THE CLINICAL MANAGEMENT OF DIABETIC RETINOPATHY
Arthur D. Fu, MD,* Sam S. Yang, MD,† and H. Richard McDonald, MD‡
ABSTRACT Meanwhile, research continues for pharmacolog-
ic interventions that prevent or interfere with the
The diagnosis of diabetic retinopathy carries pathogenesis of diabetic retinopathy, including
several negative implications. The disease may vascular endothelial growth factor inhibitors (eg,
lead to loss of visual acuity and blindness and is pegaptanib), protein kinase C-β inhibitors (eg,
often associated with the systemic complications ruboxistaurin), intravitreal triamcinolone ace-
of diabetes (eg, nephropathy and neuropathy), in tonide, pigment-epithelium–derived factor, and
addition to hypertension and hyperlipidemia. growth hormone release inhibition.
Individually, each of these conditions is detrimen- (Adv Stud Ophthalmol. 2004:18-29)
tal to the patient’s health, but they can also wors-
en retinopathy. Therefore, not only is it important
to screen, diagnose, and treat diabetic retinopa-
thy, it is also important to screen, diagnose, and
treat the comorbid conditions. The complexity of
dealing with these comorbid conditions has led to iabetes mellitus is a disease with signifi-
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 ben-
efit of treating hypertension and hyperlipidemia
in reducing progression of the disease. Evidence
D cant 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 sys-
from the Diabetic Retinopathy Study, the Early
temic complications of nephropathy and neuropathy.1-8
Treatment Diabetic Retinopathy Study, and the
Diabetic Retinopathy Vitrectomy Study has provid- In addition, the comorbid conditions of hypertension
ed insight into how best to use effective interven- and hyperlipidemia are common in patients with dia-
tions, such as photocoagulation and vitrectomy, in betes and may influence the severity and progression
patients with significant diabetic retinopathy, dia- of diabetic retinopathy.9-13 Landmark clinical trials
betic macular edema, vitreous hemorrhage, have demonstrated the correlation between the severi-
and diabetic traction retinal detachments. ty 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
*West Coast Retina Medical Group, San Francisco, can help reduce ocular and systemic complications.
California. Macular edema and proliferative diabetic retinopathy
†Fellow, California Pacific Medical Center, West Coast
are important indicators of systemic organ involve-
Retina Medical Group, San Francisco, California.
‡Associate Clinical Professor, Department of Ophthal- ment, which suggests that a multidisciplinary team-
mology, University of California, San Francisco, California. based approach to treatment is needed to reduce
Address correspondence to: H. Richard McDonald, MD, ocular and systemic complications. In addition, cer-
West Coast Retina Medical Group, 1 Daniel Burnham
Court, Suite 210C, San Francisco, CA 94109. tain systemic risk factors are thought to independent-
E-mail: email@example.com. ly exacerbate the progression of retinopathy.17,18
18 October 2004
Therefore, treating only ocular conditions without retinopathy or severe levels of nonproliferative diabetic
awareness of the myriad systemic implications can lead retinopathy was reduced by 47%, the rate of photocoag-
to reduced efficacy of therapy and increased comor- ulation treatment was reduced by 56%, and relative rates
bidity. Intensive multiorgan system therapy is the par- of diabetic macular edema were reduced by 23%.4,5,23
adigm on which the multidisciplinary team-based Additional endpoints included a reduction in incidences
strategy is based.10 of diabetic nephropathy by 34% to 57% and a lessened
clinical risk of other diabetic microvascular complica-
THE MULTIDISCIPLINARY TEAM-BASED APPROACH tions. Complications of tighter control did not lead to
increased death or macrovascular complications. A sig-
What is the multidisciplinary team-based approach? nificant finding in the group receiving intensive therapy
How is it used to prevent and treat patients at high risk was that patients may experience an initial deterioration
for diabetic retinopathy? This treatment strategy is based in diabetic retinopathy that occasionally requires oph-
on frequent patient visits to the internist and the oph- thalmologic intervention.1,4
thalmologist and increased vigilance in detecting diabet- The UKPDS randomly assigned 4209 individuals
ic retinopathy in patients with elevated serum glucose newly diagnosed with type 2 diabetes mellitus into treat-
levels, elevated hemoglobin A1c levels, or in patients who ment groups similar to the DCCT, with the intensive
have recently been initiated into intensive control that therapy cohort receiving oral sulfonylureas and met-
occasionally results in the short-term exacerbation of dia- formin therapy, along with insulin injections as recom-
betic retinopathy.2,10 Furthermore, treatment of coexist- mended by physicians.21,22 Additional randomizations
ing conditions, such a hypertension and hyperlipidemia, related to blood pressure control. Primary endpoints
by the appropriate specialists reduces the severity of dia- included rates of development of diabetic retinopathy,
betic retinopathy.19,20 The appropriate monitoring and diabetic peripheral neuropathy, diabetic nephropathy,
referral of patients for diabetic microvascular complica- and cardiomyopathy. These patients were followed for a
tions by the ophthalmologist may minimize other signif- median of 10 years. At the conclusion of the study, the
icant systemic effects. relative risk of diabetic retinopathy decreased by up to
The multidisciplinary approach to treatment involv- 76%, laser photocoagulation rates decreased by 29%,
ing ophthalmologists and other specialists starts with and the rate of legal blindness decreased by 16%.
