Вы находитесь на странице: 1из 8

n

REPORT n

Current Approaches to the Management


of Diabetic Macular Edema
Seenu M. Hariprasad, MD

iabetic retinopathy is the most common cause of vision loss in working-age


Americans.1,2 The disease can take 2
forms: diabetic macular edema (DME) and
proliferative diabetic retinopathy (PDR). An increase in
intraocular vascular endothelial growth factor (VEGF)
plays a key role in the development of both forms of the
disease.3 After the role of VEGF in diabetic retinopathy
was elucidated in the early 1990s, 3 VEGF inhibitors
have been used for DME: aflibercept, bevacizumab, and
ranibizumab. Other therapeutic approaches to the initial
management of
DME include
Managed
Carelaser
& photocoagulation
and intravitreal
implants.LLC
The Diabetic
Healthcarecorticosteroid
Communications,
Retinopathy Clinical Research Network (DRCR.net),
with sponsorship from the National Institutes of Health,
conducted a series of studies that established the role of
these modalities in DME. Most recently, the DRCR.net
completed a landmark head-to-head study of the 3 VEGF
inhibitors called Protocol T.4,5 This article reviews the
role of laser photocoagulation, intravitreal VEGF inhibitors, and intravitreal corticosteroid implants in the management of DME, and includes results from Protocol T.
Laser Photocoagulation

The efficacy of focal and grid laser photocoagulation


in DME was initially established in the Early Treatment
Diabetic Retinopathy Study (ETDRS). In the ETDRS,
photocoagulation of microaneurysms and other areas,
within a thickened macula, reduced the risk of moderate
vision loss by approximately 50%. In patients with visual
impairment, 30% experienced an improvement in vision.
However, photocoagulation failed to prevent vision loss
in approximately 15% of patients, and only 3% of patients
had an improvement in visual acuity.6 This study showed
that although photocoagulation helps to prevent progression of DME, it has more limited benefit for restoring
vision that is already lost.

S292

Abstract
Three modalities have a role in the primary management of diabetic macular edema (DME): laser
photocoagulation, intravitreal vascular endothelial
growth factor (VEGF) inhibitors, and intravitreal
corticosteroid implants. Intravitreal VEGF inhibitors are most commonly used for center-involved
DME, but laser photocoagulation and intravitreal
corticosteroids also have an important role in DME
management. Until recently, the selection of a VEGF
inhibitor for a patient was complicated by a lack of
comparative data and a much lower cost for bevacizumab compared with other agents. Two-year
results of the landmark head-to-head Protocol T trial
will inform treatment selection for ophthalmologists
and formulary decisions for managed care organizations. The study found that patients with better
baseline visual acuity benefited from aflibercept,
bevacizumab, or ranibizumab. However, aflibercept
and ranibizumab were more effective than bevacizumab for patients with worse baseline visual
acuity. A higher rate of nonfatal stroke and vascular
death with ranibizumab in the Protocol T trial has
raised concern in the community and needs to
be investigated further. Emerging drugs for DME
include VEGF inhibitors with less-frequent dosing
intervals, and new agents that target other pathologic processes that contribute to vascular leakage
and angiogenesis in DME.

n www.ajmc.com n

Am J Manag Care. 2016;22:S292-S299

For author information and disclosures, see end of text.

JULY 2016

Current Approaches to the Management of Diabetic Macular Edema


In DME, laser therapy causes a reaction in which melanin, within the retinal pigment epithelium and choroid,
absorbs laser energy.7 Although the exact mechanism of
action remains unclear, the resulting photocoagulation of
the retinal layers closes leaking microaneurysms. It may also
decrease edema via increased oxygenation, reduce metabolic load by decreasing the number of photoreceptors, and
induce endothelial cell proliferation. The tissue destruction
caused by photocoagulation may also downregulate angiogenesis and cytokines that cause macular edema.7,8
More recently, the DRCR.net Protocol I study compared ranibizumab with deferred or prompt laser, triamcinolone with prompt laser, and sham injections
with prompt laser. Improvements in visual acuity were
significantly greater with ranibizumab than with laser
photocoagulation.9 Over the last decade, other rigorous
clinical trials have also established that intravitreal VEGF
inhibitors are more effective than laser photocoagulation
for center-involved DME.10,11 The American Academy
of Ophthalmology considers laser photocoagulation the
preferred treatment for noncenter-involved DME, and it
still has a role as an adjunct to VEGF inhibitors for center-involved DME.1 Long-term follow-up of the Protocol
I study is helping to compare the benefits of prompt and
deferred laser treatment in patients who received VEGF
inhibitors, including whether laser photocoagulation can
help reduce the treatment burden with VEGF inhibitors.12
Potential adverse effects (AEs) of laser photocoagulation include a possible transient initial decrease in central
vision, paracentral scotomas if laser burns are placed
too close to the fovea, permanent central scotoma from
inadvertent foveal burns, and expansion of a laser scar
area.1 Innovative laser and imaging platforms address
some of the shortcomings of laser photocoagulation. The
Navilas navigated laser, which was approved for use in
the United States in 2010, allows for greater precision and
superimposes fluorescein angiography and the treatment
plan on a live-tracked fundus image.8,13 With a higher
microaneurysm hit rate than manual technique laser
treatment, the Navilas laser is extremely accurate.13
VEGF Inhibitors

