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Carmen A. Puliafito, MD
Editor-in-Chief
Dean, Keck School of Medicine
University of Southern California
Los Angeles, CA
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Deputy Editor
Byers Eye Institute
Stanford University School
of Medicine
Menlo Park, CA
Jay S. Duker, MD
Associate Editor
New England Eye Center
Tufts University School of Medicine
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Imaging
UPMC Eye Center
University of Pittsburgh School
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Sophie Bakri, MD
Mayo Clinic
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Francesco Bandello, MD
University Vita Salute Hospital
San Raffaele
Milan, Italy
Audina Berrocal, MD
Bascom Palmer Eye Institute
UniversityofMiamiSchoolof
Medicine
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Susanne Binder, MD
Rudolph Foundation Clinic
Vienna, Austria
Gabriel Coscas, MD
Hospital of Creteil
Creteil, France
Donald J. D’Amico, MD
Weill Cornell Medical College
New York, NY
Diana Do, MD
Stanley M. Truhlsen Eye Institute
UniversityofNebraskaMedicalCenter
Omaha, NE
Pravin U. Dugel, MD
Retinal Consultants of Arizona
Retinal Research Institute
Phoenix, AZ
Dean Eliott, MD
Massachusetts Eye & Ear Infirmary
Harvard Medical School
Boston, MA
Howard F. Fine, MD
Robert Wood Johnson University
Hospital
New Brunswick, NJ
Harry W. Flynn Jr., MD
UniversityofMiamiSchoolofMedicine
Miami, FL
Thomas R. Friberg, MD
UPMC Eye Center
University of Pittsburgh School
of Medicine
Pittsburgh, PA
James G. Fujimoto, PhD
MassachusettsInstituteofTechnology
Cambridge, MA
Alain Gaudric, MD
Hopital Laribosière
Paris, France
Evangelos S. Gragoudas, MD
Massachusetts Eye & Ear Infirmary
Harvard Medical School
Boston, MA
Seenu Hariprasad, MD
Pritzker School of Medicine
University of Chicago
Chicago, IL
Alon Harris, PhD
IndianaUniversitySchoolofMedicine
Indianapolis, IN
Tarek Hassan, MD
Oakland University
WilliamBeaumontSchoolofMedicine
Royal Oak, MI
Allen C. Ho, MD
Wills Eye Institute
Thomas Jefferson University
Philadelphia, PA
David Huang, MD, PhD
Casey Eye Institute
Oregon Health Sciences University
Portland, OR
Shuliang Jiao, PhD
DepartmentofBiomedicalEngineering
Florida International University
Miami, FL
Peter K. Kaiser, MD
Cole Eye Institute
Cleveland Clinic
Cleveland, OH
Judy E. Kim, MD
Medical College of Wisconsin
Milwaukee, WI
Shoji Kishi, MD, PhD
GunmaUniversitySchoolofMedicine
Maebashi, Japan
Szilárd Kiss, MD
Weill Cornell Medical College
New York, NY
John W. Kitchens, MD
Retina Associates of Kentucky
Lexington, KY
Theodore Leng, MD
Byers Eye institute
StanfordUniversitySchoolofMedicine
Palo Alto, CA
Martin A. Mainster, PhD, MD
University of Kansas Medical Center
Kansas City, KS
Andrew A. Moshfeghi, MD
Keck School of Medicine
Los Angeles, CA
Quan Dong Nguyen, MD
Stanley M. Truhlsen Eye Institute
UniversityofNebraskaMedicalCenter
Omaha, NE
Joan M. O’Brien, MD
Scheie Eye Institute
University of Pennsylvania
Philadelphia, PA
Gholam A. Peyman, MD
University of Arizona College
of Medicine
Phoenix, AZ
Carl D. Regillo, MD
Wills Eye Institute
Thomas Jefferson University
Philadelphia, PA
Richard B. Rosen, MD
New York Medical College
New York, NY
Philip J. Rosenfeld, MD, PhD
UniversityofMiamiSchoolof
Medicine
Miami, FL
Stephen R. Russell, MD
University of Iowa
Iowa City, IA
SriniVas R. Sadda, MD
Keck School of Medicine
Los Angeles, CA
David Sarraf, MD
Jules Stein Eye Institute
Los Angeles, CA
Ingrid U. Scott, MD, MPH
Penn State College of Medicine
Hershey, PA
Gaurav K. Shah, MD
Washington University School
of Medicine
St. Louis, MO
Lawrence J. Singerman, MD
Case Western Reserve University
Cleveland, OH

S4 Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina May 2016 · Vol. 46, No. 10 (Suppl) S5
Abstract: .