maximizing glycemic control. Two landmark studies, the Relative risk reduction for diabetic nephropathy rates
Diabetes Control and Complications Trial (DCCT) and ranged from 34% to 57%.22-25 Better blood pressure con-
the United Kingdom Prospective Diabetes Study trol also improved outcomes.
(UKPDS), documented the benefit of aggressive inten- The collective recommendations from these 2 land-
sive control of serum glucose levels.1,4,21,22 The results of mark trials (ie, UKPDS-33 and UKPDS-34) indicated
these studies form the basis for the strategy of tight con- that patients diagnosed with type 1 or type 2 diabetes
trol to maintain glucose levels near normal. mellitus who made frequent visits to physicians with the
The DCCT, a multicenter prospective study, ran- goal of maximizing insulin therapy, diet, and exercise
domly assigned 1441 patients with type 1 diabetes significantly decreased ocular and systemic diabetic
mellitus to conventional treatment or to intensive microvascular complications. Therefore, attempts by
treatment.4-6 Intensive treatment included the use of an ophthalmologists to successfully treat diabetic retinopa-
insulin pump or 3 or more insulin injections daily, thy are inextricably linked to control of serum glucose
self-monitoring of blood glucose 4 or more times daily, levels (Figure 1).9
frequent insulin dosage adjustments, initial hospital- Adequate control of serum glucose levels is only one
ization to implement treatment, and weekly to month- of many therapies that modulate the risks and course of
ly clinical visits with frequent telephone contact. After diabetic retinopathy. In addition to increased hyper-
6.5 years, the mean hemoglobin A1c level was 7.2% in glycemia as an increased risk factor for progression of dia-
the group receiving intensive therapy versus 9.1% in betic retinopathy, comorbid conditions such as systemic
the group receiving conventional therapy. Of the hypertension, nephropathy, pregnancy, anemia, and even
patients receiving intensive therapy, the relative risk for gastroparesis may exacerbate diabetic retinopathy.4,10,12,23,25-32
developing diabetic retinopathy was reduced by 27%, Prevention or better management of these conditions can
the relative risk for developing proliferative diabetic positively affect the prognosis of diabetic retinopathy.
Advanced Studies in Ophthalmology ■ 19
A significant finding of the UKPDS-38 was the fact diabetic retinopathy.39 Severe proteinuria is correlated
that systemic hypertension was an independent risk fac- with a 95% increase in the risk of developing diabetic
tor in the progression of diabetic retinopathy.23,25 macular edema.40 A large percentage of patients with
Hypertensive retinopathy can occur even in the absence end-stage renal disease who are receiving dialysis have
of diabetic retinopathy and has similar retinal findings, concomitant retinopathy, with most of these cases
including microaneurysms, flame-shaped hemor-
rhages, cotton wool spots, and macular exudates.