Sustained hyperglycemia triggers a cascade of pathophysiologic processes in the diabetic retina, including
hypoxemia, and the release of pro-inflammatory cytokines and growth factors.14 This culminates in upregulation of VEGF, the key mediator that disrupts the
blood-retinal barrier in DME.3,15 High levels of VEGF
cause capillaries to leak, leading to macular edema. They
VOL. 22, NO. 10

also promote angiogenesis and the growth of weak new


capillaries, the primary pathogenic process in PDR.14
The usual roles of VEGF are to promote angiogenesis
and the growth of vascular endothelial cells, act as a
survival factor for endothelial cells, and regulate vascular
permeability. The VEGF family has 5 structurally related
ligands: VEGF-A, -B, -C, -D, and placental growth factor (PlGF). VEGF-A has 4 isoforms that are identified
by the number of amino acids they contain: VEGF121,
VEGF165, VEGF189, and VEGF206. The most common
isoform is VEGF165. VEGF-A and VEGF-B bind with 2
tyrosine kinase receptors on the cell surface of vascular
endothelium: VEGFR-1 and VEGFR-2.16 Expression of
VEGFR-2, a key mediator of endothelial cell mitogenesis,
survival, and microvascular permeability, is increased in
diabetic retinopathy.14
VEGF inhibitors reduce capillary leakage, prevent
proliferation of weak new capillaries, and improve survival of retinal pericytes in patients with DME.17,18 The
properties of VEGF inhibitors used for DME are compared in Table 1.5,14,19-22 Bevacizumab is a complete murine
monoclonal humanized antibody that binds in a bivalent
fashion to VEGF-A.21 Ranibizumab is an antibody fragment of bevacizumab that binds with enhanced affinity,
but in a monovalent fashion, to VEGF-A.14 Aflibercept,
a fusion protein composed of the extracellular binding
domains of VEGFR-1 and VEGFR-2 attached to the
fragment crystallizable region of human immunoglobulin
G1,19 acts as a soluble decoy receptor that binds VEGF-A
and PlGF. Compared with other VEFG inhibitors, the
higher binding affinity of aflibercept and its PlGF inhibition may be responsible for a longer duration of action
and a less frequent dosing interval.23
Because circulating VEGF protects blood vessel integrity, prolonged intravitreal administration of VEGF
inhibitors theoretically has the potential to induce
thromboembolic events.24 Systemic administration of
bevacizumab and ziv-aflibercept, as antineoplastic agents,
can increase the risk of bleeding and thromboembolic
events.21,25 All of the VEGF inhibitors are detected at low
concentrations in the plasma after intravitreal administration, but bevacizumab has been reported to cause
longer and greater suppression of plasma VEGF than
ranibizumab.24,26,27 Considering that it has lower VEGF
affinity, the implications of this are unclear.24
In 2012, ranibizumab was the first VEGF inhibitor to
receive FDA approval for DME, followed by aflibercept
in 2014.19,22 Although intravenous bevacizumab received
FDA approval for various malignancies in 2004, intra-

THE AMERICAN JOURNAL OF MANAGED CARE n

S293

Report
nTable 1. Properties of VEGF Inhibitors for DME5,14,19-22
Aflibercept
(Eylea)

Bevacizumab
(Avastin)

Ranibizumab
(Lucentis)

Class

VEGF trap

Monoclonal antibody

monoclonal antibody fragment

Molecular weight

115 kDa

149 kDa

48 kDa

Target

All VEGF-A isoforms, VEGF-B, and PlGF

All VEGF-A isoforms

All VEGF-A isoforms

Kd for VEGF165

0.49 pM

58 pM

46 pM

Estimated half-life

4.8 days

5.6 days

3.2 days

FDA-approved uses

DME, DR with DME,


neovascular AMD,
and macular edema after retinal
vein occlusion

No FDA-approved
ophthalmic use

DME, DR with DME,


neovascular AMD,
and macular edema after
retinal vein occlusion

Dosage regimen for DME

2-mg intravitreal injection every month for


5 months, then every other month

1.25-mg intravitreal
injection every month

0.3-mg intravitreal injection


every month

AMD indicates age-related macular degeneration; DME, diabetic macular edema; DR, diabetic retinopathy; PlGF, placental growth factor; VEGF,
vascular endothelial growth factor.

vitreal administration is an off-label use that requires


repackaging into small doses appropriate for intravitreal
administration.5 Compounded intravitreal bevacizumab
and triamcinolone have been associated with isolated
outbreaks of endophthalmitis, but this appears to be
rare.28,29 In the largest retrospective cohort study, which
evaluated over 500,000 VEGF-inhibitor intravitreal injections, there was no difference in the endophthalmitis rate
for aflibercept (0.035%), bevacizumab (0.039%), or ranibizumab (0.035%).30 The cost of intravitreal bevacizumab
is substantially lower than that of the other agents.5
Although the earliest studies in DME were conducted
with bevacizumab, it has not been evaluated in a phase 3
FDA registration trial like ranibizumab and aflibercept.31
Ranibizumab

Ranibizumab was evaluated in DME in 2 identical


phase 3 clinical trials called RIDE and RISE. Patients with
a best-corrected visual acuity (BCVA) of 20/40 to 20/320
and a central subfield thickness (CST) of at least 275 m
on optical coherence tomography (OCT) were randomized (1 eye per subject) to receive monthly intravitreal
injections of ranibizumab 0.3 mg, ranibizumab 0.5 mg,
or a sham for 24 months. The primary outcome of the
studies was the percentage of patients achieving a gain
of at least 15 letters at 24 months (ie, 3 lines on the eye
chart). The percentage of patients achieving this outcome
compared with the percent receiving sham injections in
RIDE was 24.3% higher with ranibizumab 0.3 mg (95% CI:
13.8-34.8; P <.0001), and 20.9% higher with ranibizumab
0.5 mg (95% CI: 10.7-31.1; P <.001). In RISE, this represented a difference from sham injections of 20.8% (95%