P.
.
Carmen A. Puliafito, MD, MBA
Editor-in-Chief
OSLI Retina
Improving Outcomes for Patients With Diabetic
Macular Edema
Introduction
MODERATOR
Stephen Michels, MD,
is founder and director of Retina Health Center
in Fort Myers, Florida, and consulting associate
in the department of ophthalmology at Duke
University School of Medicine in Durham,
North Carolina. Dr. Eaton received a modest
honoraria from SLACK Inc. for his contribution
to this supplement.
Edoardo Midena, MD,
serves as General Secretary for the European
Board of Ophthalmology and is Chair of the
Ophthalmology Department at University
Hospital in Padova, Italy. Dr. Midena recieved
a modest honoraria from SLACK Inc. for his
contribution to this supplement.
Johnathan Kitchens, MD,
is ophthalmolgist and vitreoretinal surgeon
with Retina Associates of Kentucky in
Lexington. president-elect of the Kentucky
Academy of Eye Physicians and Surgeons.
Dr. Prenner received a modest honoraria
from SLACK Inc. for his contribution to this
supplement.
Jonathan Prenner, MD
is Board Certified in Ophthalmology and is
associate clinical professor in the department
of Ophthalmology at Rutgers RobertWood
Johnson Medical School. Dr. Prenner received
a modest honoraria from SLACK Inc. for his
contribution to this supplement.

Carl Regillo, MD,
is Director of the Retina Service atWills Eye
Hospital in Philadelphia. He is a fellow of
the American College of Surgeons and an
active member of the American Academy of
Ophthalmology. Dr. Regillo received a modest
to this supplement.
Elias Reichel, MD, is vice chair for
research and education in the department
of ophthalmology at the New England
Eye Center in MA, and he is a professor of
ophthalmology atTufts University School
of Medicine. Dr. Reichel received a modest
to this supplement.
FACULTY
Peter Kaiser, MD,
is the Founding Dirextor of the Digital Optical CoherenceTomography Reading Center for the Cole Eye
Institute. He is also a staff memeber at the Cole Eye Institute at the main campus in Cleveland. Dr. Kaiers
recieved a modest honoraria from SLACK Inc. for his contricution to this supplement.
DOI Number
Diabetic macular edema (DME) results from diabetic retinopathy (DR) which causes
more cases of blindness among working-age adults than all other causes and often goes unno-
ticed until patients present with vision loss which makes early detection difficult. Along with
factors such as thickness, quantity and visual acuity (VA), the location (of the edema) greatly
influences treatment decisions. DME that is center involving, that is to say, edema that threatens
the fovea thereby threatening VA, is center -involving DME (ci-DME). DME occurring safely
away from the fovea is non-center-involving DME (nci-DME). The Early Treatment of Diabetic
Retinopathy Study (ETDRS) coined the term, “clinically significant macular edema” (CSME)
to refer to DME that required treatment or affected VA. Since the development and widespread
use of optical coherence tomography (OCT), finding DME before a patient experiences vision
loss became possible even if that DME was center involving. Once OCT began identifying
DME before it affected VA, the term “CSME” became confusing because DME could be center
involving without being clinically significant. Thus, classifying DME as center involving and
non-center involving clarifies a patient’s circumstances, and in turn guides ophthalmologists
toward the best disease management path. Vascular Endothelial Growth Factor (VEGF) plays a
key role in DME progression; therapies that act by inhibiting VEGF production improve visual
acuity in patients with DME. Two anti-VEGF therapies have been approved for the treatment
of DME: ranibizumab and aflibercept. Bevacizumab, which is approvedfor the treatment of
certain types of cancer1
, is occasionally used off-label to treat DME. Anti-VEGF therapy can
stop vision loss and improve VA. Anti-VEGF therapy is one of five treatments available to oph-
thalmologists throughout the course of DME progression, a list which includes: modified grid
laser therapy, anti-VEGF injections, steroid injections or implants, panretinal photocoagulation
(PRP) therapy, and pars plana vitrecomy surgery. DME treatment combination options fuel the
need for new data and discussion2
; specifically, regarding how the different treatment options
interact with one another. Beginning with the diagnosis of diabetes, this discussion will focus
on the treatment of DME and aims to provide clinical opinions about treatment protocol sur-
rounding intravitreal anti-VEGF therapy.

2 diabetics9
. The impacts of diabetes to eye
care specialists bring particular caution because
so much about the early stages of the effect of
diabetes on eye care are unknown. Even more
concerning is the fact that almost a third of
patients with diabetes are undiagnosed10
. Caring
for these patients is costing society over $200
billion each year11
. We as physicians have a lot
of work ahead of us to improve the statistics.
