An Evolving Treatment Paradigm for Diabetic Macular Edema

An overview of how pharmacotherapy has changed treatment, with three case studies.

ARASH MOZAYAN, MD • FRANK TSAI, MD • ERIC NUDLEMAN, MD, PhD

Diabetes affects 25.8 million Americans and has become the leading cause of blindness in the working-age population.¹ Approximately one million Americans, or 3.8% of diabetics older than 40 years of age, suffer from visual morbidity due to diabetic macular edema.² The ETDRS demonstrated that focal laser for DME effectively halved the percentage of eyes that experienced vision loss and doubled the percentage of eyes that achieved visual gain.³ Until the last decade, focal laser photocoagulation was the standard of care for treating DME.

The development of anti-VEGF therapy has revolutionized the treatment for DME.^4-7 The first prospective study to compare laser monotherapy to combined laser and anti-VEGF was undertaken by the DRCRnet.⁸ Intravitreal ranibizumab (Lucentis, Genentech, South San Francisco, CA) with prompt vs deferred focal/grid laser was shown to be superior to laser alone.

Subsequently, the RESTORE study directly compared ranibizumab monotherapy or in combination with focal laser to focal laser alone.⁹ It demonstrated that ranibizumab monotherapy or the combination was superior to laser monotherapy in VA gains and in reducing central retinal thickness. Furthermore, at one year, no differences were detected between the ranibizumab and ranibizumab/laser arms.

RIDE and RISE evaluated monthly ranibizumab monotherapy vs sham over 24 months and showed a 20-30% increase in ≥15-letter gains in treated eyes, compared to sham.¹⁰

VISTA and VIVID were similarly matched studies that compared aflibercept (Eylea, Regeneron, Tarrytown, NY) to macular laser for DME, and they demonstrated more than a 10-letter mean improvement in VA in the aflibercept group, compared to the laser group.⁶

These data led to FDA approval to treat DME of ranibizumab in 2012 and of aflibercept in 2014, rapidly shifting anti-VEGF therapy to the standard of care, first-line treatment for center-involving DME.

Although anti-VEGF is effective for most patients, refractory macular edema occurs in one-quarter of eyes despite treatment.^10,11 Inflammation plays a significant role in the pathophysiology of diabetes.^12-15 Evidence has suggested that the release of inflammatory cytokines, including interleukin 1β and tumor necrosis factor (TNF) α, contributes to dysfunction of endothelial tight junctions, resulting in macular edema.^16-19

Consistent with these findings, steroids have been shown to be effective for treating macular edema.^20-23 All steroid formulations, however, accelerate cataract formation, and they also carry the risk of increased intraocular pressure.

Two intravitreal steroid implantable devices gained FDA approval for the treatment of DME in 2014. The MEAD study demonstrated that treatment with a 0.7-mg dexamethasone intravitreal implant (Ozurdex, Allergan, Irvine, CA) every six months (as needed) resulted in approximately 10% more eyes achieving ≥15-letter gains over sham.²⁴

Similarly, in the FAME study, yearly treatment (as needed) with the 0.2 μg/d fluocinolone acetonide (Iluvien, Alimera Sciences, Alpharetta, GA) implant showed nearly 10% more eyes achieving ≥15-letter gains over sham. Cataracts were common in both studies by one year, but the fluocinolone implant had a higher rate of incisional glaucoma surgery (3.7% in the FDA-approved 0.2 μg/d group) than the dexamethasone implant (0.6% in the FDA-approved 0.7-mg group). The FAME study did not require the use of a previous course of steroid without a clinically significant IOP rise, while the current label does to mitigate the risk of IOP-lowering surgery.

In some cases, a tractional component may exist that prohibits adequate response to pharmacotherapy. Traction from an epiretinal membrane or a taut internal limiting membrane can contribute to DME through tangential forces.^25,26 Surgical approaches in such cases have been shown to be effective in improving both vision and structural outcomes.^27-31 Evidence has suggested that vitrectomy for nontractional DME provides marginal benefits.^32,33

CASE STUDIES

Here we present a series of three patients with DME to illustrate the current available treatment options.