The Wisconsin Epidemiologic Study of
Diabetic Retinopathy (WESDR) also supported
the role of hypertension in the progression of Figure 1. Relationship Between Hemoglobin A1c and
retinopathy.9 Patients with the lowest degrees of sys- Retinopathy Progression*
tolic 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 treat-
ment of systemic hypertension on diabetic retinopa-
thy.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 ben-
efits were noted regardless of the type of antihyper-
tensive medication used. The Appropriate Blood *P < .001.
Data from Klein et al.9
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 Figure 2. Relationship Between Blood Pressure and
retinopathy progression. However, with the evidence Retinopathy Progression*
supporting the benefits of ACE inhibitors in reducing
diabetic microvascular complications in patients with
renal compromise, additional clinical trials examin-
ing their effects on diabetic retinopathy are likely.35
The association between diabetic nephropathy
and diabetic retinopathy has long been postulat-
ed.11,13,36 However, the association between protein-
uria 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 indi-
cated increased severity of diabetic eye disease as a
risk factor for proteinuria.9 Conversely, studies have *P < .05.
suggested that proteinuria is a predictor for future Data from Klein et al.9
20 October 2004
being proliferative diabetic retinopathy.41 It has been retinopathy and severe visual loss.27 A study that
noted that once patients begin receiving dialysis, recorded hemoglobin levels in a large population of
retinopathy tends to stabilize.41,42 The observation that Finnish patients revealed an increased risk of retinopathy
the use of ACE inhibitors reduces renal microangiopathy when hemoglobin levels were less than 12 g/dL.28
has spurred increased interest in the use of ACE The clinical trials and series discussed earlier in this
inhibitors and their potential benefits for reducing dia- paper have confirmed the strong correlation between dia-
betic retinopathy.33,40,43-45 betic retinopathy and other systemic complications.
Other factors are associated with diabetic retinopathy. However, despite overwhelming evidence that aggressive
Hyperlipidemia has been reported to increase the exuda- surveillance and treatment prevent severe visual loss and
tion seen in diabetic macular edema.19,46 According to complications secondary to diabetic retinopathy, the
analysis from the WESDR, although serum cholesterol number of patients with diabetes referred for ophthalmic
levels were not predictive of severity of diabetic retinopa- care is far below what it should be, according to the
thy, they were associated with severity of hard exudates.20 guidelines of the American Diabetes Association (ADA)63
Other cross-sectional studies in patients with type 1 dia- and the American Academy of Ophthalmology (AAO).64-
betes mellitus have suggested an association between 68
AAO guidelines are summarized in the Table.64
total serum cholesterol levels and diabetic retinopathy.47 For example, in a series of 2000 patients with diabetes
In the Early Treatment of Diabetic Retinopathy Study mellitus, 7% to 11% of patients with high-risk prolifera-
(ETDRS), serum levels were measured in 2709 patients. tive diabetic retinopathy had not been examined by an
Elevated serum cholesterol, low-density lipoprotein, and ophthalmologist within the past 2 years.69 Complicating
triglyceride levels correlated with an increased rate of the difficulties of appropriate team management is the
hard exudation in these patients.48 The severity of dia- lack of standardization of terms used to characterize
betic exudation was also correlated with high-density degrees and severity of diabetic retinopathy. Recently,
lipoprotein levels.49,50 Although elevated triglycerides at efforts have been made to standardize terminology to a
baseline have been reported as a risk factor for prolifera- simplified international disease severity scale.70
tive diabetic retinopathy,11,27,47 the WESDR did not con- The ADA has established treatment goals based on
firm any association with serum cholesterol levels and the evidence showing that glycemic control reduces
diabetic macular edema.20 the risk of diabetes-related complications.71 The target
Studies examining the effects of pregnancy on the for patients with diabetes should be a hemoglobin A1c
progression of diabetic retinopathy have allowed clini- level below 7.0%.63 Normoglycemia is the ideal goal
cians and investigators an opportunity to examine the for most patients, but it is often difficult to achieve.
