13/9/23, 21:41 EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced)

Reduced) - Fu…

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EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With

Reduced Ejection Fraction (EMPEROR-Reduced)

The safety and scientific validity of this study is the responsibility of the study
sponsor and investigators. Listing a study does not mean it has been evaluated by
the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT03057977

Recruitment Status  : Completed

First Posted  : February 20, 2017
Results First Posted  : May 18, 2021
Last Update Posted  : May 18, 2021

View this study on the modernized ClinicalTrials.gov

Sponsor:
Boehringer Ingelheim

Collaborator:
Eli Lilly and Company

Information provided by (Responsible Party):

Boehringer Ingelheim

Study Details Tabular View Study Results Disclaimer How to Read a Study Record

Study Description Go to

Brief Summary:

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13/9/23, 21:41 Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction - American College of Card…

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Empagliflozin Outcome Trial in Patients With

Chronic Heart Failure and a Reduced Ejection
Fraction - EMPEROR-Reduced
Aug 25, 2023

Author/Summarized by Dharam J. Kumbhani, MD, SM, FACC

Author:
Summary Reviewer: Deepak L. Bhatt, MD, MPH, FACC; Kim A. Eagle,
MD, MACC
Trial Sponsor: Boehringer Ingelheim and Eli Lilly
Date Presented: 08/25/2023
Date Published: 08/25/2023
Date Updated: 08/25/2023
Original Posted Date: 08/29/2020

References
Contribution To Literature:

Highlighted text has been updated as of August 25, 2023.

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.
Description:

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.
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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%
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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 (MRA): 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.
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Patients with volume overload within 4 weeks of enrollment: Primary endpoint for
empagliflozin vs. placebo among patients with recent volume overload: 28.4% vs.
24.8% (p = 0.035); without volume overload: 16.0% vs. 22.2% (p = 0.0004; p for
interaction = 0.34). Similarly, no difference was noted for the endpoint of total HF
hospitalizations by volume overload status (p for interaction = 0.09). Intensification
of diuretics was also similar between the two subgroups of patients (p for
interaction = 0.88). Similarly, there was no difference in NT-proBNP, systolic blood
pressure, or body weight for empagliflozin vs. placebo between patients with and
without recent volume overload.
Influence of MRAs: 71% on MRAs in this trial. Composite endpoint for
empagliflozin vs. placebo among MRA users: 18.6% vs. 24.4%; among nonusers:
21.2% vs. 25.8% (p for interaction = 0.83). Similarly, no interaction was observed
for secondary endpoints and adverse events (including hyperkalemia) by MRA use
as well.
Influence of region and race/ethnicity: Regional distribution: 36.3% Europe, 34.5%
Latin America, 11.4% in North America, and 13.2% in Asia; 70.5% were White, 6.9%
Black, and 18.0% Asian. Important differences were noted in baseline
characteristics. Placebo arm event rate (per 100 person-years) for the primary
outcome of cardiovascular death or HF hospitalization was highest in Asia (27.7)
and North America (26.4) and lowest in Europe (17.5). Event rate (per 100 person-
years) for the primary composite outcome of cardiovascular death or HF
hospitalization in the placebo group was highest among Black patients (34.4) and
lowest in White patients (18.7). The magnitude of the effect of empagliflozin on
the primary composite outcome and total hospitalizations for HF was most
pronounced in Asia (hazard ratios of 0.55 and 0.41, respectively); intermediate in
North America (hazard ratios of 0.69 and 0.71, respectively) and Latin America
(hazard ratios of 0.73 and 0.65, respectively); and least pronounced in Europe
(hazard ratios of 0.94 and 0.96, respectively) (p for interaction = 0.1). The
magnitude of the effect of empagliflozin on the primary composite outcome and
on total hospitalizations for HF was most pronounced in Black patients (hazard
ratios of 0.46 and 0.39, respectively) and Asian patients (hazard ratios of 0.57 and
0.45, respectively) and least pronounced in White patients (hazard ratios of 0.88
and 0.90, respectively) (p for interaction = 0.008).

Pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved:

Renal outcomes (profound and sustained decreases in eGFR or renal replacement
therapy), total n = 9,718: 2.8% vs. 3.5% for empagliflozin vs. placebo, with
significant heterogeneity between both trials (p = 0.016 for interaction).
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Potassium balance (n = 9,583): Patients with hyperkalemia (potassium >5 mmol/L)

were more likely to have lower EF, diabetes, and lower mean eGFR; they were also
more likely to be treated with sacubitril/valsartan and an MRA. Empagliflozin
reduced the composite of investigator-reported hyperkalemia or initiation of
potassium binders compared with placebo (6.5% vs. 7.7%, HR 0.82, 95% CI 0.71-
0.95, p = 0.01). Composite of investigator-reported hypokalemia or initiation of
potassium supplements was similar compared with placebo (6.4% vs. 6.7%, p >
0.05).

Uric acid balance: The prevalence of hyperuricemia at baseline was 51.6 vs. 55.3%
(empagliflozin vs. placebo, p = 0.03). Elevated serum uric acid was associated with
advanced severity of HF and with worst outcome (composite outcome, HR 1.64
[95% CI 1.28-2.10]; cardiovascular mortality, HR 1.98 [95% CI 1.35-2.91]; all-cause
mortality, HR 1.8 [95% CI 1.29-2.49], all p < 0.001) in multivariable adjusted
analyses, as compared with the lowest tertile. Serum uric acid was reduced
following treatment with empagliflozin at 4 weeks (vs. placebo: −1.12 ± 0.04
mg/dL, p < 0.0001) and remained lower throughout follow-up. Treatment with
empagliflozin reduced the risk of clinically relevant hyperuricemic events by 32%
(HR 0.68 [95% CI 0.52-0.89], p = 0.004). The effect of empagliflozin on the primary
composite endpoint and on the risk of hospitalization for HF was not influenced
by serum uric acid.

Proteomics substudy (n = 1,134): Using Olink® Explore 1536 platform, 1,283

circulating proteins were measured at baseline, week 12, and week 52. Among
these, nine proteins demonstrated the largest treatment effect of empagliflozin:
insulin-like growth factor-binding protein 1, transferrin receptor protein 1,
carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyl
transferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like
growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The
most common biological action of differentially expressed proteins appeared to be
the promotion of autophagic flux in the heart, kidney, or endothelium, a feature
of six proteins.

Blinded withdrawal of long-term randomized patients: At the end of the trials,

6,799 patients (placebo 3,381, empagliflozin 3,418) were prospectively withdrawn
from treatment in a blinded manner, and, of these, 3,981 patients (placebo 2,020,
empagliflozin 1,961) underwent prespecified in-person assessments after 30 days
off treatment. From 90 days from the start of closeout to the end of double-blind
treatment, the annualized risk of cardiovascular death or HF hospitalization was
lower in empagliflozin-treated patients than in placebo-treated patients (10.7 vs.
13.5 events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI 0.60–
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0.96]). When the study drugs were withdrawn for ~30 days, the annualized risk of
cardiovascular death or HF hospitalization increased in patients withdrawn from
empagliflozin but not in those withdrawn from placebo (17.0 vs. 14.1 events per
100 patient-years for empagliflozin and placebo, respectively). After withdrawal,
the KCCQ-CSS declined by 1.6 in patients withdrawn from empagliflozin versus
placebo (p < 0.0001).
Interpretation:

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. The use of MRAs did not influence the effect of
empagliflozin on clinical outcomes. Some regional and racial differences in efficacy
were noted. 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. The proteomics
substudy suggests that the effects of SGLT2 inhibitors are likely related to actions
on the heart and kidney to promote autophagic flux, nutrient deprivation
signaling, and transmembrane sodium transport. Benefit of SGLT2 inhibitors
disappears rapidly after withdrawal of the drug.

