R THE CLINICAL MANAGEMENT OF DIABETIC RETINOPATHY EVIEW

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THE CLINICAL MANAGEMENT OF DIABETIC RETINOPATHY
—
Arthur D. Fu, MD,* Sam S. Yang, MD,† and H. Richard McDonald, MD‡
ABSTRACT
The diagnosis of diabetic retinopathy carries
several negative implications. The disease may
lead to loss of visual acuity and blindness and is
often associated with the systemic complications
of diabetes (eg, nephropathy and neuropathy), in
addition to hypertension and hyperlipidemia.
Individually, each of these conditions is detrimental to the patient’s health, but they can also worsen retinopathy. Therefore, not only is it important
to screen, diagnose, and treat diabetic retinopathy, it is also important to screen, diagnose, and
treat the comorbid conditions. The complexity of
dealing with these comorbid conditions has led to
recommendations for routine, multidisciplinary,
team-based diabetes care. Landmark studies
have demonstrated the benefit of blood glucose
management in preventing and treating diabetic
retinopathy. Clinical studies also support the benefit of treating hypertension and hyperlipidemia
in reducing progression of the disease. Evidence
from the Diabetic Retinopathy Study, the Early
Treatment Diabetic Retinopathy Study, and the
Diabetic Retinopathy Vitrectomy Study has provided insight into how best to use effective interventions, such as photocoagulation and vitrectomy, in
patients with significant diabetic retinopathy, diabetic macular edema, vitreous hemorrhage,
and diabetic traction retinal detachments.
*West Coast Retina Medical Group, San Francisco,
California.
†Fellow, California Pacific Medical Center, West Coast
Retina Medical Group, San Francisco, California.
‡Associate Clinical Professor, Department of Ophthalmology, University of California, San Francisco, California.
Address correspondence to: H. Richard McDonald, MD,
West Coast Retina Medical Group, 1 Daniel Burnham
Court, Suite 210C, San Francisco, CA 94109.
E-mail: [email protected]
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Meanwhile, research continues for pharmacologic interventions that prevent or interfere with the
pathogenesis of diabetic retinopathy, including
vascular endothelial growth factor inhibitors (eg,
pegaptanib), protein kinase C-β inhibitors (eg,
ruboxistaurin), intravitreal triamcinolone acetonide, pigment-epithelium–derived factor, and
growth hormone release inhibition.
(Adv Stud Med. 2004;4(9A):S702-S713)
iabetes mellitus is a disease with significant negative implications for the
patient. Although ophthalmologists are
primarily concerned with the ocular
complications resulting from macular
edema and proliferative diabetic retinopathy, decades
of clinical trials and longitudinal studies indicate that
people with diabetes are also at higher risk for the systemic complications of nephropathy and neuropathy.1-8
In addition, the comorbid conditions of hypertension
and hyperlipidemia are common in patients with diabetes and may influence the severity and progression
of diabetic retinopathy.9-13 Landmark clinical trials
have demonstrated the correlation between the severity of retinopathy and elevated levels of serum glucose
and hemoglobin A1c.1-6,14-16 These multicenter clinical
studies also indicate that intensive glycemic control
can help reduce ocular and systemic complications.
Macular edema and proliferative diabetic retinopathy
are important indicators of systemic organ involvement, which suggests that a multidisciplinary teambased approach to treatment is needed to reduce
ocular and systemic complications. In addition, certain systemic risk factors are thought to independently exacerbate the progression of retinopathy.17,18
D
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Therefore, treating only ocular conditions without
awareness of the myriad systemic implications can lead
to reduced efficacy of therapy and increased comorbidity. Intensive multiorgan system therapy is the paradigm on which the multidisciplinary team-based
strategy is based.10
THE MULTIDISCIPLINARY TEAM-BASED APPROACH
What is the multidisciplinary team-based approach?