complex interactions between diabetes and preg-
nancy-induced hormonal and metabolic changes
affecting serum glucose levels. Progesterone, vas-
cular endothelial growth factors (VEGF), and
changes in systemic hemodynamics are hypothe- Table. American Academy of Ophthalmology Guidelines
sized to contribute to alterations in retinal vascula-
ture.10,26,51-59 Also, elevations in hemoglobin A1c First Exam Follow-up
levels in early pregnancy are associated with an Diabetes Type Recommended Recommended*
increased risk in progression of diabetic retinopa-
thy.60 Additional risks for progression in pregnant Type 1 5 years after onset Yearly
women with diabetes include increased duration Type 2 At time of diagnosis Yearly
of diabetes, amount of retinopathy at conception, Prior to pregnancy Prior to conception or No retinopathy to mild or
and presence of comorbid conditions, such as (type 1 or type 2) early in the first trimester moderate NPDR: every
hypertension.10,54,60 3–12 months; severe NPDR
or worse: every 1–3 months
Progression of diabetic retinopathy in patients
with anemia has also been studied.10,27-29,61,62 In the *Abnormal findings may dictate more frequent follow-up examinations.
ETDRS analysis, a low hematocrit level was deter- NPDR = nonproliferative diabetic retinopathy.
Adapted with permission from the American Academy of Ophthalmology. Diabetic
mined to be an independent risk factor for devel- retinopathy preferred practice pattern. Available at: http://www.aao.org/aao/education/
opment of high-risk proliferative diabetic library/ppp/dr_new.cfm. Accessed May 4, 2004.64
Advanced Studies in Ophthalmology ■ 21
Glycemic control should be individualized after con- high-risk proliferative diabetic retinopathy, who had
sidering the patient’s medical and social issues. Factors one eye that was treated by early photocoagulation and
to consider include life expectancy at the time of diag- treatment that was deferred in the other eye. The major
nosis, presence of microvascular complications, ability endpoints confirmed that focal photocoagulation in the
to understand and administer a complex treatment macular area for direct leaks and grid for diffuse diabetic
regimen, and level of social support. macular edema reduced the risk of doubling the visual
angle by 50%. Early scatter and deferred scatter groups
CURRENT TREATMENT STRATEGIES experienced similar rates of severe visual loss (2%–6% in
INDIABETIC RETINOPATHY the early scatter group vs 2%–10% in the deferred
group). The study authors concluded that panretinal
When diabetic retinopathy is detected, guidelines photocoagulation was not indicated for mild and mod-
for intervention to interrupt the natural progression of erate nonproliferative diabetic retinopathy but could be
diabetic retinopathy are derived from the Diabetic considered for severe nonproliferative retinopathy and
Retinopathy Study (DRS), the ETDRS, and the for patients approaching high-risk proliferative diabetic
Diabetic Retinopathy Vitrectomy Study (DRVS).72-82 retinopathy. The benefits of treatments were likely to be
These studies form the basis for predicting the natural more significant in patients with long-standing type 1
course of diabetic retinopathy and the foundation for and type 2 diabetes mellitus.72-74,76,77,84-87
offering photocoagulation and vitrectomy to patients In patients with vitreous hemorrhage secondary to
with significant diabetic retinopathy, macular edema, proliferative diabetic retinopathy, the DRVS established
vitreous hemorrhage, or diabetic traction retinal the benefits of vitrectomy.79,81,82,88 Patients with vision loss
detachments. Additional refinements in surgical tech- greater than 5/200 secondary to vitreous hemorrhage
nology, surgical techniques, and novel intravitreal and no macular retinal detachment were assigned to
pharmacotherapies offer promise in adding to the oph- early vitrectomy or conservative management (vitrecto-
thalmologist’s armamentarium in the treatment of dia- my only if detachment of the macula was noted or vitre-
betic retinopathy. ous hemorrhage persisted for 1 year). The chance of
The DRS and the ETDRS provided clinical out- significant visual improvement (>10/20) was noted in
comes in patients treated with scatter photocoagula- patients with type 1 diabetes mellitus who were younger,
tion and focal or grid photocoagulation to reduce the thus they had more severe proliferative diabetic disease.