PREPARING FOR TREATMENT
Kaiser: Moderate non-proliferative retinopa-
thy follows mild non-proliferative retinopathy.
Blood vessels responsible for the nourishment
of the retina may swell and lose their ability to
transport blood12
. When patients present with
moderate non-proliferative retinopathy, what
kinds of tests or exams are important for the
first visit?
Michels: Fundus photos, angiography and OCT
are all instrumental for the development of DR
treatment paths. I add ultra widefield fluoresce-
in angiography. It seems as if interest in wide-
field angiography is on the rise but we still have
a lot to learn about how to best use widefield
effectively. Information provided by the fluores-
cein angiography, however, contextualizes each
patient’s individual circumstances thus guiding
her/his best treatment path.
Kitchens: Ultra widefield angiography is ab-
solutely essential in patients with moderate or
worse non-proliferative retinopathy. So many
times in the past, I’ve underestimated the level
of retinopathy on my clinical examination. The
ultra widefield system, in these cases, will often
show areas of non-perfusion or even occult
neovascularization of the retina which was not
visible on routine exam. Conversely, if a pa-
tient looks really good on their ultra widefield
angiogram, I will have the confidence to bring
them back in 6 to 12 months even if they have
significant looking retinopathy. I think this rela-
tively new diagnostic entity really modifies how
we think about the DRS and ETDRS studies.
Michels: DME is a disease that presents with
systemic inflammation. The disease may re-
spond to anti-inflammatory treatment such as
steroids with increasing effectiveness through-
out treatment even though the inflammation is
continuous.
Kaiser: Intraretinal microvascular abnormality
(IrMA) is one of three qualifiers laid out in the
ETDRS “4-2-1” rule. The “4-2-1” rule refers
to three different circumstances that indicate
severe non-proliferative diabetic retinopathy
(NPDR). Twenty or more hemorrhages in 4
quadrants and/or venous beading (VB) in 2
quadrants and/or IrMA in 1 quadrant indicate
severe NPDR13
. The classification system and
diagnostic recommendations are simple to
understand and are easy to compare. The 4-2-1
rule still makes sense today14
. I use widefield
photos often in my practice where I find that
Nonprofusion shows up more often and in
larger amounts than I would have guessed.
This is most surprising to see in patients whom
I thought had no DR. When this happens to a
patient I had been seeing annually, I’ll carefully
consider seeing that patient a little more fre-
quently. Patients who present with ischemia that
eventually turns into inflammation has been a
recent topic of discussion where treatment may
need to be altered. Is the level of inflamma-
tion affected in any way by whether or not the
patient has chronic retinopathy?
Regillo: I routinely perform spectral domain
optical coherance tomography (SDOCT) and
fundus photography at the first encounter for
such a patient. In many cases, I also perform
fluorescein angiography, either traditional fun-
dus camera-based photography with peripheral
sweeps or widefield angiography. I am part of
a large retina practice with multiple offices, and
widefield imaging equipment is not available in
SCREENING AND FOLLOW UP
Peter Kaiser, MD: Diabetes affects over three
hundred million people world-wide and if rates
continue it will be the seventh leading cause
of death on Earth3
. Diabetes results in DR for
nearly 80 percent of patients with diabetes who
have had diabetes for ten years or longer. Al-
most all patients with type 1 diabetes have DR
and more than 60 percent of patients with type
2 diabetes are affected. How does diabetes lead
to both DR and eventually DME and what role
does vascular endothelial growth factor play in
the process?
Jonathan Prenner, MD: Information from our
peer-reviewed literature and the Centers for
Disease Control and Prevention (CDC) illus-
trates the shocking increase in the incidence of
diabetes in the western world. Approximately
25% of the 29 million adults who have diabetes
are not currently diagnosed. In 2005-2008 4.2
million (28.5%) of patients with diabetes over
age 40 had diabetic retinopathy, and 655,000
(4.4%) had advanced diabetic retinopathy,
including proliferative diabetic retinopathy
(PDR). Only 50-75% of Americans with diabe-
tes receive annual dilated eye exams, and nearly
one in three cases of DME goes undiagnosed.
Undiagnosed DME is problematic and requires
continued attention.
Elias Reichel, MD: The exact way in which
diabetes leads to DR and DME is still being
researched4
. A breakdown of the vascular in-
ner blood- retinal barrier causes leakage from
microaneurysms and/or leakage from capil-
lary walls which leads to DME. It is also clear
that long-term increased glucose levels lead to
both DR and DME. Increased glucose, in turn,
increases hypoxia5
. Hypoxia results in ischemia
and at some VEGF plays a role. The different
interactions between the physiological factors
make the process complex.
