Unmet Needs in Diabetic Macular Edema
In a prospective study by Jonas et al., 25mg intravitreal triamcinolone improved treated eyes versus control eyes, but there was elevation of intraocular pressure (IOP) as a side effect.21
DME is based upon their ability to reduce VEGF-induced leakage in animal models.23
In a
prospective, double-masked, placebo-controlled study by Gillies et al., 4mg intravitreal triamcinolone was compared with subconjunctival saline. Eyes treated with triamcinolone experienced an improvement in visual acuity (56% treated versus 26% placebo had improvement of >5 letters logarithm of minimum angle of resolution [logMAR] visual acuity) and IOP elevation (68% versus 10% increased by >5mmHg) compared with placebo eyes.22
The development of a steroid without the IOP- elevating side effects would be welcome.
Other steroids, such as dexamethasone and fluocinolone, have been investigated in DME eyes. These drugs are available as the dexamethasone implant Posurdex® (Allergan, Irvine, CA) and the sustained-release fluocinolone implant Retisert® (Bausch and Lomb, Rochester, NY). The fluocinolone implant was studied in diabetes patients in the Fluocinolone Acetonide Implant Study (FAIS).24
In FAIS, visual acuity
improved by three or more lines in 28% of implant-treated eyes versus 15% of standard of care eyes; edema resolved in 58% of implant-treated eyes versus 30% of standard of care eyes.24
However, there were
significant adverse events: 95% required cataract extraction and 30% required glaucoma surgery. The Posurdex implant is currently being evaluated in a phase III clinical trial for treatment of macular edema.
Another class of drugs acts upon cell adhesion molecules, which are key mediators of inflammatory processes and play a role in the pathogenesis of diabetic retinopathy.25
Efalizumab (Genentech, South
San Francisco, CA) inhibits the binding of LFA-1 (leukocyte function- associated antigen-1) to intercellular adhesion molecule-1 (ICAM-1),26 and therefore inhibits adhesion of leukocytes to other cell types. In the Combined Approach to Treatment Using Ranibizumab and Efalizumab for Diabetic Macular Edema Study: The CAPTURE DME Study, the safety and tolerability of efalizumab, administered subcutaneously as a weekly dose (1mg/kg), is compared with controls and with combination therapy with ranibizumab intravitreally.
With the potential promise of increased visual acuity, there is a need for sustained-release drug delivery devices. Durable treatments would be welcomed if studies show a need for continued monthly or other frequent injection regimens with the new drugs. Although there are clinical trials investigating sustained-release triamcinolone, devices for anti-VEGF drugs are needed. As mentioned above, there are currently sustained-release devices that deliver steroids. Perhaps this drug platform could also be utilized to deliver other drugs.
Another major unmet area of therapy is that for eyes with subfoveal deposits. At this time, there are no effective treatments for diabetic eyes with significant subfoveal lipid deposits. Following successful resolution of macular edema, foveal lipid can develop and limit visual acuity. In patients with chronic edema, foveal lipid also limits visual outcomes. Innovative treatments that could dissolve foveal lipid would be useful. Some studies have shown that surgery can remove the lipid but that visual acuity is limited.27,28
period of 43.2 months, visual acuity, which was improved in seven eyes US OPHTHALMIC REVIEW
(54%) at one year, was improved in only five eyes (38%) compared with pre-operative visual acuity. The mean final visual acuity change was not statistically significantly improved in the treatment versus the control group. Many eyes developed atrophy after removal of the submacular hard exudates and macular edema.
A treatment to also prevent lipid deposition in eyes at higher risk of foveal lipid development would be useful. Whether statins, such as atorvastatin, can lead to reduction of hard exudates in DME eyes is controversial.29
To date, there is no drug that can increase blood flow significantly enough to relieve ischemia in the retina. Perhaps treatments to improve oxygen delivery or to cause reversal of hypoxia could be developed. Currently, there is an on-going clinical trial using an siRNA inhibitor of hypoxia-inducible factor-1 alpha (HIF-1).30
A pilot study has shown that
HIF-1 is present in human proliferative diabetic membranes.30 Rapamycin (Sirolimus, MacuSight) is currently being evaluated in a phase II study as a subconjunctival injection versus placebo control for eyes with DME.31
Rapamycin has immunosuppressive, antiangiogenic, antimigratory, antiproliferative, antifibrotic, and anti-permeability activity, as well as interrupting the mammalian target of rapamycin (mTOR) pathway (HIF-1 alpha pathway). A phase I study has shown rapamycin was safe and well-tolerated in all doses tested via two different routes of administration. Improvements in visual acuity and decreased foveal thickness by OCT were found for up to 180 days following a single administration of rapamycin.
Recently, there has been discussion of neural enhancement in the area of DME. Studies conducted with brimonidine in animals have shown increased responses from retinal ganglion cells in eyes with optic neuropathy and glaucomatous optic neuropathy.32
Studies in humans are in their early stages. Perhaps applications to DME will follow.
Chronic macular edema unresponsive to treatment is a significant problem. Various studies already mentioned have focused on this area. Perhaps combinations of therapy may be useful. Use of neuroprotective agents to protect the retinal photoreceptors and ganglion cell layers in eyes with long-standing edema may be helpful, while treatments to reduce the edema are given.
Lastly, effective preventive therapies for DME would be a welcome addition to our treatment armamentarium. The Age-related Eye Disease Study (AREDS) showed the efficacy of antioxidants and zinc in preventing the progression of AMD.33
Perhaps drugs to reverse hypoxia,
or to limit its effects, would be useful in patients with diabetes. The ruboxistaurin study attempted to prevent retinopathy.34,35
were not significant for the prevention of macular edema in the vast majority of patients. However, the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2) reduced the rate of sustained moderate visual from 9% to 5.5% over three years versus placebo. Patients had a 45% reduction in the risk of development of clinically significant DME and had a 26% reduction in their need for focal laser.
Over a mean post-operative observation
It is well accepted that improved systemic management delays the progression of retinopathy. The Diabetes Control and Complications Trial (DCCT),36
the UK Prospective Diabetes Study (UKPDS),37 and the 103 The results
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