risk of long-term severe visual loss.72-74,76,77,83 The signif- An additional group of patients with extensive, active
icance of these studies is based on their empiric, evi- neovascular proliferative retinopathy was randomly
dence-based study designs. In addition, through these assigned to deferred versus immediate vitrectomy. These
studies, current terminology such as proliferative dia- patients were also found to benefit from early vitrectomy,
betic retinopathy and severe nonproliferative diabetic specifically in patients with eyes that had severe new ves-
retinopathy was introduced. sels. Since the publication of the DRVS in 1990, several
The DRS included patients with proliferative dia- innovations in vitrectomy surgery, including bimanual
betic retinopathy or bilateral severe nonproliferative delamination and endolaser, have altered the timing of
diabetic retinopathy. In one eye, patients received pho- surgery for many patients, thus a greater number of
tocoagulation with panretinal photocoagulation, patients with vitreous hemorrhage may show benefits
direct treatment of neovascularization, or focal treat- from early surgical intervention.
ment (small-sized burns used to seal leaking micro- In all cases, appropriate detection and treatment
aneurysms in the posterior fundus). Photocoagulation relies on appropriate referral to ophthalmologists
was found to reduce the risk of severe visual loss by whenever diabetic retinopathy is a possible diagnosis.
50%, with only moderate risk for decreases in visual These current treatment paradigms of scatter laser
acuity or constriction in the treatment groups. In photocoagulation for severe nonproliferative diabetic
patients with high-risk proliferative diabetes, the 5- retinopathy and proliferative diabetic retinopathy,
year rate of severe visual loss was reduced from 50% to focal and grid photocoagulation for diabetic macular
20%.72-74,76,77,84-87 edema, and vitrectomy for vitreous hemorrhage and
The ETDRS criteria included patients with mild to traction retinal detachment serve as the foundation for
severe nonproliferative diabetic retinopathy or non– current photocoagulation techniques and treatment.
22 October 2004
The National Eye Institute (Bethesda, MD) is spon- humans. However, therapy must be localized, perhaps
soring a series of additional clinical trials (Diabetic by direct intravitreal injection. Systemic anti-VEGF
Retinopathy Clinical Research Network) elucidating therapy precludes the benefit of angiogenesis to compro-
whether certain changes in laser delivery techniques may mised coronary and peripheral circulations, which is less
benefit patients with diabetic retinopathy. As a compari- than ideal. Pegaptanib, a VEGF aptamer consisting of a
son to the initial ETDRS grid laser techniques, a pilot 28-base oligonucleotide that binds to VEGF protein, is
study is enrolling patients with a milder intensity but being studied in a clinical trial for the treatment of
more confluent pattern of laser application to areas of exudative age-related macular degeneration involving
macular edema. In addition to visual acuity, ocular choroidal neovascularization.102 This aptamer may also
coherence tomography will be used to assess efficacy of be a potential treatment for diabetic retinopathy.
treatment. A second trial is investigating the safety and Another strategy to prevent the action of VEGF is
efficacy of intravitreal triamcinolone acetonide (TA) to to block specific VEGF receptors and their subsequent
treat diabetic macular edema. signal transductions.100,103 Although 3 VEGF receptors
have been identified,104,105 VEGF receptor-2 (VEGFR-
NEW DEVELOPMENTS IN THERAPY 2) appears to be most important for the mitogenic
action in the retinal vascular endothelium.105 A
Several new treatment possibilities are being VEGFR-2 blocker has already undergone preliminary
explored that may prevent the development and pro- tests as an angiogenesis inhibitor for cancer and may
gression of diabetic retinopathy. These efforts are prove useful for diabetic retinopathy.106
based on new understanding of the underlying bio-
chemical processes. PROTEIN KINASE C INHIBITORS
The protein kinase C (PKC) family comprises a large
VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS group of enzymes that transfer the terminal high-energy
Growth factors, particularly VEGF, are postulated to phosphate group of adenosine triphosphate to a site on a
be mediators in the development of late-stage diabetic target protein. This reaction may activate other enzymes,
retinopathy.89 The VEGFs are a family of peptides with cell membrane receptors, or ion transport channels.107
several isoforms produced from a single gene by alterna- Protein kinase C-β isoform is present at high levels in
tive splicing. They are potent mitogenic factors for vas- the retina and is thought to play a crucial role in the
cular endothelial cells and induce breakdown of pathogenesis of diabetic retinopathy.108-110 In patients
