Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

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Figure 9.2. Diabetic Retinopathy Study standard photograph 10A demonstrating definite disc neovascularization. (Source: Published with permission form Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study findings. Ophthalmology. 1978;85:82–106.)

Table 9.2. Estimated Percentages of Eyes with Harmful Effects

Attributable to Treatment in Diabetic Retinopathy Study

xenon-treated eyes had a persistent visual acuity decrease of one line, which was possibly due to treatment, and an additional 11% had a persistent decrease or two or more lines. Comparable estimates for the argon-treated group were 11% and 3%, respectively. Subjectively, many patients noticed difficulties with dark adaptation and driving at night after either argon or xenon scatter photocoagulation.

Based on DRS results and clinical experience, mild to moderate intensity argon laser is recommended, rather than more intense lesions created by the xenon arc, because of similar benefits but fewer side effects. Direct treatment of neovascularization, although part of the original DRS protocol, has generally been discontinued based on the comparison of xenon and argon treatment in eyes with NVD. In the DRS, the argon treatment included direct photocoagulation of NVD, whereas this was not possible with xenon. There was no increase in regression of NVD in the argon group, but there was an increased risk of hemorrhage at the time of direct treatment.

Early Treatment Diabetic Retinopathy Study, 1980–1989. Although scatter photocoagulation was shown by the DRS to be beneficial for patients with high-risk retinopathy, the question remained as to whether treatment at an earlier stage (non-high-risk PDR or severe NPDR) would be more helpful. The Early Treatment Diabetic Retinopathy Study (ETDRS) was designed to address this question, as well as questions related to the treatment of diabetic macular edema and the use of aspirin (Table 9.3) [18,19]. The 3711 ETDRS patients had mild-to-severe NDPR or early PDR, with or without diabetic macular edema. Compared with patients in the DRS, patients in the ETDRS were somewhat older (70% classified as type 2 and 52% over age 50), were less predominantly white (76%), and were equally likely to be male (56%).

All ETDRS patients were randomly assigned to 650 mg aspirin per day or placebo in order to assess whether the antiplatelet effects of aspirin would affect the microcirculation of the retina and slow the development of PDR [20–24]. One eye of each patient was randomly assigned to immediate photocoagulation, while the fellow eye was assigned to deferral of photocoagulation, that is, careful follow-up and prompt scatter photocoagulation if high-risk retinopathy developed. Eyes assigned to immediate photocoagulation received different treatments depending on the severity of the retinopathy: (1) eyes without DME were randomly assigned to full or mild scatter; (2) eyes with DME and severe NPDR or early PDR were randomly assigned to full or mild scatter and focal/grid treatment; (3) eyes with mild to moderate NPDR (for which it was thought that scatter could be deferred safely) were randomly assigned to either immediate focal/grid treatment (with deferred

Table 9.3. Early Treatment Diabetic Retinopathy Study

Study Questions

1.Is photocoagulation effective for treating diabetic macular edema?

2.Is early photocoagulation effective for treating diabetic retinopathy?

3.Is aspirin effective for preventing progression of diabetic retinopathy?

Eligibility

Mild nonproliferative diabetic retinopathy through early proliferataive diabetic retinopathy, with visual acuity 20/200 or better in each eye.

Randomization

3711 participants: one eye randomly assigned to photocoagulation (scatter and/or focal), and one eye assigned to no photocoagulation; patients randomly assigned to 650 mg/d aspirin or placebo.

Outcome Variables

Visual acuity less than 5/200 for at least 4 months; visual acuity worsening by doubling of initial visual angle (for example, 20/40 to 20/80); retinopathy progression.

Results

1.Macular edema: Table 9.4

2.Early photocoagulation: Table 9.5

3.Aspirin: Table 9.6

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scatter—mild or full) or immediate scatter—mild or full (with deferred focal/grid treatment).

Aspirin use did not affect the progression of retinopathy (Table 9.4 and Fig. 9.3), nor did it affect the risk of visual loss. Perhaps surprisingly, aspirin use did not increase the risk of vitreous hemorrhage in patients with PDR [25]. In addition, aspirin use was associated with a 17% reduction in morbidity and mortality from cardiovascular disease [26]. Therefore, aspirin use should be considered for persons with diabetes, not because of any effect on their diabetic retinopathy, but because of their increased risk of cardiovascular disease. The presence of PDR should not be considered a contraindication to aspirin use.

The ETDRS utilized a factorial study design of aspirin (persons randomized) and photocoagulation (eyes randomized). Because aspirin use had little if any effect on any of the ETDRS ocular outcome variables and aspirin use was not associated with any statistically significant interactions with photocoagulation treatment, all randomized comparisons of photocoagulation treatment versus control combined the aspirin and placebo groups.

