In parallel with medical management and optimizing the health habits of the patient, ocular therapies should be considered to maximize visual function and prevent progressive vision loss. These therapies include ocular pharmacologic management and laser photocoagulation treatment. Treatment is typically indicated when the macular edema is center-involved and affects visual acuity. For patients with DME who are asymptomatic or have normal visual acuity, the decision-making process for treatment is more complex. Factors that should be considered include the proximity of exudates or thickening to the fovea, the status and course of the fellow eye, any anticipated cataract surgery, the presence of high-risk PDR, treatment risks, and any systemic conditions or medications (such as thiazolidinediones) that might exacerbate or cause DME. It is preferable to initiate DME treatment before performing scatter photocoagulation and prior to cataract surgery to reduce the risk of DME resulting from these interventions.
Ocular pharmacologic management of diabetic macular edema
As mentioned, anti-VEGF drugs are now the first-line therapy for most eyes with center-involved DME, especially those with vision impairment caused by the DME. Corticosteroids are also useful as alternative agents for eyes that are not candidates for anti-VEGF therapy or that were incompletely responsive to previous anti-VEGF treatment.
Anti-VEGF drugs Currently available anti-VEGF drugs include aflibercept, bevacizumab, pegaptanib, and ranibizumab. Clinical trials have demonstrated that all of these medications are beneficial for eyes with DME. The DRCR.net Protocol I was the first phase 3 trial to demonstrate that intravitreal anti-VEGF therapy provides superior visual acuity outcomes as compared to laser treatment for center-involved DME. This study revealed that intravitreal ranibizumab combined with prompt or deferred (≥24 weeks) focal or grid-pattern laser treatment was more effective at both 1- and 2-year follow-up in increasing visual acuity than was focal/grid laser treatment alone or in combination with triamcinolone acetonide injections for the treatment of center-involved DME. After 1 year of treatment, eyes in the ranibizumab-treated groups gained on average 8–9 letters of visual acuity versus those in the laser monotherapy group, which gained an average of only 3 letters. Through 5 total years of follow-up, despite the number of injections given progressively decreasing, eyes in the ranibizumab treatment groups maintained the vision gains accrued in the first year of therapy (Fig 5-12). Results from this study also suggest that adding focal- or grid-pattern laser treatment at the initiation of intravitreal ranibizumab for DME is no better, and is possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more. Two additional parallel phase 3 trials, RISE and RIDE (identical study designs, both titled Ranibizumab Injection in Subjects With CSME With Center Involvement Secondary to Diabetes Mellitus) indicated that ranibizumab rapidly and sustainably improves vision, reduces the risk of further vision loss, and improves macular edema in patients with DME, with low rates of complications. At 36 months, the pooled data of these studies showed that the proportion of patients who gained 15 or more letters of visual acuity from baseline in the 0.3 mg and 0.5 mg ranibizumab-treated groups were 41% and 44%, respectively.
Figure 5-12 Results of the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol I through 3 years demonstrating the superior visual acuity outcomes of treatment with ranibizumab, with either prompt or deferred laser treatment, compared with laser alone or in combination with triamcinolone through 2 years. Starting in the third year, only patients originally assigned to the ranibizumab groups were followed up. Results from years 3–5 suggest that treatment with ranibizumab plus prompt laser therapy is no better and is possibly worse than ranibizumab with deferred laser treatment.
(From Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312–2318.)
Phase 3 trials have also demonstrated excellent efficacy of aflibercept treatment for DME. After an initial phase of 5 monthly injections, after 148 weeks, groups undergoing therapy with aflibercept, both monthly and every 2 months, had substantial visual acuity gains compared with laser photocoagulation in both the VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME) and VISTA (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) trials.