blood-retinal barriers.90,91 VEGF plays a critical role in with diabetes, hyperglycemia triggers an increase in the
the development of the fetal vascular system,92 decreasing concentration of diacylglycerol (DAG), an essential
significantly after birth. However, neural retina, choroid, cofactor for PKC.109 This increase in DAG leads to
and retinal pigment epithelium continue to secrete increased activation of PKC. Subsequently, the higher
VEGF.93 In patients with diabetes, hyperglycemia results level of PKC acts in concert with hypoxia to upregulate
in a loss of pericytes and endothelial cells, slowing the the production of VEGF in retinal tissues.108 The bind-
blood flow and causing progressive hypoxia of the retinal ing of VEGF to its receptor on a vascular endothelial cell
tissues.94 The localized hypoxia promotes expression and activates a variety of signaling molecules, including PKC
secretion of VEGF,95,96 subsequently leading to prolifera- β, to initiate angiogenesis or blood-retinal barrier break-
tion of retinal capillary endothelium and neovasculariza- down leading to macular edema.111 By interfering with
tion, in addition to increased vascular fenestrations and the biochemical pathway, PKC inhibitors may prevent
macular edema.91 the development and progression of diabetic retinopa-
In animal studies, exogenous VEGF injected into thy. However, because PKC is found throughout the
monkeys’ eyes caused neovascularization of the iris and body, a specific inhibitor for the PKC β acting locally in
retina.97,98 Other animal studies demonstrated that the retina would be preferable.104
interventions to block VEGF synthesis with intravitre- Recent data from transgenic mouse models support
al injection of anti-VEGF antibodies, VEGF-receptor– the hypothesis that PKC β is involved in mediating
binding chimeric immunoglobulin, or antisense retinal neovascularization. In mice in which PKC is
VEGF DNA appear to prevent retinal neovasculariza- overexpressed, the retinal neovascular response to pre-
tion.99-101 These strategies appear promising for proendothelin promoter is substantially increased. In
Advanced Studies in Ophthalmology ■ 23
mice in which the PKC-β gene has been “knocked- diffuse diabetic macular edema.124 They reported a
out,” exposure to retinal ischemia results in reduced reduction in macular thickness, which was measured
retinal neovascularization.111 by optical coherence tomography, at follow-up visits of
In addition, in vivo studies have shown that selective 1 month (55%), 3 months (58%), and 6 months
inhibition of the PKC-β isoform prevents VEGF-medi- (38%). Follow-up visits also revealed mean visual acu-
ated growth.112 In the animal model, selective inhibition ity improvements of 2.4 Snellen lines at 1 month and
of PKC β reduces ischemic retinal revascularization.113 at 3 months, and 1.3 at 6 months. Jonas et al also
Selective inhibition of the PKC-β inhibitor ruboxistaurin reported similar favorable results using a dose of 25 mg
has also been shown to block VEGF-induced increases in intravitreal TA injection.125 In both studies, the
retinal vascular permeability in animals and humans to improvement in visual acuity declined after 3 to 6
normalize changes in blood flow that typically occur as a months with a recurrence of diabetic macular edema.
result of diabetic retinopathy.114,115 Preliminary data from Therefore, these results suggest that the efficacy of the
animal studies suggest PKC inhibition can normalize dia- intravitreal TA injection may be limited in duration
betes-induced retinal vascular permeability in animals, and repeated treatments may be required.
even if diabetes has been established for as long as 1 Massin et al reported the first prospective controlled
month before therapy has been initiated.116 trial of intravitreal TA injection versus observation in
These studies have furthered interest in the PKC-β eyes with diffuse diabetic macular edema that failed pre-
inhibitor ruboxistaurin, a highly selective dimethyl- vious conventional laser treatment.126 They found that
amine analogue.117 In the initial testing of the oral one intravitreal injection of 4 mg of TA improved retinal
form of ruboxistaurin, it appears well tolerated.113 Two thickness in one eye relative to the untreated eye at 4-
extensive phase III clinical trials for severe preprolifer- week and 12-week follow-up, but there was no statisti-
ative diabetic retinopathy and diabetic macular edema cally significant difference in visual acuity between the
are being conducted.113 treated and untreated eye. By 3 months, there was
improved visual acuity in the eyes that had received
INTRAVITREAL TRIAMCINOLONE ACETONIDE injections. By 24 weeks, the benefit of the single injec-
The ETDRS demonstrated that focal or grid laser tion diminished considerably, with a recurrence of dia-
photocoagulation is beneficial for treating patients betic macular edema in 5 of 12 eyes that had been
whose eyes have been diagnosed as having clinically treated; this result was consistent with prior studies.
