Conference Coverage

EMPEROR-Reduced: Empagliflozin’s HFrEF benefit solidifies class effects



The SGLT2 inhibitor drug class solidified its role as a major, new treatment for patients with 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.

Dr. Milton Packer, a Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center in Dallas

Dr. Milton Packer

Patients with heart failure with reduced ejection fraction (HFrEF) treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) had a statistically significant 25% relative cut in their incidence of cardiovascular death or first heart failure hospitalization, compared with placebo-treated 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 annual congress of the European Society of Cardiology.

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 a another SGLT2 inhibitor, dapagliflozin (Farxiga), in the DAPA-HF trial (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

The performance of these two SGLT2 inhibitors was “incredibly consistent” across the their respective trials run in HFrEF patients 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), a beta-blocker, and a mineralocorticoid receptor antagonist, plus a diuretic as a fifth drug class for the many HFrEF patients who also need treatment for fluid overload. He further advocated for rapid introduction of these four cornerstone agents with proven survival benefits once a patient receives a HFrEF diagnosis, suggesting that sacubitril plus valsartan, an SGLT2 inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist could all be initiated within 6 weeks or less while acknowledging that optimal up-titration of the beta-blocker would likely take longer.

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

Dr. Athena Poppas of the ACC

Dr. Athena Poppas

In recognition of the importance of sending a message to heart failure clinicians about the newly proven efficacy of SGLT2 inhibitors in HFrEF patients, 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 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 HFrEF patients 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 Brown University in Providence, R.I. Physicians may find that they need extra backup for successfully starting both sacubitril plus valsartan and an SGLT2 inhibitor in HFrEF patients because recent history has shown substantial pushback from third-party payers in reimbursing for these relatively expensive drugs, Dr. Poppas noted. She added that this is a problem that may be compounded when patients should ideally get both drug classes.

Dr. Christopher M. O'Connor, a heart failure specialist and president of the Inova Heart and Vascular Institute in Fairfax, Va.

Dr. Christopher M. O'Connor

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

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 HFrEF patients currently 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. HFrEF patient populations, suggested Dr. Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.


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