A multimodal approach to diabetic macular edema

    A Multimodal Approach to Diabetic Macular Edema Adrian Au, Rishi P. Singh PII: DOI: Reference:

S1056-8727(15)00446-8 doi: 10.1016/j.jdiacomp.2015.11.008 JDC 6585

To appear in:

Journal of Diabetes and Its Complications

Received date: Revised date: Accepted date:

5 August 2015 7 November 2015 9 November 2015

Please cite this article as: Au, A. & Singh, R.P., A Multimodal Approach to Diabetic Macular Edema, Journal of Diabetes and Its Complications (2015), doi: 10.1016/j.jdiacomp.2015.11.008

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A Multimodal Approach To Diabetic Macular Edema Adrian Au1 and Rishi P. Singh2

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Case Western Reserve School of Medicine, 2109 Adelbert Rd. Cleveland, OH 44106 Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44106

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Corresponding Author: Rishi P. Singh, MD 9500 Euclid Avenue, Desk i32 Cleveland, OH 44195 Phone: (216) 445-9497 Email: [email protected]

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Conflicts of Interest: Au: none Singh: consulting fees: Alcon Laboratories, Genentech, Regeneron, Allergan, ThromboGenics, Shire; contract research: Genentech, Regeneron, ThromboGenics

Keywords: diabetic retinopathy, diabetic macular edema, anti-VEGF, laser photocoagulation, corticosteroids

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Summary Diabetic retinopathy is a common complication of uncontrolled diabetes. A complication is diabetic macular edema, which is the leading cause of blindness in patients with diabetic retinopathy. Historically, management of these conditions was laser photocoagulation with regulation of blood pressure, blood sugar, and cholesterol. The initial studies demonstrated that this treatment regimen prevented further visual deterioration but did not improve visual acuity. Novel studies identifying the presence of vascular endothelial growth factor (VEGF) in the eye with accompanying elucidation of diabetic pathophysiology allowed for the development of alternative therapies, namely antibodies against VEGF and corticosteroids. These two therapies revolutionized the management of diabetic macular edema by not only preventing vision loss, but also improving overall vision. In this review, we outline the major breakthroughs and underlying thought processes of the paradigm shifts that have occurred in management of these conditions. Further, we present how the evolving role of anti-inflammatory and anti-VEGF therapies, in a combinatorial approach, may provide further permutations to optimize treatment.

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Introduction Diabetic retinopathy (DR) is the most common complication of diabetes, affecting one in three diabetics (Center of Disease Control 2015). In 2005, 5.5 million patients were affected with diabetic retinopathy, with the expectation that it would triple by 2050 to 16 million (Saaddine et al., 2008). With the prevalence of diabetes in 2013 estimated at 24.4 million in the United States and 382 million worldwide, it comes as no surprise that diabetes continues to be the leading cause of blindness in the United States (International Diabetes Foundation 2015). Although advancements in systemic management for diabetes have made major strides, management of diabetic retinopathy has remained poor. Diabetic retinopathy is characterized by progressive bilateral damage to retinal blood vessels. It has four stages that extend from microaneurysms (either background retinopathy or mild nonproliferative retinopathy) to extensive abnormal blood vessel growth (proliferative retinopathy). Early in the disease, patients may not experience any symptomology. However, poor management of risk factors – hyperglycemia, chronically elevated hemoglobin A1C (HbA1c), hypertension and hyperlipidemia – can cause disease progression (Yau et al., 2012). Subsequently, patients can experience blurry vision, decrease in visual acuity, metamorphopsia, or other visual complaints. If left untreated, patients become incurably blind. Vision loss in patients affected with diabetic retinopathy commonly manifests as fluid accumulates beneath the macula, the central portion of the retina responsible for high visual acuity. This occurs in all disease stages secondarily to incompetent blood vessels causing diabetic macular edema (DME) or in end stage disease when abnormal blood vessels grow (proliferative retinopathy). As a result, targeted therapy has been directed at limiting the damaging effects of poor vasculature integrity. The main goals of treatment are to: 1) manage risk factors to minimize the effects of systemic diabetes on retinal vasculature, 2) reduce fluid accumulation, and 3) prevent the consequences of fluid disrupting the retina. As the leading cause of blindness in patients with DR is DME, we will specifically outline and discuss the evolution of multimodal management of DME in this review.

