Seminars in Ophthalmology

ISSN: 0882-0538 (Print) 1744-5205 (Online) Journal homepage: http://www.tandfonline.com/loi/isio20

Evidence-Based Treatment of Diabetic Retinopathy

Hala El Rami, Rasha Barham, Jennifer K. Sun & Paolo S. Silva

To cite this article: Hala El Rami, Rasha Barham, Jennifer K. Sun & Paolo S. Silva (2016):
Evidence-Based Treatment of Diabetic Retinopathy, Seminars in Ophthalmology, DOI:
10.1080/08820538.2016.1228397

To link to this article: http://dx.doi.org/10.1080/08820538.2016.1228397

Published online: 04 Oct 2016.

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Seminars in Ophthalmology, Early Online, 1–8, 2016
© Taylor & Francis
ISSN: 0882-0538 print / 1744-5205 online
DOI: 10.1080/08820538.2016.1228397

ORIGINAL ARTICLE

Evidence-Based Treatment of Diabetic Retinopathy

Hala El Rami1, Rasha Barham1, Jennifer K. Sun1,2, and Paolo S. Silva1,2

1
Beetham Eye Institute, Joslin Diabetes Center, Boston, MA, USA and 2Department of Ophthalmology,
Harvard Medical School, Boston, MA, USA

ABSTRACT
Diabetic retinopathy (DR) is the most frequent microvascular complication from diabetes and requires annual
screening and at least annual follow-up. A systemic approach to optimize blood glucose and blood pressure may
halt progression to severe stages of DR and obviate the need for ocular treatment. Although there is evidence of
benefit from fenofibrate or intravitreous antiVEGF treatment for eyes with nonproliferative DR (NPDR), these
therapies are not standard care for NPDR at this time. Some patients with severe NPDR, especially those with
type 2 diabetes, benefit from early panretinal photocoagulation (PRP). Once DR progresses to proliferative DR
(PDR), treatment is often necessary to prevent visual loss. PRP remains mainstay treatment for PDR with high-
risk characteristics. However, intravitreous antiVEGF injections appear to be a safe and effective treatment
alternative for PDR through at least two years. Vitreoretinal surgery is indicated for PDR cases with non-clearing
vitreous hemorrhage and/or tractional retinal detachment.
Keywords: Diabetes mellitus, panretinal photocoagulation, vascular endothelial growth factor, vitrectomy

INTRODUCTION disease level: eyes with moderate NPDR carry a 12–27%

The rapidly increasing prevalence of diabetes has been
documented worldwide. In 2013, the International
Diabetes Federation estimated that 382 million people
had diabetes, and by 2035, this was predicted to rise to
592 million.1,2 The global diabetes epidemic is expected to
also result in an increase in rates of diabetic retinopathy
(DR), the most frequently occurring microvascular
complication.3 Currently, in the United States, DR is
estimated to lead to 12,000 to 24,000 cases of blindness
per year in adults aged 30 to 60 years, making it the
leading cause of blindness in the working-age
population.4 In the early 1990s, the Early Treatment
Diabetic Retinopathy Study (ETDRS) proposed a classifi-
cation for DR severity that remains in widespread use to
provide guidance on risk of long-term DR progression
and visual loss. The severity of each of the hallmark
lesions of DR in the 7-standard 30° ETDRS fields is
classified using the modified Airlie House classification
(Table 1).5 In the absence of new vessels, DR is classified as
nonproliferative (NPDR) and ranges in severity from mild
to severe. In the presence of new vessels, DR is classified
as proliferative (PDR). The risk of progression to
advanced stages of PDR is highly dependent on baseline
one-year risk of developing PDR vs. eyes with severe
NPDR, which have a 52% risk of PDR over the same
time period.6 The Diabetic Retinopathy Study (DRS)
further identified four DR factors that increase the two-
year risk of developing severe visual loss (defined as
visual acuity of less than 5/200 on two or more consecu-
tive visits at four-month intervals).7 The four risk factors
are: presence of new vessels (NV), location of NV on or
near the optic disc, severity of NV, and presence of vitr-
eous or preretinal hemorrhage. The risk for severe visual
loss jumps from 8.5% to 26.7% as the number of risk
factors increases from two to three.7 Treatment was
recommended in eyes with three or more risk factors,
also defined as eyes with high-risk PDR.7-9
SYSTEMIC CONSIDERATIONS IN THE
TREATMENT OF DIABETIC RETINOPATHY
Glycemic Control
Glycemic control remains the foundation of care for
patients with diabetes, and perhaps the most significant
risk factor associated with DR onset and progression.