How is it used to prevent and treat patients at high risk
for diabetic retinopathy? This treatment strategy is based
on frequent patient visits to the internist and the ophthalmologist and increased vigilance in detecting diabetic retinopathy in patients with elevated serum glucose
levels, elevated hemoglobin A1c levels, or in patients who
have recently been initiated into intensive control that
occasionally results in the short-term exacerbation of diabetic retinopathy.2,10 Furthermore, treatment of coexisting conditions, such a hypertension and hyperlipidemia,
by the appropriate specialists reduces the severity of diabetic retinopathy.19,20 The appropriate monitoring and
referral of patients for diabetic microvascular complications by the ophthalmologist may minimize other significant systemic effects.
The multidisciplinary approach to treatment involving ophthalmologists and other specialists starts with
maximizing glycemic control. Two landmark studies, the
Diabetes Control and Complications Trial (DCCT) and
the United Kingdom Prospective Diabetes Study
(UKPDS), documented the benefit of aggressive intensive control of serum glucose levels.1,4,21,22 The results of
these studies form the basis for the strategy of tight control to maintain glucose levels near normal.
The DCCT, a multicenter prospective study, randomly assigned 1441 patients with type 1 diabetes
mellitus to conventional treatment or to intensive
treatment.4-6 Intensive treatment included the use of an
insulin pump or 3 or more insulin injections daily,
self-monitoring of blood glucose 4 or more times daily,
frequent insulin dosage adjustments, initial hospitalization to implement treatment, and weekly to monthly clinical visits with frequent telephone contact. After
6.5 years, the mean hemoglobin A1c level was 7.2% in
the group receiving intensive therapy versus 9.1% in
the group receiving conventional therapy. Of the
patients receiving intensive therapy, the relative risk for
developing diabetic retinopathy was reduced by 27%,
the relative risk for developing proliferative diabetic
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retinopathy or severe levels of nonproliferative diabetic
retinopathy was reduced by 47%, the rate of photocoagulation treatment was reduced by 56%, and relative rates
of diabetic macular edema were reduced by 23%.4,5,23
Additional endpoints included a reduction in incidences
of diabetic nephropathy by 34% to 57% and a lessened
clinical risk of other diabetic microvascular complications. Complications of tighter control did not lead to
increased death or macrovascular complications. A significant finding in the group receiving intensive therapy
was that patients may experience an initial deterioration
in diabetic retinopathy that occasionally requires ophthalmologic intervention.1,4
The UKPDS randomly assigned 4209 individuals
newly diagnosed with type 2 diabetes mellitus into treatment groups similar to the DCCT, with the intensive
therapy cohort receiving oral sulfonylureas and metformin therapy, along with insulin injections as recommended by physicians.21,22 Additional randomizations
related to blood pressure control. Primary endpoints
included rates of development of diabetic retinopathy,
diabetic peripheral neuropathy, diabetic nephropathy,
and cardiomyopathy. These patients were followed for a
median of 10 years. At the conclusion of the study, the
relative risk of diabetic retinopathy decreased by up to
76%, laser photocoagulation rates decreased by 29%,
and the rate of legal blindness decreased by 16%.
Relative risk reduction for diabetic nephropathy rates
ranged from 34% to 57%.22-25 Better blood pressure control also improved outcomes.
The collective recommendations from these 2 landmark trials (ie, UKPDS-33 and UKPDS-34) indicated
that patients diagnosed with type 1 or type 2 diabetes
mellitus who made frequent visits to physicians with the
goal of maximizing insulin therapy, diet, and exercise
significantly decreased ocular and systemic diabetic
microvascular complications. Therefore, attempts by
ophthalmologists to successfully treat diabetic retinopathy are inextricably linked to control of serum glucose
levels (Figure 1).9
Adequate control of serum glucose levels is only one
of many therapies that modulate the risks and course of
diabetic retinopathy. In addition to increased hyperglycemia as an increased risk factor for progression of diabetic retinopathy, comorbid conditions such as systemic
hypertension, nephropathy, pregnancy, anemia, and even
gastroparesis may exacerbate diabetic retinopathy.4,10,12,23,25-32
Prevention or better management of these conditions can
positively affect the prognosis of diabetic retinopathy.