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Evolution of treatments Historically, the treatment of DME was focused on vision stabilization. The 1985 landmark Early Treatment of Diabetic Retinopathy Study (EDTRS) established glycemic control, blood pressure regulation, and macular laser photocoagulation as standard of care (Early Treatment of Diabetic Retinopathy Study 1985). The intent of laser photocoagulation was to reduce leaky micro-aneurysms and inhibit extravasation of fluid into the macula, thereby preventing degradation of vision. The study demonstrated that laser photocoagulation decreased the risk of visual acuity loss in patients with clinically significant DME (CSDME) by 50%. Subsequent studies found that laser photocoagulation stabilized visual acuity with minimal or delayed improvements (Nguyen et al., 2012, DRCR.net et al., 2010, Scott et al., 2009). The study defined two primary outcomes as a way to establish efficacy of the treatment arm: retinal thickness and best-corrected visual acuity (BCVA). For the purposes of this review, we will report primarily on the latter as a functional evaluation of visual acuity in patients with diabetic retinopathy. As pathophysiology of DME was uncovered, alternative therapies were developed to improve rather than stabilize vision. Studies have shown chronic exposure to hyperglycemia induces a cascade of anatomical and biochemical changes that affect micro-vascular architecture

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and retinal functionality (Curtis et al., 2009, Antonetti et al., 2006, Cheung et al., 2010). Two mechanisms have primarily been implicated: increased production of vascular endothelial growth factor (VEGF), a pro-angiogenesis protein, and activation of inflammatory cascades involved in leukostasis and maintenance of vascular integrity (Curtis et al., 2009, Antonetti et al., 2006, Cheung et al., 2010, Kern 2007). An important observation that catapulted VEGF as a primary therapy target was that VEGF was elevated intravitreally in DME and DR patients and the amount of VEGF correlated with severity of DME (Aiello et al., 1994 and Funatsu et al., 2003). VEGF has multiple isoforms, but VEGF-A is purported to be the primary isoform. When VEGFA is bound to VEGF receptor 2 (VEGFR2), one of two protein-kinase activating receptors, it propagates its mitogenic, angiogenic, and permeability enhancing effects (Shibuya, 2006). Antibodies bound to VEGF inhibit activation of the VEGFR2 and ultimately prevent angiogenesis. In summary, alternative therapies, primarily focused on corticosteroids and VEGF, were investigated in clinical trials to not only stabilize but also improve vision. The multifactorial pathogenesis of diabetic retinopathy lends itself to a multimodal approach to management. Utilizing anti-VEGF antibodies, corticosteroids, and laser therapy in a combinatorial fashion can provide optimized patient outcomes in comparison to monotherapy alone. Our evolving understanding of the cellular effects of diabetes on retinal integrity and vasculature will only increase the available tools to prevent diabetes-induced blindness. The purpose of this review is to provide context and describe the evolving role of anti-VEGF, corticosteroids, and laser therapy in the multimodal approach to diabetic macular edema and diabetic retinopathy.

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Anti-VEGF Therapy Multiple clinical trials elucidated anti-VEGF in the reversal, stabilization, and prevention of future vision loss. We briefly outline the major clinical trials in Table 1 for the following three VEGF targeting drugs: ranibizumab (Lucentis), bevacizumab (Avastin), and aflibercept (Eylea).

