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Second SGLT2 Drug Scores for HFrEF, Regardless of Diabetes Status

— EMPEROR-Reduced trial "exceptionally concordant" with DAPA-HF results

Last Updated August 29, 2020
Ƶ MedicalToday

Empagliflozin (Jardiance) lowered the risk of cardiovascular death or hospitalization for heart failure among patients with heart failure with reduced ejection fraction (HFrEF), regardless of diabetes status, the showed.

The SGLT2 inhibitor reduced the composite of those events by a relative 25% (19.4% vs 24.7%, P<0.001) over a median of 16 months, for a number needed to treat of 19 to prevent one such event, reported Milton Packer, MD, of the Baylor Heart and Vascular Institute in Dallas.

While SGLT2 inhibitors were originally developed for glucose lowering in type 2 diabetes, the effect was similar in the half of EMPEROR-Reduced participants who had diabetes as in those without it (HR 0.72 and 0.78, both statistically significant).

The results, released early online in the ahead of presentation at the due to an embargo break by the ESC, were "exceptionally concordant" with those of the DAPA-HF trial with SGLT2 inhibitor dapagliflozin (Farxiga) at the same meeting last year.

"The results of the EMPEROR-Reduced 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," wrote John Jarcho, MD, of Brigham and Women's Hospital in Boston, in an editorial accompanying the simultaneous publication in the .

"Guidelines committees will now need to contend with the evidence," he noted. While Canadian societies already recommend SGLT2 inhibitors in HFrEF, Jarcho speculated that the "data will provide further impetus for other groups to address this question."

Perhaps equally important is "whether physicians are paying attention," Packer said at a press briefing for the opening ESC hot line session trials. "We have a real challenge in ... that many physicians who treat patients with heart failure are treating them in a way that resembles the state of the art 15 years ago."

In the trial, nearly 20% of patients were receiving an angiotensin receptor-neprilysin inhibitor (a larger number than in any prior trial, Packer noted), with no difference in impact of empagliflozin compared with other patients.

That the SGLT2 inhibitor was effective atop recommended treatment in both EMPEROR-Reduced and DAPA-HF suggests that the drugs aren't a replacement for any other therapy but an add-on, Packer told Ƶ.

"Many of us are saying there are now four cornerstones of the treatment of heart failure with reduced ejection fraction -- angiotensin receptor-neprilysin inhibition, beta-blocker, mineralocorticoid receptor antagonist such as spironolactone, and SGLT2 inhibitors empagliflozin or dapagliflozin," he said. "When they take all four drugs they than if they take only three or two or one."

ESC president-elect Stephen Achenbach, MD, asked as a moderator at the session whether the best strategy is a stepped approach, starting one drug at a time, "or are we now at a stage where we can combine certain therapies together and, for example, start SGLT2 inhibition earlier then based on the history of trials?"

Packer agreed that it raises a lot of clinical questions. But, he said, "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 had given me my diagnosis. That means I am recommending concomittant, nearly simultaneous initiation with therapy -- not on the same day, but within a reasonably short period of time."

"Very clear, and very challenging," responded Achenbach.

The EMPEROR-Reduced trial included 3,730 HFrEF patients, among whom 50% had diabetes, 73% had an ejection fraction of 30% or less, and 48% had an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2. Compared with DAPA-HF, this was a population with more severe heart failure and twice as much sacubitril-valsartan background therapy, Packer noted.

The two prespecified secondary outcomes also favored empagliflozin:

  • Hospitalizations for heart failure (HR 0.70, 95% CI 0.58-0.85)
  • Rate of the decline in eGFR (-0.55 vs -2.28 mL/min/1.73 m2 per year, P<0.001)

The composite of chronic dialysis, renal transplantation, or a profound, sustained reduction in eGFR was a relative 50% lower with empagliflozin, although with small numbers (30 vs 58 patients, 1.6% vs 3.1%). Renal benefits of SGLT2 inhibitors were also seen in the cardiovascular safety outcomes trials in type 2 diabetes, Packer pointed out.

The trial did not demonstrate a significant reduction in cardiovascular mortality (HR 0.92, 95% CI 0.75-1.12), whereas there was such an effect in DAPA-HF (HR 0.82, 95% CI 0.69-0.98).

Study discussant Marco Metra, MD, of the University of Brescia in Italy, noted that without heterogenity in other outcomes, it's possible this was a function of the more severe heart failure among EMPEROR-Reduced patients or even a chance finding. Only a head-to-head comparison would solve that question, he suggested.

However, Packer argued against a real difference between the trials. "The overall effect on cardiovascular death in these trials is about 15%," he said, and the difference appeared to be driven by fewer sudden deaths and heart failure death. "I think the data are actually quite consistent."

Empagliflozin was "amazingly well tolerated," Packer said, without any bradycardia and only an imbalance in genital tract infections, which is a known side effect.

Trials of both and in heart failure with preserved ejection fraction are ongoing, with results expected out within the next 18 months.

The FDA fast tracked review of empagliflozin for an indication in reduction of the risk of cardiovascular death and hospitalization for heart failure in people with heart failure, based on both the preserved and reduced EF trials. The drug also has fast track designation for treatment of chronic kidney disease, based on the EMPA-KIDNEY trial results expected out in 2022.

Disclosures

The trial was funded by Boehringer Ingelheim and Eli Lilly.

Jarcho disclosed being employed by the NEJM as deputy editor.

Primary Source

New England Journal of Medicine

Packer M, et al "Cardiovascular and renal outcomes with empagliflozin in heart failure" N Engl J Med 2020; DOI: 10.1056/NEJMoa2022190.

Secondary Source

New England Journal of Medicine

Jarcho JA "More evidence for SGLT2 inhibitors in heart failure" N Engl J Med 2020; DOI: 10.1056/NEJMe2027915.