Evaluation of the effect of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial

on behalf of the EMPEROR-Reduced Trial Committees and Investigators, Executive Committee, National Coordinators, Consulting Statistician, Clinical Events Committee, Scientific Excellence Committee, Data Monitoring Committee

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Drugs that inhibit the sodium–glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin–angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction.

Original languageEnglish (US)
Pages (from-to)1270-1278
Number of pages9
JournalEuropean Journal of Heart Failure
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2019

Fingerprint

Symporters
Heart Failure
Morbidity
Mortality
Hospitalization
Mineralocorticoid Receptor Antagonists
empagliflozin
Neprilysin
Natriuretic Peptides
Left Ventricular Dysfunction
Sudden Death
Diuretics
Pharmaceutical Preparations
Stroke Volume
Type 2 Diabetes Mellitus
Cause of Death
Placebos
Kidney

Keywords

  • Diabetes
  • Heart failure
  • Reduced ejection fraction
  • SGLT2 inhibitors
  • Trial design

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

on behalf of the EMPEROR-Reduced Trial Committees and Investigators, Executive Committee, National Coordinators, Consulting Statistician, Clinical Events Committee, Scientific Excellence Committee, & Data Monitoring Committee (2019). Evaluation of the effect of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial. European Journal of Heart Failure, 21(10), 1270-1278. https://doi.org/10.1002/ejhf.1536

Evaluation of the effect of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction : rationale for and design of the EMPEROR-Reduced trial. / on behalf of the EMPEROR-Reduced Trial Committees and Investigators; Executive Committee; National Coordinators; Consulting Statistician; Clinical Events Committee; Scientific Excellence Committee; Data Monitoring Committee.

In: European Journal of Heart Failure, Vol. 21, No. 10, 01.10.2019, p. 1270-1278.

Research output: Contribution to journalArticle

on behalf of the EMPEROR-Reduced Trial Committees and Investigators, Executive Committee, National Coordinators, Consulting Statistician, Clinical Events Committee, Scientific Excellence Committee & Data Monitoring Committee 2019, 'Evaluation of the effect of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial', European Journal of Heart Failure, vol. 21, no. 10, pp. 1270-1278. https://doi.org/10.1002/ejhf.1536
on behalf of the EMPEROR-Reduced Trial Committees and Investigators, Executive Committee, National Coordinators, Consulting Statistician, Clinical Events Committee, Scientific Excellence Committee et al. Evaluation of the effect of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial. European Journal of Heart Failure. 2019 Oct 1;21(10):1270-1278. https://doi.org/10.1002/ejhf.1536
on behalf of the EMPEROR-Reduced Trial Committees and Investigators ; Executive Committee ; National Coordinators ; Consulting Statistician ; Clinical Events Committee ; Scientific Excellence Committee ; Data Monitoring Committee. / Evaluation of the effect of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction : rationale for and design of the EMPEROR-Reduced trial. In: European Journal of Heart Failure. 2019 ; Vol. 21, No. 10. pp. 1270-1278.
@article{ba6dd7c602394a9291e657490b474962,
title = "Evaluation of the effect of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial",
abstract = "Drugs that inhibit the sodium–glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30{\%}. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40{\%}), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin–angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30{\%}, and the estimated annual event rate is expected to be at least 15{\%}. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction.",
keywords = "Diabetes, Heart failure, Reduced ejection fraction, SGLT2 inhibitors, Trial design",
author = "{on behalf of the EMPEROR-Reduced Trial Committees and Investigators} and {Executive Committee} and {National Coordinators} and {Consulting Statistician} and {Clinical Events Committee} and {Scientific Excellence Committee} and {Data Monitoring Committee} and Milton Packer and Javed Butler and Filippatos, {Gerasimos S.} and Waheed Jamal and Afshin Salsali and Janet Schnee and Karen Kimura and Cordula Zeller and Jyothis George and Martina Brueckmann and Anker, {Stefan D.} and Faiez Zannad and Milton Packer and Anker, {Stefan D.} and Javed Butler and Gerasimos Filippatos and Faiez Zannad and Jyothis George and Martina Brueckmann and Sergio Perrone and Stephen Nicholls and Stefan Janssens and Edmar Bocchi and Nadia Giannetti and Subodh Verma and Zhang Jian and Jindrich Spinar and Seronde, {Marie France} and Michael B{\"o}hm and Bela Merkely and Vijay Chopra and Michele Senni and Stefano Taddei and Hiroyuki Tsutsui and Choi, {Dong Ju} and Eduardo Chuquiure and {La Rocca}, {Hans Pieter Brunner} and Piotr Ponikowski and Juanatey, {Jose Ramon Gonzalez} and Iain Squire and Javed Butler and James Januzzi and Ileana Pina and Pocock, {Stuart J.} and Peter Carson and Wolfram Doehner and Alan Miller and Markus Haas and Steen Pehrson and Alejandro Rabinstein",
year = "2019",
month = "10",
day = "1",
doi = "10.1002/ejhf.1536",
language = "English (US)",
volume = "21",
pages = "1270--1278",
journal = "European Journal of Heart Failure",
issn = "1388-9842",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Evaluation of the effect of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction

T2 - rationale for and design of the EMPEROR-Reduced trial

AU - on behalf of the EMPEROR-Reduced Trial Committees and Investigators

AU - Executive Committee

AU - National Coordinators

AU - Consulting Statistician

AU - Clinical Events Committee

AU - Scientific Excellence Committee

AU - Data Monitoring Committee

AU - Packer, Milton

AU - Butler, Javed

AU - Filippatos, Gerasimos S.

AU - Jamal, Waheed

AU - Salsali, Afshin

AU - Schnee, Janet

AU - Kimura, Karen

AU - Zeller, Cordula

AU - George, Jyothis

AU - Brueckmann, Martina

AU - Anker, Stefan D.

AU - Zannad, Faiez

AU - Packer, Milton

AU - Anker, Stefan D.

AU - Butler, Javed

AU - Filippatos, Gerasimos

AU - Zannad, Faiez

AU - George, Jyothis

AU - Brueckmann, Martina

AU - Perrone, Sergio

AU - Nicholls, Stephen

AU - Janssens, Stefan

AU - Bocchi, Edmar

AU - Giannetti, Nadia

AU - Verma, Subodh

AU - Jian, Zhang

AU - Spinar, Jindrich

AU - Seronde, Marie France

AU - Böhm, Michael

AU - Merkely, Bela

AU - Chopra, Vijay

AU - Senni, Michele

AU - Taddei, Stefano

AU - Tsutsui, Hiroyuki

AU - Choi, Dong Ju

AU - Chuquiure, Eduardo

AU - La Rocca, Hans Pieter Brunner

AU - Ponikowski, Piotr

AU - Juanatey, Jose Ramon Gonzalez

AU - Squire, Iain

AU - Butler, Javed

AU - Januzzi, James

AU - Pina, Ileana

AU - Pocock, Stuart J.

AU - Carson, Peter

AU - Doehner, Wolfram

AU - Miller, Alan

AU - Haas, Markus

AU - Pehrson, Steen

AU - Rabinstein, Alejandro

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Drugs that inhibit the sodium–glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin–angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction.

AB - Drugs that inhibit the sodium–glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin–angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction.

KW - Diabetes

KW - Heart failure

KW - Reduced ejection fraction

KW - SGLT2 inhibitors

KW - Trial design

UR - http://www.scopus.com/inward/record.url?scp=85069817778&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069817778&partnerID=8YFLogxK

U2 - 10.1002/ejhf.1536

DO - 10.1002/ejhf.1536

M3 - Article

C2 - 31584231

AN - SCOPUS:85069817778

VL - 21

SP - 1270

EP - 1278

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

SN - 1388-9842

IS - 10

ER -