Diabetes in Cardiovascular Disease A Companion to

Braunwald's Heart Disease

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DIABETES IN
CARDIOVASCULAR
DISEASE
A Companion to Braunwald’s Heart Disease
Darren K. McGuire, MD, MHSc, FAHA, FACC
Professor of Internal Medicine
Dallas Heart Ball Chair for Research on Heart Disease in Women
Director, Parkland Hospital and Health System Cardiology Clinics
University of Texas Southwestern Medical Center
Dallas, Texas

Nikolaus Marx, MD, FAHA

Professor of Medicine/Cardiology
Head of Department of Internal Medicine I
University Hospital Aachen
Aachen, Germany
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

DIABETES IN CARDIOVASCULAR DISEASE: A COMPANION TO BRAUNWALD’S HEART DISEASE ISBN: 978-1-4557-5418-2

Copyright © 2015 by Saunders, an imprint of Elsevier Inc.

All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
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Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations
such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be
noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding,
changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information,
methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their
own safety and the safety of others, including parties for whom they have a professional responsibility.

With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information
provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended
dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying
on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for
each individual patient, and to take all appropriate safety precautions.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any liability for any injury
and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of
any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

Diabetes in cardiovascular disease: a companion to Braunwald's heart disease / [edited by] Darren K. McGuire, Nikolaus Marx.
p.; cm.
Complemented by: Braunwald's heart disease / edited by Robert O. Bonow ... [et al.]. 9th ed. 2012.
Includes bibliographical references and index.
ISBN 978-1-4557-5418-2 (hardcover: alk. paper)
I. McGuire, Darren K., editor. II. Marx, Nikolaus (Professor of medicine/cardiology), editor. III. Braunwald's heart disease.
Complemented by (work):
[DNLM: 1. Cardiovascular Diseases–complications. 2. Diabetes Complications. 3. Diabetes Mellitus–physiopathology.
4. Diabetes Mellitus–therapy. 5. Risk Factors. WG 120]
RC681
616.1'2–dc23
2014012925

Executive Content Strategist: Dolores Meloni

Content Development Specialist: Angela Rufino
Publishing Services Manager: Anne Altepeter
Project Manager: Cindy Thoms
Design Manager: Steven Stave
Illustrations Manager: Lesley Frazier

Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1

To my wife, Julia, and our children, Emma and Jack, for their support, encouragement, and
sacrifices for the time and effort required to develop this book. Thanks to each of you for keeping me
focused on what is really most important, always.

To the patients around the world afflicted with diabetes, with hopes of an increasingly bright future.

Darren K. McGuire

To Nicole, and to my children, Nadine, Julian, and Florian, for their remarkable support through this
endeavor.

In memory of my father Hans-Albert.

Nikolaus Marx
This page intentionally left blank
 Contributors

David Aguilar, MD Melanie J. Davies, MD, PhD

Assistant Professor of Medicine Diabetes Research Centre
Internal Medicine and Cardiology College of Medicine
Baylor College of Medicine Biological Sciences and Psychology
Houston, Texas University of Leicester
Leicester, United Kingdom
Sylvie A. Ahn, MD
Division of Cardiology Robert H. Eckel, MD
Cliniques Universitaires – St-Luc Professor of Medicine
Pôle de Recherche Cardiovasculaire University of Colorado Anschutz Medical Campus
Institut de Recherche Expérimentale et Clinique (IREC) Aurora, Colorado
Université Catholique de Louvain
Brussels, Belgium Leonard E. Egede, MD, MS
Professor of Medicine
Pavan K. Battiprolu, PhD Health Equity and Rural Outreach Innovation Center
Departments of Internal Medicine, Cardiology, and Ralph H. Johnson Department of Veterans Affairs Medical
Metabolic Disorders Center
University of Texas Southwestern Medical Center Center for Health Disparities Research, Division of General
Dallas, Texas Internal Medicine
Medical University of South Carolina
Charleston, South Carolina
Joshua A. Beckman, MD, MS
Associate Professor of Medicine
Frank Joachim Erbguth, MD, PhD
Harvard Medical School
Professor of Neurology
Director, Cardiovascular Fellowship Program
Department of Neurology
Cardiovascular Division
Nuremberg Municipal Academic Hospital
Brigham and Women’s Hospital
Nuremberg, Germany
Boston, Massachusetts