Carl Regillo, MD: Upregulation of VEGF
promotes an influx of inflammatory cells and
associated cytokines. A vicious cycle ensues
with further breakdown of retinal blood vessel
walls promoting additional leakage and isch-
emia which, in turn, further increases VEGF
and inflammatory cytokine production6
Edoardo Midena, MD: European telemedicine
screening systems which allow patients to be
easily examined and screened any time are nec-
essary. This system benefits both patients and
doctors because the screening centers provide
imaging equipment and staff qualified to oper-
ate that equipment [which is] inaccessible to
some ophthalmologists and thus add[s] depth to
a patient’s status. Telemedicine takes screening
out of the hands of ophthalmologist practitio-
ners which allows more time to focus on treat-
ment7
.
Reichel: I want to see patients newly diagnosed
with diabetes. I want to counsel their primary
care physician to recommend annual exams
looking for DR. I want an updated hemoglo-
bin A1C (A1C) reading. Though this approach
is arguably conservative, I believe early and
consistent follow up are important. The ground-
breaking Early Treatment Diabetic Retinopathy
Study (ETDRS) emphasized the importance of
regular screening8
. ETDRS also highlighted the
need for early detection and early treatment due
to the asymptomatic nature of DR.
Johnathan Kitchens, MD: I find it shock-
ing that 10% of the American population has
diabetes, the vast majority of whom have type
“Telemedicine. . .allows
more time to focus on
treatment.”
—EDORARDO MIDENA, md

option of many as the first line of treatment.
Focal grid laser therapy presents with some
troublesome side effects i.e., distorted or discol-
ored peripheral vision and problems with night
vision22
. Once circinate exudates outside the
fovea show up on a patient’s OCT and he/she
presents with intraretinal fluid approaching the
fovea, meaning the patient presents with notice-
able nci-DME, is laser treatment the logical
next step?
Prenner: Typically, stimulating the retinal pig-
ment epithelium (RPE) helps reabsorb diffuse
areas of fluid. These treatments are distinct and
very different. The first works well when there
are a few very leaky microaneurysms which can
be directly treated and closed without affecting
the foveal avascular zone (FAZ). The second
type is a little more nebulous as it can lead to
diffuse areas of RPE loss if performed too ag-
gressively. In these cases, I’ll usually reserve
grid laser for patients that are less responsive
to intravitreal therapies. I will always start with
sub threshold laser in these cases and I find
that pattern laser is very helpful. The DRCRnet
protocol I study did show that patients treated
with prompt laser did not have the same visual
improvements as those with deferred laser.
Michels: The biggest question revolves around
laser treatment. I believe there are other op-
tions even at this stage of nci-DME. I think it is
worth watching the patient. If the patient shows
the disease is progressing and intraretinal fluid
continues to approach the fovea, attractive treat-
ments exist outside of laser treatments. I think
laser treatment, even though some do not prefer
the term laser, is a destructive treatment and
I can say I would not want it done to my own
retina. Newer laser technologies are likely less
destructive, but their effectiveness should first
be evaluated in prospective, controlled clini-
cal trials, before a general recommendation is
given.
Prenner: Focal laser remains an excellent
option in certain cases, and has the obvious
advantage of being non-invasive. In addition,
laser may allow for sustained and prolonged
therapeutic benefit without the need for frequent
retreatment. I am building my personal experi-
ence with Micropulse laser. I also continue to
treat focal areas of nci-DME particularly when
circinate lipid is present, with standard-ETDRS
style focal laser. I no longer perform grid laser
without the Micropulse laser.
Regillo: Once the patient begins to present with
ci-DEM, I still prefer to watch the patient. The
patient’s other eye and the level of the retinopa-
thy may influence the decision at that point. If
a patient presents with ci-DME and is at risk of
proliferative diabetic retinopathy or, experienc-
es any measurable VA loss (20/32 and 20/50 on
Snellen and ETDRS scales, respectively.) from
DME, treatment is triggered and I begin with
anti-VEGF injections.
TREATING WITH ANTI-VEGF
Kaiser: Anti-VEGF injection therapy is the
most popular form of treatment for DME23
and
“Aflibercept, Bevacizumab, or Ranibizumab for
Diabetic Macular Edema” otherwise known as
Protocol T, published in the summer of 2015 by
The New England Journal of Medicine, con-
tained significant information and protocol as
it pertains to DME treatment and which anti-
VEGF therapies work in which circumstances.
