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
Diabetes Therapy
Published in: Diabetes Therapy 5/2018

Open Access 01-10-2018 | Study Protocol

Effect of Empagliflozin Versus Placebo on Cardiac Sympathetic Activity in Acute Myocardial Infarction Patients with Type 2 Diabetes Mellitus: Rationale

Authors: Yoshiaki Kubota, Takeshi Yamamoto, Shuhei Tara, Yukichi Tokita, Kenji Yodogawa, Yuki Iwasaki, Hitoshi Takano, Yayoi Tsukada, Kuniya Asai, Masaaki Miyamoto, Yasushi Miyauchi, Eitaro Kodani, Naoki Sato, Jun Tanabe, Wataru Shimizu

Published in: Diabetes Therapy | Issue 5/2018

Login to get access

Abstract

Introduction

Protection from lethal ventricular arrhythmias leading to sudden cardiac death is one of the most important problems after myocardial infarction. Cardiac sympathetic hyperactivity is related to poor prognosis and fatal arrhythmias and can be non-invasively assessed with heart rate variability, heart rate turbulence, T-wave alternans, late potentials, and 123I-meta-iodobenzylguanide (123I-MIBG) scintigraphy. Sodium glucose cotransporter 2 (SGLT2) inhibitors potentially reduce sympathetic nervous system activity that is augmented in part due to the stimulatory effect of hyperglycemia. The EMBODY trial is designed to determine whether the suppression of cardiac sympathetic activity induced by the SGLT2 inhibitor is accompanied by protection against adverse cardiovascular outcomes.

Methods

The EMBODY trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with acute MI and type 2 diabetes in Japan. A total of 98 patients will be randomized (1:1) to receive once-daily placebo or empagliflozin, an SGLT2 inhibitor, 10 mg. The primary end point is the change from baseline to 24 weeks in heart rate variability. Secondary end points include the change from baseline for other sudden cardiac death surrogate-markers such as heart rate turbulence, T-wave alternans, late potentials, and 123I-MIBG scintigraphy imaging. Adverse effects will be evaluated throughout the trial period.

Planned Outcomes

The EMBODY trial will evaluate the potential cardioprotective effect of empagliflozin and will provide additional important new data regarding its preventative effects on sudden cardiac death.