Correspondence: Paolo S. Silva, MD, Beetham Eye Institute, Joslin Diabetes Center, 1 Joslin Place, Boston, MA, USA. E-mail: paoloantonio.
silva@joslin.harvard.edu

1
2 H. El Rami et al.

TABLE 1. Diabetic retinopathy classification (from the DRS/ total of 3867 patients were randomized into conventional
ETDRS modified Airlie House Classification).5 vs. tight blood glucose control (mean HbA1c of 7.9% vs.
7.0%). Over 10 years of follow-up, there was a 17%
DIABETIC RETINOPATHY CLASSIFICATION
reduction in the risk for two-step progression of DR, a
A. Mild NPDR 29% reduction in the need for laser photocoagulation, a
At least one microaneurysm 23% reduction in the risk of vitreous hemorrhage, and a
Definition not met for the below more advanced levels 16% reduction in the risk of legal blindness with inten-
B. Moderate NPDR
H/Ma ≥ ETDRS photo 2A in less than 4 quadrants or
sive as compared to conventional control.13 More
SE, VB, and IRMA present but milder than C recently, the ACCORD eye study investigated even tigh-
C. Severe NPDR (The 4-2-1 rule) ter blood glucose control (HbA1C < 6%) vs. standard
H/MA ≥ ETDRS photo 2 A in all 4 quadrants or control (HbA1C 7.0–7.9%) in patients with type 2 dia-
VB ≥ ETDRS photo 6B in ≥ 2 quadrants or betes. Slower progression of DR was observed in the
IRMA ≥ ETDRS photo 8A in ≥ 1 quadrant
D. Very Severe NPDR
intensive group over a four-year follow-up period, espe-
Any 2 or more of C above cially in patients with baseline mild NPDR (OR = 0.3, p <
E. Early PDR 0.001).14 In general, the American Diabetes Association
NVD or NVE less severe than high-risk PDR below (ADA) recommends an HbA1c of less than 7%, although
F. High-risk PDR this is sometimes adjusted on an individual basis to
NVD ≥ ETDRS photo 10A or
NVD < ETDRS photo 10A and presence of vitreous or
avoid hypoglycemic episodes.15
preretinal hemorrhage or
NVE ≥ ½ disk area and presence of vitreous or preretinal
hemorrhage Blood Pressure
DRS: Diabetic Retinopathy Study; ETDRS: Early Treatment
Diabetic Retinopathy Study; NPDR: Nonproliferative diabetic retino- The importance of blood pressure control for DR out-
pathy; PDR: Proliferative diabetic retinopathy; H/Ma: Dot hemor- comes has been demonstrated to be an independent
rhages and microaneurysms; SE: Soft exudates; VB: Venous beading; risk factor in some randomized controlled trials. In
IRMA: Intraretinal microvascular abnormalities; NVD: New vessels of the EDIC study, there was an 11% increase in risk of
the disk; NVE: New vessels elsewhere.
progression of DR per 5 mmHg increase in mean
blood pressure (p < 0.001).12 In a substudy of the
UKPDS, 758 patients with type 2 diabetes were ran-
The Diabetes Control and Complications Trial (DCCT)
domized to tight blood pressure control and 390
investigated the effect of tight blood glucose on the
patients to less tight control.16 Over a median fol-
development/progression of DR.10 A total of 1441
low-up of 8.4 years, the mean differences in systolic
patients with type 1 diabetes were randomized to con-
and diastolic blood pressure of the two groups were
ventional vs. tight blood glucose control (mean HbA1c of
10 and 5 mmHg, respectively, with no difference in
9.1% vs. 7.3%). In the first 6 to 12 months, worsening of
mean HbA1c levels. Tight blood pressure control
DR was noted in 13.1% of patients with tight control vs.
reduced two-step progression of DR by 34%, and
7.6% of patients with conventional control (p < 0.001).11
retinal photocoagulation by 35% (78% of which was
However, this trend was reversed by 18 months and the
for macular edema).16,17 Despite evidence that uncon-
overall progression of DR was remarkably decreased in
trolled hypertension leads to worse DR outcomes in
the tight control group with 76% lower risk of three-step
some studies, other studies have not found a strong
progression over nine years of follow-up.10 In the sub-
association between blood pressure and risk of DR
sequent Epidemiology of Diabetes Interventions and
worsening. Estacio et al. found no benefit of tighter
Complications (EDIC) study, DR level in 1211 DCCT
blood pressure control with regard to the progression
participants was re-evaluated 10 years after DCCT
of DR with a mean blood pressure of 132/78 mmHg
closeout.12 Intensive glycemic control was advocated
in the intensive group vs. 138/86 mmHg in the con-
for all patients after the DCCT closeout and HbA1c levels
trol group.18 In the ADVANCE clinical trial, a mean
in both treatment groups slowly converged to a median
reduction in systolic blood pressure of 5.6 mmHg and
HbA1c of approximately 8%. Nonetheless, the risk of DR
diastolic blood pressure of 2.2 mm Hg showed no
worsening was still lower in the former intensive therapy
significant difference in the rate of new or worsening
group at years 4 and 10 of EDIC. At year 10, 35.8% had a
DR (relative risk reduction –1% [–18 to 15%], p =
three-step or more progression in the former intensive
0,94).19 In the ACCORD clinical trial, no difference
group vs. 60.6% in the former conventional group. This
on DR progression was observed between patients
highlights the concept of “metabolic memory,” which
assigned to systolic blood pressure less than
implies that glycemic control had effects on DR progres-
120 mmHg vs. less than 140 mmHg.14Although the
sion that persisted for years beyond the period of
exact role of blood pressure control in providing
control.12 The United Kingdom Prospective Diabetes
optimal ocular outcomes in diabetic patients is not
Study (UKPDS) also investigated the effect of tight
fully elucidated, tight control of blood pressure
blood glucose, but in patients with type 2 diabetes. A
should be encouraged, since there is little to no