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Ranibizumab (Lucentis) Ranibizumab, a FAB fragment with one targeted VEGF binding site, was the first VEGF therapy to be approved by the FDA for treatment of DME (Figure 1). Two-phase II clinical trials, Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE) and two-year outcomes of the ranibizimab for edema of the mAcula in Diabetes (READ-2), investigated the effectiveness of ranibizumab in the treatment of DME. In the RESOLVE study, patients were treated with ranibizumab or sham injection for their first three months with the option for dose doubling or rescue laser. RESOLVE showed ranibizumab improved BCVA by 10.3±9.1 letters from baseline while sham injection decreased BCVA by 1.4±14.2 letters (Massin et al. 2010). To determine whether ranibizumab was better than the standard of care, READ-2 compared ranibizumab versus laser photocoagulation versus a combination of ranibizumab and photocoagulation. Two-year follow up showed that patients on ranibizumab improved on average by 7.7, laser by 5.1, and combination by 6.8. Although not statistically significant, combination therapy required fewer injections during the second year, suggesting that laser therapy and ranibizumab helped reduce persistent or recurrent macular edema (Nguyen et al., 2010). Four recent clinical trials established ranibizumab as a treatment for DME that lead to its FDA approval. 12 Month Core Study to Assess the Efficacy and Safety of Ranibizumab Intravitreal Injections (RESTORE) validated READ-2 findings by comparing ranibizumab

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monotherapy, laser alone, or a combination of the two. RESTORE showed significant improvement in patients treated with three monthly injections of ranibizumab (6.1±6.43) or ranibizumab and laser therapy (5.9±7.92) as compared to laser alone (0.8±8.56) (Mitchell et al., 2011). Two concurrent clinical trials Study of Ranibizumab Injection in Subjects with CSDME and Center Involvement Secondary to Diabetes Mellitus (RISE and RIDE) further showed that at twenty-four months mean BCVA with monthly 0.3mg ranibizumab injections steadily improved BCVA by 10.9-12.5 letters while patients with 0.5mg ranibizumab and sham injections rose by 11.9-12.0 and 2.3-2.6 letters, respectively (Figure 2). 0.3mg became the preferred dosing as it maintained efficacy in treatment of DME but decreased the risk of systemic side effects, discussed later, in diabetics, a known at-risk population. Importantly, patients treated with ranibizumab were found to have reduced risk of diabetic retinopathy progression and regression of diabetic retinopathy in patients with DME (Nguyen et al., 2012). The fourth clinical trial not only performed ranibizumab efficacy and safety, it evaluated whether corticosteroid treatment was beneficial. Diabetic Retinopathy Clinical Research Network (DRCR.net), a large multicenter cohort of specialists focused on diabetic retinopathy, performed Protocol I. They designed their clinical trial to resolve ranibizumab efficacy and determine relative importance of laser therapy for DME. In addition, they included triamcinolone, a corticosteroid therapy, previously shown to be superior to untreated diabetic retinopathy in ETDRS, but not superior to laser photocoagulation (DRCR.net, 2008). Patients were randomized to receive sham injections plus prompt laser, 0.5mg ranibizumab plus prompt or deferred (>24 weeks) laser, or triamcinolone 4mg plus prompt laser. Monthly therapy was administered until stabilization or lack of further improvement. The one-year BCVA mean change, similar to two-year outcomes, was significantly greater in the ranibizumab and prompt laser group (+9±11) and ranibizumab and deferred laser (+9±12) while triamcinolone and prompt laser (+4±13) was comparable to the sham and prompt laser (+3±13) population. The import of all these clinical trials established ranibizumab as a monotherapy with or without laser therapy for DME.

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Bevacizumab (Avastin) Bevacizumab differentiates itself from ranibizumab by being a full-length monoclonal antibody (as opposed to a Fab fragment like ranibizumab) and by having two VEGF binding sites that increases its affinity to VEGF. Bevacizumab and ranibizumab are both derived from the mouse monoclonal antibody for VEGF. DRCR.net in 2007 performed a study evaluating intravitreal bevacizumab with an additional bevacizumab, sham, or laser photocoagulation treatment at twelve weeks. At 12 weeks, treatment with 1.25mg and 2.5mg bevacizumab at two initial encounter and 6 week follow-up improved BCVA by +5 and +7 letters, respectively. This was a significant increase compared to 1.25mg of bevacizumab at baseline without supplemental laser (+4) or with supplemental laser (0) and laser only at baseline (-1). This suggests an effective difference with bevacizumab as compared to laser, but variations of bevacizumab with additional dosing or laser therapy was not clinically significant (DRCR.net 2007). These positive findings were subsequently verified in Bevacizumab or Laser Therapy (BOLT), a phase 2 clinical trial. BOLT compared intravitreal bevacizumab versus laser therapy at two years with bevacizumab showing a clear benefit over laser with mean BCVA increased by 8.6±9.1 letters versus decreased mean BCVA by 0.5±10.6, respectively (Rajendram et al., 2012). Aflibercept (Eylea)