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A significant finding of the UKPDS-38 was the fact
that systemic hypertension was an independent risk factor in the progression of diabetic retinopathy.23,25
Hypertensive retinopathy can occur even in the absence
of diabetic retinopathy and has similar retinal findings,
including microaneurysms, flame-shaped hemorrhages, cotton wool spots, and macular exudates.
The Wisconsin Epidemiologic Study of
Diabetic Retinopathy (WESDR) also supported
the role of hypertension in the progression of
retinopathy.9 Patients with the lowest degrees of systolic and dia-stolic pressures had a significantly
lower risk of progression to proliferative diabetic
retinopathy compared to patients with higher levels
of hypertension (Figure 2).9
The UKPDS-38 evaluated the effects of the treatment of systemic hypertension on diabetic retinopathy.33 Patients were placed in an intensive control
group (maintain blood pressure levels below 144/82
mm Hg) or a less-controlled group (achieve blood
pressure levels below 154/87 mm Hg). Individuals in
the intensive control cohort had a 34% relative risk
reduction in diabetic retinopathy progression, a 47%
reduction in deterioration of visual acuity, and a 37%
reduction in need for photocoagulation.33 These benefits were noted regardless of the type of antihypertensive medication used. The Appropriate Blood
Pressure Control in Diabetes Trial34 found a similar
lack of significant differences between the efficacy of
angiotensin-converting enzyme (ACE) inhibitors and
calcium channel blockers in the rates of diabetic
retinopathy progression. However, with the evidence
supporting the benefits of ACE inhibitors in reducing
diabetic microvascular complications in patients with
renal compromise, additional clinical trials examining their effects on diabetic retinopathy are likely.35
The association between diabetic nephropathy
and diabetic retinopathy has long been postulated.11,13,36 However, the association between proteinuria and the progression of retinopathy is complex
because of multiple confounding factors.37 Similar
to patients with diabetic retinopathy, patients with
diabetic nephropathy are likely to have chronic
hyperglycemia, elevated hemoglobin A1c levels, and
hypertension (independently, each condition can
be a cause of retinopathy).4,5,13,38 The WESDR indicated increased severity of diabetic eye disease as a
risk factor for proteinuria.9 Conversely, studies have
suggested that proteinuria is a predictor for future
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diabetic retinopathy.39 Severe proteinuria is correlated
with a 95% increase in the risk of developing diabetic
macular edema.40 A large percentage of patients with
end-stage renal disease who are receiving dialysis have
concomitant retinopathy, with most of these cases
Figure 1. Relationship Between Hemoglobin A1c and
Retinopathy Progression*
*P < .001.
Data from Klein et al.9
Figure 2. Relationship Between Blood Pressure and
Retinopathy Progression*
*P < .05.
Data from Klein et al.9
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being proliferative diabetic retinopathy.41 It has been
noted that once patients begin receiving dialysis,
retinopathy tends to stabilize.41,42 The observation that
the use of ACE inhibitors reduces renal microangiopathy
has spurred increased interest in the use of ACE
inhibitors and their potential benefits for reducing diabetic retinopathy.33,40,43-45
Other factors are associated with diabetic retinopathy.
Hyperlipidemia has been reported to increase the exudation seen in diabetic macular edema.19,46 According to
analysis from the WESDR, although serum cholesterol
levels were not predictive of severity of diabetic retinopathy, they were associated with severity of hard exudates.20
Other cross-sectional studies in patients with type 1 diabetes mellitus have suggested an association between
total serum cholesterol levels and diabetic retinopathy.47
In the Early Treatment of Diabetic Retinopathy Study
(ETDRS), serum levels were measured in 2709 patients.