However, when to begin anti-VEGF treatment
and which treatment regimen to follow remains
one of the most prominent clinical questions
all of our offices. It should be said that I do not
feel handicapped or limited from a diagnostic
standpoint in offices without widefield imaging.
Imaging helps to quantify the level of retinopa-
thy and guide both intensity of follow-up and
type of treatment. Things I look for include
the number of intraretinal hemorrhages in
each quadrant, the status of venous beading or
dilation, the presence or absence of IrMA and
neovascularization and the degree and location
of retinal capillary nonperfusion and macular
thickening/edema Our group has OCTA in our
main office and, as Elias pointed out, its use is
primarily investigational, but clinically it can be
helpful to detect central macular ischemia in a
relatively quickly and noninvasively manner.
Kaiser: Some patients respond quite slowly
to the anti-VEGF injections. Whether or not a
particular patient will respond to anti-VEGF
therapy becomes apparent quickly. Patients
typically maintain the same relative response
to any further anti-VEGF therapies15
. The best
indicator of responsiveness to anti-VEGF treat-
ment is a dry macula. Protocol T showed 70%
of maculae fell below the pre-defined thresh-
old16
. That means that throughout the many
injections in the course of a year 30% were
not dry. That dry macula ought to be weighed
equally with vision improvement because they
are both important indicators as to whether or
not treatment is working. Drying the macula
can improve patient status. There are different
ways of modulating inflammation but steroids
may be the most impactful17
.
Reichel: VEGF does not always need to be
elevated in the vitreous or the aqueous for the
patient to present with DME. This implies
possible systemic issues at play causing the
DME. Those issues may or may not be related
to systemic inflammation but in these patients
it is not up-regulated VEGF causing the inflam-
mation. Some recent data shows interleukin-8
(IL-8) to be much higher in patients who do not
respond to anti-VEGF injections18
. If a patient
does not respond to anti-VEGF and if there are
no signs of up-regulated VEGF, steroids clearly
make sense.
Midena: Ischemia is not the only cause of
VEGF up-regulation in patients with hypergly-
cemia. In fact, VEGF-A is not the only member
of the cytokine family up-regulating; tumor
necrosis factor-a (TNF-a) and interleukin-6
(IL-6) also up-regulate19
. Cytokines in patients
with diabetes show in a very expressive way
even if retinopathy is not yet present. Early
inflammatory phenomena modulate treatment
and encourage the use of steroids; but, the
inflammation will be a long-standing issue. As
many as three injections ought to be enough to
determine whether the patient is an anti-VEGF
responder or non-responder. As many as 40% of
patients with DR do not respond to anti-VEGF
therapy. I argue that those 40% are likely the
population who present with high inflammatory
components which remain unaffected by the
anti-VEGF. Most of the published studies on
anti-VEGF treatment, including some seminal
studies published by the Diabetic Retinopa-
thy Clinical Research Network (DRCR), have
shown that about 40% of the treated popula-
tion doesn’t adequately respond to the initial
anti-VEGF treatment and that the next step is to
switch drugs20
.
MODIFIED FOCAL GRID LASER THER-
APY
Kaiser: Photocoagulation laser treatment
provided the first real treatment for DME over
30 years ago21
. Recent advancements made in
anti-VEGF therapy have made it the preferred
“Attractive treatments
exist outside of laser
treatments.”
— sTEPHAN mICHELS, md
“There are different ways of
modulateing inflammation
but steroids may be the
most impactful.”
— pETER kAISER, md

S10 Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina April 2016 · Vol. 46, No. 10 (Suppl) S11
personalized kind of treatment like treat-and-
extend include possible financial benefit for the
patient and decreased wear on the eye being
treated. Both RISE and RIDE, as well as VIVID
and VISTA studies, showed that arterial throm-
boembolic events (ATE) were considerably
higher in patients who underwent continuing in-
jections over time. Given the risks and benefits
to anti-VEGF treatment what kind of protocol
or method do you use to administer anti-VEGF
injections?
Michels: Because of patient compliance I favor
treat-and-extend. Patients being treated with
the treat-and-extend method are continuously
treated and under my watch. DME is a chronic
disease and patients with diabetes tend to pres-
ent compliance issues. It is important to help
educate patients about the risks of foregoing
treatment and to show them that the disease
is chronic and it needs to be approached that
way. I might suspend treatment if the patient
goes a year or more without ci-DME recurring.
Currently nobody can completely exclude a
systemic risk of intravitreal anti-VEGF therapy,
but if there is one, it has to be very low27
.