The comparison of early photocoagulation versus deferral in the ETDRS revealed a small reduction in the incidence of severe visual loss in the early-treated eyes (Table 9.5 and Fig. 9.4), but 5-year rates were low in both the early-treatment group and the deferral group (2.6% and 3.7%), respectively [27]. For eyes with only mild-to-moderate NPDR, rates of progression to severe vision loss were even

Table 9.4. Early Treatment Diabetic Retinopathy Study: Aspirin Use Results

1.Aspirin use did not alter progression of diabetic retinopathy

2.Aspirin use did not increase risk of vitreous hemorrhage

3.Aspirin use did not affect visual acuity

4.Aspirin use reduced risk of cardiovascular morbidity and mortality

5.Aspirin use did not increase rates of vitrectomy

Figure 9.3. Early Treatment Diabetic Retinopathy Study results: Cumulative incidence of development of high-risk proliferative diabetic retinopathy for eyes assigned to deferral of photocoagulation in patients given placebo (N = 1855) and in aspirin-treated patients (N = 1856); P = 0.58.

Table 9.6. Early Treatment Diabetic Retinopathy Study: Macular Edema Results

1.Focal photocoagulation for diabetic macular edema decreased risk of moderate visual loss (doubling of initial visual angle)

2.Focal photocoagulation for diabetic macular edema increased chance of moderate visual gain (halving of initial visual angle)

3.Focal photocoagulation for diabetic macular edema reduced retinal thickening

Figure 9.7. Early Treatment Diabetic Retinopathy Study results: Proportion of eyes with mild- to-moderate nonproliferative diabetic retinopathy and macular edema involving center of macula that has loss of three lines of visual acuity from baseline (doubling of initial visual angle, for example, 20/20 to 20/40) for eyes assigned to no treatment (N = 607) or to immediate focal treatment for macular edema (N = 292); P < 0.01 for each visit after 4 months.

the focal laser burns, although there was limited documentation of this using the visual fields as measured during the ETDRS. However, longer follow-up has demonstrated that photocoagulation scars enlarge over time and may eventually cause a decrease in visual acuity. For eyes in which involvement of the center of the macula was equivocal and there was little or no decrease in visual acuity, the ETDRS did not compare immediate photocoagulation versus careful follow-up, withholding photocoagulation until central involvement was definite and/or visual acuity has started to decrease. This would seem to be an appealing strategy to reduce the risk of visual loss while limiting the number of patients exposed to the risks of treatment.

VITRECTOMY

While photocoagulation treatment was being developed, another major advance was added to the practice of ophthalmology. New instrumentation and techniques made it possible to remove the vitreous gel and operate in the posterior aspect of the eye. This vitreous surgery offered hope of dramatic visual improvement in patients with severe vitreous hemorrhage [33–35].

Diabetic Retinopathy Vitrectomy Study, 1976–1983. The Diabetic Retinopathy Vitrectomy Study (DRVS) provides randomized clinical trial data demonstrating

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the benefits and risks of vitrectomy in eyes with severe vitreous hemorrhage or very severe neovascularization even in the absence of severe hemorrhage (Table 9.7) [36–40]. Results from the DRVS showed that conventional management at that time (deferring vitrectomy for 1 year in patients with severe vitreous hemorrhage or until tractional retinal detachment involved the macula) reduced the chance of obtaining good vision compared with doing early (<6 months) vitrectomy [37,40]. After 2 years of follow-up, 25% of the early-vitrectomy group had visual acuity of 20/40 or better, compared with 15% in the deferral group (P = 0.01). For patients with type 1 diabetes, who were on the average younger and had more severe PDR, this difference at 2 years was even greater (35% versus 12%, P = 0.001).

Early vitrectomy was also effective in saving good visual acuity in patients without severe vitreous hemorrhage, but with severe or very severe PDR [38,39]. The early-treated group had a higher percentage of eyes with 20/40 or better visual acuity at each of the 6-month visits during the 4 years of follow-up. About one third of treated eyes with more severe retinopathy had good vision at these 6-month visits, compared to less than 20% of the deferral eyes (P < 0.05 at every visit except the 6- and 24-month visits).

In both trials, the proportion of eyes with no light perception vision reached about 20% to 25% at 4 years in both the treated and the control groups, but there were more patients with no light perception in the treated group during the first several years of follow-up, especially in those eyes with the least severe retinopathy. Complications during follow-up included phthisis, endophthalmitis or uveitis, and corneal epithelial problems or neovascular glaucoma. Up to one third of treated eyes had at least one of these complications [37–40].

Table 9.7. Diabetic Retinopathy Vitrectomy Study

Study Questions

Is early vitrectomy preferable to deferral of vitrectomy in eyes with:

1.Severe vitreous hemorrhage from proliferative diabetic retinopathy?

2.Very severe proliferative diabetic retinopathy?

Eligibility

Recent severe vitreous hemorrhage from proliferative diabetic retinopathy (616 eyes); advanced, active, severe proliferative diabetic retinopathy (370 eyes, 240 with prior scatter photocoagulation)

Randomization

Early vitrectomy versus conventional management

Outcome Variable

Visual acuity 20/40 or better

Results

Visual acuity 20/40 or better was more frequent in early-vitrectomy groups (1–6 months from baseline); benefit of early vitrectomy was seen only in eyes with most severe proliferative diabetic retinopathy

Vitrectomy techniques have progressed considerably since this clinical trial. Instrumentation is markedly improved and photocoagulation can be done at the time of vitrectomy. Side effects have been reduced [41–44]. These clinical trial data, supported by additional case series, document the value of vitrectomy in eyes with very severe PDR or severe vitreous hemorrhage.