Seminars in Ophthalmology

downside to controlling hypertension and additional
systemic benefits, such as reductions in cardiovascu-
lar disease, are likely to accrue. The ADA recom-
mends that blood pressure be maintained less than
140/90 in most patients with diabetes and less than
130/80 in selected, high-risk patients.15
Renal Disease
Diabetic nephropathy is another frequent microvascular
complication of diabetes. In the Wisconsin Epidemiologic
Study of Diabetic Retinopathy (WESDR), the presence of
microalbuminuria was found to be an independent risk
factor for the presence of DR in patients with type 1
diabetes.20,21 Patients with microalbuminuria were
twice as likely to have DR compared to those without
microalbuminuria, although this association was not sta-
tistically significant among younger-onset patients
(OR=1.94; [0.93 to 4.02] in younger-onset patients.
OR=1.97; [1.05 to 3.74] in older-onset patients using insu-
lin. OR = 1.88; [1.04 to 3.37] in older-onset patients not
using insulin). Microalbuminuria was also associated
with an increased risk of having PDR among younger-
onset patients (OR = 3.17; [1.76 to 5. 71]), but not among
older-onset patients. Patients who have worsening renal
disease should be monitored closely for DR progression
and encouraged to seek appropriate follow-up and care
for their diabetic nephropathy. The ADA recommends
treatment with ACEI (Angiotensin Converting Enzyme
Inhibitor) or ARB (Angiotensin Receptor Blocker) for
elevated urinary albumin excretion (>30 mg/d).15
When needed, dialysis or renal transplant can be utilized
to compensate for end-stage renal disease.15 Patients who
have undergone these procedures and who experience
concurrent stabilization or improvement of their DR
severity level can have excellent visual outcomes. In a
study by Ramsay et al., renal transplantation in patients
with end-stage renal disease stabilized or improved
visual function in 83% of eyes over a follow-up period
of up to seven years.22
Dyslipidemia
Studies inconsistently support an association of DR
with elevated serum lipids.23-25 In the DCCT, the
total-to-HDL cholesterol ratio and the LDL predicted
development of retinal hard exudates.26 There were
no associations of multiple lipid variables and other
end points such as PDR and three-step progression
of DR.26 There is clinical evidence suggesting that
the lipid-lowering drug, fenofibrate, has positive
effects on microvascular complications of diabetes,
although benefits may be independent of its hypoli-
pemic action, mainly through anti-inflammatory,
anti-angiogenic, and retinal neuroprotective effects.27
Two large, independent, randomized controlled
© 2016 Taylor & Francis
Treatment of Diabetic Retinopathy 3
trials (FIELD and ACCORD) have demonstrated a
significant effect of fenofibrate in reducing the rates
of progression in persons with mild NPDR. In the
ACCORD clinical trial, 5518 patients with moderate
dyslipidemia were randomly assigned to statin alone
vs. statin and fenofibrate. Four-year rates of three or
more steps progression of DR or treatment with
photocoagulation or vitrectomy in either eye were
reduced from 9.8% with placebo to 6.1% with feno-
fibrate (p = 0.0049). There was little to no effect of
fenofibrate in patients with no DR at baseline, but a
strong effect in those with mild NPDR.14 Similar
results were found in the FIELD study: among
patients with no DR at baseline, progression
occurred in 43 of 368 patients (11.7%) assigned to
placebo vs. 43 of 377 (11.4%) assigned to fenofibrate
plus statin (p = 0.87), while among patients with DR
(mostly minimal or mild) the corresponding propor-
tions were 14/96 (14.6%) and 3/98 (3.1%, p =
0.004).28 Based on these studies, treatment with feno-
fibrate might be considered for patients with mild to