Although all of the available anti-VEGF agents are effective in the treatment of DME, results from the DRCR.net Protocol T study, which compared the effectiveness of aflibercept, bevacizumab, and ranibizumab for the treatment of DME, demonstrated the superiority of aflibercept over bevacizumab in improving ETDRS visual acuity gains after both 1 and 2 years of treatment. Aflibercept was also superior to ranibizumab at 1 year follow-up, but statistically similar at 2 years. The differences between the agents were due primarily to the effects of these agents in eyes with worse (≤20/50) baseline vision. In eyes with milder visual impairment (20/32 to 20/40), visual results were equivalent at both 1 and 2 years for all 3 treatment groups. At 2 years, rates of 10 or more letter visual acuity improvement in the aflibercept, bevacizumab, and ranibizumab groups were 50%, 41%, and 46%, respectively. In contrast, in eyes with worse visual impairment, 2-year rates of 10 or more letter improvement for the aflibercept, bevacizumab, and ranibizumab groups were 76%, 66%, and 71%, respectively. Rates of substantial vision loss were low in all 3 treatment groups.
In general, anti-VEGF agents are well tolerated. Associated adverse events are most commonly due to the intravitreal injection procedure rather than the medication. Serious intraocular events such as endophthalmitis are rare, with a prevalence of approximately 1 in 1000 injections. Systemic thromboembolic events are known to be associated with systemic anti-VEGF administration, but have not been shown to be more common among patients who receive intraocular anti-VEGF treatment. Combined rates of nonfatal myocardial infarction, nonfatal stroke, and vascular death were higher in the Protocol T patients treated with ranibizumab than the patients treated with the other 2 agents, but extensive analyses of adverse events across other studies have not demonstrated consistent differences in intraocular or systemic safety between the anti-VEGF agents.
Corticosteroids Use of intravitreal triamcinolone acetonide in patients with refractory DME has been reported to have beneficial effects in a number of small studies. However, at 2 years into the DRCR.net Protocol B trial, treatment with focal- or grid-pattern photocoagulation was found to be more effective, with fewer adverse effects, than treatment with 1-mg or 4-mg doses of preservative-free intravitreal triamcinolone. DRCR.net Protocol I also showed that at 2 years, treatment with intravitreal triamcinolone acetonide in combination with laser therapy was inferior to treatment with ranibizumab with or without laser therapy, as well as to laser treatment alone.
However, results from steroid-treated eyes that were pseudophakic at baseline, which therefore did not develop cataracts as a result of steroid treatment, were similar to those from anti-VEGF treated eyes and superior to the laser-treated group. Thus, steroid treatment may be a reasonable alternative to anti-VEGF in eyes with DME that have already undergone cataract surgery. Studies of 2 types of sustained-release steroid implants, made of dexamethasone and fluocinolone acetonide, respectively, have also demonstrated improved rates of 3 or more lines visual acuity gain with these agents. Nonetheless, because of the higher rates of cataract and glaucoma development in steroid-treated eyes, corticosteroids are usually considered second-line agents for the treatment of DME. They can be a useful alternative for eyes that are not candidates for anti-VEGF therapy or that have been refractory despite previous anti-VEGF treatment. The DRCR.net Protocol U study, which evaluated eyes with persistent center-involved DME and visual impairment despite at least 6 prior injections of anti-VEGF agents, demonstrated that combination therapy with continued anti-VEGF treatment and a dexamethasone implant did not provide superior vision gains when compared to continued anti-VEGF treatment alone. However, eyes in the combination group did show greater improvements in retinal thickening over the 6-month study period.
Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904–1914.
Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626–635.
Elman MJ, Aiello LP, Beck RW, et al; Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064–1077.
Elman MJ, Ayala A, Bressler NM, et al; Diabetic Retinopathy Clinical Research Network. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2):375–381.
Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193–1203.