Case 1

A 51-year-old man with a history of diabetes for 10 years presented with decreased vision in the left eye for several months. His most recent hemoglobin A1c was 8.9%. Best-corrected VA was 20/63 in the left eye. The anterior-segment exam was significant for mild nuclear sclerosis.

Dilated funduscopic examination showed severe nonproliferative diabetic retinopathy and clinically significant macular edema of the left eye (Figure 1A). Fluorescein angiography showed diffuse leakage of the macula (Figure 1B), and spectral-domain optical coherence tomography demonstrated intraretinal fluid (Figure 1C). The patient was treated with four monthly intravitreal ranibizumab injections, after which the DME significantly improved (Figure 1D) with VA recovering to 20/25.

Figure 1. A) Multicolor fundus photograph of the left eye with severe NPDR and DME. B) Fluorescein angiogram of the left eye showing diffuse macular leakage. C) OCT of the left eye at presentation with severe intraretinal fluid. D) Resolution of intraretinal fluid after four monthly intravitreal ranibizumab injections.

Case 2

A 60-year-old woman with a history of diabetes for 20 years presented with complaints of decreased vision in her left eye for many years. She had a history of PDR that required panretinal photocoagulation (Figure 2A, page 58). In addition, she had a history of DME previously treated with focal laser and monthly injections of ranibizumab over one year, with improvement in her vision from 20/100 to 20/60.

Figure 2. A) Color fundus photograph of left eye showing scattered microaneurysms, peripapillary flame-shaped hemorrhage, and focal laser scars. B) Fluorescein angiogram of left eye showing diffuse macular leakage. C) OCT of left eye showing persistent IRF after 1 year of monthly intravitreal ranibizumab injections. D) Resolution of IRF shown 3 months after intravitreal dexamethasone implant.

The patient remained at 20/60 with refractory edema despite continued treatment with monthly anti-VEGF therapy for 3 months (Figures 2B and 2C). To address the persistent edema, the patient was treated with an intravitreal dexamethasone implant. One month following treatment, the intraretinal fluid improved, and the patient achieved VA of 20/40, further improving to 20/30 at months 2 and 3 (Figure 2D).

Case 3

A 52-year-old woman was referred following vitrectomy for a diabetic tractional retinal detachment in the left eye. Her VA at presentation was 20/640. Her examination demonstrated DME with an ERM, which was confirmed by OCT (Figure 3A). She had been previously treated with anti-VEGF and intravitreal steroids without improvement.

Figure 3. A) OCT of left eye showing severe IRF with an ERM. (B) Resolution of IRF after vitrectomy with membrane peel.

Due to the evidence of an ERM with traction, the patient underwent a vitrectomy with membrane peel. The macular edema improved significantly by one month postoperatively, and she achieved VA of 20/250 (Figure 3B).

DISCUSSION

Here, we presented three patients with DME treated by a sequential approach. In the majority of eyes, anti-VEGF therapies have surpassed focal laser as the preferred first-line treatments for DME with center involvement. In refractory cases, steroids can offer an effective option; however, in advanced cases of diabetic eye disease, fibrosis can contribute significantly, necessitating a surgical approach to relieve the traction and improve the edema.

It is an exciting era in the treatment of DME, with effective therapies shifting our treatment paradigms.^34-36 New approaches are also providing promising advances. Inflammatory inhibitors, such as an ophthalmic suspension of loteprednol etabonate (Lotemax, Bausch + Lomb, Rochester, NY) and oral minocycline, are currently in early clinical trials.³⁷ Targets that modulate the blood-retinal barrier, such as inhibition of kallikrein, insulin-like growth factor 1, integrins, and upregulation of Tie2, are under investigation.

In addition, new data comparing the three major anti-VEGF drugs in DME will soon become available. With a growing population affected by diabetes, the demand for better treatments for DME will continue to rise. RP

REFERENCES