Despite major technological and scientific advances in the
past 25 years, diabetic retinopathy (DR) still remains the leading cause of
blindness in the United States. However, the development of new management
techniques manifests the benefits of scientific advances for the treatment of DR.
Numerous landmark studies during this time have promoted better understanding
of DR and provided means for reduction in morbidity associated with this
disease (Table 1).
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Study
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Population & Study Groups
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Clinical Endpoints
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Results
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Conclusions
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Diabetes Control and Complications Trial (DCCT)
1983-1989
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1441 patients with type 1 diabetes
Divided into primary prevention and secondary
intervention cohorts.
Patients in each cohort assigned to either
conventional (no glycemic goal) or intensive (near normal blood glucose)
glycemic treatment
|
A1C
7-field stereo fundus photos
4-hour standard urine collection
Neurologic examination
Autonomic neuropathy
Severe hypoglycemia
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Median A1C
Conventional: 9.1%
Intensive: 7.2%
Intensive therapy reduced DR progression 76% in
primary prevention
54% in secondary intervention cohort
Reduced microalbuminuria and neuropathy
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Significant long-term benefits of intensive treatment
outweigh the risk of early deterioration of DR in type 1 diabetes
|
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Epidemiology of Diabetes Interventions and
Complications (EDIC)
1989-1996
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1375 patients with type 1 diabetes
Observational phase of the DCCT
All patients advised to adhere to intensive glycemic
treatment
Comparison of former conventional and intensive
groups
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A1C
DR progression
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A1C (1 year)
Former Conventional: 8.3%
Former Intensive: 7.9%
DR incidence (4 years)
Former Conventional: 49%
Former Intervention: 18%
A1C (7 years)
Former Conventional: 8.3%
Former Intervention: 8.1%
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Risk reduction for DR progression persisted in the
former intensive group in spite of rising A1C levels and after several years
of follow-up
|
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The United Kingdom Prospective Diabetes Study (UKPDS)
1977-1997
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4209 patients with newly diagnosed type 2 diabetes
2 therapy groups
Conventional: dietary control
Intensive: sulfonylurea or insulin, with option of
metformin for obese participants
|
A1C
Microvascular complications
|
Median A1C (10 years)
Conventional: 7.9%
Intensive: 7.0%
25% reduction in diabetic microvascular complications
in intensive group
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Intensive glycemic control reduces A1C level and
results in a lower rate of complications
There were no significant differences in
microvascular complications among the 3 intensive therapy treatments
|
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Hypertension in Diabetes Study (embedded within the
UKPDS)
1987
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Patients with type 2 diabetes and hypertension
2 treatment groups
Tight BP control: captopril or atenolol treatment
with BP goal of ≤150/80 mm Hg
Less tight BP control: BP goal of ≤180/105 mmHg
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Blood pressure (BP)
Microvascular disease
Retinal photo-coagulation
Visual acuity
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Risk reduction in tight control group
37% microvascular diseases
35% retinal photocoagulation
47% decrease in visual acuity
Reduction in risk for nephropathy, stroke, death
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Blood pressure management should have a high priority
in the treatment of type 2 diabetes
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Early Treatment of Diabetic Retinopathy Study (ETDRS)
1980-1985
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3711 patients with type 2 diabetes and early
proliferative DR, moderate to severe nonproliferative DR, and/or clinically
significant macular edema (CSME) in each eye
Early vs deferred photocoagulation
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Severe visual loss (visual acuity)
Moderate visual loss following photo- coagulation for
CSME
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Eyes receiving early photocoagulation ~1/2 as likely
to lose ≥15 ETDRS letters compared to deferred group
Improvement of ≥6 letters in early treated
eyes compared to deferred eyes
Early group showed more benefit with respect to CSME
At 1 year, 35% of early treated eyes had retinal
thickening compared to 63% of deferred eyes
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Immediate focal photo-coagulation for CSME significantly
reduces the risk of visual loss and reduces the macular thickening by up to
50%; additionally, there is a decrease in loss of color vision and
insignificant losses of visual field
|
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Diabetic Retinopathy Vitrectomy Study (DRVS)
1976
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2 vitrectomy studies:
Group H (n=616): early vitrectomy and severe
proliferative DR
Group NR (n=370): early vitrectomy for severe
vitreous hemorrhage
1 natural history study:
Group N (n=744)
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Loss of visual acuity
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Early vitrectomy in patients with type 1 diabetes
preferred over deferral of treatment
No real advantage seen in early treatment in patients
with type 2 diabetes
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Perform early vitrectomy in patients who have
severely extensive neovascular-ization and have already received panretinal
photo-coagulation, or in patients who have vitreous hemorrhage that precludes
photo-coagulation
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Additional observations and biotechnological advances within
the past quarter century have also built on the framework of understanding
diabetic retinopathy. Several studies demonstrated the importance of lipid
control in patients with type 2 diabetes. In 1994 the major etiological growth
factor, vascular endothelial growth factor (VEGF), was first found to be
elevated in the vitreous of patients with proliferative DR. This observation was
followed by the more recent discovery of the VEGF receptors VEGFR1 and VEGFR2,
which further augmented the awareness of the mechanisms involved in the
signaling transduction pathways. Advances in laser technology and surgical
instrumentation have improved photocoagulation and vitrectomy techniques. There
are also numerous treatments for DR currently under investigation, including
the PKC inhibitor ruboxistaurin; the somatostatin agonist sandostatin, for treatment
of neovascularization; the corticosteroid triamcinolone acetonide, for diabetic
macular edema; and the fluocinolone acetonide implant Retisert and the dexamethasone
implant Posurdex, for treatment of retinal thickening. The anti-VEGF molecules pegaptanib
and ranibizumab are also in clinical trials, as are treatment methods such as pars
plana vitrectomy, purified hyaluronidase treatment, and the use of plasmin
enzyme.
The notable advances in science and biotechnology have
resulted in new concepts and methodologies. These treatment mechanisms have
allowed for a better understanding regarding the management of DR. It will be
interesting to see what the future holds in store for this disease.
