Diabetic retinopathy remains the most frequent cause of newly diagnosed blindness in adults from 20 to 74 years of age. This fact remains despite the use of a variety of treatment options including laser, vitreous surgery, intravitreal injections and more effective means for blood glucose and blood pressure control. Here, we review the clinical studies that have defined our current standard of care and present current trials that are changing the standard.
Glucose and Blood Pressure Control
While the age at onset and the duration of diabetes are the strongest predictors for development and progression of retinopathy, controlling both blood sugar and blood pressure are the most important elements of treatment. The Diabetic Control and Complications Trial (DCCT) demonstrated that tighter glycemic control reduced vision loss in Type 1 Diabetics.1 The United Kingdom Prospective Diabetic Study (UKPDS) found that every point decrease in hemoglobin A1C (HgA1C) produced a 35-percent reduction in microvascular complications.2 This study also concluded that tight blood pressure control (<150/85) reduced microvasular complications by 37 percent compared to less well-regulated blood pressure control. A 10-mm decrease in systolic and a 5-mm decrease in diastolic had a 47-percent reduction of moderate visual loss, as well as a reduction in death from the diabetes or a stroke.
Imaging, Grading and Laser Treatment
Diabetic retinopathy usually progresses from mild to moderate to severe non-proliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR). Examples of diabetic retinopathy imaged with fundus photos, angiography and optical coherence tomography are shown in Figure 1. Laser treatment remains the mainstay for each form of diabetic retinopathy. The Diabetic Retinopathy Study (DRS) showed that retinal (scatter) photocoagulation significantly reduced severe visual loss (5/200 or worse) in high-risk eyes [high risk included "significant" disk neovascularization (NVD) or neovascularization elsewhere (NVE) with vitreous hemorrhage].3 Overall, the risk of legal blindness was reduced by 50 to 60 percent. The Early Treatment Diabetic Retinopathy Study showed laser treatment of eyes with clinically significant macular edema cut the risk of doubling visual angles from 24 percent to 12 percent.4 Thus, the rate of vision loss was reduced by 50 percent. In addition, up to 20 percent of patients undergoing laser treatment had some improvement in vision.
Clinical Trials
Though glucose and blood pressure control and laser treatments are helpful, the number of patients who gain vision is small.5 New treatments are being evaluated to determine whether visual improvement can be achieved. First, we will review two large Phase III studies that have been completed; then we will discuss the newest clinical trials now under way.
Recently Completed Clinical Trials
• Protein kinase C inhibitor—Ruboxistaurin (Arxxant). Hyperglycemia increases serum and cellular levels of diacylglycerol, which is a physiologic activator of protein kinase C (PKC). Activated PKC levels are associated with both increased levels of vascular endothelial growth factor (VEGF) and increased vascular permeability.6,7 Ruboxistaurin is a selective inhibitor of PKC.
In a Phase III study involving 685 patients randomized at 70 centers, a dose of 32 mg/day taken orally was effective in delaying the occurrence of moderate visual loss. Sustained moderate visual loss occurred in 9.1 percent of placebo-treated patients versus 5.5 percent of ruboxistaurin-treated patients (40 percent reduction, p= 0.034). Visual improvement (>/=15 letters) was seen in 4.9 percent treated vs. 2.4 percent placebo. Laser treatment for macular edema was reduced in the treated group, but a reduction in progression of diabetic retinopathy from moderately severe to very severe was not observed. Eli Lilly has received an approvable letter from the Food and Drug Administration.
• Octreotide—Sandostatin LAR. Two Phase III studies (Study 802 and 804) utilizing the insulin-like growth factor antagonist octreotide have been completed.8 The purpose of the studies was to evaluate the impact of 20-mg and 30-mg doses of Sandostatin LAR, given monthly by intramuscular injection, on progression of preexisting diabetic retinopathy. Secondary end points were time to development of macular edema and loss of visual acuity. Study patients from sites in the
Ongoing Clinical Trials
Ongoing trials can be analyzed in terms of the type of retinopathy and the target tissue. Most trials are targeting VEGF or the anti-inflammatory aspects of diabetic retinopathy.
