 inhibition, in this case empagliflozin, for patients with heart faiure, regardless of ejection fraction."

Today’s announcement comes after the treatment received a Breakthrough Therapy Designation for HFpEF in September of 2021. Empagliflozin has also been approved for HF with reduced ejection fraction (HFrEF) regardless of T2D status, as of August 2021.

HFpEF is responsible for approximately 6 million HF cases in the United States and affects about 30 million people globally. Incidence increases as populations age and the condition is very common among older women. Around half of patients with HF will die within 5 years of diagnosis and risk of death increases with each HF hospitalization.

HFpEF occurs when a patient’s left ventricle is unable to fill properly, causing an inadequate amount of blood to be pumped through the body. This deprives the body and organs of adequate oxygen.

Uptake of empagliflozin and SGLT2 inhibitors for HF in the United States has been slow, due in part to reluctance of third-party payers to provide coverage. But with empagliflozin's positive impacts on diabetes, renal function, and HF, value extends beyond its price tag.

"Value-based care is a very important component of health care delivery overall," Eid said, noting the company is actively working to increase access to the medicine and incorporating empagliflozin into value-based models.

"Many systems and entities have also taken proactive decisions to really prefer Jardiance as an option for individuals with heart failure, regardless of their diabetes," he said.

"We work with those entities in a very customized manner, to really understand what's on their mind, what's really characterizing their population, and how we can work with them to...tailor modeling and understanding of how that impact will be represented in their own systems."

Whether these drugs have a class effect in HFpEF remains to be seen. An additional study, DELIVER, is currently underway to investigate dapagliflozin in HF.

Although a pooled analysis from studies of the SGLT1/2 inhibitor sotagliflozin found benefits in HFpEF, plans for a dedicated HF study lost funding.