Table Of ContentMichael W. Stewart
Diabetic
Retinopathy
Current Pharmacologic Treatment
and Emerging Strategies
Diabetic Retinopathy
Michael W. Stewart, MD
Diabetic Retinopathy
Current Pharmacologic Treatment and
Emerging Strategies
Michael W. Stewart, MD
Mayo Clinic
Jacksonville
Florida
USA
ISBN 978-981-10-3508-1 ISBN 978-981-10-3509-8 (eBook)
DOI 10.1007/978-981-10-3509-8
Library of Congress Control Number: 2017933287
© Mayo Foundation for Medical Education and Research 2017
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.
Printed on acid-free paper
This Adis imprint is published by Springer Nature
The registered company is Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore
Introduction
Diabetes mellitus (DM) currently affects more than 8% of the US population and
ranks seventh as a cause of death. Approximately 90% of affected patients have type
2 DM and because of the growing obesity epidemic, which predisposes patients to
the development of type 2 DM, the number of affected patients is increasing rapidly.
Despite the large number of patients in industrialized nations, the majority of dia-
betics live in developing countries with the greatest number found in India. The
abandonment of traditional foods in favor of westernized diets that are rich in pro-
cessed carbohydrates and saturated fats has increased the incidence of metabolic
syndrome in many of these countries. The number of patients with DM challenges
healthcare systems throughout the world with both industrialized and developing
countries struggling to manage the global diabetes epidemic.
Diabetic retinopathy (DR) is the most common neurodegenerative and microvas-
cular complication affecting patients with DM. Comorbidities such as systemic
arterial hypertension and hyperlipidemia predispose to the development of DR, but
the most important risk factors are average serum glucose levels and duration of
disease. Internists and endocrinologists have an increasing number of drugs at their
disposal to treat DM, but several factors including national and regional drug avail-
ability, drug costs, healthcare insurance coverage, access to medical care, patient
education, and patient compliance (among others) limit the effectiveness of treat-
ment and influence the development of retinopathy. Chapter 1 of this book discusses
the incidence and prevalence of DM and DR from both global and regional
perspectives.
The pathophysiology of DR is extraordinarily complex and remains incom-
pletely understood. Because 75% of diabetes-related vision loss results from dia-
betic macular edema (DME) and most of the remaining cases stem from
complications of proliferative diabetic retinopathy, research and drug development
has focused on the retinal vascular endothelial cell. Several chemokines and inflam-
matory cytokines, including vascular endothelial growth factor (VEGF), have been
associated with the development of DR. Unfortunately, the pertinent biochemical
pathways are rarely linear, with numerous crosstalk associations and feedback loops
that make it difficult to fully understand the differences between causative molecules
v
vi Introduction
and disease markers. Chapter 2 delves into the complex biochemical mix found in
eyes with DR.
Only during the past 3 decades have proven treatments for DR (laser photoco-
agulation and vitrectomy surgery) emerged. Chapter 3 discusses these alternative
treatments and highlights their effectiveness in the treatment of DR.
The relatively recent (1989) discovery of VEGF has fueled most of the recent
advances in the treatment of DR. VEGF inhibitory drugs have been available to
ophthalmologists since 2004, but their use in patients with DME has advanced more
slowly than in patients with neovascular age-related macular degeneration.
Nevertheless, anti-VEGF treatment has become the preferred treatment for DME,
and their use in PDR is increasing. Chapter 4 describes the available anti-VEGF
agents and details the important clinical studies that have shaped our current
approaches to the treatment of DR.
Inflammation plays a key role in the development of DR, and its discovery
quickly led to the use of intravitreal triamcinolone acetonide injections, and, more
recently, dexamethasone and fluocinolone sustained release inserts. Chapter 5 dis-
cusses both the off-label use of corticosteroids and the pivotal phase III trials that
have led to regulatory approval of sustained release inserts.
With data from prospective trials that have evaluated several drugs, treatment
choices for DME and DR abound. Chapter 6 constitutes the author’s attempt to
present evidence-based treatment guidelines after a synthesis of the literature.
Several important questions regarding treatment choices remain unanswered, and
these will be addressed in accordance with the best available data.