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Aflibercept, as opposed to its predecessors, is a recombinant fusion protein comprising VEGF binding domains and the Fc domain of human immunoglobulin. Rather than directly binding VEGF, it acts as a sink receptor that binds VEGF with substantially higher affinity and longer duration (Holash et al., 2002, Stewart & Rosenfeld 2008). In phase 2 clinical trials called DME And VEGF Trap-Eye: Investigation of Clinical Impact (DA VINCI), patients were randomized to five different treatment regimens varying in dosage and injection schedules of intravitreal aflibercept. In total, all aflibercept treated patients experienced 9.7-13.1 improvement in BCVA, which was significant as compared to the laser, but the different dose and time course did not affect outcomes (Do et al., 2012). Two simultaneous phase 3 clinical trials called Intravitreal Aflibercept Injection in Vision Impairment Due to DME (VIVID-DME) and Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema (VISTA-DME) looked at the effects of aflibercept at two different dosing schedules versus laser. At 52 week follow-up, aflibercept treatment every 4 or 8 months found mean BCVA gains of 10.5-12.5 and 10.7 letters, respectively. These findings were significant compared to laser alone (0.2 – 1.2) and remained consistent with the DA VINCI study (Korobelnik et al., 2014).

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Side effects of Anti-VEGF therapy With anti-VEGF therapy becoming the new standard of care, evaluation of long-term side effects and adverse events is necessary. This is of increasing significance, as management of DME requires frequent anti-VEGF administration. Here, we summarize the more frequent and alarming side effects (Table 2).

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Ocular side effects The safety evaluation of anti-VEGF therapy showed similar adverse events between all treatment arms and their respective controls, suggesting that the complications were due to the injection procedure itself. This was consistent with anti-VEGF therapy in clinical trials of age related macular degeneration (AMD) (Rosenfeld et al., 2006 and Brown et al., 2009). The most commonly reported ocular side effects were increased intraocular pressure, conjunctival hemorrhage, and eye pain. However, the most concerning side effect was endophthalmitis, a blinding infection of the inner eye. Endophthalmitis rates were reported to be between 0.0191.6% within the aforementioned clinical trials (Falavarjani & Nguyen, 2013). However, the higher rates of endophthalmitis occurred in earlier studies prior to refinement of aseptic technique and injection protocols. Subsequent meta-analysis estimated endophthalmitis risk of 0.025% with staphylococcus and streptococcus species as the most common organisms (Lyall et al., 2012 and Moshfeghi et al., 2011). Although the origin of these bacteria remains unclear, decreased rates of tissue culture inoculation were seen when no talking occurred during the procedure, indicating the respiratory tract as the possible source (McCannel, 2011). Systemic side effects Clinical trials in systemic administration of anti-VEGF therapy have shown increased risk for thromboembolic events, such as myocardial infarction or stroke (Gordon & Cunningham, 2005, Scappaticci et al., 2007). Diabetics, particularly those who present with DME, are at a higher risk for developing thromboembolic events (Hirai et al., 2008). Yet, the clinical data evaluating systemic safety of intravitreally administered anti-VEGF remains unclear. The aforementioned clinical trials were not designed and powered for detecting the true incidence of adverse side effects, but their initial findings raise some concerns, particularly since intravitreal

