Diabetic Retinopathy Management Guidelines

Rahul Chakrabarti; C Alex Harper; Jill Elizabeth Keeffe

Disclosures

Expert Rev Ophthalmol. 2012;7(5):417-439. 

In This Article

Emerging Ophthalmic Treatments

The recommendations made in the majority of the guidelines were designed to facilitate timely diagnosis and treatment. The content of the guidelines were generally tailored to planning services in their respective regions with prioritization given to meeting the demands in the context of available resources. As such, only the AAO, NHMRC, RCO, SIGN and Malaysian guidelines discussed the role of emerging ophthalmic treatments. While several excellent reviews have discussed the role of medical and ancillary therapies for DR,[4,29,140] intraocular steroids and anti-VEGF agents have consistently generated interest as having the greatest potential in treatment of diabetic macular edema and proliferative disease.

VEGF has long been considered an important mediator of neovascularization, and retinal vascular permeability, and therefore a likely therapeutic target for the treatment of proliferative DR and macular edema. Randomized clinical trials have demonstrated that the suppression of VEGF is particularly beneficial in the context of vision-threatening macular edema. Presently, three anti-VEGF medications are available for use: pegaptanib, ranibizumab and bevacizumab.

Bevacizumab is a full length humanized anti-VEGF antibody that inhibits all forms of VEGF-A. Two-year results from the prospective BOLT study suggests that intravitreal bevacizumab is beneficial in reducing DME. The study has demonstrated that among 80 patients with DME, intravitreal bevacizumab was associated with a significant gain of visual acuity, and greater improvement reduction of central macular thickness letters compared with patients assigned to macular laser treatment alone.[141]

Similarly, ranibizumab is a recombinant antibody fragment derived from humanized anti-VEGF antibody that inhibits all isoforms of VEGF-A. The preliminary RESOLVE study demonstrated that intravitreal ranibizumab monotherapy delivered as three consecutive monthly injections (plus 'as necessary' injections thereafter) compared with placebo improved visual acuity by an average of ten letters on a Snellen chart at 12 months in 151 patients with diabetic macular edema. This corresponded with a significant reduction in central retinal thickness.[142]

Several subsequent randomized control studies have explored the clinical effect of ranibizumab in combination with laser treatment. In the READ-2 study, 126 patients with DME were randomized to receive ranibizumab monotherapy (at baseline, 1, 3 and 5 months), or laser monotherapy (at baseline and 3 months), or combination (at baseline and 3 months). While all treatment groups recorded mean improvement in visual acuity, the greatest gain was recorded in the ranibizumab monotherapy group at 6 months. Importantly, this was preserved at 2-year follow-up.[143]

The diabetic retinopathy clinical research network (DRCR.net) randomized 854 eyes with DME to receive either ranibizumab with prompt laser (within 3–10 days of injection), ranibizumab with deferred laser (greater than 24 weeks after injection), triamcinolone plus prompt laser or sham injection plus prompt laser. At 2-year follow-up, greatest improvement in visual acuity from baseline was observed in patients who received intravitreal ranibizumab and deferred laser. When compared with laser plus sham injection, the ranibizumab group were less likely to have marked vision loss compared with laser alone, and sustained an average gain of one-line vision at 2-year follow-up.[144,145] Furthermore, patients in the triamcinolone group were noted to have a mean decrease in visual acuity and significantly greater central retinal thickness.

Studies of pegaptanib, a pegylated aptamer against the VEGF-A 165 isomer, have similarly demonstrated promising results for patients with diabetic macular edema. Sultan et al. randomized 260 patients with macular edema to receive pegaptanib or sham injections every 6 weeks, with photocoagulation delivered as required after 18 weeks.[146] Over the 2-year follow-up, patients treated with pegaptanib recorded an average of one-line gain in visual acuity compared with controls, with significantly fewer laser treatments required.

Despite the promising clinical benefits of anti-VEGF agents, uncertainty into long-term potential side effects including infection, retinal detachment, vitreous hemorrhage and systemic ischemic events remains. Therefore, given the absence of longer-term safety data in patients with DM, evaluating the risks and benefits for the individual patient is advised.

The role of anti-VEGF medications was discussed by the NHMRC, AAO, Malaysian and SIGN with varying detail on indications and timing. Given the emerging evidence at the time of their publications, the SIGN and AAO guidelines simply acknowledged that anti-VEGF medications were useful as an adjunct to laser for the treatment of PDR and macular edema. The Malaysian guideline indicated that intraocular anti-VEGF agents were to be considered in addition to intraocular steroids and vitrectomy in the management of advanced retinopathy. The most comprehensive recommendation was from the NHMRC that recommended anti-VEGF for consideration in use as an adjunct to laser treatment and prior to vitrectomy. The authors also acknowledged the accumulating evidence for its role in reducing macular thickness and for consideration in diabetic macular edema.

Recommendations for the use of intraocular corticosteroids in treatment of DME achieved consensus across the guidelines. In general, the NHMRC, AAO, SIGN and Malaysian guidelines all acknowledged that intravitreal corticosteroids including triamcinolone (IVTA) was widely used in managing DME that was refractory to focal/grid laser. The NHMRC further recommended that IVTA could also be considered as adjunct to PRP for proliferative DR, or for treating large hard exudates. However, guidelines were also reserved in their recommendations, by acknowledging potential adverse effects and unresolved issues such as optimal dosage, timing and duration of therapy. The recommendations were consistent with the current literature. The multicenter randomized control trial conducted by the DRCR.net failed to demonstrate benefit in visual acuity at 3 years in eyes with DME that were treated with IVTA compared with focal/grid photocoagulation.[147] Comparatively, Gillies et al., in a smaller placebo-controlled trial of patients with macular edema refractory to prior laser, demonstrated that IVTA alone improved visual acuity in 56% of patients compared with 26% (placebo injection).[148] This effect persisted after 2 years. However, in both studies, IVTA was associated with adverse events including ocular hypertension and early cataract formation. Thus, current evidence supports the use of IVTA in patients with refractory DME. However, the individualized treatment considering the risk of adverse outcomes is imperative.

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