Regillo: Anti-VEGF treatment burden is typi-
cally greatest in the first year of therapy. Pro-
tocols I and T, which utilized a PRN-like style
of treatment, showed a mean number of anti-
VEGF injections to be in the range of eight to
10 in the first year. By years 2 or 3 in Protocol I,
the mean dropped to less than half that amount,
and it was not uncommon for patients to not
need further treatment or at least very few injec-
tions going forward28,29
.
Midena: I am fully convinced that loading
phase treatment is essential. Loading phases
allow me to follow up with a personalized treat-
ment. Randomized trials, case records and pub-
lished records, show an increase in visual func-
tion and decrease in thickness on the OCT30
. I
use the loading phase to identify whether or not
the treatment is working for the patient. De-
pending on the drug, the loading phase varies
between three injections and six. The results
that a loading phase provides also involve the
retina which only provides more information
about the efficacy of the treatment and detailed
information about the patient.
Regillo: The shortcoming of the treat-and-
extend approach in this setting is not knowing
which patient can come off treatment. I treat
more like what was done in Protocol I and Pro-
tocol T – PRN (pro re nata or as needed) style.
I administer injections monthly at first until the
macula is dry. Once the macula is dry, I watch
and closely monitor for recurrence and then
treat accordingly as needed.
Reichel: Practically speaking, looking at trials
(such as RISE, RIDE, VIVID, VISTA, Protocol
T,) it generally took five or six injections to get
to the plateau in OCT or the increased plateau
on VA. It is exceptional to think that just an
injection or two adequately manages significant
ci-DME. That is not normal. In the first year
of treatment, I argue that erring on the side of
overtreatment is better than undertreatment.
Kaiser: It is exceptional to think that one or
two injections over a few months adequately
manages significant ci-DME. A treatment-
intensive timeframe will get the edema down
which will help the patient. Getting in front of
the disease is the key and that lies with treat-
ing early. Recently, an approach being labeled
“Observe-and-Plan” has been drawing atten-
tion. This approach aims to maximize efficiency
without overtreating. The observe-and-plan
surrounding DME. When will you begin treat-
ment with anti-VEGF injections?
Regillo: Anti-VEGF injections are clearly the
correct move once a patient presents with vi-
sion loss from ci-DME. Until the Protocol T
results were published, the differences between
respective anti-VEGF therapies was purely
anecdotal. Protocol T did show some differ-
ence in the efficacy of these drugs, though.
The anti-VEGFs in Protocol T did not dif-
ferentiate themselves when the patient had
milder degrees of visual acuity loss (ETDRS
Snellen equivalent of 20/32-20/40) coupled
with smaller amounts of edema. The results
were the same regardless of which anti-VEGF
was used24
. When there was worse presenting
visual acuity or more severe degrees of central
retinal thickness, some differences in efficacy
then became apparent with aflibercept being
the most effective and bevacizumab the least
effective.
Prenner: We now well recognize the common-
ly seen disconnect between the retinal anatomy
on exam and imaging tests, and associated vi-
sual function. I generally will not treat patients
who are very well seeing initially, but will fol-
low closely for a short period of time and try
to help the patient recognize signs of clinical
damage on imaging tests. OCT is quite valu-
able in this regard. I also ask patients to moni-
tor themselves for compromise of their visual
function in daily life. In cases with significant
vision loss and OCT thickening, Protocol T
suggests that aflibercept is the preferred thera-
peutic option. Protocol T also suggests that
any of the three anti-VEGF agents are appro-
priate in eyes that are relatively well seeing. I
tend to follow these guidelines generated from
the DRCRnet in clinical practice.
Kitchens: I find this proposition to be perhaps
the most controversial and thought provoking
surrounding DME. A difficult decision must be
made when asymptomatic patients present with
both good visual acuity and nci-DME. My
current modus operandi leaves that decision
up to the patient. I make perfectly clear, how-
ever, that deferring injections leads directly to
frequent follow-ups. Fortunately, the DRCRnet
is looking at this question with the protocol v
study which is evaluating patients with ci-
DME and very good vision25
.
Reichel: For me, vision loss is the key symp-
tom before treatment. Presently, any of the
three anti-VEGF therapy options are accept-
able. OCT results play a role in choosing
which anti-VEGF to use because Protocol T
and supplemental materials show that patients
who presented with 400 microns of thickness
tended to do better with aflibercept26
. Afliber-
cept’s advantage was not clinically noticeable
when patients presented with mild macula
thickness or mild VA loss (between 20/32
and 20/40 Snellen chart results) at the time
of initial treatment. However, patients who
presented with advanced thickness, visible on
the OCT, or showed a worse Snellen chart VA
than 20/40 responded to aflibercept more than
ranibizumab and bevacizumab respectively.