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administration of anti-VEGF has been shown to enter the systemic blood stream (Csaky & Do 2009). In VIVID/VISTA-DME, cardiovascular accidents (CVA) and myocardial infarction (MI) occurred in 0.9-1.0% of patients treated with intravitreal aflibercept as compared to 0.3% of patients treated with laser treatment (Korobelnik et al., 2014). These higher rates were also seen in patients in the RISE/RIDE trials with CVA occurring in 2.4-3.2% of ranibizumab patients as compared to the 0.8-1.6% of sham patients (Nguyen et al., 2012). A meta-analysis in AMD antiVEGF therapy found non-ocular adverse events occurring less than one in a hundred injections with no difference between anti-VEGF therapies (Van der Reis et al., 2011). A clinical trial evaluating intravitreal bevacizumab safety in 1173 patients found 1.5% of patients suffered systemic adverse events with transient hypertension being the most common symptom in 0.6% of the patients. 0.5% and 0.4% of patients had CVA and MI, respectively (Wu et al., 2008). The current evidence, although not definitive, warrants further investigation into the overall safety of anti-VEGF therapy.

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Comparison of Anti-VEGF therapy In 2015, DRCR.net performed a randomized clinical trial designated Protocol T to compare the efficacy of anti-VEGF therapy. The implications of Protocol T help define whether off-label bevacizumab ($50), a less costly anti-VEGF therapy, would be equivalent to its newer, FDA approved equivalents aflibercept ($1950) or ranibizumab ($1200). In patients with vision equivalent to 20/50 or worse at baseline, aflibercept (+18.9±11.5 letters of vision improvement from baseline) significantly improved vision as compared to bevacizumab (+11.8±12 letters from baseline) and ranibizumab (+14.2±10.6 letters from baseline). However, in patients with 20/32 to 20/40 vision at baseline, all three anti-VEGF therapies were essentially equivalent with mean improvements at +8.0, +7.5, and +8.3 letters from baseline for aflibercept, bevacizumab, and ranibizumab, respectively. Of note, ranibizumab and bevacizumab showed no difference in visual outcomes, consistent with studies in anti-VEGF therapy of AMD (Martin et al., 2011). Protocol T suggests that there is a differential population that should be selectively treated with aflibercept (DRCR.net 2015). However, further clinical trials are underway to validate the relative effectiveness and safety of multiple anti-VEGF therapies (NCT00545870, NCT01627249, NCT01610557). Corticosteroid therapy Based upon insights into the multifactorial pathophysiology of DME and the preliminary findings in the DRCR.net Protocol I study, corticosteroids have become an alternative therapy for treating DME. In particular, the following outlined clinical trials regarding the three major corticosteroids demonstrate how corticosteroids may play a role in refractory DME, or persistent DME despite laser therapy. Triamcinolone acetonide Early clinical trials attempted to determine whether triamcinolone was better than laser photocoagulation. DRCR.net in 2008 initiated a phase III randomized clinical trial comparing 1mg and 4mg doses of intravitreal triamcinolone with laser photocoagulation. At 2 years, visual acuity and safety were significantly better in the laser group than both triamcinolone groups (DRCR.net 2008). Gilles et al. furthered this study by evaluating intravitreal triamcinolone and laser therapy as compared to laser treatment alone. They did not find a difference between the two treatment arms in terms of BCVA. There was, however, a significant increase in percentage

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of patients that gained 10 lines or more in triamcinolone treated versus laser photocoagulation therapy (Gilles et al., 2011). Ultimately, triamcinolone failed to show improved outcomes as compared to the standard of therapy in treatment naïve DME patients. In 2002, Martidis et al. presented a case series showing intravitreal triamcinolone as a promising therapy in patients that did not respond to conventional laser (Martidis et al., 2002). A follow-up prospective clinical trial performed by Gillies et al. validated these findings. They proved that triamcinolone improved mean BCVA in patients treated with triamcinolone by +3.1 as compared to sham injections, which decreased mean BCVA by -2.9. This effect, however, did not persistent at five-year follow up as mean BCVA normalized between groups (Gilles et al., 2009), suggesting further evaluation of dosing or formulation in long-term management of refractory DME.