S294

CI: 11.4-30.2; P <.0001) for ranibizumab 0.3 mg and 33.3%


(95% CI: 23.8-42.8: P <.0001) for ranibizumab 0.5 mg. In
RISE, mean BCVA gains from baseline were 12.5 and 11.9
letters for ranibizumab 0.3 mg and 0.5 mg, respectively,
compared with 2.6 letters for sham injections (P <.0001).
Respective letters gained were 12.0, 10.9, and 2.3 letters
in RIDE (P <.0001). In RISE, the incidence of vision loss
(15 letters) was 2.4% with ranibizumab 0.3 mg and 0.5 mg,
compared with 10.2% with sham injections (P = .0086 for
ranibizumab 0.3 mg vs sham; P = .0126 for ranibizumab
0.5 mg vs sham). Respective vision loss in RIDE was 1.6%,
3.9%, and 9% (P = .0119 for ranibizumab 0.3 mg vs sham;
P = .1384 for ranibizumab 0.5 mg vs sham).32
Fewer patients who received ranibizumab required laser
procedures, with the mean number of procedures in 24
months ranging from 0.3 to 0.8 in the 2 dosage groups of
ranibizumab in RISE and RIDE compared with 1.8 and
1.6 procedures for sham injections in the respective trials (P <.0001 for all comparisons).32 In terms of anatomic
improvement, the pooled mean change in central foveal
thickness (CFT) at month 24 was 255.2 m for ranibizumab 0.3 mg, 262.0 m for ranibizumab 0.5 mg, and 129.5
m for sham injections.33 Improvements in visual acuity
and reductions in retinal thickness occurred rapidly with
ranibizumab. Fewer patients given ranibizumab developed
PDR or required panretinal photocoagulation.32
After 24 months, patients who received sham injections were allowed to cross over to ranibizumab 0.5 mg.
Patients initially randomized to ranibizumab 0.3 mg or 0.5
mg continued to receive their respective medications. At
month 36, patients who received ranibizumab from the
start of the trial maintained the improvements in BCVA

n www.ajmc.com n

JULY 2016

Current Approaches to the Management of Diabetic Macular Edema


and CFT observed at month 24. Patients who received
delayed treatment did not gain as much visual acuity
improvement as those originally randomized to ranibizumab. At 36 months, the percentage of patients in RIDE
achieving a gain of at least 15 letters was 19.2% in the
sham/0.5 mg ranibizumab group, 36.8% in the ranibizumab 0.3 mg group (P = .0026 vs sham/0.5 mg ranibizumab),
and 40.2% in the ranibizumab 0.5 mg group (P = .0001 vs
sham/0.5 mg ranibizumab). Respective increases in RISE
were 22.0%, 51.2% (P <.0001 vs sham/0.5 mg ranibizumab),
and 41.6% (P = .0005 vs sham/0.5 mg ranibizumab).33
During the first 24 months of the RIDE and RISE
studies, the most common serious ocular AE was vitreous hemorrhage, which occurred in 7 sham-treated
eyes and 2 ranibizumab-treated eyes. Injection-related
AEs were uncommon, with 4 cases of endophthalmitis,
3 cases of traumatic cataracts, and 1 rhegmatogenous
retinal detachment occurring with 10,584 injections.
Ranibizumab and sham injections had similar rates of
cataracts, intraocular inflammation, and glaucoma.32
Systemic AEs, possibly related to VEGF inhibition, were assessed according to Antiplatelet Trialists
Collaboration (APTC) criteria. At 24 months, the overall
incidence of these events was 4.9% to 5.5% for sham-injection groups (5.2% for pooled data) compared with 2.4% to
8.8% for ranibizumab groups.32,33 At 36 months, the overall incidence of APTC events was 7.2% for sham/0.5 mg
ranibizumab, 10.8% for ranibizumab 0.3 mg, and 10.4%
for ranibizumab 0.5 mg. Compared with the 0.3 mg dose,
ranibizumab 0.5 mg had higher rates of all-cause mortality (6.4% vs 4.4%) and stroke (4.8% vs 2.0%). Although
some data in RIDE and RISE suggested minimally better
efficacy for the 0.5 mg dose, pooled data found the 2
doses were equivalent. Ranibizumab was approved by the
FDA for DME at a dose of 0.3 mg once monthly, presumably because the 0.5 mg dose was associated with a higher
risk of systemic AEs and death.33
Aflibercept

Aflibercept was evaluated in DME in 2 identical


phase 3 clinical trials lasting 148 weeks called VIVID
and VISTA. Patients with a BCVA of 20/40 to 20/320
and a 1-mm CST were randomized (1 eye per subject)
to receive either intravitreal injections of aflibercept 2
mg every month (2 mg q4 weeks), aflibercept 2 mg every
month for 5 months and then every 2 months (2 mg q8
weeks), or laser photocoagulation. The primary outcome
was the change from baseline in ETDRS letter scores at
1 year. In VISTA, mean BCVA gains from baseline were
VOL. 22, NO. 10