• Intravitreal triamcinolone acetate. Intravitreous triamcinolone acetate (See Figure 2) has been used for the off-label treatment of diabetic retinopathy. Limited retrospective and prospective studies have shown improvements or stabilization in visual acuity in the short term, especially in patients with cystoid macular edema.9-14 The side effects—cataract in 20 to 100 percent of patients, depending on the number of injections and length of time the patient was followed; intraocular pressure elevation in 40 percent of patients; and a low risk of both pseudo-endophthalmitis and bacterial endophthalmitis—have limited its use. IVTA has been utilized for the treatment of diffuse macular edema, at end of vitrectomy surgery to decrease fibrin and leakage, during vitrectomy to better visualize the clear vitreous, as an adjunct of patients undergoing panretinal photocoagulation to reduce post- laser macular edema, and prior to grid and focal treatment to reduce edema. The Diabetic Retinopathy Clinical Research Network study group is currently evaluating IVTA versus laser treatment with plans for additional studies as well (see below).
• Sustained-release corticosteroid devices. Retisert (Control Delivery Systems and Bausch & Lomb) is an implantable nonbiogradable intraocular device that delivers 0.59 mg of fluocinolone acetonide for up to three years at a rate of 0.5 micrograms per day.15 The implant is constructed of a 1.5-mm core of drug and a silicone/polyvinyl acetate laminated coating affixed to a strut. At 24 months in the Phase II trial, 28 percent of treated patients improved three or more lines compared to 8.7 percent undergoing standard of care. A three-line or greater decrease in visual acuity occurred in 15.7 percent of patients treated with the implant and in 13 percent receiving standard of care. Complete resolution of macular edema occurred in 53.7 percent of patients receiving an implant versus 28.6 percent of patients receiving standard of care. Sixty percent of patients had IOP elevation; 19.5 percent of patients receiving the 0.5-mg dose needed a glaucoma filtering procedure; 74.2 percent of patients receiving the 0.5-mg dose developed serious cataract progression versus 13.3 percent in the standard of care group. The Retisert implant is currently approved for chronic non-infectious posterior uveitis. Phase III studies have yet to be undertaken for diabetic retinopathy.
Medidur (Alimera Sciences) is being evaluated in a Phase III trial in the treatment of diabetic macular edema. Medidur is an injectable device that delivers fluocinolone acetonide into the back of the eye. This is an office procedure, unlike the Retisert, which is placed in an operating room. The drug and coating of the Medidur device are similar to those used in the Retisert implant.
Posurdex (Allergan) is an intravitreal, dexamethasone, extended-release biodegradable implant. It has been shown in a Phase II, multicenter trial to significantly improve vision in patients with DME. A total of 306 patients were randomized 1:1:1 to Posurdex 350 micrograms, Posurdex 750 micrograms or observation. Efficacy results were based on 90 days of follow-up and safety, for 180 days.
The 700-microgram dose improved eyes with persistent macular edema compared to observation through six months. Visual acuity improved by 15 letters in 18.1 percent of patients receiving the 700-microgram dose versus 5.7 percent of patients in the observational group. An intraocular pressure increase of 10 mmHg or more was observed in only 2 percent of patients receiving active treatment versus 1 percent of observational cases. Though the original study was performed with an implantable biodegradable system placed in the operating room, an office-based 22-ga. injector system was tried and the results were similar. The 22-ga. office injector system is currently being used in Phase III trials.27
Anti-VEGF Drugs
• Macugen. VEGF levels have been found to be elevated in the vitreous and in anterior chamber samples in patients with proliferative diabetic retinopathy. Pegaptanib (Macugen OSI/Eyetech), an aptamer that was the first approved anti-VEGF treatment for neovascular age-related macular edema, inhibits VEGF 165. In a prospective multicenter, randomized Phase II trial, pegaptanib at 0.3 mg, 1 mg and 3 mg versus sham injection was administered at six-week intervals via intravitreal injection.16,17 Focal laser therapy was allowed prior to enrollment and after week 18. Patients received injections at baseline, week six and week 12, with additional injections as needed until week 30. There were 172 participants with 39 assigned to the 0.3-mg dose.
Visual acuity improvement of one or more letters was observed in 34 percent of study eyes compared with 10 percent of control. Central retinal thickness, measured on optical coherence tomography, was decreased by 64 µm in the 0.3-mg treated group versus a gain of 4 µm in the standard of care group and a significant improvement in visual acuity was observed. Regression of proliferative retinopathy, less severe venous beading, reduction of intraretinal microvascular abnormalities, and reduced need for photocoagulation were also observed. Phase III trials are currently recruiting.