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Fluocinolone acetonide Fluocinolone is a corticosteroid derivative of hydrocortisone with a fluorine substitution that increases its activity (Mills et al., 1960). Non-biodegradable cylindrical tubes loaded with fluocinolone were inserted into the intravitreal space by a 25-gauge needle in an outpatient setting. A randomized clinical trial called Fluocinolone Acetonide for Diabetic Macular Edema (FAME) evaluated the efficacy of fluocinolone in patients that had persistent DME. At 2 years, FAME demonstrated an increase in mean BCVA of 4.4 and 5.4 in low- (0.2 μg/d) and high-dose (0.5 μg/d) fluocinolone as compared to a 1.7 increase in the sham group. After six weeks of the study, patients were allowed to receive rescue laser therapy for persistent edema regardless of treatment arm. Sham group received significantly more laser rescue with 12.3% patients receiving 4 or more treatments during the trial compared with 4.8% and 2.6% in the low- and high-dose fluocinolone (Campochiaro et al., 2011). However, the difference between sham and fluocinolone treatment groups visual acuity equalized at 3 years post-implantation, possibly due to the 30-month life span of the FA implant (Pearson et al., 2011). These findings reinforce the efficacy but limited longevity of corticosteroid treatment in refractory DME seen in triamcinolone therapy.

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Dexamethasone Dexamethasone, another corticosteroid, differs from triamcinolone and fluocinolone in solubility, pharmacokinetics and interaction with glucocorticoid receptors (Edelman, 2010). Just as fluocinolone, dexamethasone is loaded into an implant for sustained release into the vitreous of the eye. In a phase III clinical trial performed by the Macular Edema: Assessment of Implantable Dexamethasone in Diabetes (MEAD) study group, dexamethasone implants of 0.7mg, 0.35mg were compared to a sham procedure in patients with refractory and nonrefractory DME. At three-year follow-up, BCVA improvements were seen in dexamethasone implants of 0.7mg (3.5±8.4) and 0.35 (3.6±8.1) as compared to sham (2.0±8) (Boyer et al., 2014). Although limited in duration compared to the previous corticosteroids, these findings have made dexamethasone a potential and promising therapy in patients with and without refractory DME. Side effects of corticosteroid therapy Intravitreal administration of corticosteroids is well tolerated with minimal systemic side effects. This is most likely due to the limited passage of corticosteroids into the systemic

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Ocular side effects The most common side effects of corticosteroids consistently seen throughout the clinical trials were development of premature cataract and intraocular hypertension. In fact, this may have been a confounding variable in evaluation of BCVA change. The incidence of patients that required medical or surgical intervention of their cataract or intraocular hypertension was 2388.7% and 8-56%, respectively (DRCR.net 2008, Gilles et al., 2011, Martidis et al., 2002, Gilles et al., 2009, Mills et al., 1960, Campochiaro et al., 2011, Pearson et al., 2011, Boyer et al., 2014). This was approximately three times as common as their controls. Interestingly, the FAME study demonstrated a dose-dependent increase in side effects as high-dose treated patients had approximately twice as much incidence of steroid induced ocular hypertension as compared to low-dose treatment (Campochiaro et al., 2011). Therefore, risk for interventional procedures, such as cataract surgery or invasive glaucoma surgery, increased morbidity from corticosteroid therapy.

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Systemic side effects Systemic adverse events remained similar between the treatment and controls groups. Of the clinical trials that reported systemic side effects, the incidence of serious adverse events was less than 2.5% with the highest numerical but not significant being myocardial ischemia and congestive heart failure (DRCR.net 2008, Gilles et al., 2011, Martidis et al., 2002, Gilles et al., 2009, Mills et al., 1960, Campochiaro et al., 2011, Pearson et al., 2011, Boyer et al., 2014). No evidence of arterial thromboembolic events or delayed healing occurred in the majority of the clinical trials. In fact, the MEAD dexamethasone study analyzed HBA1c levels postcorticosteroid administration. They found levels to remain below 8.1, consistent with aging and progression of underlying diabetes in some patients (Boyer et al., 2014, Glassock & Winearls 2009). This demonstrates that intravitreal corticosteroid therapy has limited systemic side effects.

