European Society of Cardiology

European Society of Cardiology

Perspective from Athena Poppas, MD, FACC
Perspective from Mark Drazner, MD, MSc
Source:

Packer M. Hot Line: EMPEROR-Reduced. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).

Disclosures: The EMPEROR-Reduced trial was sponsored by Boehringer Ingelheim and Eli Lilly and Company. Packer reports financial relationships with AbbVie, Actavis, Akcea, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics and Theravance.
August 29, 2020
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Empagliflozin lowers CV death, hospitalizations in HFrEF with or without diabetes

Perspective from Athena Poppas, MD, FACC
Perspective from Mark Drazner, MD, MSc
Source:

Packer M. Hot Line: EMPEROR-Reduced. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).

Disclosures: The EMPEROR-Reduced trial was sponsored by Boehringer Ingelheim and Eli Lilly and Company. Packer reports financial relationships with AbbVie, Actavis, Akcea, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics and Theravance.
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The SGLT2 inhibitor empagliflozin improved CV and renal outcomes in patients with HF with reduced ejection fraction, regardless of diabetes status, according to results of the EMPEROR-Reduced trial.

Among 3,730 patients with HF and an EF of 40% or less, treatment with empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) in addition to recommended therapy reduced the primary composite endpoint of CV death or HF hospitalization by 25% (P < .001), reduced total HF hospitalizations by 30% (P < .001) and reduced renal events by 50% (P < .001) compared with placebo, Milton Packer, MD, distinguished scholar in cardiovascular science at Baylor University Medical Center and chair of the executive committee for the EMPEROR program, reported during a press conference at the European Society of Cardiology Congress.

heart medication
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The EMPEROR-Reduced data were published in The New England Journal of Medicine a day before scheduled presentation at the ESC Congress, due to an embargo break.

These data follow the DAPA-HF trial, presented at the 2019 ESC Congress, in which treatment of HFrEF with another SGLT2 inhibitor, dapagliflozin (Farxiga, AstraZeneca), cut CV risk, even in the absence of diabetes, and led to FDA approval for this indication.

Milton Packer

“There is now compelling evidence that SGLT2 inhibitors should now be added to currently recommended treatments for this disease,” Packer said.

In an NEJM editorial, John A. Jarcho, MD, assistant professor of medicine at Harvard Medical School and deputy editor of NEJM, wrote, “[t]he results of the EMPEROR-Reduce trial confirm that the findings in DAPA-HF were no fluke and substantially strengthen the rationale for the use of SGLT2 inhibitors in patients with heart failure and a reduced ejection fraction. Guidelines committees will now need to content with the evidence.”

Consistent reductions with empagliflozin

EMPEROR-Reduced enrolled adults with chronic class II, III or IV HF. Mean age at baseline was 67 years, one-quarter were women and 6.9% were Black. Half of those enrolled had diabetes. Nearly three-quarters had a left ventricular EF of 30% or less, 79% had an N-terminal pro-B type natriuretic peptide level of at least 1,000 pg/ml and 48% had an estimated glomerular filtration rate of less than 60 ml/min/1.73 m2 at baseline. All patients were receiving appropriate treatments for HF, including 20% who had been prescribed the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis).

Treatment with empagliflozin or placebo was continued for a median of 16 months. During that period, the primary outcome of CV death or hospitalization for HF occurred in 19.4% of those assigned empagliflozin vs. 24.7% of those assigned placebo (HR = 0.75; 95% CI, 0.65-0.86). The difference in the primary outcome was driven by a reduction in risk for HF hospitalization.

Further, the effect of empagliflozin on the primary outcome was consistent across prespecified subgroups, including patients with diabetes (HR = 0.72; 95% CI, 0.6-0.87) vs. patients without diabetes (HR = 0.78; 95% CI, 0.64-0.97) and in those who were receiving sacubitril/valsartan (HR = 0.64; 95% CI, 0.45-0.89) vs. those not receiving sacubitril/valsartan (HR = 0.77; 95% CI, 0.66-0.9).

In other results, the total number of HF hospitalizations was 388 in the empagliflozin group vs. 553 in the placebo group (HR = 0.7; 95% CI, 0.58-0.85). Patients assigned empagliflozin had a slower rate of decline in eGFR during the treatment period (–0.55 ml/min/1.73 m2 per year vs. –2.28 ml/min/1.73 m2 per year; P < .001). Risk for serious renal outcomes, including chronic dialysis, renal transplantation or profound, sustained reduction in eGFR, was lower in the empagliflozin group (1.6% vs. 3.1%; HR = 0.5; 95% CI, 0.32-0.77).

Serious adverse events, including hypoglycemia, lower-limb amputation and bone fracture, were similar, at 41% in the empagliflozin group and 48% in the placebo group. Of note, Packer said, events related to the heart and kidney were lower with empagliflozin than placebo. Uncomplicated genital tract infection was reported more frequently in the empagliflozin group.

More evidence in HF

EMPEROR-Reduced is the second large-scale trial of an SGLT2 inhibitor in patients with HFrEF.

“When considered together with DAPA-HF, the concordant results from these trials are actually remarkable,” Packer said at the press conference.

One difference between the trials is that EMPEROR-Reduced enrolled patients with more advanced HF than in DAPA-HF, which “extends the benefits of [SGLT2 inhibitors] across the broad spectrum of HF,” he said.

“The 25% decrease in the risk of the composite cardiovascular death and heart failure hospitalization observed in EMPEROR-Reduced was identical to that seen in DAPA-HF. ... Although the effect on cardiovascular death in EMPEROR-Reduced was smaller than that seen in DAPA-HF, the reverse was true when the effects of dapagliflozin and empagliflozin on cardiovascular death were assessed in comparable patients in trials of type 2 diabetes. Accordingly, the effects of these drugs on survival is characterized by significant heterogeneity,” he said during a virtual live presentation.

Taken together, the results of EMPEROR-Reduced and DAPA-HF “now establish SGLT2 inhibition with empagliflozin and dapagliflozin as the new cornerstone of the treatment for HF,” along with angiotensin receptor-neprilysin inhibition, beta-blockers and mineralocorticoid receptor antagonists, Packer said.

Further investigation is underway: empagliflozin and dapagliflozin are being studied in patients with HF and preserved EF.

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