review article Diabetes, Obesity and Metabolism 17: 219–230, 2015.

© 2014 John Wiley & Sons Ltd

ARTICLE
REVIEW
New treatments for diabetic retinopathy
A. Das1,2 , S. Stroud1 , A. Mehta1 & S. Rangasamy3
1 Department of Surgery/Ophthalmology, University of New Mexico School of Medicine, Albuquerque, NM, USA
2 Department of Surgery, New Mexico VA Health Care System, Albuquerque, NM, USA
3 T-Gen Institute, Phoenix, AZ, USA

Diabetic retinopathy is the major cause of vision loss in middle-aged adults. Alteration of the blood–retinal barrier (BRB) is the hallmark of diabetic
retinopathy and, subsequently, hypoxia may result in retinal neovascularization. Tight control of systemic factors such as blood glucose, blood pressure
and blood lipids is essential in the management of this disease. Vascular endothelial growth factor (VEGF) is one of the most important factors responsible
for alteration of the BRB. The introduction of anti-VEGF agents has revolutionized the therapeutic strategies used in people with diabetic retinopathy,
and the use of laser therapy has been modified. In the present article, we examine the clinical features and pathophysiology of diabetic retinopathy and
review the current status of new treatment recommendations for this disease, and also explore some possible future therapies.
Keywords: blood–retinal barrier, diabetes complications, diabetes mellitus, diabetic retinopathy, vascular endothelial growth factor

Date submitted 7 June 2014; date of first decision 7 July 2014; date of final acceptance 20 August 2014

Diabetes mellitus is quickly becoming the global epidemic of
the 21st century. Currently, there are 382 million people with
diabetes mellitus worldwide, and this number is projected to
reach 559 million by the year 2035 [1]. The estimated global
healthcare expenditure for treating diabetes and its compli-
cations was $376 bn in 2010, and this number is projected to
exceed $490 bn by 2030 [1]. Diabetic retinopathy, a microvas-
cular complication of diabetes, is prevalent in ∼35% of people
with diabetes [2]. It is the leading cause of vision loss in adults
aged 20–64 years in developed countries [2,3]. Although laser
photocoagulation therapy has been the mainstay of manage-
ment therapy in addition to control of systemic factors, the use
of intravitreal anti-vascular endothelial growth factor (VEGF)
agents and steroids in recent years has revolutionized the man-
agement of diabetic macular oedema. In the present review,
we will discuss the pathogenesis of diabetic retinopathy and
the treatment strategies currently available for the treatment of
diabetic macular oedema and proliferative diabetic retinopathy
(PDR; Table 1).
Clinical Features
The earliest clinical lesions of diabetic retinopathy are microa-
neurysms, or focal dilations of retinal microvessels seen as
deep red dots, mainly in the posterior pole. Usually these
lesions appear and disappear over time and cause no symp-
toms themselves. Microaneurysms are present in almost all
people with type 1 diabetes of 20 years duration, and in 80%
of people with type 2 diabetes [4,5]. Based on the absence
or presence of new vessels, diabetic retinopathy is classified
into (i) non-proliferative (NPDR) and (ii) proliferative (PDR).
NPDR is further divided into four stages: mild, moderate,
severe and very severe (Table 1). In the mild/moderate stages,
microaneurysms and intraretinal haemorrhages are present in
the retina, mostly in the posterior pole. As the blood–retinal
barrier (BRB) breaks down, the plasma leaks out of the retinal
capillaries resulting in retina oedema. The oedema most com-
monly occurs in the macula, resulting in distortion of vision
and vision loss. Macular oedema is the most common cause of
vision loss in diabetic retinopathy (20–25% of people with dia-
betes have vision loss after 10 years). Hard exudates that look
like well-defined yellow deposits, often accompany macular
oedema, and these lesions represent lipid materials that leak
out of the retinal microvessels. NPDR becomes severe when
it shows intraretinal haemorrhages in all four quadrants, or
venous beading in two quadrants, or intraretinal microvascular
abnormalities in one quadrant (the so-called 4-2-1 rule) [6].
The retinopathy is considered very severe if two of these features
are present. Of people with severe NPDR, 50% will progress to
the PDR stage in 1 year [6]. PDR is present when new retinal
vessels grow out of the retinal capillaries into the vitreous. As
these new vessels are fragile (of endothelial tube formation),
they often lead to preretinal and vitreous haemorrhage, causing
symptoms of floaters and decreased, severe vision loss. As the
new vessels grow over the vitreous interface, other cells, such
as fibroblasts and glial cells, participate in forming epiretinal
membranes that contract and cause traction retinal detachment
with severe vision loss. Some people with PDR have growth of
the neovascular tissue on the surface of the iris into the anterior
chamber angle, causing blockage of the aqueous outflow, and a
severe type of glaucoma, called neovascular glaucoma.