MEDICAL APPROACHES

Although photocoagulation, in combination with vitrectomy when necessary, is markedly effective in reducing the risk of blindness in persons with diabetic retinopathy, prevention of the development of retinopathy would be even more effective in preserving vision.

Blood Glucose Control. For years, there was debate as to whether improved control of blood glucose would reduce the chronic complications of diabetes, including diabetic retinopathy. Definitive studies have confirmed the benefit of blood glucose control.

Diabetes Control and Complications Trial, 1983–1989, Epidemiology of Diabetes Interventions and Complications. The Diabetes Control and Complications Trial (DCCT) was initiated to address this important clinical and scientific question [45]. The DCCT enrolled 1441 patients with type 1 diabetes (726 with no retinopathy and 715 with mild-to-moderate NPDR at baseline). These patients were randomly assigned to either intensive or conventional insulin therapy. Not only was there a remarkable reduction in the rate of development or progression of retinopathy in those patients assigned to intensive treatment (Table 9.8 and Fig. 9.8), there was also a reduction in the progression of diabetic nephropathy and neuropathy [46–48].

At the completion of the DCCT, 95% of the study patients were enrolled in the follow-up study called the Epidemiology of Diabetes Interventions and Complications (EDIC) study [49]. All patients were instructed in intensive insulin treatment and were all encouraged to achieve optimal control of blood sugar. By 5 years after entry, the 2% point difference in hemoglobin A1C levels between the former intensive treatment group and the conventional treatment group had narrowed to virtually no difference between the two groups (persons in the intensive group could not maintain their former level of good blood glucose control and persons in the conventional treatment group improved their average hemoglobin A1C). Despite the similar blood glucoses over the four years after the end of the clinical trial, further progression of diabetic retinopathy continued to be 66% to 77% less in the former intensive treatment group than in the former conventional treatment group. The benefit derived from the years of difference in diabetes control during the DCCT persists even at 7 years after the randomly assigned groups reverted to “standard care.” It appears to take time for improvements in control to negate the long-lasting effects of prior prolonged hyperglycemia, and once the biological effects of prolonged improved control

are manifest, the benefits are long lasting. Furthermore, the total glycemic exposure of the patient (i.e., degree and duration) determines the degree of retinopathy observed at any one time.

A smaller randomized clinical trial of 102 patients with type 1 diabetes, observed for more than 7 years, also found that intensified insulin treatment reduced all three of the major microvascular complications of diabetes [50]. These consistent clinical trial results, combined with the strong observational study results [51], directly implicate elevated blood glucose in the development of the chronic microvascular complications of diabetes.

Evidence is accumulating to confirm the impression that microvascular complications are the result of chronic elevations of blood glucose levels. These complications take years to develop and are directly associated with long-term elevations of glycosylated hemoglobin. It also appears that it may take several years to realize the benefits of effective interventions to lower blood glucose.

Early studies of the effect of intensified glucose control on retinopathy actually demonstrated an unanticipated and paradoxical worsening of retinopathy in patients whose blood glucose control was rapidly markedly improved [46,52–58]. However, in patients with mild-to-moderate NPDR, this early worsening is not usually associated with visual loss, and the long-term benefits of intensive insulin treatment greatly outweighed this risk in the DCCT [59]. When intensive insulin treatment is to be instituted in patients who have PDR or severe NPDR, ophthalmologic consultation is desirable because photocoagulation may be desirable prior to initiating intensive insulin treatment.

The effect of glycemic control on the incidence and progression of diabetic microvascular complications, as assessed in observational studies, is similar in both type 1 and type 2 patients [60]. Randomized studies of the effect of intensive glucose control on type 2 patients in Japan and the United Kingdom have demonstrated benefits from reduced blood glucose similar to those found for type 1 patients by the DCCT [61–63].

The clinical implications of the DCCT results have been extensively discussed and the evidence is compelling that better blood glucose control lowers the risk of the chronic complications of diabetes. Data exist to suggest that avoiding prolonged blood glucose elevations may be useful for most patients with diabetes. Unfortunately, although the risk is significantly reduced with intensive effort, it is not yet eliminated for many patients. The search for additional methods of preventing and treating the chronic complications of diabetes, including retinopathy, therefore continues.

Serum Lipid Lowering. Some currently available treatments may be effective in slowing the progression of diabetic retinopathy or reducing its complications. Higher serum lipids are associated with a greater risk of developing high-risk PDR, as well as with a greater risk of developing vision loss from diabetic macular edema and associated retinal hard exudates. Therefore, in addition to reducing the risk of cardiovascular disease, lowering elevated serum lipids may also reduce the risk of vision loss from diabetic retinopathy [64].