Jason S. Fish, MD, MSHS

Deepak L. Bhatt, MD, MPH Director of Ambulatory Quality and Optimization
Executive Director of Interventional Cardiovascular Assistant Professor
Programs Internal Medicine
Brigham and Women’s Hospital Heart and Vascular Center University of Texas Southwestern Medical Center
Senior Physician Dallas, Texas
Brigham and Women’s Hospital
Senior Investigator
TIMI Study Group B. Miles Fisher, MD, MB ChB
Boston, Massachusetts Consultant Physician
Glasgow Royal Infirmary
Honorary Professor
Petter Bjornstad, MD University of Glasgow
Department of Pediatrics Glasgow, Scotland
Children’s Hospital Colorado
University of Colorado School of Medicine
Aurora, Colorado Barry A. Franklin, PhD
Director
Preventive Cardiology and Cardiac Rehabilitation
Jonathan D. Brown, MD William Beaumont Hospital
Instructor Royal Oak, Michigan
Harvard Medical School Professor of Internal Medicine
Cardiovascular Division Oakland University
Brigham and Women’s Hospital William Beaumont School of Medicine
Boston, Massachusetts Rochester, Michigan

vii
 viii

Baptist Gallwitz, MD Kelly J. Hunt, PhD

Deputy Head of Department Health Equity and Rural Outreach Innovation Center
Department of Medicine IV (Endocrinology, Diabetology, Ralph H. Johnson Department of Veterans Affairs
CONTRIBUTORS

Angiology, Nephrology, and Clinical Chemistry) Medical Center

Eberhard Karls University Tübingen Center for Health Disparities Research,
Tübingen, Germany Division of General Internal Medicine
Department of Public Health Sciences
Medical University of South Carolina
Baris Gencer, MD
Charleston, South Carolina
Fellow
Interventional Cardiology Unit
Cardiology Division Silvio E. Inzucchi, MD
University Hospital Professor
Geneva, Switzerland Internal Medicine (Endocrinology)
Yale University School of Medicine
Clinical Chief, Endocrinology
Anselm K. Gitt, MD, FESC
Director, Yale Diabetes Center
Herzzentrum Ludwigshafen
Yale-New Haven Hospital
Medizinische Klinik B, Kardiologie
New Haven, Connecticut
Stiftung Institut für Herzinfarktforschung Ludwigshafen
Ludwigshafen, Germany
Stefan K. James, MD, PhD
Department of Medical Sciences
Colin Greaves, PhD
Uppsala Clinical Research Center
Senior Research Fellow
Uppsala University
University of Exeter Medical School
Uppsala, Sweden
University of Exeter
Exeter, Devon, United Kingdom
Tracy R. Juliao, PhD, LP, NCC
Director of Psychology
Hans Ulrich Häring, MD, PhD
Weight Control Center
Head of Department
William Beaumont Hospital
Department of Medicine IV (Endocrinology, Diabetology,
Royal Oak, Michigan
Angiology, Nephrology, and Clinical Chemistry)
Assistant Professor
Eberhard Karls University Tübingen
Oakland University
Tübingen, Germany
William Beaumont School of Medicine
Rochester, Michigan
Markolf Hanefeld, MD, PhD
Professor
Wolfgang Koenig, MD, FRCP, FESC, FACC, FAHA
Study Centre Professor Hanefeld
Professor of Medicine and Cardiology
University Hospital
Department of Internal Medicine II – Cardiology
Carl Gustav Carus Technical University
University of Ulm Medical Center
Dresden, Germany
Ulm, Germany