Correspondence to: Arup Das, MD, PhD, Department of Surgery, Division of Ophthalmology, Pathophysiology
University of New Mexico School of Medicine, MSC10-5610, 1 University of New Mexico,
Albuquerque, NM 87131, USA. The alteration of the BRB is the hallmark of the pathogenesis of
E-mail: adas@unm.edu diabetic retinopathy. Normally, this BRB at the retinal capillary
review article
Table 1. International classification of the clinical features of diabetic retinopathy
International classification of diabetic retinopathy
Severity level
No retinopathy
Mild non-proliferative retinopathy
Moderate non-proliferative
retinopathy
Severe non-proliferative retinopathy
Very severe non-proliferative
retinopathy
Proliferative retinopathy
Adapted from [72].
level comprises endothelial cell–cell junctions, basement
membrane and pericytes that cover the vessels outside. In dia-
betes, three changes happen at the BRB: (i) loss of endothelial
cell–cell junctions; (ii) thickening of the basement membrane;
and (iii) selective loss of pericytes. The breakdown of the BRB
leads to intraretinal haemorrhages, hard exudates and macular
oedema. Selective pericyte loss is one of the early histopatho-
logical lesions seen in diabetic retinopathy [7]. It is not clear
why there is selective loss of pericytes in diabetes. Normally,
pericytes (modified smooth muscle cells), are contractile, and
maintain the retinal capillary flow [8]. Pericyte loss leads to
focal weakening of the capillary wall as well as uninhibited
focal endothelial cell proliferation that leads to formation of
microaneurysms [9]. Later, endothelial cells also die, resulting
in acellular capillaries and non-perfusion in the retina. Apop-
tosis, or programmed cell death, is responsible for death of
both these cell types in diabetes. Neuronal death attributable
to apoptosis may occur in the ganglion cell layer even earlier
than the vascular lesions. Such a silent death of neurons before
the vascular lesions appear may explain the defect in dark
adaptation and reduced contrast sensitivity seen in people
with diabetes before the development of retinopathy. The
hyperglycaemia-induced pathogenesis of diabetic retinopathy
is linked to four major biochemical pathways: (i) the increased
polyol pathway; (ii) increased advanced glycation end product
formation; (iii) activation of protein kinase C isoforms; and (iv)
the increased hexosamine pathway [10]. All these pathways
eventually lead to oxidative stress, inflammation and retinal
vascular dysfunction. Hypoxia is the initiating factor in the
development of new retinal vessels seen in PDR. Many angio-
genic factors, such as VEGF, basic fibroblast growth factor,
insulin-like growth factor and angiopoietin-2, play a key role
in this process [11]. Normally, there is a balance of angiogenic
factors and endogenous anti-angiogenic factors [e.g. Pigment
Epithelium Derived Factor (PEDF), endostatin], and this bal-
ance breaks down in PDR, ultimately resulting in the growth of
new vessels.
220 Das et al.
DIABETES, OBESITY AND METABOLISM
Ophthalmoscopic findings
No abnormalities
Microaneursyms only
More than just microaneursyms (retinal haemorrhages and
hard exudates), less than severe non-proliferative diabetic
retinopathy
Any one of the following three features:
20 retinal haemorrhages in each of the four quadrants
Venous beating in two quadrants
Intraretinal microvascular abnormalities in one quadrant
Any two of the above features present
One or both of the following features:
Neovascularization
Preretinal/vitreous haemorrhage
Systemic Factor Control
The beneficial effects of systemic control of blood glucose
on retinopathy have been shown in three large, randomized
clinical trials. The Diabetes Control and Complications Trial
showed that tight glucose control [glycated haemoglobin
(HbA1c) of <6% or 42.1 mmol/mol) in people with type 1
diabetes prevented the development of diabetic retinopathy by
76% and decreased progression of existing diabetic retinopathy
by 54% [12]. The United Kingdom Prospective Diabetes Study
(UKPDS) then showed that intensive glucose control (median
HbA1c of 7.0% or 53 mmol/mol versus 7.9% or 62.8 mmol/mol
in conventional glucose control group) led to a 25% reduced
rate of microvascular disease, including retinopathy, in patients
with type 2 diabetes [13]. More recently, the ACCORD Eye
Study Group [14] reported that tight glucose control in patients
with type 2 diabetes (median HbA1c of 6.4% or 46.4 mmol/mol
in the intensive group versus 7.5% or 58.5 mmol/mol in the
conventional group) reduced progression of diabetic retinopa-
thy by 35% over a 4-year span. A recent meta-analysis of the
recent clinical trials in people with type 2 diabetes concluded,
however, that intensive control of blood glucose did not prevent
the need for photocoagulation, nor the development of severe
vision loss [15]. With regard to blood pressure control, the
UKPDS found that controlling blood pressure also led to a sig-
nificant decrease in visual loss [13]. Interestingly, the ACCORD
Eye study showed that tight hypertension control did not sig-
nificantly decrease the incidence of diabetic retinopathy [14].
These results point to the notion that maintaining systolic blood
pressure at <150 mmHg probably has a therapeutic threshold of
∼130 mmHg systolic pressure, lower than which would proba-
bly have little effect on reducing visual loss in diabetic retinopa-
thy. Interestingly, a newer study, the Hypertension Intervention
Nurse Telemedicine Study, has shown that lowering systolic
blood pressure by a mean of 8 mmHg over an 18-month period
led to decreased progression of diabetic retinopathy among
mostly male veterans monitoring blood pressure at home and
receiving nurse-administered telemedicine behavioural and
Volume 17 No. 3 March 2015
DIABETES, OBESITY AND METABOLISM
medical interventions [16]. Although control of blood pressure
overall probably reduces the progression of diabetic retinopa-
thy, it has been shown that treatment with specific agents may
have additional benefits. For instance, candesartan led to a 25%
lower incidence of diabetic retinopathy in people with type 1
diabetes [17] and a 34% higher regression of diabetic retinopa-
thy in people with type 2 diabetes with mild retinopathy com-
pared with placebo [18]. With regard to lipid control, it appears
that LDL cholesterol and triglyceride levels are directly related
to the incidence and severity of diabetic retinopathy, while
HDL cholesterol level is indirectly related [19]. The Fenofibrate
Intervention and Event Lowering in Diabetes study showed that
fenofibrate (200 mg/day) reduced the need for retinopathy laser
treatment in people with type 2 diabetes [20]. This was further
confirmed in the ACCORD Eye study, which provided evi-
dence that fenofibrate added to simvastatin therapy in people
with type 2 diabetes slowed down the progression of diabetic
retinopathy at 4 years [14]. Among other risk factors, anaemia
has been associated with progression of diabetic retinopathy
[21]. The Early Treatment Diabetic Retinopathy Study (ETDRS)
showed an association between a decrease in haematocrit and
an increase in incidence of high-risk PDR. In people with type
2 diabetes, a strong correlation was observed between diabetic
retinopathy and obstructive sleep apnoea [22]. Pregnancy has
been associated with rapid progression of diabetic retinopathy,
and this has been attributed to high levels of oestrogens as well
as serum insulin-like growth factor in pregnancy [23].
In treatment of diabetic retinopathy, the ophthalmologist
should be in close consultation with the primary care physician
regarding tight control of blood glucose, blood pressure and
blood lipids. The HbA1c target should be 7%, as further lower-
ing of blood glucose may be difficult to achieve in people with
long-standing type 2 diabetes, and may cause a higher number
of cardiovascular events and mortality [14]. With regard to con-
trol of retinopathy, the aim should be a systolic blood pressure
of <140 mmHg, and fenofibrates should be added to the statin
therapy for optimum blood lipid control.
Laser Therapy
Diabetic Macular Oedema
The ETDRS in 1985 showed that the use of small, light-intensity
laser burns to microaneurysms, and/or diffuse area of thick-
ening in a grid pattern resulted in a 50% reduction in severe
vision loss [24]. The proposed underlying mechanisms behind
this approach involve increased intraocular oxygen tension, a
decreased production of vasoactive cytokines, primarily VEGF,
and increased phagocytosis by retinal pigment epithelial (RPE)
cells and glial cells. Recently, it has been proposed that RPE
cells at the margins of burns participate in their own recovery
through the modulation of various cytokines via photorecep-
tors [25,26]. Because of the efficacy of anti-VEGF agents for
diabetic macular oedema, the current indication of focal/grid
laser is now limited to those patients with non-centre-involving
diabetic macular oedema.
In recent years, treatment has shifted towards selectively
applying subthermal intensity to RPE cells, while sparing the
neurosensory retina, therefore, reducing iatrogenic side effects
Volume 17 No. 3 March 2015
review article
caused by functional loss of retinal tissue and deep burns
that caused long term scarring and fibrosis. Two principles
help achieve this goal. One, longer laser wavelengths are used,
647 nm krypton red and 810 nm diode lasers, in order to reduce
burn intensity and avoid absorption to macular chromophores.
Second, the development of micropulsar techniques, which
increase the delay between pulses and reduce the size of reti-
nal lesions by eliminating heat diffusion and lesion growth after
treatment. In 2005, a pilot study of the subthreshold diode
micropulsar (SDM) laser, which uses an 810-nm diode laser at
sub-optimum intensity applied to all areas of macular thicken-
ing, showed that SDM laser photocoagulation was similar to
previous laser treatments, without any adverse effects or evi-
dence of iatrogenic retinal damage [27–29].
Further studies showed similar effects. In 2009, a prospec-
tive randomized control trial comparing the efficacy of SDM
laser photocoagulation with conventional argon green laser
used in the modified ETDRS protocol, showed that best cor-
rected visual acuity (BCVA) remained unchanged at 12 months
in either treatment arm; however, laser scars were identified in
only 13.9% of eyes treated with SDM, while laser scars were
identified in 59% of eyes treated with conventional green laser
[30]. Furthermore, in a study conducted in Japan, fundus aut-
ofluorescence, which uses fluorescence from the retina to indi-
cate the health of RPE cells, was used to evaluate morphological
changes objectively in 24 eyes treated with SDM laser pho-
tocoagulation for centre-involving clinically significant mac-
ular oedema. At 1-year follow-up, fundus autofluorescence
remained unchanged from baseline values in the SDM laser
photocoagulation treatment arm, thus indicating that there was
no RPE cell damage [31].
The lack of damage to deeper retinal cell layers and long-term
scarring, as evidenced by these studies, helped pave the way
for the introduction of high-density SDM lasers in an effort
to improve clinical outcomes. The aim of the high-density
approach was to increase lateral spread of thermally stimulated
RPE cells, thus delivering ∼900 burns throughout the macula,
but avoiding the fovea, and even involving normal-appearing
areas of the retina. This hypothesis was investigated by Lavinsky
et al. [32] and reported in 2011. These authors showed that
high-density SDM laser photocoagulation led to a superior
improvement in BCVA and central macular thickness in com-
parison with low-density SDM laser and conventional argon
laser therapy.
Another newly developed mode of subthermal laser ther-
apy involves creating a horse-shoe shaped macular grid
pattern using a 577-nm yellow semi-automated patterned
scanning laser (PASCAL; Topcon, Capelle aan den IJssel, The
Netherlands), which allows the physician to deliver multiple
spots of photocoagulation simultaneously in a preset pattern.
