Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2019

Open Access 01-12-2019 | Empagliflozin | Study protocol

Empagliflozin in heart failure patients with reduced ejection fraction: a randomized clinical trial (Empire HF)

Authors: Jesper Jensen, Massar Omar, Caroline Kistorp, Mikael Kjær Poulsen, Christian Tuxen, Ida Gustafsson, Lars Køber, Finn Gustafsson, Emil Fosbøl, Niels Eske Bruun, Lars Videbæk, Peter Hartmund Frederiksen, Jacob Eifer Møller, Morten Schou

Published in: Trials | Issue 1/2019

Login to get access

Abstract

Background

Data from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown.

Methods

This is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5–10.0% (48–86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included.

Discussion

The Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials.

Trial registration

Clinicaltrialsregister.eu, EudraCT Number 2017-001341-27. Registered on 29 May 2017.
ClinicalTrials.gov, NCT03198585. Registered on 26 June 2017.
Appendix
Available only for authorised users
Literature
1.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.CrossRef
2.
Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(21):2099.PubMed
3.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.CrossRef
4.
Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136(3):249–59.CrossRef
5.
Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018;71(23):2628–39.CrossRef
6.
Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108–17.CrossRef
7.
Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(15):1845–55.CrossRef
8.
Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation. 2017;136(17):1643–58.CrossRef
9.
Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2017;2(9):1025–9.CrossRef
10.
Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37(19):1526–34.CrossRef
11.
Radholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;138(5):458–68.CrossRef
12.
Al-Jobori H, Daniele G, Cersosimo E, Triplitt C, Mehta R, Norton L, et al. Empagliflozin and kinetics of renal glucose transport in healthy individuals and individuals with type 2 diabetes. Diabetes. 2017;66(7):1999–2006.CrossRef
13.
Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018;20(3):479–87.CrossRef
14.
Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2018;41(2):356–63.CrossRef
15.
Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110(15):2168–74.CrossRef
16.
Gardner RS, Ozalp F, Murday AJ, Robb SD, McDonagh TA. N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J. 2003;24(19):1735–43.CrossRef
17.
Schou M, Gustafsson F, Nielsen PH, Madsen LH, Kjaer A, Hildebrandt PR. Unexplained week-to-week variation in BNP and NT-proBNP is low in chronic heart failure patients during steady state. Eur J Heart Fail. 2007;9(1):68–74.CrossRef
18.
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190–5.CrossRef
19.
Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis. Diabetes Care. 2016;39(7):1108–14.CrossRef
20.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200.CrossRef
21.
Egstrup M, Schou M, Gustafsson I, Kistorp CN, Hildebrandt PR, Tuxen CD. Oral glucose tolerance testing in an outpatient heart failure clinic reveals a high proportion of undiagnosed diabetic patients with an adverse prognosis. Eur J Heart Fail. 2011;13(3):319–26.CrossRef
22.
Kistorp C, Galatius S, Gustafsson F, Faber J, Corell P, Hildebrandt P. Prevalence and characteristics of diabetic patients in a chronic heart failure population. Int J Cardiol. 2005;100(2):281–7.CrossRef
23.
Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, et al. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015;373(24):2314–24.CrossRef
24.
Christensen HM, Kistorp C, Schou M, Keller N, Zerahn B, Frystyk J, et al. Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status. Endocrine. 2013;43(3):626–34.CrossRef
25.
Duarte K, Monnez JM, Albuisson E, Pitt B, Zannad F, Rossignol P. Prognostic value of estimated plasma volume in heart failure. JACC Heart Fail. 2015;3(11):886–93.CrossRef
26.
Fritzsche I, Buhrdel P, Melcher R, Bohme HJ. Stability of ketone bodies in serum in dependence on storage time and storage temperature. Clin Lab. 2001;47(7–8):399–403.PubMed
27.
Laun RA, Rapsch B, Abel W, Schroder O, Roher HD, Ekkernkamp A, et al. The determination of ketone bodies: preanalytical, analytical and physiological considerations. Clin Exp Med. 2001;1(4):201–9.CrossRef
28.
Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol. 2006;47(10):1987–96.CrossRef
29.
