Evaluation of the effects of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial

on behalf of the EMPEROR-Preserved Trial Committees and Investigators

Research output: Contribution to journalArticle

Abstract

Background: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium–glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. Study design: The EMPEROR-Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities. Study aims: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death,. all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

Original languageEnglish (US)
Pages (from-to)1279-1287
Number of pages9
JournalEuropean Journal of Heart Failure
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2019

Fingerprint

Symporters
Heart Failure
Morbidity
Mortality
Hospitalization
Fibrosis
Sodium
empagliflozin
Inflammation
Biological Phenomena
Vascular Stiffness
Treatment Failure
Stroke Volume
Dyspnea
Type 2 Diabetes Mellitus
Blood Glucose
Adipose Tissue
Theoretical Models
Biomarkers
Placebos

Keywords

  • Diabetes
  • Heart failure
  • SGLT2 inhibitors
  • Trial design

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{374f273385dc48f1b0313856e5a58215,
title = "Evaluation of the effects of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial",
abstract = "Background: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium–glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. Study design: The EMPEROR-Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40{\%}), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities. Study aims: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death,. all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.",
keywords = "Diabetes, Heart failure, SGLT2 inhibitors, Trial design",
author = "{on behalf of the EMPEROR-Preserved Trial Committees and Investigators} and Anker, {Stefan D.} 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 Faiez Zannad and Milton Packer and Milton Packer and Anker, {Stefan D.} and Javed Butler and Filippatos, {Gerasimos S.} 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 {Gomez Mesa}, {Juan Esteban} and Jindrich Spinar and Michael B{\"o}hm and Bela Merkely and Vijay Chopra and Michele Senni and Stefano Taddi and Hiroyuki Tsutsui and Eduardo Chuquiure and {La Rocca}, {Hans Pieter Brunner} and Piotr Ponikowski and Dragos Vinereanu and David Sim and Choi, {Dong Ju} 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 Alejandro Rabinstein",
year = "2019",
month = "10",
day = "1",
doi = "10.1002/ejhf.1596",
language = "English (US)",
volume = "21",
pages = "1279--1287",
journal = "European Journal of Heart Failure",
issn = "1388-9842",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

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

T2 - rationale for and design of the EMPEROR-Preserved Trial

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

AU - Anker, Stefan D.

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 - Zannad, Faiez

AU - Packer, Milton

AU - Packer, Milton

AU - Anker, Stefan D.

AU - Butler, Javed

AU - Filippatos, Gerasimos S.

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 - Gomez Mesa, Juan Esteban

AU - Spinar, Jindrich

AU - Böhm, Michael

AU - Merkely, Bela

AU - Chopra, Vijay

AU - Senni, Michele

AU - Taddi, Stefano

AU - Tsutsui, Hiroyuki

AU - Chuquiure, Eduardo

AU - La Rocca, Hans Pieter Brunner

AU - Ponikowski, Piotr

AU - Vinereanu, Dragos

AU - Sim, David

AU - Choi, Dong Ju

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 - Rabinstein, Alejandro

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Background: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium–glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. Study design: The EMPEROR-Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities. Study aims: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death,. all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

AB - Background: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium–glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. Study design: The EMPEROR-Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities. Study aims: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death,. all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

KW - Diabetes

KW - Heart failure

KW - SGLT2 inhibitors

KW - Trial design

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U2 - 10.1002/ejhf.1596

DO - 10.1002/ejhf.1596

M3 - Article

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VL - 21

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JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

SN - 1388-9842

IS - 10

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