Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction - EMPEROR-Reduced

Contribution To Literature:

The EMPEROR-Reduced trial showed that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤40%) on excellent baseline GDMT, irrespective of diabetes status.


The goal of the trial was to assess the safety and efficacy of empagliflozin in patients with symptomatic heart failure with reduced ejection fraction (HFrEF), irrespective of diabetes status.

Study Design

Patients were randomized in a 1:1 fashion to either empagliflozin 10 mg (n = 1,863) or matching placebo (n = 1,867). All the patients were receiving appropriate treatments for heart failure.

  • Total screened: 7,220
  • Total number of enrollees: 3730
  • Duration of follow-up: 16 months (median)
  • Mean patient age: 67 years
  • Percentage female: 24%

Inclusion criteria:

  • Age ≥18 years
  • Chronic HF, New York Heart Association (NYHA) functional class II/III/IV
  • Left ventricular EF (LVEF) ≤40%
  • HF hospitalization within 12 months
  • N-terminal pro–B-type natriuretic peptide (NT-proBNP ≥600 pg/ml if EF ≤30%; ≥1000 pg/ml if EF 31-35%; ≥2500 pg/ml if EF >35%
  • If concomitant atrial fibrillation, then above thresholds were doubled)

Exclusion criteria:

  • Acute coronary syndrome, stroke, or transient ischemic attack (TIA) within 90 days
  • Listed for orthotopic heart transplantation, currently implanted LV assist device (LVAD)
  • Cardiomyopathy based on infiltrative/accumulation diseases, muscular dystrophies, reversible causes, hypertrophic cardiomyopathy, pericardial restriction, peripartum, cardiomyopathy caused by chemotherapy within 12 months
  • Severe valvular heart disease
  • Acute decompensated HF
  • Implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT) within 3 months

Other salient features/characteristics:

  • White 70%, Asian 18%
  • North America: 11%, Europe: 36%, Asia: 13%, Latin America: 34%
  • NYHA functional class II: 75%
  • Mean LVEF: 27%
  • Type 2 diabetes: 50%
  • Estimated glomerular filtration rate (eGFR) <60: 48%
  • Medications: angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker: 70%, angiotensin receptor-neprilysin inhibitor: 19%, mineralocorticoid receptor antagonist: 71%, beta-blocker: 94%
  • ICD: 31%, CRT 12%

Principal Findings:

The primary outcome, cardiovascular death or HF hospitalization, for empagliflozin vs. placebo, was 19.4% vs. 24.7% (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65-0.86, p < 0.001)

  • Cardiovascular death: 10% vs. 10.8% (HR 0.92, 95% CI 0.75-1.12)
  • HF hospitalization: 13.2% vs. 18.3% (HR 0.69, 95% CI 0.59-0.81)

Secondary outcomes:

  • Total hospitalizations: 388 vs. 553 (p < 0.001)
  • Composite renal outcome (chronic hemodialysis, renal transplantation, profound sustained reduction in eGFR): 1.6 vs. 3.1 (HR 0.50, 95% CI 0.32-0.77, p < 0.01)
  • All-cause mortality: 13.4% vs. 14.2% (HR 0.92, 95% CI 0.77-1.10, p > 0.05)
  • New-onset type 2 diabetes among patients with prediabetes: 11.2% vs. 12.6% (p > 0.05)
  • Change in hemoglobin A1c between baseline and week 52 (patients with diabetes): -0.28 vs. -0.12% (p < 0.05)
  • Systolic blood pressure -2.4 vs. -1.7 mm Hg (p > 0.05)
  • Confirmed hypoglycemic event: 1.4% vs. 1.5%
  • Death/HF hospitalization/emergent or urgent HF visit requiring intravenous treatment or diuretic intensification/deterioration of NYHA class: 32.7% vs. 43% (p < 0.0001)
  • Intensification of diuretics: 15.9% vs. 22.2% (p < 0.0001)
  • Emergent or urgent HF visit requiring intravenous treatment: 6.8% vs. 9.9% (p = 0.0004)
  • Hospitalization for HF requiring cardiac care unit/intensive care unit care: 4.8% vs. 5.7% (p = 0.002)

Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS): Benefit of empagliflozin vs. placebo was maintained across tertiles of baseline KCCQ-CSS for the primary endpoint, total HF hospitalizations and eGFR slope. In addition, benefit of empagliflozin vs. placebo for mean KCCQ-CSS was noted as early as 3 months, and noted to be sustained over 12 months.


The results of this trial indicate that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤40%) on excellent baseline guideline-directed medical therapy (GDMT), irrespective of diabetes status. Benefit is primarily driven by a reduction in HF hospitalizations, not mortality. There was an early and sustained benefit on KCCQ-CSS. There was also a benefit in renal outcomes. This is a very important trial, and mirrors similar findings from the DAPA-HF trial for dapagliflozin. Even patients with severe LV dysfunction appeared to benefit. Of note, the DAPA-HF trial was larger, and did show a benefit in cardiovascular and all-cause mortality with dapagliflozin use.

Even though the sodium-glucose cotransporter 2 (SGLT2) inhibitors were introduced as type 2 diabetes management drugs, the results of the EMPA-REG OUTCOME trial and others indicated a clear benefit in HF management. This trial enrolled a dedicated HF population, and conclusively shows a benefit in this patient population, irrespective of diabetes status. These drugs will likely have a prominent role in future HF management guidelines.


Presented by Dr. Javed Butler at the American Heart Association Virtual Scientific Sessions, November 13, 2020.

Packer M, Anker SD, Butler J, et al., on behalf of the EMPEROR-Reduced Trial Committees and Investigators. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation 2020;Oct 21:[Epub ahead of print].

Packer M, Anker SD, Butler J, et al., on behalf of the EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes With Empagliflozin in Heart Failure. N Engl J Med 2020;383:1413-24.

Editorial: Jarcho JA. More Evidence for SGLT2 Inhibitors in Heart Failure. N Engl J Med 2020;383:1481-2.

Presented by Dr. Milton Packer at the European Society of Cardiology Virtual Congress, August 29, 2020.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: AHA20, AHA Annual Scientific Sessions, ESC Congress, ESC20, Atrial Fibrillation, Blood Pressure, Cardiac Resynchronization Therapy, Diabetes Mellitus, Type 2, Heart Failure, Defibrillators, Implantable, Metabolic Syndrome X, Natriuretic Peptide, Brain, Renal Insufficiency, Secondary Prevention, Stroke Volume

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