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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.
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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
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nTable 1. Properties of VEGF Inhibitors for DME5,14,19-22
Aflibercept
(Eylea)
Bevacizumab
(Avastin)
Ranibizumab
(Lucentis)
Class
VEGF trap
Monoclonal antibody
Molecular weight
115 kDa
149 kDa
48 kDa
Target
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
No FDA-approved
ophthalmic use
1.25-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.
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DRCR.net Protocol T Study
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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
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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
BRVO indicates branch retinal vein occlusion; CRVO, central retinal vein occlusion; DME, diabetic macular edema; IOP, intraocular pressure.
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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.
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