EMPEROR-Reduced: Empagliflozin Cuts Hospitalizations, CV Mortality in HFrEF

(UPDATED) Adding empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) to optimal medical therapy slashed the risk of cardiovascular events, specifically heart failure hospitalizations and CV mortality, in patients with heart failure and reduced ejection (HFrEF), according to the results of the EMPEROR-Reduced study. It also lowered the risk of adverse renal outcomes.

Those benefits of treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug initially approved for glucose control, was observed in patients with and without diabetes.

Presented today as a Hot Line clinical trial during the virtual European Society of Cardiology (ESC) Congress 2020, the paper was released one day early by the New England Journal of Medicine following an embargo break by the ESC. EMPEROR-Reduced joins DAPA-HF with dapagliflozin (Farxiga; AstraZeneca) as the second randomized, clinical trial to show that the addition of an SGLT2 inhibitor to optimal medical therapy reduces hard clinical events in patients with HFrEF.

“We think that EMPEROR-Reduced will have major implications for clinical practice,” said lead investigator Milton Packer, MD (Baylor Heart and Vascular Institute, Houston, TX), during a press conference announcing the results. “When considered together with DAPA-HF, the concordant results from these trials are remarkable. The SGLT2 inhibitors have clinically important benefits, they’re given once daily, require no dose adjustment, and are very well tolerated. I believe, and I think others share this view, that there’s now compelling evidence that SGLT2 inhibitors should now be added to currently recommended treatments for the disease.”

Commenting on the study for TCTMD, Julia Grapsa, MD, PhD (Guy’s and St. Thomas’ NHS Foundation Trust, London, England), congratulated the EMPEROR-Reduced investigators for their rigorous statistical analyses and noted that the trial included the kinds of severe patients that doctors frequently encounter in clinical practice. In the trial, the mean LVEF was 27.7% and nearly three-quarters of patients had an LVEF of 30% or less. Additionally, roughly 80% of patients had NT-proBNP levels 1,000 pg/mL or higher.

“We know already that the SGLT2 inhibitors reduce the risk of hospitalization for heart failure,” said Grapsa, referring to the initial trials in patients with type 2 diabetes. “We’ve known that since 2015.  But this is the first time we’re seeing a study with a large number of patients with a low ejection fraction. . . . It’s a unique difference when compared with DAPA-HF. We’re seeing a large number of patients who have quite advanced heart failure. [The study] proves that empagliflozin is quite effective in this group of patients.”

The new study, she added, is great news and SGLT2 inhibitors should be added to the arsenal of physicians treating patients with HFrEF. “I think it will change clinical practice,” said Grapsa. “I’m very optimistic.”

In an editorial, NEJM Deputy Editor John Jarcho, MD, states the EMPEROR-Reduced trial proves DAPA-HF was “no fluke,” and the new findings strengthen the case for using SGLT2 inhibitors in HFrEF. “Guideline committees will now need to contend with the evidence,” he writes. This past May, the US Food and Drug Administration approved dapagliflozin for patients with HFrEF, but the US guidelines have not yet incorporated the DAPA-HF findings into their formalized treatment recommendations.

The Emperor, Fully Clothed

In the initial large-scale randomized trials testing SGLT2 inhibitors in diabetic patients, there was an approximate 30% to 35% lower risk of heart failure hospitalization with active treatment versus placebo. In EMPA-REG OUTCOME, for example, empagliflozin reduced not only the risk of MACE, but also the risk of heart failure hospitalization and CV mortality. As reported at the time, researchers say the CV and renal effects cannot be explained by the reduction in blood glucose with SGLT2 inhibition.

In EMPEROR-Reduced, 3,730 patients with HFrEF were randomized to treatment with empagliflozin or placebo on top of appropriate background medical therapy with diuretics, inhibitors of the renin-angiotensin system and neprilysin, beta-blockers, mineralocorticoid receptor antagonists, and cardiac devices (when indicated). The trial included an equal number of patients with and without diabetes.