moderate NPDR who have no contraindications to
the therapy in order to help lessen the risk of DR
worsening.
Pregnancy
Pregnancy is associated with progression of DR, with
faster progression seen in patients with more severe
DR and/or poorer glycemic control and/or faster gly-
cemic improvement at conception.29,30 In the Diabetes
in Early Pregnancy Study, a two-step or greater pro-
gression of DR was seen in 10.3%, 21.1%, 18.8%, and
54.8% of pregnant patients with no DR, microaneur-
ysms only, mild NPDR, and moderate-to-severe
NPDR at baseline, respectively. PDR developed in
6.3% with mild and 29% with moderate-to-severe
NPDR.29 Given the rapid worsening of DR severity
that can occur, especially in the first trimester of preg-
nancy, it is important to treat patients aggressively
who are at high risk for vision-threatening complica-
tions (e.g., those with severe NPDR or PDR) in the
months before they become pregnant or in early preg-
nancy. PRP can be utilized either before or during
pregnancy without harm to the fetus. However, the
use of anti-VEGF should be avoided during pregnancy
and within 1–2 months prior to conception in order to
prevent teratogenic complications. Current guidelines
recommend an eye examination prior to conception
and on the first trimester, with close follow-up for
the remainder of the pregnancy, especially in those
patients with more advanced retinopathy at baseline.-
29,30
Finally, vaginal delivery is contraindicated in
pregnant patients with active PDR in order to avoid
vitreous hemorrhage from neovascularization that can
result from Valsalva maneuvers. Patients with active
PDR should be scheduled for Cesarean section.
4 H. El Rami et al.
INTRAOCULAR TREATMENTS FOR
DIABETIC RETINOPATHY
Panretinal Photocoagulation
Rationale and historical perspective. Initially, the xenon
arc photocoagulator developed by Meyer-Schwickerath
was used directly to ablate retinal new vessels.31
However, regrowth of the new vessels was observed.
Beetham and Aiello were the first to report on the appli-
cation of scattered ruby laser burns from the posterior
pole to the mid-periphery of the retina in eyes with PDR
with the goal to inducing regression of new vessels.32
This panretinal photocoagulation (PRP) technique has
since reduced the five-year risk of blindness in eyes
with PDR by over 90%.33 There are two main hypotheses
to explain the remarkable efficacy of PRP in reducing
neovascularization: (1) destroying the hypoxic retina
decreases the production of vascular endothelial growth
factor, which reduces the development of new vessels34;
(2) thinning of the retina in the treated areas improves
the oxygenation of the inner retina from the choroid.35,36
Treatment indications. In the early 1970s, the Diabetic
Retinopathy Study (DRS) group established PRP as the
gold-standard treatment of eyes with high-risk PDR.7,8
In the DRS, 1700 patients with PDR in at least one eye or
severe NPDR in both eyes and visual acuity ≥ 20/100
were recruited. One eye was randomly assigned to scat-
ter photocoagulation and the other eye to observation. It
was found that PRP reduced the risk of severe visual loss
by more than 50% in eyes with high-risk PDR.9,37 The
ETDRS analyzed whether extending treatment to earlier
stages of DR would significantly prevent further severe
visual loss. In the ETDRS, 3711 patients with DR ranging
from mild NPDR to early PDR were recruited. One eye
was randomly assigned to early PRP and the other eye to
observation with PRP initiated if DR reached high-risk
PDR. The five-year rates of severe visual loss were low in
both the early treatment and deferral groups (2.6% and
3.7%, respectively).38 Consequently, the ETDRS did not
recommend laser treatment for eyes with mild to mod-
erate NPDR.38 However, for patients with severe NPDR