Funding

Nippon Boehringer Ingelheim and Eli Lilly and Company.
Literature
1.
Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262–74.CrossRefPubMed
2.
Villafana S, Huang F, Hong E. Role of the sympathetic and renin angiotensin systems in the glucose-induced increase of blood pressure in rats. Eur J Pharmacol. 2004;506:143–50.CrossRefPubMed
3.
Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90–100.CrossRefPubMedPubMedCentral
4.
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;373:2117–28.CrossRefPubMed
5.
6.
Alabas OA, Hall M, Dondo TB, Rutherford MJ, Timmis AD, Batin PD, et al. Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study. J Epidemiol Community Health. 2016;71:25–32.CrossRefPubMed
7.
Verschure DO, van Eck-Smit BL, Somsen GA, Knol RJ, Verberne HJ. Cardiac sympathetic activity in chronic heart failure: cardiac 123I-mIBG scintigraphy to improve patient selection for ICD implantation. Neth Heart J. 2016;24:701–8.CrossRefPubMedPubMedCentral
8.
Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E, et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. J Diabetes Investig. 2010;19:212–28.
9.
O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;127:e362–425.CrossRefPubMed
10.
Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Circulation. 2014;130:2354–94.CrossRefPubMed
11.
Malfatto G, Facchini M, Sala L, Branzi G, Bragato R, Leonetti G. Effects of cardiac rehabilitation and beta-blocker therapy on heart rate variability after first acute myocardial infarction. Am J Cardiol. 1998;81:834–40.CrossRefPubMed
12.
Ulgen MS, Akdemir O, Toprak N. The effects of trimetazidine on heart rate variability and signal-averaged electrocardiography in early period of acute myocardial infarction. Int J Cardiol. 2001;77:255–62.CrossRefPubMed
13.
Lampert R, Ickovics JR, Viscoli CJ, Horwitz RI, Lee FA. Effects of propranolol on recovery of heart rate variability following acute myocardial infarction and relation to outcome in the beta-blocker heart attack trial. Am J Cardiol. 2003;91:137–42.CrossRefPubMed
14.
Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation. 1988;78:969–79.CrossRefPubMed
15.
Camm AJ, Pratt CM, Schwartz PJ, Al-Khalidi HR, Spyt MJ, Holroyde MJ, et al. Mortality in patients after a recent myocardial infarction: a randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation. 2004;109:990–6.CrossRefPubMed
16.
Schwartz PJ, La Rovere MT. ATRAMI: a mark in the quest for the prognostic value of autonomic markers. Autonomic tone and reflexes after myocardial infarction. Eur Heart J. 1998;19:1593–5.CrossRefPubMed
17.
Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256–62.CrossRefPubMed
18.
Cripps TR, Malik M, Farrell TG, Camm AJ. Prognostic value of reduced heart rate variability after myocardial infarction: clinical evaluation of a new analysis method. Br Heart J. 1991;65:14–9.CrossRefPubMedPubMedCentral
19.
Farrell TG, Bashir Y, Cripps T, Malik M, Poloniecki J, Bennett ED, et al. Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrocardiographic variables and the signal-averaged electrocardiogram. J Am Coll Cardiol. 1991;18:687–97.CrossRefPubMed
20.
Bigger JT Jr, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation. 1992;85:164–71.CrossRefPubMed
21.
Camm AJ, Malik M, Bigger JT, Breithardt G, Cerutti S, Cohen R, et al. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task force of the European society of cardiology and the North American society of pacing and electrophysiology. Circulation. 1996;93:1043–65.CrossRef
22.
Odemuyiwa O, Malik M, Farrell T, Bashir Y, Poloniecki J, Camm J. Comparison of the predictive characteristics of heart rate variability index and left ventricular ejection fraction for all-cause mortality, arrhythmic events and sudden death after acute myocardial infarction. Am J Cardiol. 1991;68:434–9.CrossRefPubMed
23.
Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation. 1992;85:I77–91.PubMed
24.
La Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R, et al. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation. 2001;103:2072–7.CrossRefPubMed
25.
Shimizu W, Antzelevitch C. Cellular and ionic basis for T-wave alternans under long-QT conditions. Circulation. 1999;99:1499–507.CrossRefPubMed
26.
Grabowski M, Karpinski G, Filipiak KJ, Opolski G. Images in cardiovascular medicine. drug-induced long-QT syndrome with macroscopic T-wave alternans. Circulation. 2004;110:e459–60.CrossRefPubMed
27.
Armoundas AA, Nanke T, Cohen RJ. Images in cardiovascular medicine. T-wave alternans preceding torsade de pointes ventricular tachycardia. Circulation. 2000;101:2550.CrossRefPubMed
28.
Salerno-Uriarte JA, De Ferrari GM, Klersy C, Pedretti RF, Tritto M, Sallusti L, et al. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA Study. J Am Coll Cardiol. 2007;50:1896–904.CrossRefPubMed