12.5 and 10.7 letters for the 2 mg q4 and 2 mg q8 regimens


of aflibercept compared with 0.2 letters for laser therapy
(P <.0001). Respective letter increases were 10.5, 10.7, and
1.2 letters in VIVID (P <.0001). The respective percentage of patients eyes gaining at least 15 letters was 41.6%,
31.1%, and 7.8% in VISTA (P <.0001), and 32.4%, 33.3%,
and 9.1% in VIVID (P <.0001). The incidence of vision
loss (15 letters) with laser therapy was 9.1% in VISTA
and 10.6% in VIVID, compared with less than 1% in any
of the aflibercept groups. At 1 year, mean reductions in
central retinal thickness (CRT) with aflibercept 2 mg q4,
2 mg q8, and laser therapy were 185.9, 183.1, and 73.3
m (P <.0001) in VISTA, and 195.0, 192.4, and 66.2 m
(P <.0001) in VIVID, respectively.34
At 100 weeks, patients receiving either dosage regimen
of aflibercept maintained significant improvements in
visual outcomes compared with those receiving laser therapy. In VISTA, mean BCVA gains from baseline were
11.5 and 11.1 letters for the 2 mg q4 and 2 mg q8 regimens
of aflibercept, respectively, compared with 0.9 letters for
laser therapy (P <.0001). Respective mean letter increases
were 11.4, 9.4, and 0.7 letters in VIVID (P <.0001). The
respective percentages of patients eyes gaining at least 15
letters were 38.3%, 33.1%, and 13.0% in VISTA (P <.0001),
and 38.2%, 31.1%, and 12.1% in VIVID (P .0001 for 2 mg
q4 vs laser; P = .001 for 2 mg q8 vs laser). In VISTA, the
incidence of vision loss (15 letters) was 3.2% and 0.7% for
the 2 mg q4 and 2 mg q8 regimens of aflibercept, respectively, compared with 9.7% for laser therapy (P = .022 for 2
mg q4 vs laser; P = .0004 for 2 mg q8 vs laser). Respective
vision loss in VIVID was 2.2%, 1.5%, and 12.9% (P = .0008
for 2 mg q4 vs laser; P = .0002 for 2 mg q8 vs laser). At 100
weeks, mean reductions in CRT with aflibercept 2 mg q4,
2 mg q8, and laser therapy were 191.4, 191.1, and 83.9
m (P <.0001) in VISTA, and 211.8, 195.8, and 85.7 m
(P <.0001) in VIVID, respectively.11
At 1 year, the treatment groups had a similar incidence
of ocular and systemic AEs.34 In addition, the incidence
of APTC systemic AEs was similar across treatment
groups. At 100 weeks, the incidence of serious ocular AEs
was 3.8% for aflibercept 2 mg q8, 4.2% for aflibercept 2 mg
q4, and 5.9% for laser therapy.11 Cataracts were the most
frequent serious ocular AE, with an incidence of 1.0%,
2.4%, and 0.3%, respectively. The respective incidence of
any APTC-defined arterial thrombotic event was 5.6%,
7.2%, and 4.2%. Considering that the 2 regimens had
comparable efficacy, aflibercept was approved by the
FDA at a dose of 2 mg every month for 5 months, followed by 2 mg every other month.11,19

THE AMERICAN JOURNAL OF MANAGED CARE n

S295

Report
DRCR.net Protocol T Study

The landmark Protocol T study was a head-to-head


comparison of aflibercept, bevacizumab, and ranibizumab in patients with DME. This single-blind, multicenter
trial randomized 660 patients (1 eye each) with centerinvolved DME and a BCVA letter score of 78 to 24 to
receive 2 years of treatment with aflibercept 2 mg, bevacizumab 1.25 mg, or ranibizumab 0.3 mg every 4 weeks.
Starting at the 6-month visit, persistent DME that was
not improving was treated with a focal and/or grid laser.
Following the publication of 1-year trial results, treatment
groups were unblinded. At that time, patients could be
switched to an anti-VEFG agent not used in the study.
The primary end point of the study was the mean change
from baseline in visual acuity at 1 year.4,5
At 1 year, in the entire study cohort, the increase
in mean visual acuity letter score was 13.3 with aflibercept, 11.2 with ranibizumab, and 9.7 with bevacizumab
(P = .03 for aflibercept vs ranibizumab; P <.001 for aflibercept vs bevacizumab). For patients with better visual
acuity scores at baseline (78 to 69; roughly equivalent to
20/32 to 20/40 vision), there was no significant difference in primary outcome for the 3 drugs (mean improvement of 8.0 with aflibercept, 7.5 with bevacizumab, 8.3
with ranibizumab; P >.50). For patients with poor vision
at baseline (initial letter score <69; equivalent to approximately 20/50 or worse), aflibercept was associated with
significantly greater improvement than bevacizumab
(18.8 vs 11.8; P <.001) and ranibizumab (18.9 vs 14.2;
P = .003). For the entire cohort, the decrease in OCT CST
was 210 m with aflibercept, 176 m with ranibizumab,
and 135 m with bevacizumab (P <.001 for aflibercept vs
bevacizumab and ranibizumab vs bevacizumab).5
Over the 2-year treatment period, there was an insignificant difference in the median number of injections
for the 3 drugs. In the second year of the study, patients
required approximately half the number of injections
that they required in the first year. The proportion
of patients receiving at least 1 laser treatment was
41% with aflibercept, 64% with bevacizumab, and 52%
with ranibizumab (P <.001 aflibercept vs bevacizumab;
P = .04 aflibercept vs ranibizumab; P = .01 bevacizumab
vs ranibizumab). Similar to 1-year results, improvements
in visual acuity varied according to baseline visual acuity. In patients with better baseline visual acuity, respective mean increases of 7.8, 6.8, and 8.6 letters were not
significantly different. In patients with worse baseline
visual acuity, the mean improvement was 18.3, 13.3, and
16.1 letters (P = .02 aflibercept vs bevacizumab). Similar