Elevated serum cholesterol, low-density lipoprotein, and
triglyceride levels correlated with an increased rate of
hard exudation in these patients.48 The severity of diabetic exudation was also correlated with high-density
lipoprotein levels.49,50 Although elevated triglycerides at
baseline have been reported as a risk factor for proliferative diabetic retinopathy,11,27,47 the WESDR did not confirm any association with serum cholesterol levels and
diabetic macular edema.20
Studies examining the effects of pregnancy on the
progression of diabetic retinopathy have allowed clinicians and investigators an opportunity to examine the
complex interactions between diabetes and pregnancy-induced hormonal and metabolic changes
affecting serum glucose levels. Progesterone, vascular endothelial growth factors (VEGF), and
changes in systemic hemodynamics are hypothesized to contribute to alterations in retinal vasculature.10,26,51-59 Also, elevations in hemoglobin A1c
levels in early pregnancy are associated with an
increased risk in progression of diabetic retinopathy.60 Additional risks for progression in pregnant
women with diabetes include increased duration
of diabetes, amount of retinopathy at conception,
and presence of comorbid conditions, such as
hypertension.10,54,60
Progression of diabetic retinopathy in patients
with anemia has also been studied.10,27-29,61,62 In the
ETDRS analysis, a low hematocrit level was determined to be an independent risk factor for development of high-risk proliferative diabetic
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retinopathy and severe visual loss.27 A study that
recorded hemoglobin levels in a large population of
Finnish patients revealed an increased risk of retinopathy
when hemoglobin levels were less than 12 g/dL.28
The clinical trials and series discussed earlier in this
paper have confirmed the strong correlation between diabetic retinopathy and other systemic complications.
However, despite overwhelming evidence that aggressive
surveillance and treatment prevent severe visual loss and
complications secondary to diabetic retinopathy, the
number of patients with diabetes referred for ophthalmic
care is far below what it should be, according to the
guidelines of the American Diabetes Association (ADA)63
and the American Academy of Ophthalmology (AAO).6468
AAO guidelines are summarized in the Table.64
For example, in a series of 2000 patients with diabetes
mellitus, 7% to 11% of patients with high-risk proliferative diabetic retinopathy had not been examined by an
ophthalmologist within the past 2 years.69 Complicating
the difficulties of appropriate team management is the
lack of standardization of terms used to characterize
degrees and severity of diabetic retinopathy. Recently,
efforts have been made to standardize terminology to a
simplified international disease severity scale.70
The ADA has established treatment goals based on
the evidence showing that glycemic control reduces
the risk of diabetes-related complications.71 The target
for patients with diabetes should be a hemoglobin A1c
level below 7.0%.63 Normoglycemia is the ideal goal
for most patients, but it is often difficult to achieve.
Table. American Academy of Ophthalmology Guidelines
Diabetes Type
First Exam
Recommended
Follow-up
Recommended*
Type 1
5 years after onset
Yearly
Type 2
At time of diagnosis
Yearly
Prior to pregnancy
(type 1 or type 2)
Prior to conception or
No retinopathy to mild or
early in the first trimester moderate NPDR: every
3–12 months; severe NPDR
or worse: every 1–3 months
*Abnormal findings may dictate more frequent follow-up examinations.
NPDR = nonproliferative diabetic retinopathy.
Adapted with permission from the American Academy of Ophthalmology. Diabetic
retinopathy preferred practice pattern. Available at: http://www.aao.org/aao/education/
library/ppp/dr_new.cfm. Accessed May 4, 2004.64
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Glycemic control should be individualized after considering the patient’s medical and social issues. Factors
to consider include life expectancy at the time of diagnosis, presence of microvascular complications, ability
to understand and administer a complex treatment
regimen, and level of social support.
CURRENT TREATMENT STRATEGIES
DIABETIC RETINOPATHY
IN
When diabetic retinopathy is detected, guidelines
for intervention to interrupt the natural progression of
diabetic retinopathy are derived from the Diabetic
Retinopathy Study (DRS), the ETDRS, and the
Diabetic Retinopathy Vitrectomy Study (DRVS).72-82
These studies form the basis for predicting the natural
course of diabetic retinopathy and the foundation for
offering photocoagulation and vitrectomy to patients
with significant diabetic retinopathy, macular edema,
vitreous hemorrhage, or diabetic traction retinal
detachments. Additional refinements in surgical technology, surgical techniques, and novel intravitreal
pharmacotherapies offer promise in adding to the ophthalmologist’s armamentarium in the treatment of diabetic retinopathy.