Michel P. Hermans, MD, PhD, DipNatSci, DipEarthSci,

Frank D. Kolodgie, MD
DipGeogEnv, PGCert(SocSc)
CVPath Institute
Professor
Gaithersburg, Maryland
Endocrinology and Nutrition
Cliniques Universitaires Saint-Luc
Brussels, Belgium Mikhail Kosiborod, MD
Professor of Medicine
St. Luke’s Mid America Heart Institute
Adrian F. Hernandez, MD, MHS
University of Missouri – Kansas City
Director, Outcomes Research
Kansas City, Missouri
Duke Clinical Research Institute
Associate Professor of Medicine
Cardiology Elena Ladich, MD
Duke University School of Medicine Chief, Cardiovascular Pathology
Durham, North Carolina CVPath Institute
Gaithersburg, Maryland
Joseph A. Hill, MD, PhD
Departments of Internal Medicine (Cardiology) and Harold L. Lazar, MD
Molecular Biology Professor of Cardiothoracic Surgery
Division of Cardiology Department of Cardiothoracic Surgery
University of Texas Southwestern Medical Center Boston Medical Center
Dallas, Texas Boston, Massachusetts
 ix

Kasia J. Lipska, MD, MHS Fumiyuki Otsuka, MD

Instructor in Medicine CVPath Institute
Section of Endocrinology Gaithersburg, Maryland

CONTRIBUTORS
Department of Medicine Yale School of Medicine
New Haven, Connecticut Anushka A. Patel, MBBS, SM, PhD, FRACP
Professor
Cheryl P. Lynch, MD, MPH Sydney Medical School
Physician-Investigator Chief Scientist
Health Equity and Rural Outreach Innovation Center The George Institute for Global Health
Ralph H. Johnson, Department of Veterans Affairs Medical Cardiologist
Center Royal Prince Alfred Hospital
Assistant Professor of Medicine Sydney, Australia
Center for Health Disparities Research, Division of General
Internal Medicine Mark C. Petrie, MD
Medical University of South Carolina Scottish National Advanced Heart Failure Service
Charleston, South Carolina Golden Jubilee National Hospital
Clydebank
Glasgow Royal Infirmary
David M. Maahs, MD, PhD Glasgow, Scotland
Assistant Professor of Pediatrics
Barbara Davis Center for Diabetes Frank Pistrosch, MD
Department of Medicine Study Centre Professor Hanefeld
Aurora, Colorado University Hospital
Carl Gustav Carus Technical University
Dresden, Germany
John J.V. McMurray, MSc(Hons), MB ChB(Hons), MD,
FESC, FACC, FAHA
British Heart Foundation Cardiovascular Research Centre Jorge Plutzky, MD
University of Glasgow Director
Glasgow, Scotland Vascular Disease Prevention Program
Co-Director, Preventive Cardiology
Brigham and Women’s Hospital
Wendy M. Miller, MD Associate Professor
Director Harvard Medical School
Nutrition and Preventive Medicine Boston, Massachusetts
William Beaumont Hospital
Royal Oak, Michigan
Professor of Internal Medicine Paul Poirier, MD, PhD, FRCPC, FACC, FAHA
Oakland University Chief, Cardiac Prevention and Rehabilitation
William Beaumont School of Medicine Cardiology
Rochester, Michigan Institut Universitaire de Cardiologie et de Pneumologie de
Québec
Professor
Masataka Nakano, MD Faculty of Pharmacy
CVPath Institute Laval University
Gaithersburg, Maryland Quebec City, Quebec, Canada

Ravichandran Ramasamy, PhD

K.M. Venkat Narayan, MD Diabetes Research Program
Hubert Department of Global Health Division of Endocrinology
Rollins School of Public Health Department of Medicine
Emory University New York University School of Medicine
Atlanta, Georgia New York, New York

Franz-Josef Neumann, MD Marian J. Rewers, MD, PhD

Professor Barbara Davis Center for Diabetes
Cardiology and Angiology II University of Colorado School of Medicine
University Heart Center Freiburg – Bad Krozingen Aurora, Colorado
Bad Krozingen, Germany
Marco Roffi, MD
Associate Professor
Michelle L. O’Donoghue, MD, MPH Vice-Chairman of Cardiology
TIMI Study Group Director
Cardiovascular Division Interventional Cardiology Unit
Brigham and Women’s Hospital University Hospital
Boston, Massachusetts Geneva, Switzerland
 x

Michel F. Rousseau, MD, PhD, FACC, FAHA Zhao V. Wang, PhD

Professor, Division of Cardiology Department of Internal Medicine (Cardiology)
Cliniques Universitaires Saint-Luc University of Texas Southwestern Medical Center
CONTRIBUTORS

