Treatment of diabetic macular edema- the current perspective

             

                     Treatment of diabetic macular edema- the current perspective

                            Dr Dhanashree Ratra, Dr Vineet Ratra

Prevalence of diabetes WHO figures. India leading with maximum number of patients with diabetes in the country

Macular edema is a leading cause of vision loss in about 15% of diabetic patients

Macular edema - leakage seen in fluorescein angiogram despite prior laser treatment.

                   

 Macular edema (ME) is one of the main vision-threatening complications associated with diabetic retinopathy.  Till recently the gold standard for treatment of  diabetic macular edema (DME) was laser photocoagulation .  But we know that laser was not always effective for the treatment of ME especially in the presence of ischemia and the only option available was observation. The past decade has seen introduction of various new drugs and drug delivery systems which have revolutionized the treatment of ME. Recently published clinical trials have shown that intravitreal dexamethasone (Ozurdex®; Allergan, Irvine, Calif., USA) and ranibizumab (Lucentis®; Novartis Pharma) are effective in the treatment of DME.  In this article we review the recent  developments in this field.

Emerging pharmacotherapies for the treatment of DME-

In India, the prevalence of diabetic retinopathy varies from 18-20.8% in known diabetics and 0.27 to 17.6% in general population.^1,2,3,4 The incidence of ME varies from 10- 25% in these studies. Reported risk factors for diabetic retinopathy and DME include duration of diabetes, as well as the severity of hyperglycemia, hypertension, and hyperlipidemia. Apart from these microalbiminuria, anemia are also considered responsible.⁵ Intensive control of the systemic factors and macular photocoagulation have been shown to be effective in treating DME. In the recent times new pharmacotherapies have emerged for the treatment of DME.

Corticosteroids-

Triamcinolone acetonide

In addition to their anti-inflammatory properties, corticosteroids have been reported to reduce the activity of VEGF.  Currently various formulations and delivery systems are being evaluated. The Diabetic Retinopathy Clinical Research Network (DRCR) protocol B compared two doses (1 and 4 mg) of intravitreal triamcinolone acetonide( IVTA) versus photocoagulation for DME.⁶ For most patients, photocoagulation produced more favorable outcomes than did IVTA at 24 months of follow up. Similar results were reported at 3-year follow-up.⁷ The most common complications of IVTA are cataract formation  and increased intraocular pressure (IOP). Pseudoendophthalmitis and infectious endophthalmitis occur much less commonly. The rate of infectious endophthalmitis after IVTA is low in reported series. For example, in an analysis of two large randomized controlled trials (RCT) (from the DRCR network and the Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE) trials), the rate of endophthalmitis after IVTA was 0.05%.⁸ A triamcinolone-eluting intravitreal implant (I-vation, SurModics, Inc., MN, USA) for the treatment of DME was suspended in a phase 2b RCT after the publication of the DRCR network results showing a benefit of laser photocoagulation over IVTA in treatment of DME

Fluocinolone acetonide

To reduce the need for repeated intravitreal injections, several extended-release corticosteroid delivery systems have been studied. A fluocinolone-acetonide- (FA-) eluting intravitreal implant (Retisert, Bausch and Lomb, NY, USA) a nonbiodegradable device that releases 0.59 μg/day of FA into the vitreous cavity has been studied. It must be implanted in an operating room or similar setting. In an RCT, the effects of the device versus photocoagulation for DME were studied. At one year, DME was resolved in 57% of patients with the FA implant versus 20% of patients with photocoagulation. There were no statistically significant differences in final visual acuity between the two groups.⁹ At 3 years, patients randomized to receive the FA implant had persistent treatment of macular edema, but 95% of phakic eyes developed significant cataract, and about one-third of eyes had IOP above 30 mm Hg.¹⁰

A smaller fluocinolone acetonide-eluting device (Iluvien, Alimera Sciences, Alpharetta, GA, USA) may be administered through a 25-gauge device in a clinic setting. The Fluocinolone Acetonide for Macular Edema (FAME) study comprised 2 phase 3 RCTs assessing the efficacy and safety of 0.2 μg/day (low dose) and 0.5 μg/day (high dose) inserts in patients with DME with persistent edema despite at least one macular laser treatment.¹¹ The primary study endpoint was defined as improvement in visual acuity by 15 or more letters at 2 years. At 24 months, the primary endpoint was achieved in 28.7% and 28.6% of low- and high- dose insert groups compared with 16.2% in the sham group. Elevated intraocular pressure requiring incisional surgery occurred in 3.7%, 7.6%, and 0.5% of the low-dose, high-dose, and sham groups, respectively.

