Empagliflozin lowers CV death, hospitalizations in HFrEF with or without diabetes
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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.
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.
“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.
References:
- Jarcho JA. N Engl J Med. 2020;doi:10.1056/NEJMe2027915.
- Packer M, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2022190.
Perspective
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The results of EMPEROR-Reduced are encouraging for a number of reasons. This trial confirms what we saw last year in DAPA-HF — a decrease in death and hospitalization in patients with diabetes, now extended to the nondiabetic population. Importantly, EMPEROR-Reduced also confirmed a class effect of SGLT2 inhibitors, in that empagliflozin is similar in effect to dapagliflozin for these hard outcomes.
EMPEROR-Reduced enriched the population to include a sicker population than in DAPA-HF. Importantly, investigators noted that the number needed to treat is only 19, and the number of HF hospitalizations with empagliflozin were greatly reduced. A drug that can protect the kidneys and the heart is quite impressive.
Some important questions are raised from this trial. It was encouraging that the investigators enrolled a broad range of patients, half of whom were nonischemics, but it would be great to see more women and Black patients included. Results are anticipated in the future on empagliflozin and dapagliflozin in patients with HFpEF— a group for whom we continue to struggle to find good medications. I would also like to see data on patients with mid-range EF, a group in whom we don’t have as much data. A medication that may have pleiotropic effects greater than blood sugar alone, on both kidney and cardiac protection, theoretically, should be helpful in the complex patients.
Finally, the question has also been raised whether the same effect in this study would be observed if all patients were also on an angiotensin receptor-neprilysin inhibitor. In DAPA-HF, only 11% of patients were on an angiotensin receptor-neprilysin inhibitor, compared with 20% in EMPEROR-Reduced. Education to help clinicians understand more about the new HF therapies and manage polypharmacy, as well as step-wise approach to add these medications and in which order, is needed. The American College of Cardiology is committed to filling this knowledge gap; an Expert Consensus Decision Pathway is in the works to help clinicians choose and understand the nuts and bolts about these newer HF medications.
Perspective
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Mark Drazner, MD, MSc
This is now the second study showing meaningful clinical benefits of an SGLT2 inhibitor in patients with HFrEF, even in the absence of diabetes. The reduction in HF hospitalizations and favorable impact on renal function are impressive. Further, the benefits of empagliflozin in EMPEROR-Reduced seemed present even in those on state-of-the-art guideline-directed medical therapy, including sacubitril/valsartan.
As new therapies emerge, practitioners need to assess the evidence supporting their use and determine if that evidence base warrants adoption into routine clinical practice. Personally, I am always more convinced when the putative benefits of a therapy in one trial are confirmed by a second trial. In essence, you are repeating the experiment and duplicating the results. Now, we have two trials demonstrating important clinical benefits of SGLT2 inhibitors in patients with HFrEF, even in the absence of diabetes. These data support the concept that SGLT2 inhibitors join angiotensin receptor-neprilysin inhibitors, beta-blockers and mineralocorticoid receptor antagonists as foundational therapies for patients with HFrEF unless there is intolerance or a contraindication.
It would be of interest to test the benefit of SGLT2 inhibitors in large trials of hospitalized patients with decompensated HF, rather than those with chronic HF. That population is at high risk and in desperate need of beneficial pharmacological therapies. Also, it would be of interest to test SGLT2 inhibitors in patients with even more advanced HF than those in EMPEROR-Reduced.
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Packer M. Hot Line: EMPEROR-Reduced. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).
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