Pôle de Recherche Cardiovasculaire Dallas, Texas

Institut de Recherche Expérimentale et Clinique (IREC)
Université Catholique de Louvain
Brussels, Belgium Mary Beth Weber, MPH, PhD
Assistant Professor
Hubert Department of Global Health
Kenichi Sakakura, MD
Rollins School of Public Health
CVPath Institute
Emory University
Gaithersburg, Maryland
Atlanta, Georgia
Frank Schaper, MD
Study Centre Professor Hanefeld Neil J. Wimmer, MD
University Hospital Fellow in Cardiovascular Medicine
Carl Gustav Carus Technical University Division of Cardiovascular Medicine
Dresden, Germany Brigham and Women’s Hospital
Boston, Massachusetts
Ann Marie Schmidt, MD
Diabetes Research Program
Division of Endocrinology Yee Weng Wong, MD
Department of Medicine Advanced Heart Failure and Cardiac Transplant Unit
New York University School of Medicine The Prince Charles Hospital
New York, New York Chermside, Queensland, Australia

Peter E.H. Schwarz, MD, PhD, MBA Shi Fang Yan, MD

Professor Diabetes Research Program
Department for Prevention and Care of Diabetes Division of Endocrinology
Medical Clinic III Department of Medicine
University Hospital New York University School of Medicine
Carl Gustav Carus Technical University New York, New York
Dresden, Germany

Paul Valensi, MD Thomas Yates, PhD

Professor Diabetes Research Centre
Endocrinology Diabetology Nutrition College of Medicine
Jean Verdier Hospital Biological Sciences and Psychology
Bondy, France University of Leicester
Leicester, United Kingdom
Renu Virmani, MD
Medical Director, President Barak Zafrir, MD
CVPath Institute Cardiovascular Division
Gaithersburg, Maryland Department of Medicine
Brigham and Women's Hospital
Lars Wallentin, MD, PhD Harvard Medical School
Department of Medical Sciences Boston, Massachusetts
Uppsala Clinical Research Center
Uppsala University
Uppsala, Sweden
 Foreword

Science often takes great strides when two fields intersect disease. The book is eminently readable, thorough but not
and when each contributes its special knowledge, expertise, encyclopedic. Part I presents the epidemiology, pathophys-
and technology to create a powerful hybrid. An example is iology, and management of diabetes and of the metabolic
astrophysics, in which principles of physics are applied to syndrome. Part II focuses on the pathobiology of diabetic
astronomical observations. Such intersections abound in atherosclerosis, as well as the risk and epidemiology of this
biomedical science. For example, the relatively new field condition. The management of chronic coronary heart dis-
of pharmacogenetics combines the expertise of the found- ease in diabetic patients is complex and is described in Part
ing sciences – pharmacology and genetics – to provide an III. It involves lifestyle interventions and management of glu-
understanding of the (sometimes enormous) differences cose, blood pressure, lipids, and anti-platelet drugs, as well
in the response of individual patients to identical doses of as coronary revascularization. Part IV presents similar con-
drugs, and this has advanced the field of personalized med- siderations for acute coronary syndromes, while Part V
icine. In cardiology, an understanding of the electrical prop- focuses on the special features of heart failure in patients
erties of cardiac cells and clinical arrhythmology has been with diabetes. Last – but certainly not least important – Part
combined to form the important new subspecialty of clinical VI deals with diabetes-accelerated atherosclerosis in other
electrophysiology. vascular beds, including the peripheral and the cerebrovas-
The substantial increase in caloric intake and reduction in cular arteries, as well as autonomic neuropathy.
physical activity throughout the world have resulted in a The 60 authors, ably led by the talented editors,
pandemic of obesity that, in turn, has led to an enormous Drs. McGuire and Marx, are international authorities who
increase in the incidence of type 2 diabetes mellitus. It is have provided excellent and up-to-date information in this
widely appreciated that diabetes accelerates atherogenesis, rapidly expanding field, which is positioned at the intersec-
and along with hypertension and dyslipidemia, is a cardinal tion of these two specialties. The optimum care of patients
risk factor for atherosclerotic disease of coronary, carotid, with diabetes now requires a team approach involving both
and other systemic arteries. Therefore, cardiologists must diabetologists and cardiologists (as well as nephrologists,
learn how to assess and manage diabetes in patients with neurologists, and ophthalmologists). It is likely that, if the
this diagnosis and clinical evidence of atherosclerotic dis- incidence of diabetic cardiovascular disease continues to
ease in the same manner in which they have become accus- mushroom, it may become necessary to create a new sub-
tomed to managing hypertension and hyperlipidemia. specialty, Diabetocardiology, and this book would be an
Similarly, diabetologists (or endocrinologists) must learn excellent text to prepare physicians for this important,
how to prevent and recognize atherosclerotic complications emerging field.
that are responsible for the most frequent cause of death or
serious illness of their patients with diabetes. As a conse- Eugene Braunwald
quence, these two specialties – cardiology and diabetology–
Douglas L. Mann
are now “joined at the hip.”
We are pleased to welcome Diabetes in Cardiovascular Douglas P. Zipes
Disease as a new companion to Braunwald’s Heart Disease.
Peter Libby
It has succeeded in placing into a single text much of what is
known about the effects of diabetes on cardiovascular Robert O. Bonow