The PASCAL uses either 20 or 10-ms burns localized to the
outer retina without changes to adjacent RPE cells or inner
neuroretina, similarly to the SDM laser [33,34]; however,
unlike the invisible nature of the SDM laser burn, the burn
from the PASCAL is able to be tracked 1 h after treatment
by frequency domain-optical coherence tomography, which
shows localized defects at the junction of the photoreceptor
doi:10.1111/dom.12384 221
review article
inner and outer segments and apical RPE. At 12 months, fre-
quency domain-optical coherence tomography shows a normal
inner and outer segment layer with burns localized only to the
uppermost RPE layer of the retina [23]. The use of the 577-nm
yellow laser also gives it the ability to be titrated to a certain
power. A new navigated laser photocoagulator (NAVILAS ,
NAVILAS Laser System, Irvine, CA, USA), a prototype of
® to 200 internal degrees (sometimes without pupillary dilation),
retinal eye-tracking laser delivery system with integrated dig-
ital fundus imaging, allows registered image overlay and laser
stabilization on the retina and thus a higher rate of accuracy in
the treatment of diabetic retinopathy lesions [35]. The Com-
bination of Anti-VEGF and Navigational Laser in Diabetic
Macular Edema (CAVNAV) study, a 12-month prospective
cohort study, showed a reduced number of anti-VEGF injec-
tions and a higher proportion of injection-free patients with
the combination therapy of anti-VEGF drugs and NAVILAS
laser compared with the monotherapy of anti-VEGF injections
in diabetic macular oedema [36].
Proliferative Diabetic Retinopathy
The Diabetic Retinopathy Study [37] showed that panretinal
photocoagulation (PRP) reduced the risk of severe visual loss
by ∼50% over 5 years. Furthermore, the preservation of vision
from PRP was shown in the ETDRS follow-up study [38]. In
this procedure, stronger-intensity, large-sized burns (500 μm)
are placed in the mid-peripheral retina in a 360 degree fashion
in one or two sessions. The treatment does not target new ves-
sels directly, and causes regression of new vessels in ∼6 weeks.
The mechanism for new vessel regression is probably increased
oxygen tension in the remaining retina, and thus decreased pro-
duction of angiogenic factors (such as VEGF). PRP laser ther-
apy has been established as a mainstay of treatment for PDR, but
there are notable side effects that should be considered, includ-
ing the worsening of pre-existing macular oedema and impair-
ment of peripheral retina function and night vision [39]. The
reduction of these side effects with favourable clinical outcomes
has been (and will likely continue to be) the focus of evolv-
ing therapies. The administration of PRP laser therapy did not
fundamentally change until the introduction of the PASCAL in
recent years. The aim of this device was to shorten the proce-
dure time of PRP laser treatment and to decrease patient pain
by decreasing stimulation of the ciliary nerves in the choroid,
while providing the same therapeutic outcomes [40]. The PAS-
CAL requires a shorter duration of photocoagulation, but more
power, which has indeed been shown to decrease patient pain
with similar outcomes when compared with conventional PRP
[41]. Recently, the PETER PAN study [42] reported that a lower
power setting achieved similar results with less vision loss com-
pared with standard PRP settings. Additionally, it has been
shown that single-session multi-spot PASCAL photocoagula-
tion is as efficacious as multi-session single-spot photocoagula-
tion, and resulted in no difference in adverse macular oedema
effects [43]. This finding has the potential to increase patient
compliance and result in cost savings from reduced numbers
of visits.
Retina visualization technologies have also affected the
treatment options for PDR and may have the potential to
make targeted retinal photocoagulation a viable treatment
222 Das et al.
DIABETES, OBESITY AND METABOLISM
option. Conventionally, a clinician dilates a patient’s eyes
and uses a slit-lamp or indirect lens technique to visualize
the retina during photocoagulation procedures; however,
new technology, specifically the Optos camera (Optos,
Dunfermline, UK), allows a clinician to visualize the retina up
perform fluorescein angiography and autofluorescence to map
sub-threshold laser burns on the retina. The PETER PAN
study also concluded that targeted retinal photocoagulation
could be used in conjunction with visible peripheral retinal
ischaemia on Optos angiography [42]. The Optos device has a
favourable safety profile and will probably continue to become
more prominent in the treatment of retinopathy [44].
Pharmacotherapies
Anti-VEGF Therapy
VGEF has been the most important factor that has been inves-
tigated extensively in relation to the pathophysiology retinal
neovascularization and alteration of the BRB. VEGF levels are
significantly elevated in the vitreous of patients with diabetic
macular oedema when compared with non-diabetic eye condi-
tions [45]. VEGF is a potent vaso-permeability factor. It affects
endothelial tight junction proteins, resulting in extravasation of
fluid and retinal oedema. VEGF induces the phosphorylation
of vascular endothelial cadherin, occludin and ZO-1, and thus
causes a breakdown of the barrier [46]. VEGF also increases
leukostasis in the retinal microvessels, and the sticky leukocytes
may migrate via the interendothelial or transendothelial route
[47]. There are several drugs that target the molecule, VEGF.
Drugs that directly inhibit the VEGF molecule include the
anti-VEGF aptamer, pegaptanib (Macugen; OSI Pharmaceuti-
cals, Long Island, NY, USA), the monoclonal antibody fragment
ranibizumab (Lucentis; Genentech, San Francisco, CA, USA),
and the full-length antibody bevacizumab (Avastin; Genen-
tech). Other treatments include soluble VEGF receptor ana-
logues, VEGF-Trap (Regeneron, Tarrytown, NY, USA), small
interfering RNAs bevasiranib (Opko Health, Miami, FL, USA),
and rapamycin (Sirolimus; MacuSight, Union City, CA, USA).
Anti-VEGF drugs are injected into the eye in the form of
intravitreal injections under topical anaesthesia as office pro-
cedures. Currently, the indication for use of anti-VEGF agents
in diabetic macular oedema is centre-involving diabetic macu-
lar oedema, while the indication for laser treatment is limited
to non-centre-involving diabetic macular oedema.
Diabetic Macular Oedema
Ranibizumab is a monoclonal antibody that blocks all iso-
forms of VEGF-A, and is ’affinity-enhanced’ to provide stronger
affinity to bind to VEGF-A. It is the only drug that has been
approved by the US Food and Drug Administration for use in
patients with diabetic macular oedema (Figure 1). The READ-2
Study [48] compared focal/grid laser treatment with intrav-
itreal injection of ranibizumab only, as well as a combina-
tion therapy of ranibizumab plus focal/grid laser. Three-year
results of the study showed a mean improvement in visual
Volume 17 No. 3 March 2015
DIABETES, OBESITY AND METABOLISM
Figure 1. Optical coherence tomography images of the study eye retina of a patient with diabetic macular oedema at baseline and 1, 3 and 6 months. The
patient received 0.3 mg of ranibizumab (adapted from [71]).
acuity from baseline of 10.3 letters compared with −1.6 let-
ters in the laser group and +2.0 letters in the combination
therapy group. Two more studies also showed the beneficial
effects of intravitreal ranibizumab injections in patients with
diabetic macular oedema. In the RISE and RIDE study [49],
where patients were randomized to either two different doses
of intravitreal ranibizumab (0.3 and 0.5 mg) or sham injec-
tion, the proportion of patients showing >15 letter improve-
ment was 19% in the sham group compared with 37% in the
0.3 mg ranibizumab group and 40% in the 0.5 mg ranibizumab
group after 36 months. Interestingly, that study reported a ben-
eficial effect of ranibizumab in slowing down the progression
of diabetic retinopathy and improvement of the severity of
retinopathy. The Diabetic Retinopathy Clinical Research Net-
work (DRCR), a National Institutes of Health-sponsored mul-
ticentre, randomized clinical trial, concluded that intravitreal
ranibizumab with prompt or deferred laser was more effec-
tive for up to at least 1 year compared with prompt laser alone
for centre-involving diabetic macular oedema [50]. Three-year
data from that study indicated that visual improvement was
greater in the ranibizumab + deferred laser group (57% with
>10 letters improvement) than in the ranibizumab + prompt
laser group (42% with >10 letters improvement), and thus
suggested no benefit of earlier initiation of focal/grid laser
for better visual outcome [51]. Although the first-line treat-
ment of centre-involving diabetic macular oedema is currently
anti-VEGF injections, focal/grid laser therapy can be added
to this anti-VEGF regimen if the oedema persists and is no
longer improving with two consecutive injections after an ini-
tial period of 24 weeks of monthly anti-VEGF injections [52].
Bevacizumab (Avastin; Genentech) is a full-length human-
ized monoclonal antibody, almost three times the size of
the ranibizumab molecule, which also blocks all isoforms of
VEGF-A. It has been used as an off-label drug for the treat-
ment of age-related macular degeneration, retinal vascular
occlusions, PDR and diabetic macular oedema. Because of
its much lower cost compared with other available drugs,
such as ranibizumab and aflibercept, bevacizumb has gained
worldwide popularity among eye clinics for the treatment
of retinal vascular diseases. The BOLT study that compared
intravitreal injections of bavacizumab (1.25 mg, 6 weekly) with
Volume 17 No. 3 March 2015
review article
focal/grid laser treatment for 12 months showed an improve-
ment of eight letters with bevacizumab injections, whereas
the laser group lost a median of 0.5 letters [53]. Two-year
results of that study showed a similar improvement with
bevacizumab.
Aflibercept (Eylea; Regeneron) is a soluble protein that
contains extracellular VEGF receptor sequences fused to an
immunoglobulin G molecule, and blocks all isoforms of VEGF
as well as placental growth factor. The prolonged biological
activity of this drug offers the advantage of injections every
second month rather than more frequent monthly injec-
tions. In the phase III VIVID-diabetic macular oedema and
VISTA-diabetic macular oedema trials [54], patients receiv-
ing aflibercept (2 mg monthly or every second month) had
a mean BCVA change from baseline of 12.5 and 11.1 letters,
respectively, after 2 years, compared with a mean change from
baseline in BCVA of 0.2 letters in patients receiving laser
photocoagulation. Currently, the DRCR is evaluating protocol
T, a head-to-head comparison of the efficacy and safety of
these three drugs, ranibizumab, bevacizumab and aflibercept
in the treatment of patients with diabetic macular oedema
[55]. Until we have the results published from that pivotal
study, ophthalmologists are left to make their own personal
choice of anti-VEGF drugs in patients with diabetic macular
oedema. In addition, there remains a large disconnect between
what the randomized clinical trials publish and what the oph-
thalmologists actually do in their clinical practice in terms of
the number of intravitreal injections. The issue of which drug
to choose and how frequently to inject after the initial three
monthly injections is still a matter of personal choice.
Proliferative Diabetic Retinopathy
Anti-VEGF therapy has been found to be very effective in the
rapid regression of retinal neovascularization seen in patients
with PDR [56]; however, the effects of anti-VEGF agents appear
to be transient, and therefore PRP may still be necessary to
allow more permanent regression of new vessels. Caution is
necessary in using anti-VEGF agents in those patients with
PDR with significant fibrovascular proliferation as these agents
may worsen traction retinal detachment. Currently, a phase
III prospective clinical trial is comparing prompt PRP with
doi:10.1111/dom.12384 223
review article DIABETES, OBESITY AND METABOLISM