The DRS and the ETDRS provided clinical outcomes in patients treated with scatter photocoagulation and focal or grid photocoagulation to reduce the
risk of long-term severe visual loss.72-74,76,77,83 The significance of these studies is based on their empiric, evidence-based study designs. In addition, through these
studies, current terminology such as proliferative diabetic retinopathy and severe nonproliferative diabetic
retinopathy was introduced.
The DRS included patients with proliferative diabetic retinopathy or bilateral severe nonproliferative
diabetic retinopathy. In one eye, patients received photocoagulation with panretinal photocoagulation,
direct treatment of neovascularization, or focal treatment (small-sized burns used to seal leaking microaneurysms in the posterior fundus). Photocoagulation
was found to reduce the risk of severe visual loss by
50%, with only moderate risk for decreases in visual
acuity or constriction in the treatment groups. In
patients with high-risk proliferative diabetes, the 5year rate of severe visual loss was reduced from 50% to
20%.72-74,76,77,84-87
The ETDRS criteria included patients with mild to
severe nonproliferative diabetic retinopathy or non–
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high-risk proliferative diabetic retinopathy, who had
one eye that was treated by early photocoagulation and
treatment that was deferred in the other eye. The major
endpoints confirmed that focal photocoagulation in the
macular area for direct leaks and grid for diffuse diabetic
macular edema reduced the risk of doubling the visual
angle by 50%. Early scatter and deferred scatter groups
experienced similar rates of severe visual loss (2%–6% in
the early scatter group vs 2%–10% in the deferred
group). The study authors concluded that panretinal
photocoagulation was not indicated for mild and moderate nonproliferative diabetic retinopathy but could be
considered for severe nonproliferative retinopathy and
for patients approaching high-risk proliferative diabetic
retinopathy. The benefits of treatments were likely to be
more significant in patients with long-standing type 1
and type 2 diabetes mellitus.72-74,76,77,84-87
In patients with vitreous hemorrhage secondary to
proliferative diabetic retinopathy, the DRVS established
the benefits of vitrectomy.79,81,82,88 Patients with vision loss
greater than 5/200 secondary to vitreous hemorrhage
and no macular retinal detachment were assigned to
early vitrectomy or conservative management (vitrectomy only if detachment of the macula was noted or vitreous hemorrhage persisted for 1 year). The chance of
significant visual improvement (>10/20) was noted in
patients with type 1 diabetes mellitus who were younger,
thus they had more severe proliferative diabetic disease.
An additional group of patients with extensive, active
neovascular proliferative retinopathy was randomly
assigned to deferred versus immediate vitrectomy. These
patients were also found to benefit from early vitrectomy,
specifically in patients with eyes that had severe new vessels. Since the publication of the DRVS in 1990, several
innovations in vitrectomy surgery, including bimanual
delamination and endolaser, have altered the timing of
surgery for many patients, thus a greater number of
patients with vitreous hemorrhage may show benefits
from early surgical intervention.
In all cases, appropriate detection and treatment
relies on appropriate referral to ophthalmologists
whenever diabetic retinopathy is a possible diagnosis.
These current treatment paradigms of scatter laser
photocoagulation for severe nonproliferative diabetic
retinopathy and proliferative diabetic retinopathy,
focal and grid photocoagulation for diabetic macular
edema, and vitrectomy for vitreous hemorrhage and
traction retinal detachment serve as the foundation for
current photocoagulation techniques and treatment.