• Ranibizumab. Ranibizumab (Genentech) is the only approved anti-VEGF drug that has been shown to improve vision in patients with choroidal neovascularization and is a pan-isoform VEGF suppressor. A single center, dose-escalating pilot study of ranibizumab for patients (n=10) with central clinically significant macular edema has been reported, and the investigators noted improved vision in the majority of patients, particularly at higher doses. Improvement of macular edema was also observed with a reduction of 45.3 ±196.3 µm in the low-dose group and 197.8 ±85.9 µm in the high-dose group.26
In a Phase I study, Ranibizumab for Edema of the Macula in Diabetes (READ-1), there was an improvement in both visual acuity and OCT in patients (n=10) who received 0.5-mg ranibizumab at baseline, and months one, two, four and six. At month seven, a mean of 14 ETDRS letters was gained, and there was an OCT reduction of 246 µm from baseline.25 A Phase II study utilizing the 0.5-mg dose is currently enrolling.
• Avastin. Because of the cost of the currently available anti-VEGF treatments and the availability of bevacizumab (Avastin, Genentech), a number of case reports and limited retrospective and prospective studies have utilized this drug off-label. Avastin is a full-length antibody against the VEGF molecule. Small series have shown short-term improvement in DME (See Figure 3), regression of proliferative retinopathy, clearing of vitreous hemorrhage and regression of rubeosis.18-22 The DRCR.net study group is currently evaluating Avastin in the treatment of diabetic retinopathy (see below).
• VEGF Trap. The VEGF Trap (Regeneron and Bayer Health Care) is a fully human soluble decoy, smaller than an antibody, consisting of the Ig-2 domain of VEGF receptor 1 and the Ig-3 domain of VEGF receptor 2. It is fused to an Fc fragment protein that binds all forms of VEGF isoforms, as well as placental growth factor.24 The VEGF trap is now completing Phase II studies for the treatment of choroidal neovascularization secondary to AMD and will begin Phase II trials for the treatment of diabetic eye disease.
Pharmacological Vitrectomy
A posterior vitreous detachment has been shown to help in decreasing macular edema, and may slow the development of serious proliferative retinopathy. Vitrectomy has been suggested as an adjunct to the treatment of DME in selective cases. The rational for vitrectomy surgery includes relief of anterioposterior and tangential traction, removal of vasoproliferative and vasopermeable factors from the vitreous, and increasing the oxygen consumption of the retina. Pharmacological vitrectomy involves the dissolution of the mechanical forces in the vitreous by chemical means. The goal is to achieve some of the results of vitrectomy surgery without surgical interventions. The results of small uncontrolled studies have been encouraging.
• Vitrase. A specially purified form of hyaluronidase, Vitrase (ISTA Pharmaceuticals), was studied in Phase III trials and showed a clinically significant reduction in vitreous hemorrhage which allowed laser treatment, but the primary endpoint of improved visual acuity was not achieved.23 The drug was therefore not approved for treatment of vitreous hemorrhage, although it has been used off-label for this purpose. A pilot study of Vitrase-injected patients did show a higher chance of developing a posterior vitreous detachment compared to an injection of saline or gas.
• iCo-007. Discovered and designed by ISIS Pharmaceuticals, iCo-007 is a second-generation, anti-sense drug that inhibits production of c-Raf Kinase, an enzyme associated with the formation of new, abnormal and fragile blood vessels in the eye.
DRCR
The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a collaborative network dedicated to facilitating multicenter clinical research of diabetic retinal diseases. The network was formed in September 2002 and currently includes more than 150 participating sites with more than 500 physicians. The network is funded by the National Eye Institute. The network has recently completed a study looking at the temporal variation in OCT measurements of retinal thickening in DME.
The following studies are in a follow-up phase: 1) a pilot study of laser photocoagulation for DME; 2) a randomized trial comparing intravitreal triamcinolone acetonide and laser photocoagulation for DME; 3) a pilot study of peribulbar triamcinolone acetonide for DME; and 4) a Phase II evaluation of anti-VEGF therapy (bevacizumab) for DME (See Figure 3).
Active recruitment is currently ongoing for the following studies: 1) an evaluation of vitrectomy for DME; 2) an observational study of the development of DME following scatter laser photocoagulation; and 3) a study to follow subclinical DME found on OCT for progression. Several additional studies are planned looking at the effects of cataract surgery on retinopathy and the treatment of DME with anti-VEGF therapy. Additional information concerning the network can be obtained from its website: public.drcr.net.
Diabetic retinopathy remains a major cause of blindness. With the addition of pharmacotherapy, either alone or in combination, improved visual results with less vision loss may be possible.
Drs. Boyer and Gallemore are in practice with the Retina-Vitreous Associates Medical Group. Dr. Boyer is an associate clinical professor at Doheny Eye Institute, USC School of Medicine and Dr. Gallemore is an assistant clinical professor at the Jules Stein Eye Institute, UCLA School of Medicine. Contact them at vitdoc@aol.com (DSB) and retina2000@yahoo.com (RPG).
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