Lloyd Paul Aiello, MD, PhD
In addition to the gold standard treatments for DR/DME (systemic control and laser therapies), there are currently 3 lines of investigation for new pharmaceutical DR/DME treatments: anti-VEGF, PKC inhibitors, and intravitreal steroids.
Systemic control includes blood glucose, blood pressure, and blood lipids. Two clinical trials have established the importance of lowering A1C to reduce the progression of DR. The Diabetes Control and Complications Trial (DCCT) showed that intensive glycemic control reduced the likelihood of a 3-step reduction in visual acuity by about 5-fold over 10 years compared to conventional control in patients with type 1 diabetes. The Epidemiology of Diabetes Interventions and Complications (EDIC), a follow-on observational study of the DCCT, further showed that even after the DCCT concluded, former members of the DCCT intensive control group continued to have lower average A1C over 4 years than former members of the DCCT conventional control group who were switched to intensive treatment for EDIC. The cumulative incidence of further progression of retinopathy has been about 3-fold higher in the former conventional control group than in the former intensive control group over the 4-year span of the EDIC. Likewise, the United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive glucose control and intensive blood pressure control resulted in statistically significant reductions in the development of retinopathy, the need for photocoagulation, and the incidence of other microvascular outcomes in patients with type 2 diabetes.
The Early Treatment of Diabetic Retinopathy Study (ETDRS) showed that laser panretinal photocoagulation (PRP) virtually halted the progression of PDR over 3-5 years compared to the rate of progression observed in the earlier Diabetic Retinopathy Study (DRS), in which approximately 30% of eyes progressed over 3 years. The effect of laser photocoagulation on DME is not as durable as for PDR, but still reduced the development of moderate vision loss by more than half over 3 years in the ETDRS. A new technique known as Pascal laser is in clinical trials for DME. Pascal laser puts up to 56 localized laser burns per treatment. Each treatment is 20 milliseconds in duration, rather than the 0.2 seconds duration for conventional photocoagulation. The Diabetic Retinopathy Clinical Research Network (DRCR.net) is currently conducting a clinical trial of mild macular grid photocoagulation versus modified ETDRS focal/grid photocoagulation. The investigational laser procedures are less destructive to the retina than conventional treatment.
Several anti-VEGF approaches are in or nearing evaluation for DME. VEGF has a number of characteristics that suggest it as a target for therapy. VEGF is endothelial-cell selective, and is an angiogenic and vasopermeability factor. It is produced by numerous ocular cell types and is diffusible within the eye. Its expression increases with hypoxia, and is closely correlated with retinal neovascularization and edema in human ischemic retinal disorders, including DR. Pegaptanib is an anti-VEGF aptamer that selectively binds and inhibits 1 of 4 VEGF isoforms. It has been FDA-approved for age-related macular degeneration (AMD) and shows little toxicity. It is administered as an intravitreal injection about every 6 weeks. A Phase II, multicenter, randomized, controlled, double-masked, parallel, dose-ranging study showed it had a modest statistically significant effect on reducing macular thickness and improving visual acuity in DME, with a potential effect on the regression of neovascularization. A Phase III trial in DME is ongoing. Ranibizumab is a monoclonal, modified, humanized anti-VEGF antibody fragment with a high affinity for all isoforms of VEGF. Like pegaptanib, it is also administered as a repetitive intravitreal injection. Phase II trials for DME have been completed and Phase III studies are planned. A pilot study of 10 eyes in 10 patients receiving 1 injection of ranibizumab each month for 3 months followed by monitoring for 24 months was reported in October, 2006. This study found that 4 of 10 patients gained at least 15 letters of visual acuity with treatment, 5 of 10 gained 10 or more letters, and 8 of 10 gained at least 1 letter. Central retinal thickness was reduced in a dose-dependent manner. No systemic adverse events were reported, but 5 instances of mild to moderate ocular inflammation were noted. A nonrandomized study of ranibizumab now in press has shown that VEGF is a critical stimulus for DME. Treated patients experienced improvements in visual acuity and foveal thickness, with no systemic or ocular adverse events. DRCR.net is conducting a Phase II evaluation of bevacizumab for DME in 121 patients treated with bevacizumab with and without laser photocoagulation. All 12-week visits for this study have been completed, and data is forthcoming.
PKC inhibition represents an antisignaling approach to the treatment of DR/DME. PKC β inhibition has been investigated in at least 5 completed or ongoing clinical trials. The goal of these trials is to reduce moderate visual loss for at least 6 months. In a trial of 813 patients randomized to placebo or 32 mg ruboxistaurin, treated patients were significantly less likely to lose 15 or more letters of visual acuity. Selective PKC β inhibition with orally administered ruboxistaurin is well tolerated and reduces the risk of significant moderate visual loss by 41% in patients with moderately severe to very severe nonproliferative DR (NPDR). It also reduces the need for initial focal laser treatment, and increases the chance of moderate visual gain. The FDA has deemed ruboxistaurin approvable. Additional requirements for another controlled trial and regulatory approval are currently under discussion.
Intravitreal triamcinolone acetonide has been used in numerous case series and small controlled studies as a treatment for DME despite the fact that it is not formulated for intraocular use, not preservative-free, and not FDA-approved for treatment of DME. It appears to have a substantial effect on retinal thickness and may improve visual acuity in some eyes. However, there also appears to be a need for repetitive injections, and side effects include intraocular pressure increase, cataract formation, and inflammation. DRCR.net is conducting a randomized trial of 693 patients comparing intravitreal corticosteroids and laser photocoagulation for DME using a triamcinolone forumulation specifically designed for intravitreal use. Follow-up for this trial is ongoing, with some patients having been followed for over 2 years. DRCR.net is also conducting a trial of peribulbar triamcinolone with and without focal photocoagulation for mild DME in a multicenter, randomized phase II trial. The 34-week primary endpoint follow-up for this trial has been completed, and a 2-year safety follow-up is ongoing.
Much progress has been made in the development of new treatments for DR/DME, but there is still much work to be done. Much progress on the road from bench to bedside has been accomplished recently, and the rate of new information is accelerating. We are nowhere near the end of our investigations into new treatments for DR/DME.
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