Surgical management of diabetic macular edema
Focal- or grid-pattern macular laser photocoagulation still has an important role as an adjunctive treatment in eyes that are resistant to anti-VEGF agents; it is also appropriate as occasional first-line treatment in eyes with DME from clearly focal leakage that can be easily targeted by the laser. In addition, laser therapy may be a useful first-line treatment for patients who are not good candidates for anti-VEGF therapy because they are medically unstable or who are unable to adhere to near monthly treatment, especially in the first year. Pars plana vitrectomy is often effective in improving retinal thickening in eyes with DME, but is not always successful at improving vision. Further, definitive studies are needed to clearly define the role of vitrectomy in DME treatment.
Laser treatment of DME Although anti-VEGF therapy has largely supplanted laser photocoagulation for most cases of DME, laser treatment remains a well-proven treatment modality with minimal associated adverse events. In the ETDRS, macular focal- or grid-pattern laser photocoagulation treatment of CSME versus observation reduced the risk of moderate vision loss, increased the chance of vision improvement, and was associated with only minor visual field loss. Eyes with less than CSME showed no treatment benefit over the control group at 2 years. In current clinical practice, treatment of eyes with DME can usually be delayed until progression of edema threatens the center of the macula.
Potential adverse effects of macular laser therapy include paracentral scotomas, transient increases of edema and/or decreases in vision, laser scar expansion, subretinal fibrosis, choroidal neovascularization, and inadvertent foveal burns. However, if the laser treatment is carefully and appropriately applied, most of these complications should be avoided. Clinical features associated with poorer visual acuity outcomes after photocoagulation treatment for DME include the following:
Fluorescein angiography, along with an OCT thickness map, can be used to guide laser treatment for DME. The laser parameters typically used include spot sizes of 50–100 μm and burn durations of 0.1 second or less. For focal leakage, direct laser treatment using green or yellow wavelengths is applied to all leaking microaneurysms between 500 μm and 3000 μm from the center of the macula. For diffuse leakage or zones of capillary non-perfusion in the macula, a light-intensity grid pattern can be applied. Burns are typically separated by 1 burn width, and a green- or yellow-wavelength laser is used. Treatment should include areas of diffuse leakage more than 500 μm from the center of the macula and 500 μm from the temporal margin of the optic nerve head.
Laser sessions are typically repeated as often as every 16 weeks until retinal thickening has resolved or all of the leaking microaneurysms have been adequately treated. Some studies have suggested that micropulse, or sub–threshold intensity burns, may be as effective as standard macular laser treatment while reducing damage to the retinal pigment epithelium and outer retinal layers. Treatment of peripheral nonperfusion as visualized on ultra-wide-field FA with scatter photocoagulation does not improve visual acuity or retinal thickening in eyes with DME.
Pars plana vitrectomy for DME Pars plana vitrectomy may be useful for treating DME. If there is evidence of posterior hyaloidal traction or an associated epiretinal membrane leading to mechanical traction, creation of a posterior vitreous detachment and possible ILM or epiretinal membrane peeling can be effective in reducing retinal thickening. Although the use of vitrectomy as first-line therapy for treatment of eyes with DME without vitreomacular traction is uncommon in the United States, it is more widely prevalent internationally. Vitrectomy generally improves retinal thickening in eyes with DME. However, multiple studies have demonstrated inconsistent effects of vitrectomy on visual acuity in eyes with DME, despite consistent improvements in edema. Eyes can experience either substantial vision gain or vision loss after vitrectomy. The DRCR.net Protocol D, which was a prospective observational case series, confirmed that after vitrectomy, retinal thickening was reduced in most eyes; however, median visual acuity remained unchanged over the 6-month follow-up period. As mentioned, the exact role of vitrectomy in the treatment of DME remains to be determined through future, large-scale definitive studies.
Haller JA, Qin H, Apte RS, et al; Diabetic Retinopathy Clinical Research Network Writing Committee. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010;117(6):1087–1093.
Jackson TL, Nicod E, Angelis A, Grimaccia F, Pringle E, Kanavos P. Pars plana vitrectomy for diabetic macular edema: a systematic review, meta-analysis, and synthesis of safety lterature. Retina. 2017; 37(5):886–895.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.