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The National Eye Institute (Bethesda, MD) is sponsoring a series of additional clinical trials (Diabetic
Retinopathy Clinical Research Network) elucidating
whether certain changes in laser delivery techniques may
benefit patients with diabetic retinopathy. As a comparison to the initial ETDRS grid laser techniques, a pilot
study is enrolling patients with a milder intensity but
more confluent pattern of laser application to areas of
macular edema. In addition to visual acuity, ocular
coherence tomography will be used to assess efficacy of
treatment. A second trial is investigating the safety and
efficacy of intravitreal triamcinolone acetonide (TA) to
treat diabetic macular edema.
NEW DEVELOPMENTS IN THERAPY
Several new treatment possibilities are being
explored that may prevent the development and progression of diabetic retinopathy. These efforts are
based on new understanding of the underlying biochemical processes.
VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS
Growth factors, particularly VEGF, are postulated to
be mediators in the development of late-stage diabetic
retinopathy.89 The VEGFs are a family of peptides with
several isoforms produced from a single gene by alternative splicing. They are potent mitogenic factors for vascular endothelial cells and induce breakdown of
blood-retinal barriers.90,91 VEGF plays a critical role in
the development of the fetal vascular system,92 decreasing
significantly after birth. However, neural retina, choroid,
and retinal pigment epithelium continue to secrete
VEGF.93 In patients with diabetes, hyperglycemia results
in a loss of pericytes and endothelial cells, slowing the
blood flow and causing progressive hypoxia of the retinal
tissues.94 The localized hypoxia promotes expression and
secretion of VEGF,95,96 subsequently leading to proliferation of retinal capillary endothelium and neovascularization, in addition to increased vascular fenestrations and
macular edema.91
In animal studies, exogenous VEGF injected into
monkeys’ eyes caused neovascularization of the iris and
retina.97,98 Other animal studies demonstrated that
interventions to block VEGF synthesis with intravitreal injection of anti-VEGF antibodies, VEGF-receptor–
binding chimeric immunoglobulin, or antisense
VEGF DNA appear to prevent retinal neovascularization.99-101 These strategies appear promising for
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humans. However, therapy must be localized, perhaps
by direct intravitreal injection. Systemic anti-VEGF
therapy precludes the benefit of angiogenesis to compromised coronary and peripheral circulations, which is less
than ideal. Pegaptanib, a VEGF aptamer consisting of a
28-base oligonucleotide that binds to VEGF protein, is
being studied in a clinical trial for the treatment of
exudative age-related macular degeneration involving
choroidal neovascularization.102 This aptamer may also
be a potential treatment for diabetic retinopathy.
Another strategy to prevent the action of VEGF is
to block specific VEGF receptors and their subsequent
signal transductions.100,103 Although 3 VEGF receptors
have been identified,104,105 VEGF receptor-2 (VEGFR2) appears to be most important for the mitogenic
action in the retinal vascular endothelium.105 A
VEGFR-2 blocker has already undergone preliminary
tests as an angiogenesis inhibitor for cancer and may
prove useful for diabetic retinopathy.106
PROTEIN KINASE C INHIBITORS
The protein kinase C (PKC) family comprises a large
group of enzymes that transfer the terminal high-energy
phosphate group of adenosine triphosphate to a site on a
target protein. This reaction may activate other enzymes,
cell membrane receptors, or ion transport channels.107
Protein kinase C-β isoform is present at high levels in
the retina and is thought to play a crucial role in the
pathogenesis of diabetic retinopathy.108-110 In patients
with diabetes, hyperglycemia triggers an increase in the
concentration of diacylglycerol (DAG), an essential
cofactor for PKC.109 This increase in DAG leads to
increased activation of PKC. Subsequently, the higher
level of PKC acts in concert with hypoxia to upregulate
the production of VEGF in retinal tissues.108 The binding of VEGF to its receptor on a vascular endothelial cell
activates a variety of signaling molecules, including PKC
β, to initiate angiogenesis or blood-retinal barrier breakdown leading to macular edema.111 By interfering with
the biochemical pathway, PKC inhibitors may prevent
