Combination Treatment of Diabetic Macular Edema with Anti-Vascular Endothelial Growth Factor and Steroids: Analysis of DRCR.net Protocol U

INTRODUCTION

Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetes, with a reported cumulative 25-year incidence of 29% of type 1 diabetics according to the Wisconsin Epidemiologic Study of Diabetic Retinopathy.^[1,2] It is characterized by capillary leakage, fluid accumulation, and macular thickening following the breakdown of the blood-retinal barrier.^[3] Vascular endothelial growth factor (VEGF) is a key contributor to the development of DME by increasing permeability of the retinal vessels.^[4] Consequently, intravitreal anti-VEGF therapy is the first-line treatment option in the management of DME and is effective in reducing the central retinal thickness and improving best-corrected visual acuity (BCVA) in patients with DME.^[5]

Although anti-VEGF monotherapy is effective as a treatment for most patients with center-involved DME, a significant proportion of patients have a suboptimal response to treatment. In Protocol I, approximately 40% of ranibizumab-treated eyes had persistent macular thickening after 1 year of monthly injections.^[6] In the RISE and RIDE studies, macular edema persisted in approximately 23% of patients after 2 years of monthly ranibizumab injections, and 40% of patients had not achieved a BCVA of ≥20/40.^[5]

Inflammatory mediators and pathways appear to also be involved in the development of DME, and it may be important to treat this component in patients who do not respond to anti-VEGF therapy. Corticosteroids have reemerged as an alternative therapy for persistent DME or refractory to anti-VEGF monotherapy. Corticosteroids have a broad spectrum of biologic action, including downregulation of inflammatory cytokines and growth factors such as VEGF,^[7] and enhancement of the barrier function of vascular tight junctions.^[8,9] Although intraocular corticosteroids are associated with cataract formation and elevated intraocular pressure (IOP) for some patients, they have been shown to lower the central subfield thickness and improve visual acuity for suboptimal responders to anti-VEGF.^[10,11]

There are now several different steroids and delivery mechanisms available for DME. Prior studies have examined the beneficial effects of triamcinolone for DME.^[12] Dexamethasone has been shown to be more potent with theoretically fewer steroid complications, compared to triamcinolone in in vitro studies.^[13] The dexamethasone intravitreal implant (Ozurdex, Allergan, Irvine, CA) is currently approved by the US Food and Drug Administration for the treatment of DME, macular edema associated with retinal vein occlusion,^[14] and noninfectious posterior uveitis.^[15] It delivers a potent corticosteroid through a biodegradable polymer that releases the medication in a sustained and safe dose over several months.^[9] The Macular Edema: Assessment of Implantable Dexamethasone in Diabetes (MEAD) study showed that dexamethasone intravitreal implant improved vision in patients over a 3-year period, compared to sham.^[10] Patients’ vision improved overall by 4 letters and pseudophakic patients improved by 6 letters over a year period.

Combination therapy consisting of an anti-VEGF agent and a corticosteroid may have a synergistic effect by reducing levels of VEGF, cytokines, and other inflammatory mediators. Several studies have shown that combination treatment with bevacizumab (Avastin; Genentech, South San Francisco, CA) and triamcinolone is possible with good outcomes.^[16,17] Because corticosteroids consistently reduce retinal thickening, the addition of a steroid might benefit patients with persistent DME and vision loss despite treatment with an anti-VEGF agent. The recent DRCR.net Protocol U study sought to compare the combination of a steroid and anti-VEGF therapy to anti-VEGF monotherapy regarding visual acuity and anatomic outcomes.

DCRC.NET PROTOCOL U

Protocol U was a multicenter, phase 2, randomized clinical trial evaluating a combination of dexamethasone and ranibizumab (Lucentis; Genentech, South San Francisco, CA) versus ranibizumab monotherapy for the treatment of persistent center-involving DME. The study was funded by the National Eye Institute, Allergan, and Genentech and involved forty clinical sites.

The study involved 236 eyes who had persistent DME despite receiving at least three anti-VEGF injections within 20 weeks of study enrollment. To ensure that enrolled eyes truly had persistent DME, patients were entered into a run-in phase in which they were treated with 3 month injections of ranibizumab. At the end of the run-in phase, there were 129 eyes with persistent edema who were randomized to receive either the intravitreous sustained dexamethasone implant, 700 μg, injection or sham treatment, both in addition to continued 0.3 mg ranibizumab treatment as often as every 4 weeks. Retreatment with ranibizumab occurred as often as every 4 weeks if the Snellen equivalent was 20/25 or worse or if there was persistent edema. The combination arm was eligible for a second dexamethasone implant beginning at 3^rd month and patients were followed to week 24.

The primary outcome for efficacy was mean change in BCVA from baseline to the 24-week visit. The secondary endpoint was central subfield retinal thickness, as measured by optical coherence tomography at 24 weeks. Among the 129 eyes, 65 eyes underwent combination treatment and 64 had ranibizumab alone. At 24 weeks, results showed no significant difference in visual acuity outcome between the two treatment arms, with mean improvements of 2.7 letters in the combination arm and 3.0 letters in the ranibizumab monotherapy arm (adjusted group difference, 0.5 letter; P = 0.73).

However, anatomic outcomes did differ between the treatment groups, with the combination group having a significantly greater reduction in retinal thickness, with mean central subfield thickness decreases of 110 µm with combination therapy compared to 62 µm with monotherapy (P < 0.001). Furthermore, 52% versus 31% of patients in the combination versus monotherapy arms had a resolution of DME.

CONSIDERATIONS

CLINICAL RELEVANCE

Although Protocol U did not show that there was a significant visual acuity benefit to adding a dexamethasone implant to ranibizumab within the confines of the clinical trial design and follow-up period, corticosteroid therapy continues to have an important adjunctive role in the management of complex DME. Treatment duration was relatively short at 6 months. It would be interesting to see if there is any improvement in visual acuity outcomes with long-term data especially in a larger pseudophakic cohort or following cataract extraction. All benefits would have to be balanced with the possibility of ocular hypertension and associated complications.^[10] Findings from these studies may further help guide corticosteroid use in the treatment of DME.

CONCLUSION

The management of DME remains complex, and often multiple treatment approaches are needed. Despite the significantly greater reduction in retinal thickness in the combination group, adding dexamethasone to ranibizumab treatment did not lead to greater improvement in vision in patients with persistent DME compared to ranibizumab with a sham dexamethasone injection.^[25] Understanding the detailed study designs of clinical trials will hopefully allow us to recognize the strengths and limitations of the studies, as well as to identify which patients are more similar to the subjects enrolled in the studies, and which are not, to allow optimal treatment for the individual patient.