S296

to results at 1 year, bevacizumab was less effective at


reducing retinal thickness. At 2 years, the mean change
in OCT CST in the entire cohort was 171 m with
aflibercept, 149 m with ranibizumab, and 126 m
with bevacizumab (P <.001 aflibercept vs bevacizumab;
P = .001 ranibizumab vs bevacizumab).4
After 2 years, the incidence of APTC-defined events
was 5% with aflibercept, 8% with bevacizumab, and 12%
with ranibizumab (P = .047 for aflibercept vs ranibizumab). This result was driven by more nonfatal strokes and
vascular deaths with ranibizumab.4 It has raised concern
and warrants further investigation, as a dose-response
increase in rate of death was also observed in the RISE
and RIDE ranibizumab FDA registration trials.32 Overall,
after 2 years, all VEGF inhibitors had a low incidence
of ocular AEs, including endophthalmitis, inflammation, vitreous hemorrhage, retinal tear or detachment, or
increased intraocular pressure.4
In summary, the DRCR.net Protocol T study found
little difference in efficacy among the 3 VEGF inhibitors
for patients with mild visual acuity loss. For patients
with worse baseline visual acuity, aflibercept was more
effective than bevacizumab and ranibizumab after 1 year
of treatment. After 2 years, aflibercept was still more
effective than bevacizumab for improving visual acuity,
but it was no longer more effective than ranibizumab.4,5
Aflibercept was shown to achieve vision gains more
rapidly and dry the retina more quickly compared with
the other 2 agents. A special communication from the
American Society of Retina Specialists (ASRS), based
on the 1-year results of the DRCR.net Protocol T study,
endorsed continued use of bevacizumab in patients with
good initial visual acuity (20/32 to 20/40) when adequately packaged bevacizumab is available. The ASRS
also recommended that ophthalmologists have access to
all 3 agents to provide individualized therapy.35
Intravitreal Corticosteroids

Recognition that DME has an inflammatory component led to the evaluation of intravitreal corticosteroids
for DME. Corticosteroids reduce edema, at least in part,
by reducing VEGF expression.36 Two intravitreal corticosteroid implants have received FDA approval for the
management of DME: dexamethasone and fluocinolone
acetonide. They differ according to dosage, biodegradability, and duration of action (Table 237-39). Intravitreal
corticosteroids that have been used off label for DME
include another fluocinolone formulation (Retisert) and
triamcinolone acetonide suspension.9,40

n www.ajmc.com n

JULY 2016

Current Approaches to the Management of Diabetic Macular Edema


nTable 2. Properties of Intravitreal Corticosteroids for DME37-39
Dexamethasone
(Ozurdex)

Fluocinolone acetonide
(Iluvien)

Dose

0.7 mg

0.19 mg

Duration of action

6 months

Up to 36 months

Biodegradable

Yes

No

Insertion device

Prefilled, single-use,
22-gauge applicator

Prefilled, single-use,
25-gauge applicator

FDA-approved uses

DME; non-infectious uveitis; macular edema


after BRVO or CRVO

DME in patients who did not have increased IOP


with previous course of intravitreal corticosteroids

BRVO indicates branch retinal vein occlusion; CRVO, central retinal vein occlusion; DME, diabetic macular edema; IOP, intraocular pressure.

Intravitreal triamcinolone was evaluated for DME


in a series of DRCR.net-conducted studies. In a phase 3
clinical trial (Protocol B) conducted over 2 years with an
additional year of follow-up, improvements in visual acuity and retinal thickness were greater with laser therapy
than intravitreal off-label triamcinolone.41,42 A second
2-year trial (Protocol I) confirmed that intravitreal offlabel triamcinolone was inferior to ranibizumab plus
laser therapy or laser therapy alone in phakic eyes.9,43
However, for eyes that were pseudophakic at baseline,
triamcinolone plus prompt laser therapy produced visual
acuity improvements comparable to ranibizumab and
better than laser therapy alone. In these studies, off-label
triamcinolone increased intraocular pressure (IOP) and
the need for cataract surgery.9,41-43
Results from 2 phase 3, randomized, double-blind,
multicenter clinical trials utilizing intravitreal dexamethasone (MEAD study) and fluocinolone acetonide (FAME
study) have been published. In both studies, which
included approximately 1000 patients each, intravitreal
dexamethasone and fluocinolone acetonide improved
BCVA compared with sham injections, with a relatively
few number of injections needed compared with antiVEGF agents. Some patients receiving either corticosteroid developed cataracts requiring surgery and increased
IOP.44,45 These intraocular AEs were found to be manageable in the vast majority of patients; therefore, their use
in the management of DME is expanding. The role of
corticosteroids in combination with VEGF inhibitors is
currently being investigated in clinical trials.46
Emerging Therapies for DME