We think that EMPEROR-Reduced will have major implications for clinical practice. Milton Packer

The primary endpoint—a composite of CV death or hospitalization for worsening HF—occurred in 19.4% of patients treated with empagliflozin and 24.7% of those who received placebo (HR 0.75; 95% CI 0.65-0.86) over a median of 16 months. The reduction in the primary endpoint was observed in patients with and without diabetes at baseline. Hospitalizations for worsening HF were significantly reduced among patients treated with empagliflozin (HR 0.70; 95% CI 0.58-0.85). The mean slope of the change in the estimated glomerular filtration rate (eGFR) over time, a reflection of dynamic changes of renal function, was significantly improved with empagliflozin. Additionally, empagliflozin reduced the composite renal endpoint by 50%, an endpoint which includes the need for chronic dialysis and renal transplantation, among other measures.

With respect to safety, serious adverse events related to cardiac disorders or worsening renal function were lower in patients treated with empagliflozin.

“A lot of the side effects that we typically see with heart failure drugs, such as volume depletion, hypotension, renal insufficiency, we just didn’t see with this drug in this heart failure trial,” said Packer.

In the editorial, Jarcho notes that the two components of the primary endpoint—CV mortality and hospitalization for worsening HF—were analyzed individually but were not formally tested for significance. In DAPA-HF, there appeared to be a significant reduction of CV mortality with dapagliflozin, but this wasn’t observed with empagliflozin. In EMPA-REG OUTCOME, though, empagliflozin lowered the risk of CV mortality by 41% in patients with similar CV risk profiles, whereas dapagliflozin had no effect on CV mortality in the large-scale study of patients with diabetes. Jarcho said the only way to determine if one drug is better than the other for preventing CV mortality is a head-to-head randomized trial. 

For their part, the EMPEROR-Reduced investigators say the effect of SGLT2 inhibitors on mortality is heterogeneous, “with no consistent evidence that one member of the drug class is superior to another with respect to the effects on survival.” To the media, Packer said both EMPEROR-Reduced and DAPA-HF yielded very similar results, even though they studied slightly sicker patients.    

“When you put the two trials together, the concordance of the findings is really striking and now extend the benefits of these drugs across a broad spectrum of heart failure patients,” he said.

Marco Metra, MD (University of Brescia, Italy), the scheduled the discussant following the hotline presentation, also highlighted the sicker patients in EMPEROR-Reduced, which may explain the difference in CV mortality seen in the different trials. In DAPA-HF, he noted, there were also a relatively small number of renal events over 18 months of follow-up, and as such dapagliflozin had no significant impact on worsening renal function compared with placebo, whereas use of empagliflozin yielded significant renal protection. In terms of the big picture, Metra said one of the key messages from EMPEROR-Reduced is that the new trial broadens the benefit of SGLT2 inhibitors to yet more patients with HFrEF.

‘Physicians Really Should Take Notice’

Packer said the past several years have seen the introduction of two new drug classes for the treatment of HFrEF. In 2014, Packer, along with John McMurray, MD (University of Glasgow, Scotland), published results from PARADIGM-HF, a large-scale randomized trial that showed sacubitril/valsartan (Entresto; Novartis), the angiotensin receptor–neprilysin inhibitor, reduced the risk of all-cause mortality and HF hospitalization in HFrEF patients.

“Physicians really should take notice of both drugs for the benefit of patients,” said Packer. “In our trial, the benefits of empagliflozin were present whether patients were taking a neprilysin inhibitor or not. The two classes of drugs are additive.” Unfortunately, there are challenges in the treatment of HF as many physicians “are treating [patients] in a way which resembles the state-of-the-art 15 years ago,” he added. For that reason, Packer hopes physicians pay attention to these new findings and incorporate them into practice.  

Asked about the plethora of available drug options—beta blockers, sacubitril/valsartan, potassium-sparing diuretics (spironolactone/eplerenone), and SGLT2 inhibitors—for patients with HFrEF, Packer said one of the ways he likes to frame the question is to imagine himself as a patient. “If I was just given the diagnosis of heart failure with reduced ejection fraction, I would want my physician to initiate therapy with all four classes of drugs within the first 4 to 6 weeks after they made my diagnosis,” he said. “That means I’m recommending concomitant, nearly simultaneous initiation of therapy—not on the same day—but within a reasonably short period of time.  

Both empagliflozin and dapagliflozin are being studied in HF patients with preserved ejection fraction (HFpEF) in EMPEROR-Preserved and DELIVER, respectively.