Multiple lines of evidence implicate the vitreoretinal interface in the develop-
ment of DR. Several drugs and preparations that induce posterior vitreous detach-
ment are being evaluated in patients with DR. Chapter 7 discusses the off-label use
of both approved and investigational drugs that promote vitreous detachments.
Despite our available treatments, many patients still respond poorly to current
therapies. Development of new drugs, novel formulations of existing medications,
and extended duration drug-release devices are proceeding on several fronts.
Chapter 8 discusses off-label use of approved medications as well as the current
status of investigational products.
Drug safety is an important outcome during the development and approval of all
pharmaceuticals, and it becomes particularly important in diabetic patients, many of
whom have advanced vascular disease. The pivotal trials found acceptable safety
profiles for each of the approved drugs, but important ocular and systemic risks
must be considered when treating patients. Chapter 9 discusses the risks associated
with pharmacotherapy.
Pharmacotherapy for DME comes at a significant cost to patients, medical care
insurance companies, and national healthcare programs. The cost-effectiveness of
available treatment strategies has been calculated in several economic analyses.
Chapter 10 discusses some of the economic impacts of pharmacotherapy.
The diabetic retinopathy body of literature has become vast, and published
reports vary from case discussions through multicenter, randomized, phase III trials.
With tens of thousands of manuscripts published in hundreds of journals, this book
Introduction vii
is not and cannot be a complete review of the literature. Contradictions in the litera-
ture are frequent and recommendations for nearly every contingency have been
advanced. The best data come from carefully planned, multicenter, randomized,
prospective, double-blind trials. This book attempts to discuss these studies in the
greatest detail as they provide the most reliable information. Other studies that lack
the same rigorous methodology have been included, but these are fewer in number,
and their conclusions must be viewed with greater skepticism. Despite the focus on
the pivotal trials, some important studies have undoubtedly been omitted.
This book comes after years of writing about drug pharmacokinetics, pharmaco-
dynamics, and clinical pharmacotherapy. My interest in academic writing has been
nurtured and supported by several excellent physicians including Mayo Clinic col-
leagues James Bolling, MD; Tom Liesegang, MD (past editor-in-chief of the
American Journal of Ophthalmology); and George Bartley, MD (editor-in-chief of
Ophthalmology). Others who have significantly supported my academic develop-
ment include Phil Rosenfeld, MD; David Browning, MD; Kurt Gitter, MD; son-in-
law Gregory P. Forlenza, MD; and son Michael Llort Stewart. I am forever indebted
to Maurice B. Landers, III, MD, who has served as my mentor and valued colleague
for 30 years.
I dedicate this work to the ladies in my life: my daughter-in-law Gwen Hochman
Stewart, JD; daughter Tania Llort Stewart, MBA; and granddaughters Olympia
Stewart Forlenza, Julia Claire Stewart, and Genevieve Stewart Forlenza. Most
importantly, I thank my wife Enid Llort, MBA, from whom I have received never-
ending support and encouragement. She is the smartest, most intuitive woman I
have ever met, and without her pushing and pulling me for the past 37 years, I would
never have been able to compose this volume.
Contents
1 Diabetes and Diabetic Retinopathy: Overview of a Worldwide
Epidemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Incidence of Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 Incidence of Diabetic Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.4 Comorbidities for Diabetes and Diabetic Retinopathy . . . . . . . . . . . 13
1.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2 The Diabetic Retina: Anatomy and Pathophysiology . . . . . . . . . . . . . . 29
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2 The Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.2.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.2.2 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.2.3 Microanatomy of the Retina Neurons . . . . . . . . . . . . . . . . . . 34
2.2.4 Intercellular Spaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.2.5 Internal Limiting Membrane . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.2.6 Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.2.7 Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.2.8 Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
2.2.9 Capillaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
2.3 Hemodynamics, Macular Edema, and Starling’s Law . . . . . . . . . . . . 39
2.4 Biochemical Basis for Diabetic Retinopathy . . . . . . . . . . . . . . . . . . . 41
2.4.1 Increased Polyol Pathway Flux . . . . . . . . . . . . . . . . . . . . . . . 44
2.4.2 Advanced Glycation End Products (AGEs) . . . . . . . . . . . . . . 44
2.4.3 Activation of Protein Kinase C (PKC) . . . . . . . . . . . . . . . . . . 45
2.4.4 Increased Hexosamine Pathway Flux . . . . . . . . . . . . . . . . . . 46
2.5 Early Pathophysiology of Diabetic Retinopathy . . . . . . . . . . . . . . . . 46
2.6 Macular Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
2.6.1 Blood-Retinal Barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
2.6.2 Biochemical Abnormalities Responsible for Diabetic
Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
ix
x Contents
2.6.3 Mechanism of Blood-Retinal Barrier Breakdown . . . . . . . . 53