The treatment burden of intravitreal injections is driving


the search for strategies that lengthen the treatment interval.
One approach is drug delivery implants that release currently available VEGF inhibitors over a longer period of time.47,48
Another approach is to design molecules with improved
VOL. 22, NO. 10

binding capacity, such as RTH258, an antibody fragment


with a molecular weight of only 25 kDa that may have a
longer duration of action than ranibizumab.49 Conbercept, a
VEGF inhibitor with a 7-day half-life, also has the potential
to provide a longer dosing interval.47 It is a fusion protein
of the extracellular binding domains of VEGFR-1 and
VEGFR-2 similar to aflibercept, but inclusion of the fourth
binding domain of VEGFR-2 may enhance VEGF binding.
In China, where it is already approved for macular degeneration, a phase 3 trial in DME is under way.47,50
A number of investigational agents target unique pathologic processes that contribute to vascular leakage and
angiogenesis in DME. A few agents that have advanced
to phase 2 clinical trials are described here. ALG-1001
(Luminate) is an integrin antagonist that reduces vascular
leakage and inhibits angiogenesis.48,51 A single intravitreal
dose may improve visual acuity for up to 3 months.48 A
phase 2 trial is comparing ALG-1001 to bevacizumab.52
In DME, high levels of angiopoietin-2 inhibit TIE-2 (also
known as TEK receptor tyrosine kinase) signaling, a process that normally stabilizes blood vessels and maintains
vascular integrity. Vascular endothelial-protein tyrosine
phosphatase (VE-PTP) is a negative regulator at the TIE-2
receptor. By competitively inhibiting VE-PTP, AKB-9778,
a competitive inhibitor of VE-PTP, restores TIE-2 signaling and blocks the pathologic effects of angiopoietin-2.53
Because AKB-9778 is given by subcutaneous injection, it
has the potential to be self-administered.54 A phase 2 trial
evaluated AKB-9778 alone or in combination with ranibizumab.55 DMI-5207 (Optina) is a very low dose of oral danazol (15-45 mg twice daily) that reduces endothelial leakage
by enhancing endothelial cell barrier function.56,57
Conclusion

The Protocol T trial established that patients with


better baseline visual acuity can benefit from aflibercept,
bevacizumab, or ranibizumab. Aflibercept and ranibi-

THE AMERICAN JOURNAL OF MANAGED CARE n

S297

Report
zumab are more effective than bevacizumab for patients
with worse baseline visual acuity. A higher rate of nonfatal stroke and vascular death was observed with ranibizumab in the Protocol T trial. The results of Protocol
T support an individualized approach to the selection
of a VEGF inhibitor. Because DME has a multifactorial etiology, combination approaches with laser therapy,
anti-VEGF agents, and corticosteroids may be sensible
and are gaining popularity. Healthcare professionals are
hopeful that drugs in development for DME will reduce
the treatment burden of frequent injections.
Author affiliation: University of Chicago, Chicago, IL.
Funding source: This activity is supported by an educational grant
from Genentech.
Author disclosure: Dr Hariprasad reports serving as a consultant or
being on speakers bureaus for Alcon, Alimera Sciences, Allergan, Bayer,
Biomedical, Clearside, Janssen, Ocular Therapeutix, OD-OS, Optos,
Regeneron, and Spark.
Authorship information: Concept and design, drafting of the manuscript,
and critical revision of the manuscript for important intellectual content.
Address correspondence to: retina@uchicago.edu.

REFERENCES
1. American Academy of Ophthalmology Retina/Vitreous Panel.
Preferred practice panel guidelines. Diabetic retinopathy.
American Academy of Ophthalmology website. http://www.aao.
org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2016. Published 2016. Accessed May 26, 2016.
2. American Diabetes Association. 9. Microvascular complications and foot care. Diabetes Care. 2016;(39 suppl 1):S72-S80.
doi: 10.2337/dc16-S012.
3. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial
growth factor in ocular fluid of patients with diabetic retinopathy
and other retinal disorders. N Engl J Med. 1994;331(22):14801487. doi: 10.1056/nejm199412013312203.
4. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy
Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology.
2016;123(6):1351-1359. doi: 10.1016/j.ophtha.2016.02.022.
5. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy
Clinical Research Network. Aflibercept, bevacizumab, or
ranibizumab for diabetic macular edema. N Engl J Med.
2015;372(13):1193-1203. doi: 10.1056/NEJMoa1414264.
6. Early Treatment Diabetic Retinopathy Study research group.
Photocoagulation for diabetic macular edema. Early Treatment
Diabetic Retinopathy Study report number 1. Arch Ophthalmol.
1985;103(12):1796-1806.
7. Blumenkranz MS. The evolution of laser therapy in ophthalmology: a perspective on the interactions between photons,
patients, physicians, and physicists: the LXX Edward Jackson
Memorial Lecture. Am J Ophthalmol. 2014;158(1):12-25.e1. doi:
10.1016/j.ajo.2014.03.013.
8. Yun SH, Adelman RA. Recent developments in laser treatment of diabetic retinopathy. Middle East Afr J Ophthalmol.
2015;22(2):157-163. doi: 10.4103/0974-9233.150633.
9. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone
plus prompt laser for diabetic macular edema. Ophthalmology.
2010;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031.