ADMINISTERING ANTI-VEGF THERA-
PY
Kaiser: Data is still needed to recommend an
injection administering protocol for anti-VEGF
therapy. The treat-and-extend approach, where
anti-VEGF is administered monthly until
the macula is dry and injection date intervals
are extended with each visit, has been rising
in popularity recently. Reasons to follow a
“. . .patients who presented
with 400 microns of
thickness tended to do
better with aflibercept.”
— eLIAS rEICHEL, md
“Anti-VEGF treatment
burden is typically greatest
in the first year of therapy.”
— cARL rEGILLO, md

effective anti-VEGF treatment. I found that
aflibercept showed supremacy in the following
categories: overall visual acuity, visual acuity
in patients 20/50 or worse, OCT improvements,
rescue laser therapy, number of re-treatments
needed, etc. Additionally, if the patient is failing
to respond, I want to consider steroids as soon
as possible.
COMBINATION THERAPY
Kaiser: Three good steroid options exist in the
United States—two are FDA approved (dexa-
methasone and fluocinolone implants) and
one is off-label (triamcinolone.) When usV-
ing triamcinolone, I inject a 2 mg dose which
gives me a good effect and typically lasts about
3 months or so. The FDA approved the dexa-
methasone implant for DME over a year ago
and I find that it provides an effect that averages
about 4 months, sometimes a bit longer in the
setting of DME. The final steroid option is the
fluocinolone implant. It is an option for patients
who respond well to the shorter acting steroids
and don’t have secondary significant intraocular
pressure elevation. Furthermore, it is very long
lasting, and its continuous effect may also slow
the progression of DR like anti-VEGF drugs.
Once other treatment options are exhausted,
Proliferative Diabetic Retinopathy (PDR) may
require vitrectomy. All surgery poses risks to
patients and removing vitreous gel has a major
impact on the eye and can cause cataract and
retinal detachment along with endophthlamitis.
However, when this procedure is necessary,
how does that affect your treatment plan for a
patient? How does the state of DME affect your
treatment plan?
Regillo: I have never been convinced that using
PRP for a patient with peripheral non-perfusion
had a significant impact on DME. I have tried
scatter laser to areas of peripheral nonperfusion
for the purpose of reducing macular edema in
both DR and retinal vein occlusions and did
method has seen success in the treatment of wet
age-related macular degeneration (AMD).
Prenner: I generally manage patients with a
treat-and-extend approach when treating wet
AMD, as the consequences of under treatment
can be devastating. I tend to treat with serial
monthly injections in DME until the retinal
anatomy mostly normalizes. Subsequently, I
switch to a PRN treatment approach in many
patients, as there is little downside risk to most
recurrences of DME. Often, this change to a re-
duced treatment burden is patient driven in the
younger, less compliant population of patients
who have DME compared to those with wet
AMD.
SWITCHING TO AFLIBERCEPT
Kaiser: Protocol T revealed different suc-
cess rates in the respective anti-VEGFs. For a
minimum of one focal grid laser treatment in
the course of the study: aflibercept 37%; beva-
cizumab 56%; ranibizumab 46%31
.Protocol T
clearly showed that aflibercept improved VA
and reduced edema under certain circumstances
including a worse initial VA and a macula
more than 400 microns thick. At which point
in a patient’s treatment plan does switching
anti-VEGFs make sense and is that anti-VEGF
aflibercept?
Midena: Switching to aflibercept is the correct
move when treatment reaches plateau. If the
most recent OCT shows no change and the pa-
tient begins experiencing VA issues, aflibercept
makes the most sense. Patients with DME have
systemic endothelial issues resulting from dia-
betes. The easiest way to measure those issues
may be by checking the progenitor endothelial
cells in the blood. It is important to remember
that DME is a chronic disorder. Despite its
chronicity, this disorder is self-limiting. The
decreased need for injections is evidence for the
limiting nature of the condition.
Regillo: Patient progress indicates whether or
not a switch is the right course of action. As
long as the OCT shows improvement in thick-
ness or the VA is improving, I stay the course of
treatment. However, should a patient undergo
four to six monthly treatments without signifi-
cant improvement in either parameter, I would
look to make a change. If I started with beva-
cizumab or ranibizumab, I would first switch
to aflibercept. If already on aflibercept, I will
consider switching to a steroid. Steroids work
well to treat inflammation-related disorders of
the eye, and that includes DME. For nearly fif-
teen years now, we have known that DME and
associated decreased visual acuity improve after
intravitreal steroid injections.32
Long-acting
intravitreal steroid exposure may also decrease
DR progression33
.
