EMPEROR-Reduced: Empagliflozin's HFrEF Benefit Solidifies Class Effects

Mitchel L. Zoler, PhD

August 29, 2020

The SGLT2 inhibitor drug class solidified its role as a major, new treatment for patients who have heart failure with reduced ejection fraction and no diabetes, with results from a second large, controlled trial showing clear efficacy and safety in this population.

Patients with heart failure with reduced ejection fraction (HFrEF) treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) had a statistically significant 25% relative cut in their incidence of cardiovascular death or heart failure hospitalization, compared with placebo controls, when added on top of standard HFrEF treatment, and this benefit was consistent regardless of whether the treated patients also had type 2 diabetes, Milton Packer, MD, reported at the virtual European Society of Cardiology (ESC) Congress 2020. Their results were also simultaneously published in the New England Journal of Medicine.

This 25% drop in the primary endpoint with empagliflozin treatment in the EMPEROR-Reduced trial exactly matched the cut in incidence of cardiovascular death or heart failure hospitalization produced by treatment with another SGLT2 inhibitor, dapagliflozin (Farxiga, AstraZeneca), in the previously reported DAPA-HF trial.

The performance of these two SGLT2 inhibitors was "incredibly consistent" across their respective trials run in patients who had HFrEF with and without type 2 diabetes, and the combined evidence base of the two trials makes for "really compelling evidence" of both safety and efficacy that should prompt a change to U.S. practice, with both of these drugs forming a new cornerstone of HFrEF treatment, Dr. Packer said.

Results Plant Drug Class Firmly as HFrEF Treatment

Dr. Packer stressed in his presentation that optimal treatment of patients with HFrEF now demands use of one of these two SGLT2 inhibitors, as well as sacubitril plus valsartan (Entresto, Novartis), a β-blocker, and a mineralocorticoid receptor antagonist, plus a diuretic as a fifth drug class for the many patients with HFrEF who also need treatment for fluid overload.

He further advocated rapid introduction of these four cornerstone agents with proven survival benefits once a patient receives an HFrEF diagnosis, suggesting that sacubitril plus valsartan, an SGLT2 inhibitor, a β-blocker, and a mineralocorticoid receptor antagonist could all be initiated within 6 weeks or less, while acknowledging that optimal up-titration of the β-blocker would likely take longer.

The order in which a patient starts these drugs shouldn't matter, and currently no evidence clearly points toward using either dapagliflozin or empagliflozin over the other, Dr. Packer added.

Recognizing the importance of sending a message to heart failure clinicians about the newly proven efficacy of SGLT2 inhibitors in patients with HFrEF, the American College of Cardiology and American Heart Association are now drafting an "expert decision pathway" to help clinicians as they enter this new prescribing space. This interim-guidance document should come out before the end of 2020, prior to release of fully revised HFrEF management guidelines in 2021, said Athena Poppas, MD, president of the ACC, in an interview.

"There is clearly need for education" that can help guide physicians who care for patients with HFrEF on how to introduce an SGLT2 inhibitor, along with the additional, lengthy list of drug classes proven to benefit these patients, noted Dr. Poppas, who is also a professor and chief of cardiology at the Alpert Medical School of Brown University in Providence, Rhode Island.

Physicians may find that they need extra backup for successfully starting both sacubitril plus valsartan and an SGLT2 inhibitor in patients with HFrEF because recent history has shown substantial pushback from third-party payers in reimbursing for these drugs, Dr. Poppas noted. She added that this problem may be compounded when patients should ideally get both drug classes.

Physicians who care for patients with heart failure have their own history of dragging their feet when adding new drugs to the regimens patients with HFrEF receive. The angiotensin-converting enzyme inhibitors and β-blockers took about 17 years each to start reaching a majority of U.S. patients with HFrEF, and sacubitril plus valsartan is now used on perhaps a quarter to a third of these patients despite receiving U.S. Food and Drug Administration (FDA) approval for them in mid-2015, noted Christopher M. O'Connor, MD, a heart failure specialist and president of the Inova Heart and Vascular Institute in Fairfax, Virginia.

Despite dapagliflozin receiving FDA approval in May 2020 for treating HFrEF in patients without diabetes, early uptake in U.S. practice has been very slow, with findings from large U.S. patient registries suggesting that perhaps 1% of suitable patients with HFrEF get the drug, estimated Dr. O'Connor in an interview.

Given how strong the evidence now is for benefit and safety from dapagliflozin and empagliflozin, it may take as little as 5 years to reach greater than 50% penetration of one of these drugs into U.S. patients with HFrEF, suggested Dr. Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas, Texas.

The road to routine use of these SGLT2 inhibitor drugs should be hastened by empagliflozin's impressive performance in EMPEROR-Reduced, in which the drug scored highly significant benefits over placebo for the prespecified primary and two major secondary endpoints, one of which was a measure of preserved renal function.

Treatment with empagliflozin also achieved a notable, statistically significant 50% drop in major adverse renal events, consistent with the performance of other drugs in the class.  

"Renal protection is a big plus" of empagliflozin in this trial as well as from the other SGLT2 inhibitors in prior studies, noted Dr. O'Connor.

The EMPEROR-Reduced results also showed a benefit from empagliflozin in patients with HFrEF not previously seen as quickly with any other drug class. The SGLT2 inhibitor led to statistically significant slowing in the progression of patients from New York Heart Association class 2 to class 3 function, and it also hastened the recovery of patients from class 3 to class 2, an effect that became apparent within the first month of treatment, and a benefit that is a "big deal" for patients, Dr. Packer said.

EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. Dr. Packer has received personal fees from Boehringer Ingelheim and Eli Lilly and from several other companies. Dr. Poppas and Dr. O'Connor had no relevant disclosures.

European Society of Cardiology (ESC) Congress 2020. Presented August 29, 2020.

N Engl J Med. Published online August 29, 2020. Abstract, Editorial

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