S298

10. Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE


study group. The RESTORE study: ranibizumab monotherapy or
combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615-625. doi: 10.1016/j.
ophtha.2011.01.031.
11. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal
aflibercept for diabetic macular edema: 100-week results from
the VISTA and VIVID studies. Ophthalmology. 2015;122(10):20442052. doi: 10.1016/j.ophtha.2015.06.017.
12. Elman MJ, Ayala A, Bressler NM, et al; Diabetic Retinopathy
Clinical Research Network. Intravitreal ranibizumab for diabetic
macular edema with prompt versus deferred laser treatment:
5-year randomized trial results. Ophthalmology. 2015;122(2):375381. doi: 10.1016/j.ophtha.2014.08.047.
13. 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(6):1119-1124. doi: 10.1016/j.ophtha.2010.10.007.
14. Simo R, Sundstrom JM, Antonetti DA. Ocular anti-VEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis
of diabetic retinopathy. Diabetes Care. 2014;37(4):893-899. doi:
10.2337/dc13-2002.
15. Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S.
Vitreous levels of interleukin-6 and vascular endothelial growth
factor are related to diabetic macular edema. Ophthalmology.
2003;110(9):1690-1696. doi: 10.1016/s0161-6420(03)00568-2.
16. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581-611. doi:
10.1210/er.2003-0027.
17. Jampol LM, Bressler NM, Glassman AR. Revolution to a
new standard treatment of diabetic macular edema. JAMA.
2014;311(22):2269-2270. doi: 10.1001/jama.2014.2536.
18. Giurdanella G, Anfuso CD, Olivieri M, et al. Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in
human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A
pathway. Biochem Pharmacol. 2015;96(3):278-287. doi: 10.1016/j.
bcp.2015.05.017.
19. Eylea (aflibercept) [package insert]. Tarrytown, NY:
Regeneron Pharmaceuticals: 2016.
20. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and
related ligands by VEGF Trap, ranibizumab and bevacizumab.
Angiogenesis. 2012;15(2):171-185. doi: 10.1007/s10456-011-9249-6.
21. Avastin (bevacizumab) [package insert]. South San Francisco,
CA: Genentech Inc; 2015.
22. Lucentis (ranibizumab injection) [package insert]. South San
Francisco, CA: Genentech Inc; 2015.
23. Stewart MW, Rosenfeld PJ. Predicted biological activity of
intravitreal VEGF Trap. Br J Ophthalmol. 2008;92(5):667-668. doi:
10.1136/bjo.2007.134874.
24. Semeraro F, Morescalchi F, Duse S, Gambicorti E, Cancarini
A, Costagliola C. Pharmacokinetic and pharmacodynamic properties of anti-VEGF drugs after intravitreal injection. Curr Drug
Metab. 2015;16(7):572-584.
25. Zaltrap (ziv-aflibercept) [package insert]. Bridgewater, NJ:
sanofi-aventis US, LLC; 2016.
26. Carneiro AM, Costa R, Falcao MS, et al. Vascular endothelial growth factor plasma levels before and after treatment of
neovascular age-related macular degeneration with bevacizumab or ranibizumab. Acta Ophthalmol. 2012;90(1):e25-30. doi:
10.1111/j.1755-3768.2011.02240.x.
27. Zehetner C, Kirchmair R, Huber S, Kralinger MT, Kieselbach
GF. Plasma levels of vascular endothelial growth factor before
and after intravitreal injection of bevacizumab, ranibizumab and
pegaptanib in patients with age-related macular degeneration,
and in patients with diabetic macular oedema. Br J Ophthalmol.
2013;97(4):454-459. doi: 10.1136/bjophthalmol-2012-302451.
28. Staes C, Jacobs J, Mayer J, Allen J. Description of outbreaks
of health-care-associated infections related to compounding

n www.ajmc.com n

JULY 2016

Current Approaches to the Management of Diabetic Macular Edema


pharmacies, 2000-12. Am J Health Syst Pharm. 2013;70(15):13011312. doi: 10.2146/ajhp130049.
29. VanderBeek BL, Bonaffini SG, Ma L. Association of compounded bevacizumab with postinjection endophthalmitis. JAMA
Ophthalmol. 2015;133(10):1159-1164. doi: 10.1001/jamaophthalmol.2015.2556.
30. Rayess N, Rahimy E, Storey P, et al. Postinjection endophthalmitis rates and characteristics following intravitreal bevacizumab,
ranibizumab and aflibercept. Am J Ophthalmol. 2016;165:88-93.
doi: 10.1016/j.ajo.2016.02.028.
31. Scott IU, Edwards AR, Beck RW, et al; Diabetic Retinopathy
Clincial Research Network. A phase II randomized clinical
trial of intravitreal bevacizumab for diabetic macular edema.
Ophthalmology. 2007;114(10):1860-1867. doi: 10.1016/j.ophtha.2007.05.062.
32. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE
Research Group. Ranibizumab for diabetic macular edema:
results from 2 phase III randomized trials: RISE and RIDE.
Ophthalmology. 2012;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039.
33. Brown DM, Nguyen QD, Marcus DM, et al; RISE and RIDE
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(10):2013-2022.
doi: 10.1016/j.ophtha.2013.02.034.
34. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal
aflibercept for diabetic macular edema. Ophthalmology.
2014;121(11):2247-2254. doi: 10.1016/j.ophtha.2014.05.006.
35. Heier JS, Bressler NM, Avery RL, et al; American Society
of Retina Specialists Anti-VEGF for Diabetic Macular Edema
Comparative Effectiveness Panel. Comparison of aflibercept,
bevacizumab, and ranibizumab for treatment of diabetic macular edema: extrapolation of data to clinical practice. JAMA
Ophthalmol. 2016;134(1):95-99. doi: 10.1001/jamaophthalmol.2015.4110.
36. Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou
E, Roth M. Corticosteroids inhibit the expression of the vascular
endothelial growth factor gene in human vascular smooth muscle cells. Eur J Pharmacol. 1998;341(2-3):309-315.
37. Ozurdex (dexamethasone intravitreal implant) [package
insert]. Irvine, CA: Allergan, Inc; 2014.
38. Iluvien (fluocinolone acetonide) [package insert]. Alpharetta,
GA: Alimera Sciences Inc; 2014.
39. Dugel PU, Bandello F, Loewenstein A. Dexamethasone intravitreal implant in the treatment of diabetic macular edema. Clin
Ophthalmol. 2015;9:1321-1335. doi: 10.2147/opth.s79948.
40. Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide
intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology.
2011;118(8):1580-1587. doi: 10.1016/j.ophtha.2011.02.048.
41. Diabetic Retinopathy Clincal Research Network. A randomized trial comparing intravitreal triamcinolone acetonide
and focal/grid photocoagulation for diabetic macular edema.
Ophthalmology. 2008;115(9):1447-1449, 1449.e1-10. doi: 10.1016/j.
ophtha.2008.06.015.
42. Beck RW, Edwards AR, Aiello LP, et al; Diabetic Retinopathy
Clinical Research Network (DRCR.net). Three-year follow-up of
a randomized trial comparing focal/grid photocoagulation and
intravitreal triamcinolone for diabetic macular edema. Arch
Ophthalmol. 2009;127(3):245-251. doi: 10.1001/archophthalmol.2008.610.
43. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy

VOL. 22, NO. 10

Clinical Research Network. Expanded 2-year follow-up of


ranibizumab plus prompt or deferred laser or triamcinolone
plus prompt laser for diabetic macular edema. Ophthalmology.
2011;118(4):609-614. doi: 10.1016/j.ophtha.2010.12.033.
44. Campochiaro PA, 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;119(10):2125-2132. doi:
10.1016/j.ophtha.2012.04.030.
45. Boyer DS, Yoon YH, Belfort R, Jr, et al; Ozurdex MEAD Study
Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular
edema. Ophthalmology. 2014;121(10):1904-1914. doi: 10.1016/j.
ophtha.2014.04.024.
46. Maturi RK, Bleau L, Saunders J, Mubasher M, Stewart MW.
A 12-month, single-masked, randomized controlled study of eyes
with persistent diabetic macular edema after multiple anti-VEGF
injections to assess the efficacy of the dexamethasone-delayed
delivery system as an adjunct to bevacizumab compared with
continued bevacizumab monotherapy. Retina. 2015;35(8):16041614. doi: 10.1097/iae.0000000000000533.
47. Lally DR, Shah CP, Heier JS. Vascular endothelial growth
factor and diabetic macular edema. Surv Ophthalmol. 2016. pii:
S0039-6257(15)30035-7. doi: 10.1016/j.survophthal.2016.03.010.
48. Kaiser PK. The DME pipeline. Retina Today website. retinatoday.com/2015/04/the-dme-pipeline. Accessed April 13, 2016.
49. Holz FG, Dugel PU, Weissgerber G, et al. Single-chain antibody fragment VEGF inhibitor RTH258 for neovascular agerelated macular degeneration: a randomized controlled study.
Ophthalmology. 2016;123(5):1080-1089. doi: 10.1016/j.ophtha.2015.12.030.
50. Safety and efficacy study of conbercept in diabetic macular
edema (DME) (Sailing). ClinicalTrials.gov website. clinicaltrials.
gov/ct2/show/NCT02194634. Updated January 5, 2016. Accessed
April 10, 2016.
51. Das A, McGuire PG, Rangasamy S. Diabetic macular edema:
pathophysiology and novel therapeutic targets. Ophthalmology.
2015;122(7):1375-1394. doi: 10.1016/j.ophtha.2015.03.024.
52. A phase 2 randomized, controlled, double-masked, multicenter
clinical trial designed to evaluate the safety and exploratory efficacy of luminate (ALG-1001) as compared to avastin and focal
laser photocoagulation in the treatment of diabetic macular edema.
ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT02348918.
Updated January 23, 2015. Accessed April 13, 2016.
53. Shen J, Frye M, Lee BL, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest.
2014;124(10):4564-4576. doi: 10.1172/jci74527.
54. Campochiaro PA, Sophie R, Tolentino M, et al. Treatment of
diabetic macular edema with an inhibitor of vascular endothelialprotein tyrosine phosphatase that activates Tie2. Ophthalmology.
2015;122(3):545-554. doi: 10.1016/j.ophtha.2014.09.023.
55. The TIME-2 study: A phase 2 study of AKB-9778, a novel
Tie-2 activator, in patients with diabetic macular edema (TIME2). ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/
NCT02050828. Updated August 24, 2015. Accessed April 13, 2016.
56. Thomas GW, Rael LT, Bar-Or R, et al. Biphasic effect of
danazol on human vascular endothelial cell permeability and
f-actin cytoskeleton dynamics. Biochem Biophys Res Commun.
2012;421(4):707-712. doi: 10.1016/j.bbrc.2012.04.066.
57. Efficacy and safety study to evaluate two doses of oral DMI5207 in adult subjects with diabetic macular edema. ClinicalTrials.
gov website. clinicaltrials.gov/ct2/show/NCT02002403. Updated
December 5, 2013. Accessed April 13, 2016.

THE AMERICAN JOURNAL OF MANAGED CARE n

S299