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Combinatorial therapies Although many of the aforementioned clinical trials establish effectiveness with monotherapy of laser, anti-VEGF, or corticosteroids, evaluation of combinatorial management has shown promise. These synergistic effects may be explained pathophysiologically with targeting multiple mechanistic pathways, promoting laser effectiveness by reducing macular thickness, reducing respiratory requirements in photocoagulated regions, or steroids modulating the function of the retinal pigment epithelium. Ranibizumab is the primary anti-VEGF therapy that has been evaluated in combination with laser therapy. The previously described READ2 study indicated that at two year follow up ranibizumab with laser improved visual outcomes and decreased persistent or recurrent DME. Importantly, patients with combination therapy required less frequent re-treatment injections compared to ranibizumab or laser monotherapy and patients previously treated with laser therapy had sustained BCVA gains at 18 months (Nguyen et al., 2010). Similar findings were seen in DRCR.net Protocol I study where BCVA was improved in ranibizumab with prompt or deferred laser (DRCR.net, 2010). In contrast, the RESTORE study found no significant difference between ranibizumab and laser versus ranibizumab monotherapy, despite both being superior to laser alone. Furthermore, there was no significant difference in the number of re-treatment

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injections, but follow-up beyond 1 year may be required to assess the benefits of combination therapy (Mitchell et al., 2011). These studies suggest that ranibizumab and laser therapy may have a role in reducing the recurrence or persistence of DME at long-term follow-up. In juxtaposition, evaluation of triamcinolone has had more conflicting results. Multiple studies have reported that intravitreal triamcinolone combined with laser in a short period (up to 9 weeks) is superior to either alone (Tunc et al., 2005, Kang et al., 2006, Avitabile et al., 2005). However, DRCR.net Protocol I did not recapitulate these findings with triamcinolone and laser showing no improvement over laser therapy alone at one and two year follow-up (DRCR.net, 2010). One exception, interestingly, was in pseudophakic patients. When treated with triamcinolone plus laser therapy, pseudophakic patients had improvements in BCVA comparable to anti-VEGF plus laser (DRCR.net, 2010, Gilles et al., 2011). The major limitations of triamcinolone were the short duration of action, need for multiple injections, and risk of developing cataracts and glaucoma. Therefore, new drug delivery systems are being developed, as discussed previously, to diminish the risk of side effects. In short, triamcinolone and laser may have a role in pseudophakic patients but further investigation is necessary to evaluate this combination as primary treatment. Albeit anti-VEGF and triamcinolone work on different mechanisms of diabetic retinopathy, corticosteroids and anti-VEGF combination therapy has shown limited improvements. Soheilian et al. demonstrated that at 36 weeks, bevacizumab and intravitreal triamcinolone had comparable BCVA improvements with bevacizumab alone. This suggests that triamcinolone provided no additional adjunctive benefit (Soheilian et al., 2009). Longer followup may be necessary to determine long-term benefits of anti-VEGF and corticosteroid cotreatment.

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Evolving anti-inflammatory and anti-VEGF management strategies The establishment of pharmacologic therapies against diabetic retinopathy has allowed further investigation in novel therapeutics that go beyond the broad scope of steroids and antiVEGF antibodies. We will briefly highlight a few of the drugs that are currently in development.