Prenner: If I do not see sufficient anatomic im-
provement on OCT after treatment with beva-
cizumab, I will change anti-VEGF agents and
treat with aflibercept. After multiple additional
injections, if an acceptable clinical response is
not achieved, I will add a regional depot steroid
to the treatment regimen, typically utilizing
Ozurdex. In these difficult cases, continued
anti-VEGF therapy may be required while the
steroid is active. I have recently had encourag-
ing results with Iluvein, and look forward to
gaining more experience with this novel tech-
nology in challenging eyes with DME.
Kitchens: I start with aflibercept because I want
to make sure I am treating with the most effec-
tive anti-VEGF therapy. My interpretation of
Protocol T is that aflibercept is the most

Figure 1. Mean Change in Visual Acuity over Timev
Shown are the changes in visual acuity overall (Panel A) and according to baseline visual acuity (Panel B). In Panel B, solid
lines indicate baseline visual acuity of 20/50 or worse, and dashed lines indicate baseline visual acuity of 20/32 to 20/40.
Outlying values were truncated to 3 SD from the mean. The number of eyes assessed at each 4-week interval ranged from
195 to 224 in the aflibercept group, 188 to 218 in the bevacizumab group, and 188 to 218 in the ranibizumab group (see Fig.
S2 in the Supplementary Appendix for the exact number assessed at each 4-week interval). I bars indicate 95% confidence
intervals.
Reprinted from The New England Journal of Medicine, volume 372, pages 1193-1203, Aflibercept, Bevacizumab, Ranibizumab for
Diabetic Macular Edema.
“My interpretation. . . is
that aflibercept is the
most effective anti-VEGF
treatment.”
— Johvnathan Kitchens, md

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not see significant benefit and published data to
date appear to support the lack of effect. Fur-
thermore, non-perfusion can be a moving target
in DR especially if the eye is also receiving an-
ti-VEGF therapy. Because regular anti-VEGF
injections in the setting of DR can reduce the
level of DR, the area of non-perfusion could
change in a positive way.
Kitchens: I do think that PRP may affect the
pharmacokinetics of future injections. To me,
the most important aspect of injections in
patients requiring surgery is to ensure that they
have received an anti-VEGF medication preop-
eratively. This seems to reduce the risk of post-
operative vitreous hemorrhage and may reduce
rates of intraoperative complications.
Michels: In our setting I reassure patients that
endophthalmitis is extremely rare with anti-
VEGF treatment34
. OSLI Retina reported the
instances to be below 200 for over 350,000
patients35
. Retinal detachment and lens damage
are rare with rates as low as 1 in 20,000. When
risks are that low, I can confidently assure my
patients of their safety.
Midena: In my experience, adverse effects
from anti-VEGF injection procedures are purely
anecdotal and unpredictable. The biggest con-
cern about systemic safety does not have to do
with what we know now but what might still be
discovered. We know when laser therapy started
and was approved. We know studies backed
safety and efficacy of laser therapy at the time.
However, some 20 years later, we saw patients
with scarring. In patients with diabetes, nerve
fiber thinning can be seen even before retinopa-
thy can be seen and we know that nerve fiber
thinning has been associated with anti-VEGF36
.
I consider what might happen to a patient who
was treated for DME with anti-VEGF injections
ten years or more after his/her last injection.
Prenner: I am always concerned about en-
dophthalmitis despite the low incidence rate,
particularly in well seeing eyes. While endo-
phthalmitis is fortunately rare in modern prac-
tice, the outcomes of these infections are often
devastating. My general impression is that all
three anti-VEGF agents may carry a low associ-
ated risk of systemic adverse events, although
we are limited in prospective evidence concern-
ing this issue. In addition, studies that demon-
strate a safety imbalance between anti-VEGF
agents do not exist, as registration trials of
these agents were not powered to demonstrate a
safety difference.
Kaiser: I think we have some great studies in
anti-VEGF head-to-head but we have very little
anti-VEGF with steroids and other treatments,
including things we have mentioned like vit-
rectomy. I think DRCR ought to be looking at
this situation. We need better guidance regard-
ing the relationship between multiple treatment
paths. We need to know when steroids should
be added and whether or not we should con-
tinue with anti-VEGF therapy thereafter. I do
not want to be doing a disservice to the patient.
I think that it is important that the ophthalmolo-
gist community, particularly involved with
DME, understand that diabetes does not always
have a consistent VEGF or anti-VEGF protocol.
There are a lot of pathways involved that are
well outside even the VEGF pathway.
“Studies that demonstrate
a safety imbalance between
anti-VEGF agents do no
exist.”
— Jonathan prenner, md

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