Dramatic advances are being made in the emerging field of retinal pharmacotherapy.1 It is important to remember, however, that laser photocoagulation remains the gold standard of treatment for diabetic retinopathy2 until it can be directly compared to pharmacotherapy or alternative treatments in well-controlled prospective, randomized clinical trials.

Various studies of corticosteroids to treat diabetic macular edema (DME) are under way. Some are being conducted by the Diabetic Retinopathy Clinical Research Network.3-5 The following is a brief survey of some of the steroid implants under development for DME, known to the author of the time of the preparation of this lecture.

FLUOCINOLONE ACETONIDE
Early data on a fluocinolone acetonide bioerodable intravitreal implant (Retisert; Bausch & Lomb, Rochester, NY) suggested that steroids work but also highlighted that steroids can be dangerous.6 The study is being repeated using lower doses.

In the initial study, patients showed significant improvement, albeit with complications. If we consider only the reduction in macular thickening and the visual acuity at 6 months, the improvements are obvious. After that, however, the problems appear to overwhelm the benefits with the longer-acting, high-dose steroids. Fifty percent of the eyes had elevated pressures, and approximately 40% required filtration surgery.

A small, nonbioerodable fluocinolone acetonide implant (Medidur; Alimera Sciences, Alpharetta, GA) is also under development. It stays in the vitreous cavity and releases drug for up to 2 years, according to the manufacturer. Clinical trials are under way.

DEXAMETHASONE
The results were somewhat better with this bioerodable polymer implant, which contains the long-acting steroid dexamethasone (Posurdex; Allergan, Inc., Irvine, CA) This was likely because less drug was being released and possibly because of differences in the inherent potency of the active agent.

A phase 2 study showed a positive dose response relationship for all groups combined (Figure 1).7 At day 90 and day 180, there was a statistically significant increase in patients achieving 2 and 3 lines or more of visual acuity after receiving the steroid, compared with no treatment. These were patients who had previously failed laser therapy. Angiograms graded by masked readers indicated that there was a 2-step reduction in leakage compared with untreated controls (Figure 2).

This was the first randomized, prospective clinical trial that used optical coherence tomography (OCT) as an endpoint. When used as a surrogate measure for improvement, as opposed to vision or fluorescein angiography, OCT showed a fairly dramatic improvement that was also dose-related (Figure 3). Later observations may be confounded by cataract or glaucoma, which impact visual acuity.7

TRIAMCINOLONE ACETONIDE
De Juan and colleagues have developed a nonbioerodable helical coil containing triamcinolone acetonide (Ivation, Surmodics, Eden Prairie, MN), which essentially can be screwed into the eye and removed as needed. A clinical trial is under way.8

AWAITING FURTHER STUDY
One oversimplification that we occasionally use in teaching is that steroids for DME are beneficial in the short term but less so in the long term. On the other hand, laser therapy is less effective in the short term but very good in the long term. Perhaps combining the two modalities will provide the optimum benefit of short-term plus long-term efficacy while minimizing side effects. We await results from further studies to make this determination.9

For now, as a monotherapy, intravitreal steroids have not been shown to be superior to focal/grid photocoagulation at improving the chance for vision gain, decreasing the risk of vision loss, or causing regression of edema.3 This outcome is true whether the eye is pseudophakic at baseline, has had prior macular laser for DME, has a very thickened retina, or relatively poor visual acuity.3 Whether combining these drugs with laser is shown to be superior to focal/grid laser alone remains to be determined. For now, the standard care for DME remains focal/grid photocoagulation. ■

1. Blumenkranz MS. The current status of steroids in treating diabetic retinopathy. Retinal Physician. 2007;9:42-47.
2. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report No. 2. Ophthalmology. 1987;94:761-774.
3. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447–1459.
4. Chieh JJ, Roth DB, Liu M, et al. Intravitreal triamcinolone acetonide for diabetic macular edema. Retina. 2005;25:828-834.
5. Blumenkranz MS. Ongoing studies of intraocular sustained release drug delivery implants for macular edema. Retinal Physician. 2008;Jan.
6. Pearson P, Levy B, Comstock T, and Fluocinolone Acetonide Implant Study Group. Fluocinolone acetonide intravitreal implant to treat diabetic macular edema: 3-Year results of a multicenter clinical trial. Invest Ophthalmol Vis Sci. 2006;47: E-Abstract 5442.
7. Kuppermann BD, Blumenkranz MS, Haller JA, Williams, GA et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125:309-317.
8. Dugel PU, Cantrill HL, Eliott D, et al. Clinical safety and preliminary efficacy of an intravitreal triamcinolone implant (I-vation TA) in DME. Poster presented at the Association for Research in Vision and Ophthalmology, May 6–10, 2007, Fort Lauderdale, FL. Abstract 1413.
9. Grover D, Li t, Chang C. Intravitreal steroids for macular edema in diabetes. Cochrane Database of Systematic Reviews. 2008;23:CD005656.