29.
Exner DV, Kavanagh KM, Slawnych MP, Mitchell LB, Ramadan D, Aggarwal SG, et al. Noninvasive risk assessment early after a myocardial infarction the REFINE study. J Am Coll Cardiol. 2007;50:2275–84.CrossRefPubMed
30.
Chow T, Kereiakes DJ, Onufer J, Woelfel A, Gursoy S, Peterson BJ, et al. Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (microvolt T wave alternans testing for risk stratification of post-myocardial infarction patients) trial. J Am Coll Cardiol. 2008;52:1607–15.CrossRefPubMed
31.
Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for practice guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death). J Am Coll Cardiol. 2006;48:e247–346.CrossRefPubMed
32.
Schmidt G, Malik M, Barthel P, Schneider R, Ulm K, Rolnitzky L, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet. 1999;353:1390–6.CrossRefPubMed
33.
Ghuran A, Reid F, La Rovere MT, Schmidt G, Bigger JT Jr, Camm AJ, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (the autonomic tone and reflexes after myocardial infarction substudy). Am J Cardiol. 2002;89:184–90.CrossRefPubMed
34.
Miwa Y, Miyakoshi M, Hoshida K, Yanagisawa R, Abe A, Tsukada T, et al. Heart rate turbulence can predict cardiac mortality following myocardial infarction in patients with diabetes mellitus. J Cardiovasc Electrophysiol. 2011;22:1135–40.CrossRefPubMed
35.
Savard P, Rouleau JL, Ferguson J, Poitras N, Morel P, Davies RF, et al. Risk stratification after myocardial infarction using signal-averaged electrocardiographic criteria adjusted for sex, age, and myocardial infarction location. Circulation. 1997;96:202–13.CrossRefPubMed
36.
Gomes JA, Cain ME, Buxton AE, Josephson ME, Lee KL, Hafley GE. Prediction of long-term outcomes by signal-averaged electrocardiography in patients with unsustained ventricular tachycardia, coronary artery disease, and left ventricular dysfunction. Circulation. 2001;104:436–41.CrossRefPubMed
37.
el-Sherif N, Denes P, Katz R, Capone R, Mitchell LB, Carlson M, et al. Definition of the best prediction criteria of the time domain signal-averaged electrocardiogram for serious arrhythmic events in the postinfarction period. The cardiac arrhythmia suppression trial/signal-averaged electrocardiogram (CAST/SAECG) substudy investigators. J Am Coll Cardiol. 1995;25:908–14.CrossRefPubMed
38.
Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol. 2010;55:2212–21.CrossRefPubMed
39.
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland coronary prevention study group. N Engl J Med. 1995;333:1301–7.CrossRefPubMed
40.
Boutitie F, Boissel JP, Connolly SJ, Camm AJ, Cairns JA, Julian DG, et al. Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT investigators. Circulation. 1999;99:2268–75.CrossRefPubMed
41.
Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–93.CrossRefPubMed
42.
Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: a position statement by the American diabetes association. Diabetes Care. 2017;40:136–54.CrossRefPubMed
43.
Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14:528.CrossRefPubMedPubMedCentral
Metadata
Title
Effect of Empagliflozin Versus Placebo on Cardiac Sympathetic Activity in Acute Myocardial Infarction Patients with Type 2 Diabetes Mellitus: Rationale
Authors
Yoshiaki Kubota
Takeshi Yamamoto
Shuhei Tara
Yukichi Tokita
Kenji Yodogawa
Yuki Iwasaki
Hitoshi Takano
Yayoi Tsukada
Kuniya Asai
Masaaki Miyamoto
Yasushi Miyauchi
Eitaro Kodani
Naoki Sato
Jun Tanabe
Wataru Shimizu
Publication date
01-10-2018
Publisher
Springer Healthcare
Published in
Diabetes Therapy / Issue 5/2018
Print ISSN: 1869-6953
Electronic ISSN: 1869-6961
DOI
https://doi.org/10.1007/s13300-018-0480-7

Other articles of this Issue 5/2018

Diabetes Therapy 5/2018 Go to the issue

Original Research

Male Patients with Longstanding Type 2 Diabetes Have a Higher Incidence of Hypoglycemia Compared with Female Patients

Case Report

Optimizing a Hybrid Closed Loop System in Type 1 Diabetes: A Case Report

Original Research

Could Intensive Blood Pressure Control Really Reduce Diabetic Retinopathy Outcomes? Evidence from Meta-Analysis and Trial Sequential Analysis from Randomized Controlled Trials

Original Research

A Prospective Cohort Study on the Management of Young Patients with Newly Diagnosed Type 2 Diabetes Using Mobile Medical Applications

Study Protocol

Rationale and Design of the STOP-OB Study for Evaluating the Effects of Tofogliflozin and Glimepiride on Fat Deposition in Type 2 Diabetes Patients Treated with Metformin/DPP-4 Inhibitor Dual Therapy

Brief Report

Durability of Glucose-Lowering Effect of the First Administration of Dulaglutide: A Retrospective, Single-Center, Single-Arm Study
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits