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

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In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (Table 14.3) [58], among 9795 participants with type 2 diabetes, those treated with fenofibrate were less likely than controls to need laser treatment (5.2% vs. 3.6%, P < 0.001). However, the severity of diabetic retinopathy, indications for laser treatment, and type of laser treatment (focal or pan-retinal) were not reported.

The Collaborative Atorvastatin Diabetes Study (CARDS), a randomized clinical trial of 2830 patients with type 2 diabetes, did not find atorvastatin to be effective in reducing diabetic retinopathy progression [68,69]. The study was limited by substantial missing data (only 65% had retinopathy status at baseline) and lack of photographic grading for diabetic retinopathy. There are several ongoing RCTs that may clarify the role of lipid reduction in diabetic retinopathy. The Atorvastatin Study for Prevention of Coronary Endpoints in NIDDM (ASPEN) [70] will evaluate the effects of atorvastatin in diabetic retinopathy and the ACCORD-EYE study [53] will compare treatment to increase high density lipoprotein (HDL) and reduce low density lipoprotein (LDL) (fibrate + statin) with LDL reduction only (statin and placebo) on diabetic retinopathy.

SECONDARY INTERVENTION

Medical Interventions. Various other medical interventions for diabetic retinopathy are described in Table 14.3 and summarized below.

Antiplatelet Agents. With regards to the efficacy and safety of aspirin, the ETDRS showed that aspirin (650 mg/day) had no beneficial effect on diabetic retinopathy progression or loss of visual acuity in patients with diabetic macular edema or severe nonproliferative diabetic retinopathy during 9-years of follow-up [59,60]. Aspirin treatment was not associated with an increased rate of vitrectomy [59,60]. A smaller randomized clinical trial evaluating aspirin alone and in combination with dipyridamole reported a reduction in microaneurysms on fluorescein angiograms in both groups as compared to placebo [61]. A similar trend was seen in a small randomized clinical trial [62] evaluating ticlodipine although results were not statistically significant.

Protein Kinase C Inhibitors. In recent years, there has been significant interest in the use of protein kinase C (PKC) inhibitors for treatment of diabetic retinoipathy. Hyperglycemia induces synthesis of diacylglycerol in vascular cells, leading to activation of PKC isozymes, particularly PKC-ß. Excessive PKC activation is thought to be a key pathophysiological mechanism of diabetic retinopathy. The PKC-Diabetic Retinopathy Study evaluated the effects of ruboxistaurin, an orally active, selective PKC-ß inhibitor [63]. The study randomized 252 patients with moderate to severe nonproliferative diabetic retinopathy to receive ruboxistaurin (8, 16, or 32 mg) or placebo. No significant difference in diabetic retinopathy progression was seen after 36 months of follow-up, although patients treated with 32 mg of ruboxistaurin had a significant reduction in the risk of moderate visual loss. Treatment was well tolerated with few adverse events, largely mild gastrointestinal symptoms. A larger study, which randomized 685 patients, showed similar results [71].

VH = vitreous hemorrhage; NPDR = nonproliferative diabetic retinopathy, NV = neovascularization; NVD = neovascularization of the disk, PDR = proliferative diabetic retinopathy, DME = diabetic macular edema, PRP = panretinal photocoagulation; RR = risk reduction; MVL = moderate visual loss, SVL = severe visual loss; Hex = hard exudates, vs. = versus; BP = blood pressure.

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The PKC-Diabetic Macular Edema Study reported no significant reduction in progression of diabetic retinopathy or incidence of diabetic macular edema in 686 patients with mild to moderate nonproliferative diabetic retinopathy with no prior laser therapy [64,72]. However, there was a trend for a reduction in clinically significant diabetic macular edema among patients treated with 32 mg ruboxistaurin (P = 0.041), with a larger effect when patients with HbA1c levels of 10% or greater were excluded (P = 0.019).

Aldose Reductase Inhibitors. The rate controlling enzyme in the polyol pathway of glucose metabolism is aldose reductase. Excess glucose is converted into fructose and sorbitol in the retina and may play a key role in the pathogenesis of diabetic retinopathy. Two aldose reductase inhibitors, sorbinil (Pfizer, New York, NY) and tolrestat (Wyeth-Ayerst, St. Davids, PA) showed no statistically significant effect in reducing diabetic retinopathy incidence or progression in RCTs of 3 to 5 years duration [65]. About 7% of the patients assigned to sorbinil in one randomized clinical trial developed a hypersensitivity reaction in the first 3 months [65].

Growth Hormone/Insulin-like Growth Factor Inhibitors. Studies showing improvements in diabetic retinopathy following surgical hypophysectomy [73,74], and of elevated serum and ocular levels of insulin-like growth factor in patients with severe diabetic retinopathy led to researchers investigating the use of agents inhibiting the growth hormone–insulin-like growth factor pathway for prevention of diabetic retinopathy [75]. A small randomized clinical trial over 15 months among 23 patients reported reduction in retinopathy severity with octreotide, a synthetic analogue of somatostatin that blocks growth hormone [67], but another trial conducted over 1 year among 20 patients [76] evaluating continuous subcutaneous infusion of octreotide found no significant benefits. Two larger trials currently evaluating extended release octreotide injection [77,78] have reported inconclusive preliminary results [79], with significant adverse effects (e.g., diarrhoea, cholelithiasis, hypoglycemic episodes).

Laser and Surgical Interventions for Severe Nonproliferative Diabetic Retinopathy and Proliferative Diabetic Retinopathy

Panretinal Laser Photocoagulation. There is strong evidence that panretinal laser photocoagulation (PRP) is useful for treating severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy [80] (Table 14.4). Two landmark clinical trials, the Diabetic Retinopathy Study (DRS) [80,81] and the ETDRS [82], provide high-quality data on the effectiveness and safety of PRP on clinically relevant outcomes.

The DRS randomized 1758 patients with proliferative diabetic retinopathy in at least one eye or bilateral severe nonproliferative diabetic retinopathy to PRP or no treatment. At 2 years, severe visual loss (visual acuity <5/200 on two successive visits) was seen in 6.4% of treated versus 15.9% of untreated eyes, with the greatest benefit in eyes with high-risk characteristics (new vessels at the optic disc or vitreous hemorrhage with new vessels elsewhere), in which the risk of severe visual

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loss was reduced by 50% [80]. The ETDRS [82] randomized 3711 patients with less severe diabetic retinopathy and visual acuity >20/100 to early PRP or deferral (4-monthly observation, and treatment if high-risk proliferative diabetic retinopathy developed). Early PRP treatment decreased the risk of high-risk proliferative diabetic retinopathy by 50% as compared to deferral, although the incidence of severe visual loss was low in both early and deferral groups (2.6% vs. 3.7%).

The effectiveness of PRP has been confirmed by other RCTs [86–88] and a meta-analysis with a combined data of 2243 patients [83].

There are well-known adverse effects of PRP. These include visual field constriction (important for driving [97,98]), reduced night vision, color vision changes, reduced contrast sensitivity, inadvertent laser burn, macular edema exacerbation, acute glaucoma, and traction retinal detachment [99]. The possibility of visual loss immediately following PRP is also well recognized. The DRS reported vision loss of 2 to 4 lines within 6 weeks of PRP in 10% to 23% of patients versus 6% for controls [100].

Surgical Vitrectomy for Proliferative Diabetic Retinopathy. Vitrectomy is used for treatment of eyes with advanced diabetic retinopathy, including proliferative diabetic retinopathy with nonclearing vitreous hemorrhage or fibrosis, areas of traction involving or threatening the macula, and more recently, persistent diabetic macular edema with vitreous traction (Table 14.5) [101]. The Diabetic Retinopathy Vitrectomy Study (DRVS) randomized 616 eyes with recent vitreous hemorrhage and visual acuity ≤5/200 for at least 1 month to early vitrectomy within 6 months or observation [102–105]. After 2 years follow-up, 25% of the early vitrectomy group versus 15% of the observation group had ≥20/40 vision, with the benefits maintained at 4 years and longer in type 1 diabetes. The DRVS also randomized 381 eyes with severe proliferative diabetic retinopathy and visual acuity >10/200 to early vitrectomy or conventional management. Treatment increased the probability of visual acuity ≥20/40.

The indications of vitrectomy have expanded in the last few years because of advances in vitrectomy, including wide-field viewing, endolaser treatment, heavy liquids, and bimanual instrumentation to manipulate the retina [112].

Laser and Surgical interventions for Diabetic Macular Edema

Focal Laser Photocoagulation. There is high quality evidence that focal laser photocoagulation preserves vision in eyes with diabetic macular edema. The ETDRS [91] randomized 1490 eyes with diabetic macular edema to receive focal laser treatment or observation. At 3 years, treatment significantly reduced moderate visual loss as compared with observation [91], with the greatest benefits in eyes with clinically significant diabetic macular edema [113]. However, there remains limited evidence that the type (argon, diode, dye, krypton) or method of laser used influences outcomes [92,114–116].

Adverse effects of focal laser treatment are well documented, and include inadvertent foveal burn, central visual field defect, color vision abnormalities, subretinal fibrosis, and spread of laser scars.