Systemic Factor Control DIABETES

Polyol, AGE, PKC & Hexosamine

Hyperlipidemia
Pathway Activation

ROS

INFLAMMATION
Hypertension
Anti-VEGF Therapies
Growth Factors (VEGF),
(for center-involving DME)
Chemokines & Cytokines
(Ang-2, CCL2, TNF-α, IL-1β ) Steroids

Altered Blood-Retinal Barrier

Increased vascular permeability

Diabetic
Focal/Grid LASER Vitrectomy
Macular
(for non-center involving DME) (for Vitreo-macular traction)
Edema

Figure 2. Pathophysiology and current strategies of therapies in diabetic macular oedema. Systemic factor control targeting blood glucose, blood pressure
and lipids is still the ’gold standard’ treatment for diabetic retinopathy. Focal/grid laser is now indicated in those with non-centre-involving diabetic macular
oedema only. Anti-vascular endothelial growth factor (VEGF) intravitreal injections are the first line of treatment in patients with centre-involving diabetic
macular oedema. Steroids are reserved for those who are poor responders to anti-VEGF therapies. Finally, a small number of patients with vitreo-macular
traction are treated with vitrectomy surgery. Other potential novel target molecules are angiopoietin 2 (Ang-2), chemokine ligand 2 (CCL2), tumour necrosis
factor-𝛼 (TNF-𝛼) and interleukin-1𝛽 (IL-1𝛽). AGE, advanced glycation end-products; PKC, protein kinase C.

intravitreal ranibizumab and deferred PRP in patients with
PDR [57].
Steroids
Inflammation plays an important role in the pathogenesis of
diabetic retinopathy [58]. All the features of inflammation
[increased blood flow, increased vascular permeability, tissue
oedema, leukostasis, microglial activation, macrophages and
neutrophil infiltration, complement activation and increased
cytokines (VEGF, tumour necrosis factor -𝛼, interleukin)] have
been reported in animal models as well as in human dia-
betic retinopathy [59]. The inflammatory cytokines are upreg-
ulated in the serum, vitreous and aqueous samples in sub-
jects with diabetic retinopathy. Inflammation can alter the BRB
by acting on the following steps in the cascade: (i) increased
expression of endothelial adhesion molecules such as ICAM1,
VCAM1, PECAM-1, and P-selectin; (ii) adhesion of leukocytes
to the endothelium (leukostasis); (iii) release of chemokines,
and cytokines; (iv) alteration of adherens and tight junctional
proteins between the endothelial cells; and (v) infiltration of
leukocytes into the neuro-retina, resulting in the alteration of
the BRB [58].
Diabetic Macular Oedema
The beneficial effects of steroids in diabetic macular oedema
are attributable to the fact that inflammatory cytokines and
chemokines involved in the inflammatory cascade of diabetic
macular oedema are susceptible to steroids, whereas inhibi-
tion of VEGF itself may not result in neutralization of these
molecules (Figure 2).
The efficacy of intravitreal steroids in diabetic macular
oedema has been shown in the DRCR Protocol I. In that trial,
the effect of intravitreal triamcinolone and laser was equivalent
to that of ranibizumab and laser up to 24 weeks, and then
the effect of triamcinolone gradually diminished because of
increased rates of cataract formation [50]. In the subgroup of
patients with pseudophakia, the triamcinolone + laser treat-
ment was superior to the laser-alone treatment and equivalent
to ranibizumab treatment [50].
In another randomized, multicentre 3-year long trial, the
FAME study [59], intravitreal inserts of fluocinolone acetonide
(0.2 and 0.5 μg/day) provided the substantial benefit of visual
improvement in patients with diabetic macular oedema; how-
ever, almost all patients receiving fluocinolone acetonide had
cataract formation, and the incidence of incisional glaucoma
surgery was 4.8% (low dose) and 8.1% (high dose). Although
the US Food and Drug Administration did not approve this
drug for diabetic macular oedema because of its side effects,
it has recently been approved in UK. It is interesting to note
that the FAME study showed enhanced benefits of using
fluocinolone acetonide in chronic diabetic macular oedema