significant diabetic macular edema.76 However, Lee The safety of intravitreal TA is supported by prior
and Olk reported that despite treatment with grid-pat- animal studies and by human trials.123,127 The main
tern laser photocoagulation, 25% of eyes of patients adverse effect observed was intraocular pressure (IOP)
diagnosed with diffuse diabetic macular edema lost elevation, which was reported in 20% to 80% of the
more than 2 lines of vision within 3 years.118 patients.124,128-130 Most patients with elevated IOP levels
Corticosteroids have been used to suppress intraoc- were successfully treated with topical antiglaucoma
ular inflammation by reducing extravasation from therapy, and pressure levels returned to normal within
leaking blood vessels and inhibiting fibroblast prolifer- 6 months without further medication. However,
ation. Early research efforts by Machemer et al, intravitreal TA injection may be contraindicated in the
Graham and Peyman, and Tano et al suggest that an eyes of patients with glaucoma or a history of corti-
intravitreal injection of corticosteroid can safely and costeroid-induced IOP elevation.126 Another potential
effectively suppress intraocular inflammatory patholo- adverse effect is cataract progression; however, because
gies, such as persistent uveitis and proliferative vitreo- of the relatively short length of follow-up studies, few
retinopathy.119-121 Machemer also advocated using a cataract formations were reported. Other potential injec-
crystalline form of cortisone, which has an intravitreal tion-related complications include retinal detachment,
absorption time of 2 months, to provide longer anti- vitreous hemorrhage, and endophthalmitis.131 In a retro-
inflammatory effect.122 TA, a crystalline corticosteroid spective multicenter case series, Moshfeghi et al reported
suspension, has been shown experimentally to reduce 8 of 922 cases of culture-positive, acute, postinjection
breakdown of the blood-retinal barrier.123 endophthalmitis, resulting in an incidence rate of
In an uncontrolled study, Martidis et al used an 0.87%.132 To decrease the risk of some injection-related
intravitreal injection of 4 mg of TA to treat refractory complications and reduce the need for periodic reinjec-
24 October 2004
tion, sustained drug delivery devices containing steroids has been abandoned because of the high rates of mor-
that maintain a constant intraocular drug level for an tality and morbidity associated with its use.143 Later
extended period are being investigated.133 studies identified the insulin-like growth factor 1 (IGF-
The mechanism of action of corticosteroids on dia- 1) as a mediator for the actions of growth hormone in
betic macular edema remains unclear. One hypothesis the development of diabetic retinopathy.144 IGF-1 is
proposes that corticosteroids reduce retinal capillary thought to be a permissive agent necessary for the
permeability by increasing the activity or density of the occurrence of neovascularization, although IGF-1 must
tight junctions in the retinal capillary endothelium.134 be accompanied by other molecules, such as VEGF, to
Another hypothesis suggests that corticosteroids inhib- induce neovascularization.145
it the arachidonic acid pathway from producing Octreotide, a somatostatin analogue that inhibits
prostaglandins (known endogenous vascular perme- the release of growth hormone, was shown at a high
ability mediators).124 Also, corticosteroids downregu- concentration to prevent the progression of diabetic
late the production of VEGF, which may reduce the retinopathy to the proliferative stage over a 15-month
vascular permeability and macular edema.135 period.146 A multicenter clinical trial is in progress that
The Diabetic Retinopathy Clinical Research may offer a possible treatment to prevent or delay the
Network, sponsored by the National Eye Institute, is progression of diabetic retinopathy to proliferative dia-
conducting a large prospective, randomized, multicenter betic retinopathy.146
clinical trial comparing intravitreal TA injections to mac-
ular 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 modali- REFERENCES
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