UPDATE IN OFFICE MANAGEMENT

Diabetic Retinopathy: An Update on Treatment

Ryan J. Fante, BS,a Vikram D. Durairaj, MD,b Scott C.N. Oliver, MDa,b
a
University of Colorado School of Medicine, Denver; bDepartment of Ophthalmology, Rocky Mountain Lions Eye Institute, University
of Colorado Denver, Aurora, Colo.

ABSTRACT

Diabetic retinopathy is a progressive disease that results from vascular injury due to chronic hyperglyce-
mia. It is the leading cause of blindness in working-age adults in the US and is usually asymptomatic until
late stages. Treatment with laser photocoagulation is effective at preventing severe vision loss; thus,
diabetic patients should be referred for regular screening by an ophthalmologist. New inhibitors of vascular
endothelial growth factor may provide targeted nonsurgical treatment to improve vision in diabetic
retinopathy.
2010 Elsevier Inc. All rights reserved. The American Journal of Medicine (2010) 123, 213-216

KEYWORDS: Antiangiogenic therapy; Diabetic retinopathy; Intravitreal injection; Laser photocoagulation; Macular
edema; Neovascularization; Retina; Vascular Endothelial Growth Factor; Vitrectomy

Two patients presented with mildly blurred central vision
(20/30) in their left eyes. Patient 1 (Figure 1) has had
diabetes and hypertension for 10 years. Patient 2 (Figure 2)
has had uncontrolled diabetes for 30 years. Figure 1 dem-
onstrates yellow exudates near the fovea with microaneu-
rysms and dot-blot hemorrhages. Figure 2 reveals large
neovascular fronds growing into the vitreous, capillary non-
perfusion in the temporal macula, and laser photocoagula-
tion scars superotemporally.
DIAGNOSIS
Patient 1 has clinically significant macular edema and
mild nonproliferative retinopathy. Focal macular laser
photocoagulation is required to prevent further vision
loss. Patient 2 has high-risk proliferative diabetic reti-
nopathy and a small tractional retinal detachment. She is
at high risk for severe vision loss and will require ag-
gressive intervention with panretinal photocoagulation
and possible vitrectomy.
Funding: None.
Conflict of Interest: None.
Authorship: All authors participated in the preparation of the manu-
script.
Requests for reprints should be addressed to Scott C.N. Oliver, MD,
Department of Ophthalmology, Rocky Mountain Lions Eye Institute, Uni-
versity of Colorado Denver, PO Box 6510, Mail Stop F731, Aurora, CO
80045.
E-mail address: scott.oliver@ucdenver.edu
Diabetes mellitus is estimated to affect 23.6 million
individuals in the US,1 and most patients with type I or
type II diabetes have evidence of retinopathy after 20
years.2,3 Diabetic retinopathy is the primary cause of
blindness in adults aged 20-74 years in the US, causing
an estimated 12,000 to 24,000 new cases of blindness
annually.1
The major risk factors for diabetic retinopathy are hy-
perglycemia and increased duration of diabetes. Other risk
factors include hypertension, hyperlipidemia, pregnancy,
and microalbuminuria.3,4 All of these risk factors contribute
to retinal metabolic changes and microvascular injury that
result in diabetic retinopathy.
Nonproliferative diabetic retinopathy is an early stage in
disease progression. Loss of retinal capillary pericytes and
endothelial cells has been demonstrated early in diabetes5
and underlies the clinical signs of nonproliferative diabetic
retinopathy, which include intraretinal dot-blot hemor-
rhages, microaneurysms, and venous beading. Microvascu-
lar injury with infarction of small areas of the nerve fiber
layer leads to puffy white patches on the retina called
cotton-wool spots (Table).
Proliferative diabetic retinopathy is a later and more
severe stage of the disease characterized by neovasculariza-
tion. Sustained retinal ischemia causes release of vascular
endothelial growth factor and insulin-like growth factor,
which induce growth of new vessels on the optic disk, iris,
retinal surface, and into the vitreous. The abnormal vessels
are fragile and may hemorrhage into the vitreous or form

