Posterior Segment Diabetic Macular Edema
endothelial growth factor (VEGF) therapy for age-related macular degeneration (AMD) ushered in pharmacologic treatments that actually improve visual acuity in about one-third to 40% of AMD eyes with subfoveal choroidal neovascularization (CNV).5,6
Previously, physicians
could only hope to stabilize vision in these eyes. These treatments are currently undergoing clinical trials for the treatment of DME and proliferative diabetic retinopathy. The use of anti-VEGF treatments in diabetic retinopathy is based upon the well-demonstrated presence of elevated VEGF concentrations in eyes with proliferative diabetic retinopathy and DME.7,8
The first anti-VEGF drug studied in clinical trials for treatment of macular edema was pegaptanib sodium (Macugen®, Eyetech Pharmaceuticals/ Novartis). Although intraocular injections of pegaptanib sodium given every six weeks for up to six months did result in decreased ocular coherence tomography (OCT) thickness as compared with that in sham-treated eyes, there was not a large change in visual acuity in treated versus sham eyes. Visual acuity improved by three or more lines in 18% versus 7% in control eyes (p=0.12) at year one.9
The difference at
three years is not yet published. The need for laser photocoagulation (between weeks 12 and 36 in the study) was much less in treated eyes than control eyes (0.3mg versus sham, 25% versus 48%; p=0.04).
Recently, bevacizumab (Avastin®, Genentech, South San Francisco, CA), as well as ranibizumab (Lucentis®, Genentech, South San Francisco, CA) have been used in limited case series for treatment of DME.10–15
bevacizumab have been shown to rapidly decrease macular edema and thus normalize the ultrastructure of the macula in these diabetic eyes. In these case series, these anatomic changes seen on OCT have been associated with improved visual acuity.10–15
In the DRCR Network phase II study, 121 subjects were randomized to one of three groups: laser versus bevacizumab (two doses) versus bevacizumab with laser. There was evidence of reduced macular thickness in some eyes. In a study by Chun et al., 10 patients with center- involving macular edema underwent three intravitreal ranibizumab injections (baseline, month one, and month two).14
At six months, both
the low dose (0.3mg) and high dose (0.5mg) groups experienced significant decreases in central OCT thickness compared with baseline.14
There are on-going studies comparing intravitreal anti-VEGF and other therapies both with each other and with standard laser photocoagulation. There are also studies looking at combination therapies (laser with adjunctive intravitreal anti-VEGF or steroid injections) compared with laser alone or anti-VEGF treatments alone. Some of these treatments have recently shown greater improvements in visual acuity outcomes compared with the ETDRS laser photocoagulation results.
The Ranibizumab for Edema of the Macula in Diabetes-1 (READ-1) study showed evidence of resolution of macular edema and improvement of visual acuity in treated eyes. At the primary end-point at month seven, median and mean OCT thicknesses were reduced by 261 and 246µm respectively from baseline—an 85% reduction in excess foveal thickness.15
Based on the positive results seen with READ-1, READ-2 was initiated. In READ-2, 126 eyes were randomized to ranibizumab versus ranibizumab with laser versus laser alone. The six-month primary
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outcome results from the READ-2 study have recently been evaluated.16 At six months, about one-quarter of patients gained three or more lines in the ranibizumab group versus 12% in the ranibizumab with laser group versus no eyes in the laser alone group. Two-year data are now available. After the initial six months, all three groups of patients were eligible to receive intravitreal ranibixumab every two months. At two years, there was no significant difference in the visual acuity outcomes, which were a gain of 7.7 (ranibizumab group initially), 5.1 (laser group initially), and 6.8 (combination group initially) letters. However, there were fewer injections required in year two for those eyes that received some laser treatment. Therefore, it appears that there is long-term benefit for the use of ranibizumab for DME.17
Ranibizumab and
More recently, a DRCR study of 854 DME eyes has shown that intravitreal injections of ranibizumab with either prompt (three to 10 days) laser or deferred (24 weeks) laser resulted in superior visual acuity results at 12 months compared with intravitreal triamcinolone with laser or laser with sham injections. At one year, the mean change (± standard deviation [SD]) in the visual acuity letter score from baseline was significantly greater in both the ranibizumab with prompt laser group (+8±11 letters; p<0.001) and the ranibizumab with deferred laser group (+9±12 letters; p<0.001), but not in the triamcinolone with laser group (+4±13 letters; p<0.31), compared with the sham-injection-plus-prompt- laser group (+3±13 letters). In fact 28–30 % of the ranibizumab group eyes gained ≥15 letters from baseline at one year versus 15% for the laser with sham injection eyes. Therefore, we are finally seeing a treatment that can improve visual acuity in DME eyes.18
A clinical trial investigating the efficacy of ranibizumab as compared with controls (RESOLVE) is also under way. Phase III clinical trials are ongoing: A Study of Ranibizumab Injection in Subjects with Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus (RIDE); A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus (RISE); and DRCR Protocol I.
Apart from anti-VEGF antibodies, there are other drugs which inhibit VEGF, such as small interfering RNA (siRNA).19
Use of an siRNA molecule
which prevents the transcription of messenger RNA and thus prevents the formation of VEGF is another approach. Such a molecule, Cand5 (bevasiranib, OPKO Health, Miami, FL), was used in a phase II study, the RNAi Assessment of Bevasiranib in Diabetic Macular Edema (RACE) trial. This pilot phase II study enrolled 48 patients with DME in a double-masked, randomized trial. There was a trend towards decreased macular thickness between eight and 12 weeks. Further work is needed before this drug is accepted for DME.
Studies using these molecules are ongoing in eyes with DME. CLEAR-DME is a phase II study investigating the safety and efficacy of VEGF Trap in DME eyes. Recently, six-month and one-year positive results have been presented at meetings.
There is also a VEGF Trap molecule that inhibits all isoforms of VEGF-A, other VEGF subtypes, such as VEGF-B and -C, and placental growth factor.20
Corticosteroids, such as triamcinolone, have been used in the treatment of DME.21,22
The use of corticosteroids in the treatment of US OPHTHALMIC REVIEW
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