224 Das et al. Volume 17 No. 3 March 2015

DIABETES, OBESITY AND METABOLISM
(>3 years duration) compared with non-chronic diabetic mac-
ular oedema (<3 years duration) [60]. It has been hypothesized
that the disease may be driven by VEGF early in the disease,
but in chronic diabetic macular oedema microenvironmen-
tal changes necessitate the targeting of multiple mediator
molecules with steroids. The beneficial effect of steroids in
diabetic macular oedema has further been reported with the
use of slow-release intravitreal dexamethasone implant (Ozur-
dex; Allergan Inc., Irvine, CA, USA) that releases sustained
levels of dexamethasone for 6 months [61]. Because of an
increased rate of elevated intraocular pressure and cataract
formation with triamcinolone, the use of intravitreal steroids
in clinical practice is currently reserved for those patients with
pseudophakia who respond poorly to intravitreal anti-VEGF
therapy. The combination of anti-VEGF agents and steroids
may be more effective in certain patients with diabetic mac-
ular oedema who are difficult to control with anti-VEGF
agents alone.
Proliferative Diabetic Retinopathy
Although steroids may be effective in the treatment of neo-
vascular age-related macular degeneration, these drugs are
not used in retinal neovascularization, as seen in PDR. The
PRP laser is still the ’gold standard’ treatment for PDR, and
anti-VEGF drugs are currently used as supplementary options;
this is being explored in ongoing trials, as mentioned above.
All therapies for diabetic retinopathy are summarized in
Table 2 [11–13,15,16,18,19,25,30,36–38,53,55–60].
Surgical Therapies
Despite laser and pharmacotherapies, a small number of
patients with PDR and diabetic macular oedema undergo
surgery.
Diabetic Macular Oedema
The majority of people with diabetic macular oedema benefit
from pharmacotherapies (anti-VEGF and steroids) and laser
treatment. In selected patients with significant vitreo-macular
traction in diabetic macular oedema, vitrectomy with peel-
ing of the inner limiting membrane can be combined with
or without indocyanine green dyes. In a multicentre DRCR
study in patients with diabetic macular oedema and macu-
lar traction, retinal thickening was reduced in most patients’
eyes, but visual acuity improved by 10 letters in 38% patients
only [62].
Proliferative Diabetic Retinopathy
Persistent non-clearing vitreous haemorrhage and traction reti-
nal detachment are two common indications for vitrectomy
surgery in PDR. The Diabetic Retinopathy Vitrectomy Study
showed a benefit of earlier surgery in patients with type 1 dia-
betes and in those with active neovascularization [63]. The vit-
rectomy surgery involves a three-port technique, with removal
of vitreous, along with blood and endolaser photocoagula-
tion similar to PRP laser treatment. The recent introduction of
Volume 17 No. 3 March 2015
review article
the Constellation System with ultra-speed cutters, duty cycle
controls, improved fluidics and powerful endoillumination,
and small-gauge surgery (23- and 25-gauge) has significantly
improved visual outcomes in these patients. Extramacular trac-
tion retinal detachment can be observed safely until it threatens
to involve the fovea. In patients with macula-involving trac-
tion retinal detachment, the traction can be relieved by vitrec-
tomy using segmentation, delamination and en bloc delamina-
tion techniques. Currently, some surgeons prefer using preop-
erative anti-VEGF agents now 1 week before surgery so as to
decrease intra-operative and postoperative haemorrhage from
the neovascular membranes, reduce surgical time and improve
visual acuity [64]; however, this might also increase the traction
exerted by the epiretinal membranes.
Future Directions
Anti-VEGF Agents
As the VEGF level varies in the vitreous of patients with diabetic
macular oedema, it has been proposed that poor responders to
anti-VEGF therapy may need much higher doses of anti-VEGF
drugs because of their higher levels of VEGF. With this concept,
a new study, READ-3 has examined the efficacy of ranibizumab
at two different doses (0.5 and 2.0 mg) in patients with diabetic
macular oedema. The 1-year results from that study, however,
show no significant difference in the effectiveness between these
two different doses [65]. Other anti-VEGF approaches include
targeting a central regulator, such as Raf kinase, mammalian
target of rapamyacin and the RTP 801 gene.
Extended Drug Delivery
As the monthly intravitreal anti-VEGF injections are a treat-
ment burden not only for the patients, but also for the
physicians, investigations into extended drug delivery are ongo-
ing, using bioerodable implants, bioerodable microspheres and
encapsulated cells. Recently, a phase I clinical trial using a
refillable, non-biodegradable long-term drug delivery implant
for ranibizumab has been completed on 20 patients with wet
macular degeneration. The trial showed a constant mean
improvement of vision of 10 letters throughout 1 year [66].
Other Novel targets
As inflammation releases several cytokines and chemokines
in diabetic macular oedema, it is possible that targeting
only VEGF may not be the best approach to treating dia-
betic macular oedema. Other potential target molecules
include angiopoietin-2, tumour necrosis factor, interleukins,
proteinases, chemokines (CCL2 and CCL5) and kallikrein.
Angiopoietin-2. Angiopoietin-2, a growth factor that binds to
the endothelial receptor tyrosine kinase Tie-2, has been shown
to be upregulated in retinas in an animal model of diabetes, and
increased angiopoietin-2 levels leads to increased retinal vascu-
lar permeability [67]. This pathway has been targeted in a recent
ongoing clinical trial with a Tie-2 activator [angiopoietin-2
antagonist; AKB 9778 (Aerpio Therapeutics, Blue Ash, OH,
USA)] in patients with diabetic macular oedema.
doi:10.1111/dom.12384 225
 Table 2. List of clinical trial results for prevention and intervention of diabetic retinopathy using systemic factor control, laser therapy, anti-vascular endothelial growth factor and steroid injections, and
combination therapies
226 Das et al.
Prevention/intervention of diabetic retinopathy
Systemic
Outcome affected glycaemic control Blood pressure control
Severity of HbA1c <6% in patients 144/82 mmHg mean blood
retinopathy with type 1 diabetes pressure versus
reduced risk of diabetic 154/87 mmHg led to a 34%
retinopathy by 76%, reduction in progression of
decreased progression diabetic retinopathy [12]
of existing retinopathy
by 54%, and reduced Prevents development of
development of severe diabetic retinopathy in
NPDR by 47% [11] patients with type 1
diabetes (25 vs. 31%) [15]
HbA1c of 7.0 versus 7.9%
led to a 25% reduced No significant effect on
rate of laser progression of diabetic
photocoagulation for retinopathy in patients
retinopathy [12] with type 1 or type 2
diabetes [15,16]
Tight control decreases
progression of diabetic Regression of diabetic
retinopathy (7.3 vs. retinopathy in 19% of
10.4%) [13] participants versus 14%
taking placebo in people
with type 2 diabetes [16]
Visual acuity Decreases risk of legal Tight blood pressure control Fenofibrate has no
blindness by 16% [12] (mean pressure of
144/82 mmHg) versus
Prevents visual acuity loss mean pressure of
(23.8 vs. 26.3%) [13] 154/87 mmHg led to 47%
risk reduction of vision loss
[12]
Intensive-treatment blood
pressure control (mean
systolic pressure of
117 mmHg) versus
standard treatment blood
pressure control (mean
systolic pressure of
133 mmHg) led to rates of
moderate vision loss of
27.7% and 24.7%,
respectively [13]
Volume 17 No. 3 March 2015
Laser (conventional,
Lipid control SDM, PASCAL)
Decreases in progression PASCAL success rate
of diabetic retinopathy significantly higher (28/30)
(6.5 vs. 10.2%) [13] compared with
conventional laser for PDR
Decreases in progression (20/30) [53]
of diabetic retinopathy
in patients with PASCAL multi-spot 20 ms
pre-existing diabetic with mean power of
retinopathy (3.1 vs. 157 mW compared with
14.6%) [18] 20 ms PASCAL with mean
power of 280 mW
produced similar outcomes
[30]
Argon conventional laser
significant effect reduces risk of visual acuity
versus placebo [13] loss by 50% in clinically
significant macular
oedema [19]
SDM equally effective in
correcting visual acuity in
diabetic macular oedema
versus conventional green
laser [55]
PRP reduced the rate of
severe vision loss by 50% in
PDR [25]
Combined
Steroid therapy Anti-VEGF therapy (laser and anti-VEGF)
Triamcinolone injections led 3.9% of ranibizumab-treated
to a 88% relative decrease (0.5 mg injection) patients
in fluorescein leakage at progressed to PDR versus
12 months [56] 11.5% of patients treated
review article
with sham treatment [37]
1% of patients receiving
ranibizumab (0.5 mg
injection) underwent PRP
versus 14% of patients in
sham group [37]
Visual acuity is transiently Bevacizumab and Ranibizumab combined with
better with triamcinolone ranibizumab improve prompt focal laser or
injections in the first visual acuity in diabetic deferred focal
4 months compared with macular oedema by an photocoagulation resulted
focal laser therapy; focal average of 1–2 Snellen in greater improvement of
laser group was found to chart lines [38,60] visual acuity than focal
have better visual acuity at laser alone [38]
follow-up of 16 months and Ranibizumab improved visual
3 years. A total of 83% of acuity in diabetic macular
patients who received 4 mg oedema from baseline by
triamcinolone injection 10.3 ± 9.1 letters versus a
had developed cataracts at decline by 1.4 ± 14.2 letters
3-year follow-up [57] with sham [60]
Visual acuity is increased >5 Ranibizumab (0.5 mg
letters in 56% of eyes injection) improved visual
receiving triamcinolone acuity by ≥15 letters in
versus 26% of eyes 45.7% patients versus
receiving placebo [58] 12.3% patients treated with
sham injection [37]
DIABETES, OBESITY AND METABOLISM
 Table 2. Continued