0002-9343/$ -see front matter 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2009.09.020
214
fibrous bands, causing tractional retinal detachment. Neo-
vascularization of the iris may occlude aqueous outflow,
resulting in neovascular glaucoma.
Clinically significant macular edema is the most com-
mon cause of moderate vision loss (20/40 vision) in all
types of diabetic retinopathy. As microvascular damage
weakens the blood-retinal barrier, plasma leaks from vessels
into the retina; when this fluid is resorbed, lipid and lipopro-
tein elements are retained in the retina and are visible as
yellow exudates.
The majority of severe vision loss (20/200 vision) in
diabetic retinopathy is the result of complications from pro-
liferative diabetic retinopathyvitreous hemorrhage, retinal
detachment, and neovascular glaucoma. Most patients with
diabetic retinopathy are asymptomatic until very late stages
of the disease. Symptoms, when present, may include de-
creased visual acuity and contrast sensitivity, new onset
floaters, or dark curtain.
MANAGEMENT
Current treatment strategies for diabetic retinopathy are
thought to be 90% effective in preventing severe vision
loss.6 Given the asymptomatic nature of diabetic retinopa-
thy until its latest stages and the effectiveness of early
intervention,7 referral for regular screening by an ophthal-
mologist is essential. The American Academy of Ophthal-
mology recommends type I diabetics be examined 3-5 years
after diagnosis and yearly thereafter; type II diabetics
should be examined at the time of diagnosis and yearly
thereafter.6
Primary prevention of diabetic retinopathy involves
strict glycemic and blood pressure control. The Diabetes
Figure 1 Fundus photograph of the left eye of a patient with
nonproliferative diabetic retinopathy demonstrating microan-
eurysms, dot-blot intraretinal hemorrhages, and yellow exu-
dates. (Courtesy of Peter McKay, COMT).
The American Journal of Medicine, Vol 123, No 3, March 2010
Control and Complications Trial8 and the United King-
dom Prospective Diabetes Study9 showed that intensive
glycemic control substantially reduces the incidence and
progression of diabetic retinopathy in type I and II dia-
betes. Blood pressure control also significantly reduces
the incidence and progression of diabetic retinopathy,
although the specific antihypertensive agent utilized does
not appear to be significant.10,11
Established secondary interventions for diabetic retinop-
athy include pan-retinal photocoagulation, focal laser pho-
tocoagulation, and surgical vitrectomy. Pan-retinal photo-
coagulation applies hundreds of laser burns to the peripheral
retina, reducing the amount of ischemic retina that drives
angiogenesis. Pan-retinal photocoagulation has been the
cornerstone of treatment for severe retinopathy since the
Diabetic Retinopathy Study, which showed that it reduces
the risk of severe vision loss by 50% in patients with severe
diabetic retinopathy.12
Focal laser photocoagulation is indicated for patients
with clinically significant macular edema; it targets microa-
neurysms near the macula, reducing the plasma leakage
responsible for intraretinal swelling. The Early Treatment
Diabetic Retinopathy Study showed that focal laser photo-
coagulation reduces the risk of moderate vision loss by
50%-70% in patients with macular edema.7
Vitrectomy involves surgical removal of the vitreous,
blood, and fibrovascular retinal tissue. It is recommended
for severe proliferative diabetic retinopathy when it is un-
responsive to pan-retinal photocoagulation, associated with
severe vitreous hemorrhage, or associated with traction on
the macula. The Diabetic Vitrectomy Study first demon-
strated the ability of early vitrectomy to preserve or restore
vision in patients with severe proliferative diabetic retinop-
Figure 2 Fundus photograph of the left eye of a patient with
proliferative diabetic retinopathy demonstrating large neovas-
cular fronds and old laser photocoagulation scars. (Courtesy of
Peter McKay, COMT).
Fante et al Diabetic Retinopathy: An Update on Treatment
Table Funduscopic Findings in Diabetic Retinopathy
Nonproliferative Diabetic Microaneurysms; venous beading;
Retinopathy intraretinal hemorrhages;
cotton-wool spots
Proliferative diabetic Abnormal new vessels of the
retinopathy retina, optic disc, or iris;
vitreous hemorrhage
Diabetic macular edema Retinal thickening; yellow
exudates
athy;13 since this study, many advances have been made in
vitreoretinal surgery.
Vascular endothelial growth factor is produced by
multiple retinal cell types in response to ischemia. It is a
potent promoter of vascular permeability and neovascu-
larization, making it the primary target for emerging
treatment for diabetic retinopathy. Intravitreal injection
of vascular endothelial growth factor into healthy primate
eyes induces changes similar to proliferative diabetic
retinopathy.14 The concentration of vascular endothelial
growth factor is increased by a factor of 20 in the vitreous
of patients with proliferative diabetic retinopathy, and
levels subsequently fall after pan-retinal photocoagu-
lation.15
Currently, 4 intravitreal inhibitors of vascular endo-
thelial growth factor provide promising possibilities for
targeted nonsurgical treatment of diabetic retinopathy.
Pegaptanib (Macugen, OSI/Eyetech, Melville, NY) and
bevacizumab (Avastin, Genentech, Inc., South San Fran-
cisco, CA) have been demonstrated to reduce neovascu-
larization and improve diabetic macular edema, respec-
tively.16-18 Ranibizumab (Lucentis, Genentech, Inc.) and
VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tar-
rytown, NY) are currently being evaluated for treatment
of macular edema.
All of the vascular endothelial growth factor antagonists
appear to require repeated intravitreal injections to sustain
benefits, increasing the likelihood of local complications
including uveitis, cataract, retinal detachment, and endoph-
thalmitis. Theoretical concerns about occlusion of native
retinal vessels, hypertension, stroke, myocardial infarction,
and thrombosis have not been demonstrated in large studies
of these agents.
The central role of vascular endothelial growth factor
in severe, vision-threatening diabetic retinopathy war-
rants further investigation to determine if inhibitors of
this protein will become part of routine care of diabetic
retinopathy.
Intravitreal triamcinolone acetonide also has received
significant attention for the treatment of diabetic macular
edema. While triamcinolone does reduce macular thickness
in the short term,19 its 3-year visual benefit was found to be
215
inferior to standard focal macular laser, with higher rates of
glaucoma and cataract.20
CONCLUSION
As the leading cause of new-onset blindness in the working-
age population in the US, diabetic retinopathy causes a
profound burden of psychologic, functional, and economic
morbidity. Diabetic retinopathy progresses predictably from
the early nonproliferative stage to the later proliferative
stage. It is largely asymptomatic until its latest stages, em-
phasizing the importance of early referral by primary care
providers for regular screening examinations. Application
of focal macular laser and panretinal photocoagulation at
appropriate disease stages reduces the risk of further vision
loss. Ongoing research will determine the utility of inhibi-
tors of vascular endothelial growth factor as an additional
tool in the management of diabetic retinopathy.
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