the development and progression of diabetic retinopathy. However, because PKC is found throughout the
body, a specific inhibitor for the PKC β acting locally in
the retina would be preferable.104
Recent data from transgenic mouse models support
the hypothesis that PKC β is involved in mediating
retinal neovascularization. In mice in which PKC is
overexpressed, the retinal neovascular response to preproendothelin promoter is substantially increased. In
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mice in which the PKC-β gene has been “knockedout,” exposure to retinal ischemia results in reduced
retinal neovascularization.111
In addition, in vivo studies have shown that selective
inhibition of the PKC-β isoform prevents VEGF-mediated growth.112 In the animal model, selective inhibition
of PKC β reduces ischemic retinal revascularization.113
Selective inhibition of the PKC-β inhibitor ruboxistaurin
has also been shown to block VEGF-induced increases in
retinal vascular permeability in animals and humans to
normalize changes in blood flow that typically occur as a
result of diabetic retinopathy.114,115 Preliminary data from
animal studies suggest PKC inhibition can normalize diabetes-induced retinal vascular permeability in animals,
even if diabetes has been established for as long as 1
month before therapy has been initiated.116
These studies have furthered interest in the PKC-β
inhibitor ruboxistaurin, a highly selective dimethylamine analogue.117 In the initial testing of the oral
form of ruboxistaurin, it appears well tolerated.113 Two
extensive phase III clinical trials for severe preproliferative diabetic retinopathy and diabetic macular edema
are being conducted.113
INTRAVITREAL TRIAMCINOLONE ACETONIDE
The ETDRS demonstrated that focal or grid laser
photocoagulation is beneficial for treating patients
whose eyes have been diagnosed as having clinically
significant diabetic macular edema.76 However, Lee
and Olk reported that despite treatment with grid-pattern laser photocoagulation, 25% of eyes of patients
diagnosed with diffuse diabetic macular edema lost
more than 2 lines of vision within 3 years.118
Corticosteroids have been used to suppress intraocular inflammation by reducing extravasation from
leaking blood vessels and inhibiting fibroblast proliferation. Early research efforts by Machemer et al,
Graham and Peyman, and Tano et al suggest that an
intravitreal injection of corticosteroid can safely and
effectively suppress intraocular inflammatory pathologies, such as persistent uveitis and proliferative vitreoretinopathy.119-121 Machemer also advocated using a
crystalline form of cortisone, which has an intravitreal
absorption time of 2 months, to provide longer antiinflammatory effect.122 TA, a crystalline corticosteroid
suspension, has been shown experimentally to reduce
breakdown of the blood-retinal barrier.123
In an uncontrolled study, Martidis et al used an
intravitreal injection of 4 mg of TA to treat refractory
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diffuse diabetic macular edema.124 They reported a
reduction in macular thickness, which was measured
by optical coherence tomography, at follow-up visits of
1 month (55%), 3 months (58%), and 6 months
(38%). Follow-up visits also revealed mean visual acuity improvements of 2.4 Snellen lines at 1 month and
at 3 months, and 1.3 at 6 months. Jonas et al also
reported similar favorable results using a dose of 25 mg
intravitreal TA injection.125 In both studies, the
improvement in visual acuity declined after 3 to 6
months with a recurrence of diabetic macular edema.
Therefore, these results suggest that the efficacy of the
intravitreal TA injection may be limited in duration
and repeated treatments may be required.
Massin et al reported the first prospective controlled
trial of intravitreal TA injection versus observation in
eyes with diffuse diabetic macular edema that failed previous conventional laser treatment.126 They found that
one intravitreal injection of 4 mg of TA improved retinal
thickness in one eye relative to the untreated eye at 4week and 12-week follow-up, but there was no statistically significant difference in visual acuity between the
treated and untreated eye. By 3 months, there was
improved visual acuity in the eyes that had received
injections. By 24 weeks, the benefit of the single injection diminished considerably, with a recurrence of diabetic macular edema in 5 of 12 eyes that had been
treated; this result was consistent with prior studies.