Volume 17 No. 3 March 2015

Prevention/intervention of diabetic retinopathy

Systemic Laser (conventional, Combined

Outcome affected glycaemic control Blood pressure control Lipid control SDM, PASCAL) Steroid therapy Anti-VEGF therapy (laser and anti-VEGF)

Central retinal Fenofibrate decreases SDM equally effective as Intravitreal triamcinolone Ranibizumab (0.5 mg Ranibizumab plus focal/grid
thickness progression of macular conventional green laser injections are superior to injection) decreased laser reduced foveal
oedema by 34% (optical coherence posterior sub-tenon macular oedema by thickness more than
DIABETES, OBESITY AND METABOLISM

compared with tomography; measured
placebo [18] central retina thickness of
255 vs. 248.9 μm,
respectively) with less
scarring [55]
PASCAL laser equally
effective in treating
clinically significant
macular oedema versus
conventional laser (28/30
vs. 27/30) [53]
PASCAL laser reduced
frequency domain-optical
coherence tomography by
20+/−21 um at 3 months
[24]
capsule injections in
reducing foveal thickness
[59]
Intravitreal triamcinolone
injections decreased
macular thickness by a
mean of 125 μm as
compared with a mean
decrease of 71 μm with
placebo [58]
270.7 μm compared with a focal/grid laser alone in
decrease of 125.8 μm in DME [38,60]
sham groups [37]
Ranibizumab injections
decreases foveal thickness
less than laser therapy in
DME [36]
Forty-four patients receiving
Ranibizumab (0.5 mg inj.)
received macular laser
treatments versus 94
patients in sham group [37]

SDM and PASCAL

(double-frequency
neodymium YAG laser
532 nm) have equally
efficacy in reducing
diabetic macular oedema
[54]

VEGF, vascular endothelial growth factor; SDM, subthreshold diode micropulse laser; PASCAL, patterned scanning laser; HbA1c, glycated haemoglobin; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy;
PRP, panretinal photocoagulation.