2.6.4 Renin/Angiotensin System . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.7 Development of Proliferative Diabetic Retinopathy . . . . . . . . . . . . 57
2.8 Clinical Findings of Diabetic Retinopathy . . . . . . . . . . . . . . . . . . . 58
2.9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
3 Treatment of Diabetic Retinopathy: A Historical
Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
3.2 Pituitary Ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
3.3 Interferon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
3.4 Laser Photocoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.4.1 Techniques for Performing Laser Photocoagulation . . . . . . 77
3.5 Treatment of Background Diabetic Retinopathy . . . . . . . . . . . . . . . 83
3.6 Treatment of Proliferative Diabetic Retinopathy (PDR) . . . . . . . . . 85
3.7 New Laser Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3.7.1 Micropulse Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3.7.2 Navigated Laser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
3.8 Pars Plana Vitrectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
3.9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
4 Targeting Vascular Endothelial Growth Factor . . . . . . . . . . . . . . . . . . 99
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4.2 Vascular Endothelial Growth Factor . . . . . . . . . . . . . . . . . . . . . . . . 100
4.3 Anti-VEGF Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4.3.1 Pegaptanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.3.2 Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
4.3.3 Ranibizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
4.3.4 Aflibercept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
4.4 Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
4.5 Comparison Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
4.6 Conclusions and Outstanding Questions . . . . . . . . . . . . . . . . . . . . . 130
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
5 Corticosteroids: Targeting Multiple Cytokines
and Chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5.2 Characteristics of Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5.3 Corticosteroid Delivery to the Eye . . . . . . . . . . . . . . . . . . . . . . . . . . 144
5.4 Triamcinolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5.5 Dexamethasone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
5.6 Fluocinolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
5.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Contents xi
6 Current Treatment Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . 163
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
6.2 General Medical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
6.2.1 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
6.2.2 Systemic Arterial Hypertension . . . . . . . . . . . . . . . . . . . . . . 166
6.2.3 Hyperlipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6.2.4 Sleep Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6.3 Screening Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6.3.1 Screening Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
6.4 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
6.5 Treatment of Diabetic Macular Edema . . . . . . . . . . . . . . . . . . . . . . 171
6.5.1 Non-Center-Involving Diabetic Macular Edema . . . . . . . . . 171
6.5.2 Center-Involving Diabetic Macular Edema . . . . . . . . . . . . . 172
6.6 Treatment Failures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
6.7 Cataract Surgery and DME . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
6.8 Proliferative Diabetic Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . 180
6.9 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
6.10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
7 Vitreolysis: Targeting the Vitreoretinal Interface . . . . . . . . . . . . . . . . 187
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
7.2 Vitreous Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
7.3 Posterior Vitreous Detachment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
7.4 Anomalous Posterior Vitreous Detachment . . . . . . . . . . . . . . . . . . . 189
7.5 Association Between Posterior Hyaloid and Diabetic Retinopathy 191
7.6 Treatment of Vitreomacular Traction . . . . . . . . . . . . . . . . . . . . . . . . 192
7.6.1 Streptokinase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
7.6.2 Hyaluronidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
7.6.3 Nattokinase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
7.6.4 Chondroitinase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
7.6.5 Plasmin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
7.6.6 Tissue Plasminogen Activator (tPA) . . . . . . . . . . . . . . . . . . 197
7.6.7 Autologous Plasmin Enzyme (APE) . . . . . . . . . . . . . . . . . . 197
7.6.8 Vitreosolve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
7.6.9 Ocriplasmin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
7.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
8 Investigational Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
8.1 Corticosteroid-Related Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . 206
8.1.1 Danazol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
8.1.2 Dexamethasone-Cyclodextrin Microparticle Drops . . . . . . 207
8.1.3 Difluprednate Ophthalmic Emulsion . . . . . . . . . . . . . . . . . . 208
8.1.4 EGP-437 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
8.1.5 Loteprednol Etabonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