xi
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 Preface

Over the past several decades, obesity and diabetes mellitus care providers, nutritionists, exercise physiologists, pharma-
have become an increasing problem that constitutes a cists, and diabetes educators—reflected in the diverse
global epidemic, representing one of the most important authorship of chapters in this textbook.
chronic disease conditions in the world with critically impor- The first edition of Diabetes in Cardiovascular Disease: A
tant public health implications. Patients with diabetes Companion to Braunwald’s Heart Disease includes 31 chap-
exhibit an increased propensity to develop myriad cardio- ters that address the spectrum of topics relevant to the nexus
vascular diseases; its key sequelae are myocardial infarction, of diabetes and cardiovascular disease. These chapters
heart failure, stroke, and cardiovascular death. Over this cover the epidemiology, pathophysiologic and genetic
same time period, the cardiology community has increas- underpinnings, clinical presentation and consequences,
ingly recognized the adverse cardiovascular prognosis of and diagnostic and therapeutic approaches for prevention
patients with diabetes, with increasing understanding of and treatment of high-risk diabetes patients, and review sys-
the heterogeneity of efficacy of available medical and inter- tems approaches to apply such interventions. Each of the
ventional strategies by diabetes status and a notable unmet chapters is written by international leaders in their respective
clinical need to mitigate the incremental “residual” cardio- fields, and for us it has been a true pleasure and honor to
vascular risk associated with diabetes. Based on these obser- work with such a fabulous group of experts. They are our col-
vations and resultant evolution of regulatory requirements leagues, collaborators, and friends and represent the
for diabetes drug development around the world, it is only remarkable interdisciplinary collaborative spirit bridging
within the past few years that the cardiovascular effects our specialties and advancing the field of science and health
and safety of glucose-lowering therapies have begun to care for the betterment of our patients.
undergo rigorous assessment in large-scale randomized car- We believe that this book will be an invaluable resource
diovascular outcome trials focusing specifically on patients for cardiologists, diabetologists, and all other health care
with diabetes. Thus the field of cardiovascular disease in dia- providers taking care of patients with diabetes and cardio-
betes has gained momentum over the past years, resulting in vascular disease.
joint activities and guidelines from cardiology and diabetes We thank our many friends, our colleagues, and the
associations around the world, requiring and fostering a experts from around the world who contributed to this book.
truly interdisciplinary collaborative research and clinical Without their expertise and contribution the text could not
partnership among cardiologists, endocrinologists, primary have been completed.

xiii
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 Acknowledgments

We offer our heartfelt gratitude to those who have supported who accepted our invitation to author chapters and deliv-
the development of this textbook. First, to Professors ered such excellent content that most commonly exceeded
Braunwald and Libby, who had the confidence to allow our highest expectations. Finally, to the editorial staff at Else-
us to edit an addition to the family of texts with the interna- vier who so ably assisted and facilitated the development of
tionally revered imprimatur of Braunwald’s Heart Disease. this book at every step of the way: Dolores Meloni, Angela
Second, to our colleagues and friends around the world Rufino, and Cindy Thoms. To each of you, thank you.

xv
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