doi:10.1111/dom.12384 227
review article
review article
Tumour Necrosis Factor. Tumor necrosis factor-𝛼 has been
implicated in many inflammatory diseases, including rheuma-
toid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque
psoriasis and Crohn’s disease, and a monoclonal antibody,
infliximab, has been approved for treating these disorders. A
double-blind, randomized, placebo-controlled, crossover study
in patients with diabetic macular oedema (persisting after
two sessions of laser photocoagulation) showed significant
improved visual acuity and reduction in retinal thickness with
intravenous infliximab (5 mg/kg) [68].
Chemokines. One of the most common chemokines that is sig-
nificantly elevated in serum and vitreous in diabetic retinopa-
thy has been identified as the chemokine ligand, CCL2. CCL2,
also known as monocyte chemotactic protein-1, is considered
to play an important role in vascular inflammation by induc-
ing leukocyte recruitment and activation. Animal studies have
shown the role of the CCL2 gene in alteration of the BRB in
diabetic retinopathy [69]. A CCR2/CCR5 receptor antagonist
(Pfizer, New York, NY, USA) is currently being tested in an
ongoing clinical trial in patients with diabetic macular oedema.
Kallikrein–kinin Inhibitors. Intraocular activation of the plasma
kallikrein–kinin pathway may contribute to increased retinal
vascular permeability in many patients with diabetic macular
oedema [70]. A phase I single-ascending dose study to inves-
tigate the safety and tolerability of the novel plasma kallikrein
inhibitor, KVD001 (intravitreal) in people with diabetic macu-
lar oedema is in progress.
Although the anti-VEGF effect is beneficial in PDR for
regression of new vessels, the effect is much less robust in dia-
betic macular oedema. Multiple, frequent monthly anti-VEGF
injections are needed in patients with diabetic macular oedema
to reduce the macular oedema. Nevertheless, a large number
of these patients respond poorly to these anti-VEGF drugs.
For such patients, steroids may be an alternative approach as
a second-line treatment, with careful consideration of poten-
tial side effects. It is possible that other molecules in addition to
VEGF play a key role in the inflammatory process in diabetic
macular oedema. A combination therapy with inhibitors of
these molecules combined with laser treatment or anti-VEGF
agents may be more effective in treating macular oedema in
people with diabetes in the future.
Conflict of Interest
The authors have no conflicts of interest to declare.
References
1. International Diabetes Federation. Diabetes: facts and figures 2013. Avail-
able from URL: http://www.idf.org/worlddiabetesday/toolkit/gp/facts-figures.
Accessed 19 September 2014.
2. Yau JW, Rogers SL, Kawasaki R et al. Global prevalence and major risk factors of
diabetic retinopathy. Diabetes Care 2012; 35: 556–564.
3. Klein R. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic
Epidemiol 2007; 14: 179–183.
4. Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic
Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy
228 Das et al.
DIABETES, OBESITY AND METABOLISM
when age at diagnosis is less than 30 years. Arch Ophthalmol 1984; 102:
520–526.
5. Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic
Study of Diabetic Retinopathy. III. Prevalence and risk of diabetic retinopathy
when age at diagnosis is 30 or more years. Arch Ophthalmol 1984; 102:
527–532.
6. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photo-
graphic risk factors for progression of diabetic retinopathy. ETDRS Report # 12.
Ophthalmology 1991; 98(Suppl): 823–833.
7. Kuwabara T, Cogan DG. Retinal vascular patterns. VI. Mural cells of the retinal
capillaries. Arch Ophthalmol 1963; 69: 492–502.
8. Das A, Frank RN, Weber M et al. ATP causes retinal pericytes to contract in vitro.
Exp Eye Res 1988; 46: 349–362.
9. Frank RN. Diabetic retinopathy. N Engl J Med 2004; 350: 48–58.
10. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism.
Diabetes 2005; 54: 1615–1625.
11. Das A, McGuire PG. Retinal and choroidal angiogenesis: Pathophysiology and
strategies for inhibition. Prog Retin Eye Res 2003; 22: 721–748.
12. The Diabetes Control and Complications Trial Research Group. The effect
of intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N Engl J Med
1993; 329: 977–986.
13. King P, Peacock I, Donnelly R. The UK Prospective Diabetes Study (UKPDS):
clinical and therapeutic implications for Type 2 diabetes. Br J Clin Pharmacol
1999; 48: 643–648.
14. The ACCORD, Study Group ACCORD, Eye Study Group. Effects of medical
therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;
363: 233–244.
15. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M et al. Effect of intensive
glucose lowering treatment on all cause mortality, cardiovascular death, and
microvascular events in type 2 diabetes: meta-analysis of randomised controlled
trials. Br Med J 2011; 343: d4169.
16. Muir KW, Grubber J, Mruthyunjaya P, McCant F, Bosworth HB. Progression of
diabetic retinopathy in the hypertension intervention nurse telemedicine study.
JAMA Ophthalmol 2013; 131: 957–958.
17. Chaturvedi N, Porta M, Klein R et al. Effect of candesartan on prevention
(DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1
diabetes: randomised, placebo-controlled trials. Lancet 2008; 372: 1394–1402.
18. Sjølie AK, Klein R, Porta M et al. Effect of candesartan on progression and
regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised
placebo-controlled trial. Lancet 2008; 372: 1385–1393.
19. Benarous R, Sasongko MB, Qureshi S et al. Differential association of serum
lipids with diabetic retinopathy and diabetic macular edema. Invest Ophthalmol
Vis Sci 2011; 52: 7464–7469.
20. Keech AC, Mitchell P, Summanen PA et al. Effect of fenofibrate on the need for
laser treatment for diabetic retinopathy (FIELD study): a randomised controlled
trial. Lancet 2007; 370: 1687–1697.
21. Davis MD, Fisher MR, Gangnon RE et al. Risk factors for high-risk proliferative
diabetic retinopathy and severe visual loss: early Treatment Diabetic Retinopa-
thy Study Report #18. Invest Ophthalmol Vis Sci 1998; 39: 233–252.
22. West SD, Groves DC, Lipinski HJ et al. The prevalence of retinopathy in men with
type 2 diabetes and obstructive sleep apnoea. Diabet Med 2010; 27: 423–430.
23. Klein R, Klein B. The epidemiology of diabetic retinopathy. In: Ryan SJ, ed. Retina
II. London: Elsevier, 2013; 907–924.
24. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation
for diabetic macular edema: early treatment diabetic retinopathy study report
number 1. Arch Ophthalmol 1985; 103: 1796–1806.
25. Duh EJ, Yang HS, Suzuma I, Miyagi M et al. Pigment epithelium-derived fac-
tor suppresses ischemia-induced retinal neovascularization and VEGF-induced
migration and growth. Invest Ophthalmol Vis Sci 2002; 43: 821–829.
Volume 17 No. 3 March 2015
DIABETES, OBESITY AND METABOLISM
26. Miura Y, Treumer F, Klettner A et al. VEGF and PEDF secretions [68] over time
following various laser irradiations on an RPE organ culture. Invest Ophthalmol
Vis Sci 2010; 51: 469.
27. Luttrull JK, Musch DC, Mainster MA. Subthreshold diode micro- pulse photoco-
agulation for the treatment of clinically significant diabetic macular oedema. Br
J Ophthalmol 2005; 89: 74–80.
28. Laursen ML, Moeller F, Sander B, Sjoelie AK. Subthreshold micropulse diode laser
in patients with diabetic macular edema. Br J Ophthalmol 2004; 88: 1173–1179.
29. Sivaprasad S, Dorin G. Subthreshold diode micropulse photocoagulation for the
treatment of diabetic macular edema. Expert Rev Med Devices 2012; 9: 189–197.
30. Figueira J, Khan J, Nunes S et al. Prospective randomised controlled
trial comparing sub-threshold micropulse diode laser photocoagulation
and conventional green laser for clinically significant diabetic macular oedema.
Br J Ophthalmol 2009; 93: 1341–1344.
31. Vujosevic S, Bottega E, Casciano M et al. Microperimetry and fundus autofluo-
rescence in diabetic macular edema: subthreshold micropulse diode laser versus
modified early treatment diabetic retinopathy study laser photocoagulation.
Retina 2010; 30: 908–916.
32. Lavinsky D, Cardillo JA, Melo LA Jr et al. Randomized clinical trial evaluating