or early PDR, it may be reasonable to consider PRP if
there is high risk of rapid progression to high-risk
PDR.38,39 In addition, early PRP may be beneficial in
preventing severe vision loss or vitrectomy in patients
with type 2 diabetes and severe NPDR.40Alternatively,
stable, compliant patients with good metabolic control
can be observed, particularly when NV is flat with no
retinal traction, and in some cases, new vessels may
remain stable and asymptomatic for years.
Treatment technique. The ETDRS and DRS estab-
lished the initial parameters for PRP. Current treatment
recommendations remain mostly unchanged and are
summarized in Table 2.40-49 The availability of pattern
scan laser delivery systems, which use short durations of
10 to 20 milliseconds as opposed to conventional 100 to
200 milliseconds, may potentially reduce the conduction
of heat to the choroid and to the neurosensory retina
resulting in less inflammation, less pain, less damage to
the nerve fiber layer, and less subsequent chorio-retinal
atrophy. The pattern scanning laser platforms utilize
patterns of 8 to 25 simultaneous spots, which signifi-
cantly decrease the duration of the treatment session
and make a single-session PRP more feasible.43,45
Treatment complications. The most frequent complica-
tion of PRP is decreased visual field due to destruction of
peripheral photoreceptors.8,38 In the ETDRS, eyes
assigned to immediate full scatter photocoagulation
had significantly greater loss of visual field than eyes
assigned to deferral (p < 0.001).38 In addition, some
eyes experience a transient, usually self-limited decrease
in vision, often related to the development of diabetic
macular edema (DME). Breakdown of the blood-ocular
barrier results in the new onset or the worsening of pre-
existing DME.47,50,51 The DRS showed a transient mod-
erate worsening in visual acuity at the four-month and
the one-year post-PRP visit. Compared to the deferral
PRP group, treated eyes were more likely to have a 2- to
4-line decrease at four months (9.8% vs. 6.3%) and at one
year (10.2% vs. 8.9%), with a reversal at two years (10.3%
vs. 11.4%).8 The ETDRS showed comparable results: the
six-week and the four-month rate for moderate visual
loss was 3.1% and 3.8% in the treated group and 0.4%
and 0.6% in the deferral group. This difference appeared
for over two years after PRP, with a reversal at five years
(15.5% vs. 17.6%).38 In the ETDRS, which was performed
prior to OCT availability, 18% of eyes that had been
treated with full PRP were noted to have DME graded
on fundus photographs at four months.47 When present,
DME should be treated before performing PRP.38 A pro-
spective trial by the DRCR.net did not show a difference
in the incidence of new DME when performing single-
session vs. four-session PRP: a total of 155 patients with
severe NPDR to early PDR and no DME were rando-
mized to either PRP within one session (1200–1600
burns) or within four sessions (spread over 12 weeks).
At four weeks, the one-sitting group had a greater med-
ian change in OCT macular thickness from baseline than
the four-sitting group (+13 μm vs. +5 μm, p = 0.003). At
34 weeks (approximately 34 weeks after the one-sitting
group regimen had been completed and 22 weeks after
the four-sitting group regiment had been completed), the
median change in the central subfield thickening in the
one-sitting group was stable at +14 μm but there was a
further increase in the four-sitting group to +22 μm (p =
0.06).47 Ciliary body and choroidal detachment is
another potential complication of PRP. While this is
asymptomatic and transient in the majority of cases, it
Seminars in Ophthalmology
 Treatment of Diabetic Retinopathy 5
40-49
TABLE 2. Summary of the current protocol for panretinal photocoagulation.

PRP characteristics Slit-lamp delivery system Indirect laser Comment

Wavelength Argon Green (532 nm) Blue-green: originally used in the ETDRS, now abandoned due
to increased absorption by the xanthophyll pigments.
Red: penetrates better through vitreous hemorrhage, and
deeper into the choroid (more painful).
Yellow: penetrates better through nuclear cataract.
Intensity Mild White Less laser energy is usually required in the more peripheral
retina and more laser energy is usually required in eyes with
pale fundi due to a decreased concentration of melanin in the
retinal pigment epithelium.
Spot Diameter 500 μm (conventional), 400 μm 400–500 μm With the newer slit-lamp widefield contact lenses, the spot size
(PSL), with a 3-mirror contact with 20-28-30 magnification factor of the lens needs to be taken into account
lens D lens when choosing the diameter of the laser spot (e.g., 200 μm
spot size with Mainster 165, Volk Quadraspheric or
SuperQuad 160).
Exposure 100 ms (conventional) 50–100 ms Longer duration can be used to achieve the desired intensity,
20 ms (PSL) but is associated with more spread of the heat energy to the
neurosensory retina and to the choroid, causing increased risk
of damage to the nerve fiber layer and more pain.
Number of 1 to 3 sessions PRP is started in the inferior quadrants when a vitreous
sessions hemorrhage threatens to occur and mask the inferior retina.
Number of burns 1200–1600 (conventional) 1200–2000
1800–2400 (PSL)
Spacing of burns 1 burn apart (conventional) 1 burn apart With conventional slit-lamp delivery, the DRCR.net
0.5 burn apart (PSL) recommended a one-burn spacing pattern instead of the half-
burn spacing pattern that was initially adopted by the
ETDRS. This seemed more adequate, knowing that laser scars
tend to expand overtime, which might result in confluent
areas of chorio-retinal atrophy. With less heat conduction to
the nerve fiber layer and the choroid, there is less spread of
laser scars with the PSL.
Extent Arcades (2 DD from macula) to equator or Treatment avoids major vessels, fibrous tissue, and retinal
beyond. 500 μm away from the disc nasally hemorrhages.
and 2 DD away from the macula temporally. Newer studies show that treatment well anterior to the
equator might help prevent anterior neovascularization in
severe ischemia.

PRP: Panretinal photocoagulation; PSL: Pattern scan laser; DD: Disc diameter.

can lead to anterior chamber narrowing and angle clo-
sure, especially in hyperopic eyes. The presence of uveal
effusion resulting in choroidal detachment is related to
the total laser energy applied to the fundus.52-54 In the
study by Yuki et al.,54 21 eyes (90%) showed subclinical
ciliochoroidal detachment on ultrasound three days after
partial PRP (350 burns, 200–320 mW, 0.4–0.5 s, 400–500
μm). Likewise, Gentile et al.53 observed a high incidence
of ciliochoroidal effusion on UBM (39 eyes (59%), one
day after PRP). Doft and Blankenship52 observed chor-
oidal detachment in 68% of eyes after a single session
PRP (1200–1290 spots) and in 40% of eyes after PRP
divided into three sessions. Less frequent complications
include rupture of Bruch’s membrane associated with
small highly intense laser burns and the red wavelength,
and mydriasis/loss of accommodation related to injury
to the long posterior ciliary nerves.55-57 In addition, cor-
neal epithelial erosions might occur due to mechanical
rubbing of the contact lens, especially in patients with
diabetic corneal neuropathy and poor epithelial
adhesion.58
Intravitreal antiVEGF Injections
The adverse effects of PRP, mostly on visual field, have
prompted researchers to consider alternative treatments
for PDR. Early studies of antiVEGF monoclonal antibo-
dies found these agents to decrease both vascular perme-
ability and proliferation.59-62 When used in the treatment
of DME, antiVEGF agents have also been found to
reduce the severity or at least stabilize NPDR in many
cases, but anti-VEGF agents are not yet recommended as
first-line therapy for NPDR in eyes without co-existing
DME.60,61 A multicenter randomized clinical trial con-
ducted by DRCR.net evaluated the noninferiority of
intravitreous ranibizumab compared to PRP in the treat-
ment of PDR.63 A total of 203 eyes were randomly
assigned to PRP and 191 eyes were randomly assigned
to ranibizumab injections. The primary outcome was
mean visual acuity change at two years. No statistically
significant difference was found between the two groups
in terms of visual acuity at two years (mean visual acuity
improvement +0.2 in the PRP group vs. +2.8 in the