Brøchner-Mortensen J. A simple single injection method for determination of the extracellular fluid volume. Scand J Clin Lab Invest. 1980;40(6):567–73.CrossRef
30.
Jackson CE, Solomon SD, Gerstein HC, Zetterstrand S, Olofsson B, Michelson EL, et al. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet. 2009;374(9689):543–50.CrossRef
31.
Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation. 2003;107(15):1991–7.CrossRef
32.
Tsutamoto T, Kawahara C, Nishiyama K, Yamaji M, Fujii M, Yamamoto T, et al. Prognostic role of highly sensitive cardiac troponin I in patients with systolic heart failure. Am Heart J. 2010;159(1):63–7.CrossRef
33.
von Haehling S, Filippatos GS, Papassotiriou J, Cicoira M, Jankowska EA, Doehner W, et al. Mid-regional pro-adrenomedullin as a novel predictor of mortality in patients with chronic heart failure. Eur J Heart Fail. 2010;12(5):484–91.CrossRef
34.
Paraskevaidis IA, Ikonomidis I, Simitsis P, Parissis J, Stasinos V, Makavos G, et al. Multidimensional contractile reserve predicts adverse outcome in patients with severe systolic heart failure: a 4-year follow-up study. Eur J Heart Fail. 2017;19(7):846–61.CrossRef
35.
Motoki H, Borowski AG, Shrestha K, Troughton RW, Tang WH, Thomas JD, et al. Incremental prognostic value of assessing left ventricular myocardial mechanics in patients with chronic systolic heart failure. J Am Coll Cardiol. 2012;60(20):2074–81.CrossRef
36.
Patel CB, DeVore AD, Felker GM, Wojdyla DM, Hernandez AF, Milano CA, et al. Characteristics and outcomes of patients with heart failure and discordant findings by right-sided heart catheterization and cardiopulmonary exercise testing. Am J Cardiol. 2014;114(7):1059–64.CrossRef
37.
Heidenreich PA, Spertus JA, Jones PG, Weintraub WS, Rumsfeld JS, Rathore SS, et al. Health status identifies heart failure outpatients at risk for hospitalization or death. J Am Coll Cardiol. 2006;47(4):752–6.CrossRef
38.
Mitchell PM, Al-Janabi H, Richardson J, Iezzi A, Coast J. The relative impacts of disease on health status and capability wellbeing: a multi-country study. PLoS One. 2015;10(12):e0143590.CrossRef
39.
Andersen MJ, Ersboll M, Bro-Jeppesen J, Moller JE, Hassager C, Kober L, et al. Relationships between biomarkers and left ventricular filling pressures at rest and during exercise in patients after myocardial infarction. J Card Fail. 2014;20(12):959–67.CrossRef
40.
Andersen MJ, Ersboll M, Axelsson A, Gustafsson F, Hassager C, Kober L, et al. Sildenafil and diastolic dysfunction after acute myocardial infarction in patients with preserved ejection fraction: the Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction (SIDAMI) trial. Circulation. 2013;127(11):1200–8.CrossRef
41.
Jorsal A, Wiggers H, Holmager P, Nilsson B, Nielsen R, Boesgaard TW, et al. A protocol for a randomised, double-blind, placebo-controlled study of the effect of LIraglutide on left VEntricular function in chronic heart failure patients with and without type 2 diabetes (The LIVE Study). BMJ Open. 2014;4(5):e004885.CrossRef
42.
Jorsal A, Kistorp C, Holmager P, Tougaard RS, Nielsen R, Hanselmann A, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017;19(1):69–77.CrossRef
Metadata
Title
Empagliflozin in heart failure patients with reduced ejection fraction: a randomized clinical trial (Empire HF)
Authors
Jesper Jensen
Massar Omar
Caroline Kistorp
Mikael Kjær Poulsen
Christian Tuxen
Ida Gustafsson
Lars Køber
Finn Gustafsson
Emil Fosbøl
Niels Eske Bruun
Lars Videbæk
Peter Hartmund Frederiksen
Jacob Eifer Møller
Morten Schou
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Trials / Issue 1/2019
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-019-3474-5

Other articles of this Issue 1/2019

Trials 1/2019 Go to the issue

Research

Core Outcome Set-STAndardised Protocol Items: the COS-STAP Statement

Methodology

Interval-cohort designs and bias in the estimation of per-protocol effects: a simulation study

Study protocol

Impact of renin-angiotensin system inhibitors continuation versus discontinuation on outcome after major surgery: protocol of a multicenter randomized, controlled trial (STOP-or-NOT trial)

Study protocol

A disorder-specific group cognitive behavior therapy for social anxiety disorder in adolescents: study protocol for a randomized controlled study

Study protocol

Enhancing SKIN health and safety in aged CARE (SKINCARE Trial): a study protocol for an exploratory cluster-randomized pragmatic trial

Study protocol

A combination of multimodal physical exercises in real and virtual environments for individuals after chronic stroke: study protocol for a randomized controlled trial