Even though the 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. The mechanism of benefit is unclear. The
subgroup analysis of this trial suggests that this benefit may not necessarily be
driven by a diuretic effect alone (as noted among patients with and without recent
volume overload), but further studies are needed to clarify this and other
potential mechanisms of benefit. The pooled analysis of EMPEROR-Reduced and
EMPEROR-Preserved suggests that the renal benefit is primarily among patients
with HFrEF, and eGFR slope analysis may not be predictive of renal outcomes
among patients with HF. In both groups, empagliflozin reduced the incidence of
hyperkalemia without a significant increase in hypokalemia.
References:

Packer M, Butler J, Zeller C, et al. Blinded Withdrawal of Long-Term Randomized

Treatment With Empagliflozin or Placebo in Patients With Heart Failure.
Ci l i 2023 A 24 [E b h d f i ]
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Circulation 2023;Aug 24:[Epub ahead of print].

Presented by Dr. Milton Packer at the European Society of Cardiology Congress,
Amsterdam, Netherlands, August 25, 2023.
Zannad F, Ferreira JP, Butler J, et al. Effect of Empagliflozin on Circulating
Proteomics in Heart Failure: Mechanistic Insights From the EMPEROR Program. Eur
Heart J 2022;43:4991-5002.

Presented by Dr. Faiez Zannad at the European Society of Cardiology Congress

(ESC 2022), Barcelona, Spain, August 26, 2022.
Doehner W, Anker SD, Butler J, et al. Uric acid and sodium-glucose cotransporter-2
inhibition with empagliflozin in heart failure with reduced ejection fraction: the
EMPEROR-Reduced trial. Eur Heart J 2022;Jul 5:[Epub ahead of print].

Ferreira JP, Zannad F, Butler J, et al. Empagliflozin and serum potassium in heart
failure: an analysis from EMPEROR-Pooled. Eur Heart J 2022;43:2984-93.
Editorial: Verma S, Dhingra NK, Pandey AK, Cosentino F. Emerging role for SGLT2
inhibitors in mitigating the risk of hyperkalemia in heart failure. Eur Heart J
2022;43:2994-6.

Letter to the Editor: Packer M, Butler J, Zannad F, et al. Empagliflozin and Major
Renal Outcomes in Heart Failure. N Engl J Med 2021;385:1531-3.
Presented by Dr. Milton Packer at the European Society of Cardiology Virtual
Congress, August 27, 2021.
Lam CS, Ferreira JP, Pfarr E, et al. Regional and ethnic influences on the response
to empagliflozin in patients with heart failure and a reduced ejection fraction: the
EMPEROR-Reduced trial. Eur Heart J 2021;42:4442-51.

Butler J, Anker SD, Filippatos G, et al. Empagliflozin and Health-Related Quality of

Life Outcomes in Patients With Heart Failure With Reduced Ejection Fraction: The
EMPEROR-Reduced trial. Eur Heart J 2021;42:1203-12.

Editorial Comment: Spertus JA. Quality of Life in EMPEROR-Reduced: Emphasizing

What Is Important to Patients While Identifying Strategies to Support More
Patient-Centered Care. Eur Heart J 2021;42:1213-15.

Packer M, Anker SD, Butler J, et al., on behalf of the EMPEROR-Reduced Trial

Committees and Investigators. Empagliflozin in Patients With Heart Failure,
Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial. J Am
Coll Cardiol 2021;77:1381-92.
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Editorial Comment: Kosiborod MN, Vaduganathan M. SGLT-2 Inhibitors in Heart

Failure: Volume or Value? J Am Coll Cardiol 2021;77:1393-6.
Ferreira JP, Zannad F, Pocock SJ, et al. Interplay of Mineralocorticoid Receptor
Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced. J Am Coll
Cardiol 2021;77:1397-407.

Editorial Comment: Greene SJ, Khan MS. Quadruple Medical Therapy for Heart
Failure: Medications Working Together to Provide the Best Care. J Am Coll Cardiol
2021;77:1408-11.

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 2021;143:326-36.
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: ESC21, ESC22, ESC23, ESC Congress, AHA20, AHA Annual Scientific Sessions,
ESC20, Atrial Fibrillation, Blood Pressure, Cardiac Resynchronization Therapy, Diabetes
Mellitus, Type 2, Heart Failure, Defibrillators, Implantable, Ethnic Groups, Metabolic
Syndrome, Natriuretic Peptide, Brain, Potassium, Proteomics, Renal Insufficiency, Secondary
Prevention, Stroke Volume, Uric Acid

© 2023 American College of Cardiology Foundation. All rights reserved.

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