© 2016 Taylor & Francis

6 H. El Rami et al.
ranibizumab group, [–0.5 to +5.0], p<0.001 for noninfer-
iority). More peripheral visual field loss (mean
peripheral sensitivity loss of –422 dB vs. –23 dB, p <
0.001), more vitrectomies (15% vs. 4%, p < 0.001), and
more DME onset (28% vs. 9%, p < 0.001) were found in
the PRP group compared to the ranibizumab group.
Although longer-term follow-up is needed, ranibizumab
appears to be a safe and efficacious treatment option, at
least through two years, in patients with PDR. In clinical
practice, it is important to note that PRP is less expensive
and can sometimes be performed in a single session,
whereas antiVEGF treatment requires high compliance
with continuous, often monthly injections, and carries a
risk of endophthalmitis. However, when DME is pre-
sent, antiVEGF injections will treat both DME and PDR
and might defer or avoid the need for PRP.63 Future
studies will determine whether antiVEGF injections
might also prove to be an effective preventive treatment
in eyes with severe NPDR at high risk for progression. In
order to address this issue, a DRCR.net multicenter ran-
domized clinical trial is currently underway to investi-
gate the efficacy and safety of antiVEGF injections vs.
sham injections in eyes with severe NPDR and no base-
line DME over a follow-up period of two years.64
Vitreoretinal Surgery
In PDR, retinal capillary occlusion results in the growth of
fragile, preretinal NV from the surface of the disk and at
the posterior border of areas of nonperfusion. The status
of the vitreous is an important factor in the severity of the
fibrovascular proliferation. In the presence of complete
posterior vitreous detachment, severe, tractional neovas-
cularization does not usually occur. In the absence of
posterior vitreous detachment, the clinical picture can be
more severe because the vitreous cortex provides a scaf-
fold on which NV proliferate. With continued growth,
firm attachments develop between the adherent vitreous
cortex and the retina, creating traction membranes that
contract, promote vitreous hemorrhage, and can cause
optic nerve/macular dragging and traction retinal detach-
ment (TRD).65,66 In these advanced cases, vitreoretinal
surgery becomes the standard of care. The Diabetic
Retinopathy Vitrectomy Study (DRVS) demonstrated
the benefit of early (1–4 months) compared to deferred
vitrectomy (one year) in severe, non-clearing vitreous
hemorrhage (visual acuity < 5/200 for at least one
month). The two-year visual outcome in the early group
was better, especially in patients with type 1 diabetes (25%
of all patients/36% of type 1 patients in the early group vs.
15% of all patients/12% of type 1 patients in the deferral
group had visual acuity >10/20 at two years, p=0.01/
0.0001).67 PRP—when part of the retina can be visua-
lized—and/or antiVEGF injections can accelerate the
regression of active NV and allow resolution of vitreous
hemorrhage.68-70 However, great care must be taken
when traction membranes are present, since both PRP
and antiVEGF might accelerate the progression to a TRD
by promoting fibrosis. New-onset TRD has been reported
at a mean of 13 days (range 3 to 21 days) following
antiVEGF injection.68,70-73 Functional results following
macula-off TRD repair are disappointing, especially in
cases with chronic retinal ischemia and atrophy.
Consequently, vitreoretinal surgery with peeling of mem-
branes is most often performed at an earlier macula-on
stage.73,74 Combined traction-rhegmatogenous retinal
detachment (TRRD) is more convex and extends more
anteriorly. Hydration lines indicate the presence of a ret-
inal break. Silicone oil tamponade is usually required
when a TRRD is present and can reduce the incidence of
postoperative rubeosis and phthisis.75,76
CONCLUSION
The management of DR requires optimal control of
systemic risk factors to best prevent further progres-
sion to vision-threatening complications. Although
PRP has been the gold-standard treatment for high-
risk PDR for decades, antiVEGF intravitreal injections
have emerged more recently as a valuable alternative
therapy in eyes with PDR. Studies with longer–term
follow-up will demonstrate whether antiVEGF mono-
therapy will continue to be safe and efficacious over
the chronic periods needed for the successful manage-
ment of diabetic ocular complications.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the
article.
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