The safety of intravitreal TA is supported by prior
animal studies and by human trials.123,127 The main
adverse effect observed was intraocular pressure (IOP)
elevation, which was reported in 20% to 80% of the
patients.124,128-130 Most patients with elevated IOP levels
were successfully treated with topical antiglaucoma
therapy, and pressure levels returned to normal within
6 months without further medication. However,
intravitreal TA injection may be contraindicated in the
eyes of patients with glaucoma or a history of corticosteroid-induced IOP elevation.126 Another potential
adverse effect is cataract progression; however, because
of the relatively short length of follow-up studies, few
cataract formations were reported. Other potential injection-related complications include retinal detachment,
vitreous hemorrhage, and endophthalmitis.131 In a retrospective multicenter case series, Moshfeghi et al reported
8 of 922 cases of culture-positive, acute, postinjection
endophthalmitis, resulting in an incidence rate of
0.87%.132 To decrease the risk of some injection-related
complications and reduce the need for periodic reinjec-
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tion, sustained drug delivery devices containing steroids
that maintain a constant intraocular drug level for an
extended period are being investigated.133
The mechanism of action of corticosteroids on diabetic macular edema remains unclear. One hypothesis
proposes that corticosteroids reduce retinal capillary
permeability by increasing the activity or density of the
tight junctions in the retinal capillary endothelium.134
Another hypothesis suggests that corticosteroids inhibit the arachidonic acid pathway from producing
prostaglandins (known endogenous vascular permeability mediators).124 Also, corticosteroids downregulate the production of VEGF, which may reduce the
vascular permeability and macular edema.135
The Diabetic Retinopathy Clinical Research
Network, sponsored by the National Eye Institute, is
conducting a large prospective, randomized, multicenter
clinical trial comparing intravitreal TA injections to macular laser photocoagulation in the treatment of diabetic
macular edema. The study is also comparing 1-mg and
4-mg intravitreal TA. The results of the study will help to
solidify the role of intravitreal TA injection as a modality in the management of diabetic macular edema.
PIGMENT-EPITHELIUM–DERIVED FACTOR
Pigment-epithelium–derived factor (PEDF) was
first isolated from fetal retinal pigmented epithelial
cells.136 Experimental studies show that it inhibits retinal neovascularization in mice.137 Evidence suggests
PEDF and VEGF have a reciprocal relationship that
becomes imbalanced with uncontrolled diabetes, as
PEDF levels fall and VEGF levels rise.138 VEGF and
PEDF play an important role in maintaining the normal anatomy and function of the retinal and choroidal
blood vessels.139 In an animal experiment model, the
intravitreal injection of adenovirus vector containing
the PEDF gene resulted in the inhibition of retinal and
choroidal neovascularization,140 suggesting the possibility of using gene therapy to treat diabetic retinopathy in humans. A phase I study of this strategy in
patients with advanced neovascular age-related macular degeneration is under way.141
INHIBITION OF GROWTH HORMONE ACTION
Growth hormones secreted by the pituitary gland are
thought to play a part in the pathogenesis of diabetic
retinopathy.142 Hypophysectomy, once considered beneficial in inhibiting the production of growth hormone
and its action for the treatment of diabetic retinopathy,
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has been abandoned because of the high rates of mortality and morbidity associated with its use.143 Later
studies identified the insulin-like growth factor 1 (IGF1) as a mediator for the actions of growth hormone in
the development of diabetic retinopathy.144 IGF-1 is
thought to be a permissive agent necessary for the
occurrence of neovascularization, although IGF-1 must
be accompanied by other molecules, such as VEGF, to
induce neovascularization.145
Octreotide, a somatostatin analogue that inhibits
the release of growth hormone, was shown at a high
concentration to prevent the progression of diabetic
retinopathy to the proliferative stage over a 15-month
period.146 A multicenter clinical trial is in progress that
may offer a possible treatment to prevent or delay the
progression of diabetic retinopathy to proliferative diabetic retinopathy.146
REFERENCES
1. Diabetes Control and Complications Trial Research Group.
Progression of retinopathy with intensive versus conventional
treatment in the Diabetes Control and Complications Trial.
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