mETDRS versus normal or high-density micropulse photocoagulation for dia-
betic macular edema. Invest Ophthalmol Vis Sci 2011; 52: 4314–4323.
33. Muqit MM, Henson DB, Young LB et al. Laser tissue interactions. Ophthalmology
2010; 117: 2039.
34. Muqit MM, Gray JC, Marcellino GR et al. Barely visible 10-millisecond pascal
laser photocoagulation for diabetic macular edema: observations of clinical
effect and burn localization. Am J Ophthalmol 2010; 149: 979–986.
35. Kozak I, Oster SF, Cortes MA et al. Clinical evaluation and treatment accuracy
in diabetic macular edema using navigated laser photocoagulator NAVILAS.
Ophthalmology 2011; 118: 1119–1124.
36. Barteselli G, Kozak I, El-Emam S, Chhablani J, Cortes MA, Freeman WR. 12-month
results of the standardised combination therapy for diabetic macular oedema:
intravitreal bevacizumab and navigated retinal photocoagulation. Br J Ophthal-
mol 2014; 98: 1036–1041.
37. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of
proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy
Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981; 88: 583–600.
38. Chew EY, Ferris FL, Csaky KG etal. The long-term effects of laser photocoag-
ulation treatment in patients with diabetic retinopathy (the early treatment
diabetic retinopathy follow-up study). Ophthalmology 2003; 110: 1683–1689.
39. Fong DS, Girach A, Boney A. Visual side effects of successful scatter laser
photocoagulation surgery for proliferative diabetic retinopathy: a literature
review. Retina 2007; 27: 816–824.
40. Blumenkranz MS, Yellachich D, Andersen DE et al. Semiautomated patterned
scanning laser for retinal photocoagulation. Retina 2006; 26: 370–376.
41. Al-Hussainy S, Dodson PM, Gibson JM. Pain response and follow-up of patients
undergoing panretinal laser photocoagulation with reduced exposure times. Eye
2008; 22: 96–99.
42. Muqit MM, Young LB, McKenzie R et al. Pilot randomised clinical trial of Pascal
TargETEd Retinal versus variable fluence PANretinal 20 ms laser in diabetic
retinopathy: PETER PAN Study. Br J Ophthalmol 2013; 97: 220–227.
43. Muqit MMK, Marcellino GR, Henson DB et al. Single-session vs multiple-session
pattern scanning laser panretinal photocoagulation in proliferative diabetic
retinopathy. Arch Ophthalmol 2010a; 128: 525–533.
44. Muqit MM, Marcellino GR, Henson DB et al. Optos-guided pattern scan laser
(Pascal)-targeted retinal photocoagulation in proliferative diabetic retinopathy.
Acta Ophthalmol 2013; 91: 251–258.
45. Funatsu H, Yamashita H, Ikeda T, Nakanishi Y, Kitano S, Hori S. Angiotensin II
and vascular endothelial growth factor in the vitreous fluid of patients with
diabetic macular edema and other retinal disorders. Am J Ophthalmol 2002;
133: 537–543.
Volume 17 No. 3 March 2015
review article
46. Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW. Vascular
endothelial growth factor induces rapid phosphorylation of tight junction
proteins occludin and zonula occluden 1. A potential mechanism for vascu-
lar permeability in diabetic retinopathy and tumors. J Biol Chem 1999; 274:
23463–23467.
47. Joussen AM, Murata T, Tsujikawa A, Kirchhof B, Bursell SE, Adamis AP.
Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am
J Pathol 2001; 158: 147–152.
48. Do DV, Nguyen QD, Khwaja AA et al. Ranibizumab for edema of the Macula
in Diabetes study: 3 year outcomes and the need for prolonged frequent
treatment. JAMA Ophthalmol 2013; 131: 139–145.
49. Brown DM, Nguyen QD, Marcus DM et al. RIDE and RISE Research Group.
Long-term outcomes of ranibizumab therapy for diabetic macular edema: the
36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013;
120: 2013–2022.
50. The Diabetic Retinopathy Clinical Research Network. Randomized trial evalu-
ating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt
laser for diabetic macular edema. Ophthalmology 2010; 117: 1064–1077.
51. Diabetic Retinopathy Clinical research Network. Intravitreal ranibizumab for
diabetic macular edema with prompt versus deferred laser treatment: three year
randomized trial results. Ophthalmology 2012; 119: 2312–2318.
52. Diabetic Retinopathy Clinical Research Network; Writing Committee, Aiello LP
et al. Rationale for the diabetic retinopathy clinical research network treatment
protocol for center-involved diabetic macular edema. Ophthalmology 2011;
118: e5–e14.
53. Michaelides M, Kaines A, Hamilton RD et al. A prospective randomized trial
of intravitreal bevacizumab or laser therapy in the management of diabetic
macular edema (BOLT study) 12-month data: report 2. Ophthalmology 2010;
117: 1078–1086.
54. American Society of Retina Specialists (ASRS) News. Industry news – clinical
updates. Two-year results of phase 3 VISTA trial of Aflibercept for DME treatment
show sustained vision improvement. Available from URL: http://www.asrs.org.
Accessed 19 September 2014.
55. Diabetic Retinopathy Clinical Research Network. A comparative effectiveness
study of intravitreal aflibercept, bevacizumab and ranibizumab for diabetic mac-
ular edema. Available from URL: http://drcrnet.jaeb.org/Studies.aspx. Accessed
4 June 2014.
56. Avery RL, Pearlman J, Pieramici DJ et al. Intravitreal bevacizumab (Avastin) in
the treatment of proliferative diabetic retinopathy. Ophthalmology 2006; 113:
1695–1705.
57. Diabetic Retinopathy Clinical Research Network. Prompt panretinal pho-
tocoagulation versus intravitreal ranibizumab with deferred panretinal
photocoagulation for proliferative diabetic retinopathy. Available from URL:
http://clinicaltrials.gov/show/NCT01489189. Accessed 19 September 2014.
58. Rangasamy S, McGuire P, Das A. Diabetic retinopathy and inflammation: novel
therapeutic targets. Middle East Afr J Ophthalmol 2012; 19: 52–59.
59. Campochiaro P, Brown DM, Pearson A et al., FAME Study Group. Sustained
delivery fluocinolone acetonide vitreous inserts provide benefit for at least
3 years in patients with diabetic macular edema. Ophthalmology 2012; 110:
2125–2132.
60. Cunha-Vaz J, Ashton P, Iezzi R et al., FAME Study Group. Sustained delivery
fluocinolone acetonide vitreous implants: long-term benefit in patients with
chronic diabetic macular edema. Ophthalmology 2014; 119: 2125–2132.
61. Boyer D. Ozurdex diabetic macular edema study. Paper presented at the Annual
Meeting of the America Academy of Ophthalmology, New Orleans, LA, 16–19
November 2013.
62. Diabetic Retinopathy Clinical Research Network. Vitrectomy outcomes in eyes
with diabetic macular edema and vitreomacular traction. Ophthalmology 2010;
117: 1087–1093.
doi:10.1111/dom.12384 229
review article
63. Diabetic Retinopathy Vitrectomy Study. Early vitrectomy for severe vitreous
hemorrhage in diabetic retinopathy. Report No. 5. Arch Ophthalmol 1990; 108:
958–964.
64. Ossadon P, Fagan XJ, Lifshitz T, Levy J. A review of anti-VEGF agents for
proliferative diabetic retinopathy. Eye 2014; 28: 510–520.
65. Nguyen Q. Higher anti-VEGF approach. Presented at the World Ophthalmology
Congress, Tokyo, Japan, 2–6 April 2014.
66. Rubio R. Long-acting anti-VEGF delivery: How close are we? Presented at the
World Ophthalmology Congress, Tokyo, Japan, 2–6 April 2014.
67. Rangasamy S, Srinivasan R, Maestas J, McGuire P, Das A. A potential role
of angiopoietin-2 in the alteration of the blood-retinal barrier in diabetic
retinopathy. Invest Ophthalmol Vis Sci 2011; 52: 3784–3791.
68. Sfikakis P, Grigoropoulos V, Emfietzoglou I et al. Infliximab for diabetic mac-
ular edema refractory to laser photocoagulation. Diabetes Care 2010; 33:
1523–1528.
230 Das et al.
DIABETES, OBESITY AND METABOLISM
69. Das A, Rangasamy S, Maestas J, McGuire P. CC Chemokines play an important
role in alteration of the blood-retinal barrier in diabetes. ARVO Abstract ARVO
Meeting, Ft Lauderdale, FL, 2011, Program# 997.
70. Feener EP. Plasma kallikrein and diabetic macular edema. Curr Diab Rep 2010;
10: 270–275.
71. Chun DW, Heier JS, Topping TM et al. A pilot study of multiple intravitreal
injections of ranibizumab in patients with center-involving clinically significant
diabetic macular oedema. Ophthalmology 2006; 113: 1706–1712.
72. American Academy of Ophthalmology. 2002. Available from URL:
http://one.aao.org/asset.axd?id=4b0447c9-24c6-411e-a888-3081553693d2.
Accessed 19 September 2014.
Volume 17 No. 3 March 2015