Dexamethasone

The dexamethasone drug delivery system (DDS) [Ozurdex, Allergan, Irvine, California] is a biodegradable, sustained-release device approved by the US FDA for the treatment of macular edema associated with retinal vein occlusion and noninfectious posterior segment uveitis. A phase 2 RCT in patients with persistent macular edema secondary to various etiologies, including DME, showed that the dexamethasone DDS produced improvements in visual acuity, macular thickness, and fluorescein leakage that were sustained for up to 6 months.¹²  In an RCT, the safety and efficacy of the dexamethasone DDS in the treatment of DME was studied.¹³  Patients with persistent macular edema (at least 90-day duration) were randomized to treatment with 700 μg or 350 μg of dexamethasone DDS or observation. At 3 months, visual acuity improved by 10 letters or more in 30% of eyes in the 700 μg group, 20% of eyes in the 350 μg group, and 12% of eyes in the observation group. A more recent study reported that the dexamethasone DDS improved visual acuity and macular edema in previously vitrectomized eyes with diffuse DME.¹⁴

Vascular Endothelial Growth Factor Antagonists-

Four intravitreal anti-VEGF agents are currently available commercially.

Pegaptanib

Pegaptanib (Macugen, Eyetech Pharmaceuticals, Palm Beach Gardens, FL, USA) is a pegylated aptamer that targets the VEGF165 isoform  and was the first anti-VEGF medication reported to have efficacy in the treatment of DME. The Macugen Diabetic Retinopathy Study Group conducted a phase 2 RCT of pegaptanib for fovea-involving DME.¹⁵ After 36 weeks of followup, the pegaptanib-treated eyes had better visual acuity, more reduction in central retinal thickness, and less need for laser photocoagulation compared to the sham group. More recently, a phase 2/3 RCT reported that pegaptanib therapy was associated with improved visual outcomes in patients with DME for up to 2 years.¹⁶

Bevacizumab

Bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA, US) is a full-length recombinant humanized antibody against all isoforms of VEGF-A. The agent is used commonly as an off-label intravitreal injection. The DRCR network conducted a randomized study of 121 eyes with DME over a 12-week period.¹⁷ There were five treatment arms: focal photocoagulation, 2 consecutive 1.25 mg bevacizumab injections, 2 consecutive 2.5 mg bevacizumab injections, 1.25 mg bevacizumab followed by sham injection, and combination of photocoagulation with 2 consecutive 1.25 mg bevacizumab injections. The groups that received two bevacizumab injections without laser had a significant improvement in visual acuity over the laser-only group. There were no detectable differences between the 1.25 mg and 2.5 mg doses. The single injection group had no advantage over the laser-only group. The combination of laser and bevacizumab had comparable results to the laser-only group with a trend toward worse short-term vision than eyes that received two bevacizumab injections.  In the BOLT (Bevacizumab Or Laser Therapy in the Management of DME) study, repeated intravitreal bevacizumab injections were compared with modified ETDRS photocoagulation in patients with persistent DME.¹⁸ A total of 80 patients with center-involving DME and at least one prior photocoagulation without evidence of advanced macular ischemia were included. Patients were randomized to 2 arms: intravitreal bevacizumab (injections at baseline, 6- and 12-week follow up with subsequent injections every 6 weeks based on OCT-guided retreatment protocol) or photocoagulation (at baseline with subsequent retreatment every 4 months if clinically indicated by ETDRS guidelines). At 12 months, bevacizumab had a greater treatment effect than did photocoagulation. The bevacizumab arm gained a median of 8 ETDRS letters, whereas the photocoagulation group lost a median of 0.5 ETDRS letters. Approximately 31% of patients in the bevacizumab arm versus 7.9% of patients in the laser arm gained ≥10 ETDRS letters (p=0.01). The decrease in central macular thickness was significantly more in the bevacizumab group compared to the photocoagulation group.

Ranibizumab

Ranibizumab (Lucentis, Genentech, Inc. South San Francisco, CA, USA) is a recombinant humanized monoclonal antibody fragment that binds all isoforms of VEGF-A with high affinity. Various clinical trials have been conducted to assess the efficacy and safety in DME. The Ranibizumab for Edema of the Macula in Diabetes (READ-2) study randomized 126 eyes with DME to 3 groups: ranibizumab only (injection at baseline, months 1, 3, and 5); photocoagulation (at baseline and at 3 months if needed); combined ranibizumab and photocoagulation (photocoagulation and ranibizumab at baseline, and ranibizumab at 3 months if needed).¹⁹ Patients randomized to ranibizumab only showed a significantly better visual outcome at 6 months compared with the other 2 groups. For patients with data available at 6 months, improvement of 3 lines or more in vision occurred in 22% of patients in the ranibizumab-only arm, none in the photocoagulation-only arm, and 8% in combined arm. At 24 months, the study reported that intravitreal ranibizumab provided persistent treatment benefits.²⁰ DRCR protocol I evaluated ranibizumab and IVTA in combination with photocoagulation by randomizing patients into four arms: ranibizumab with prompt (within one week) photocoagulation, IVTA with prompt photocoagulation, sham injection with prompt photocoagulation, and ranibizumab with photocoagulation deferred for at least 24 weeks.²¹ The treatment protocol included a baseline treatment followed by intravitreal study medication or sham injection retreatments every 4 weeks through the 12-week visit. After the 16-week visit, retreatment was at the investigator’s discretion according to web-based predetermined criteria. Ranibizumab with prompt or deferred photocoagulation resulted in more favorable visual acuity and central macular thickness outcomes compared with photocoagulation alone at 1 and 2 years of follow up. In ranibizumab-treated eyes, the results were similar whether photocoagulation was given with the first injection or deferred for at least 24 weeks. IVTA combined with photocoagulation did not result in better visual outcomes compared with photocoagulation alone. However, in pseudophakic eyes, the IVTA with prompt photocoagulation group had similar visual outcomes to the 2 ranibizumab groups, suggesting that cataract formation may have affected the visual acuity outcomes in phakic eyes treated with IVTA. Two-year visual outcomes were similar to 1-year results and reinforced the conclusion that ranibizumab with prompt or deferred photocoagulation should be considered for patients with vision impairment of worse than 20/32 secondary to DME.²² The RESTORE phase 3 study also reported that ranibizumab monotherapy or combined with laser photocoagulation provided superior visual acuity gain over standard photocoagulation in the treatment of DME.²³ Two additional phase 3 RCTs (RISE and RIDE) were conducted to evaluate the efficacy, durability, and long-term safety of monthly ranibizumab injections in patients with center-involving DME.  The safety and efficacy of double dose of ranibizumab was  compared in the RESOLVE phase 2 trial. The incidence and severity of systemic and ocular adverse events that are associated with repeated intravitreal injections of two doses of ranibizumab (0.5 mg versus 2.0 mg) in subjects with DME are being investigated in READ-3 study.

Aflibercept

Aflibercept, or VEGF trap-eye, (Eylea, Regeneron, Tarrytown, NY, USA), is a recombinant fusion protein with activity against all VEGF-A isoforms and PlGF that is FDA-approved for the treatment of neovascular AMD and has been shown to have short-term efficacy in the treatment of DME.²⁴  The DA-VINCI study assessed the efficacy and safety of intravitreal aflibercept versus laser photocoagulation in the treatment of DME. Patients were randomized to one of the following treatment arms: 0.5 mg aflibercept every 4 weeks, 2 mg aflibercept every 4 weeks, 2 mg aflibercept every 8 weeks, 2 mg aflibercept as needed, or photocoagulation. At 24 weeks, the mean change in BCVA for aflibercept arms ranged from +8.5 to +11.4 letters compared to the mean change of +2.5 letters in the laser-treated eyes (p<0.01). There was no statistical significant difference between the aflibercept arms. Anatomic effects (mean change in central retinal thickness) ranged from −127 μm to −195 μm in aflibercept arms compared to −68 μm in laser-treated eyes at 24 weeks (p<0.01).  At 52 weeks, the mean change in BCVA for aflibercept arms ranged from +9.7 to +13.1 letters compared to the mean change of −1.3 letters in the laser-treated eyes (p<0.01).²⁵  In this study population, intravitreal aflibercept produced significant improvements in visual acuity and retinal thickness as compared to laser photocoagulation at both 24 and 52 weeks. At this time, aflibercept is not approved by the US FDA for the treatment of DME.

Many more agents are being studied and are in various phases of clinical trials. Exciting times are ahead when we await the results of these trials. However that does not make laser obsolete. It still has its place in the treatment of DME.

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