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VEGF-Related Therapeutics Since the study of the three anti-VEGF antibodies (bevacizumab, ranibizumab, and aflibercept), two major drawbacks have spurred advancements in anti-VEGF related therapeutics: non-responders and burdensome monthly injections. A conceivable explanation for both limitations is that molar concentrations of anti-VEGF therapies are inadequate. In support, the inverse may explain why aflibercept, possibly at higher molar concentrations as compared to its anti-VEGF counterparts, showed improved outcomes in the aforementioned DRCR.net Protocol T study (DRCR.net, 2015). Two possible solutions are to further optimize the pharmacokinetics of antibody mediated inhibition of VEGF or targeting the effects or upstream targets of VEGF. To build upon the pharmacokinetics of ranibizumab and aflibercept, RTH258 and designed ankyrin repeat proteins (DARPins) show how anti-VEGF therapy is evolving. These drugs capitalize on two desirable pharmacologic traits: increased affinity to and prolonged inhibition of VEGF. This would allow increase effectiveness at lower molar concentrations and require fewer recurrent injections. RTH258 (Alcon and Novartis) is a humanized single-chain, fragmented antibody that is currently in phase III clinical trials (NCT02307682, NCT02434328). OSPREY and OWL, a pair of phase 2 clinical trials, demonstrated that RTH258 is as effective as

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aflibercept and that 10-μL microinfusion of concentrated (1.2mg) RTH258 showed improvements in visual acuity and correlative imaging thickness, respectively (Medscape, 2015). Separately, DARPins create multiple binding domains to tightly bind VEGF-A. In a limited population, DARPins reduced edema and improved visual acuity in preliminary results from phase I/II clinical trials. However, treated patients developed ocular inflammation, possibly secondary to response against the preparation (Campochiaro et al, 2013). As VEGF-related pathways are identified, targeting upstream markers or downstream effects of VEGF has become a novel therapeutic approach. Sirolimus (MacuSight), also known as rapamycin, is an immunosuppressive agent that targets mammalian target of rapamycin (mTOR), the upstream regulator of VEGF and hypoxia inducible factor-alpha (HIF-α) (Dugel et al., 2012). Squalamine is a small molecule applied intravitreally or topically that inhibits plasma membrane ion channels, affecting downstream VEGF activity. It currently is in phase II clinical trials (NCT02511613) (Ohr Pharmaceuticals, 2015). Src kinase inhibitors prevent VEGFinduced permeability established in animal models (Scheppke et al., 2008, Doukas et al., 2008). iCo-007 (iCo Therapeutics) is an antisense inhibitor targeting C-raf kinase mRNA that ultimately inhibits VEGF and HIF-1; it currently is in phase II clinical trials (NCT01565148) (Hnik et al., 2009). RTP801 is a gene that is preferentially expressed when oxidative stress and DNA damage occurs in patients with diabetic retinopathy. SiRNA designed to inhibit RTP801 (Quark Pharmaceuticals) is also currently in phase II clinical trials (Shoshani et al., 2002, Brafman et al., 2004).

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Anti-Inflammatory Therapeutics Understanding the role of inflammatory markers in diabetic retinopathy and DME has grown significantly, introducing new proteins or pathways to target separate from corticosteroids. Tumor necrosis factor alpha (TNF-α) regulates retinal leukostasis and injection of TNF-α causes blood-retinal barrier (BRB) breakdown. In mouse models, etanercept, an inhibitor antibody against TNF-α, has showed decreased BRB breakdown despite unaffected VEGF levels (Adamis & Berman, 2008). Furthermore, a double-blinded randomized placebocontrolled study of 11 patients with persistent DME showed improved visual acuity after infliximab treatment (Sfikakis et al., 2010). CCR2/5 receptor antagonist, an inhibitor of a chemokine pathway, showed reduced BRB permeability in animal models and is currently in phase II clinical trials (NCT01994291) (Rangasamy et al., 2014). SAR 1118 (SARcode Bioscience) is a small molecule antagonist inhibiting lymphocyte function-associated antigen-1 (LFA-1) from binding intercellular adhesion molecule 1 (ICAM-1), thereby preserving the integrity of the BRB (Rao et al., 2010). Reducing Side Effects: Endophthalmitis The most concerning side effect is endophthalmitis and significant measures have been taken to reduce the likelihood of intraocular infection. There are four main procedural tasks, as seen in DRCRnet and SCORE clinical trials, performed to prevent endophthalmitis. They are as follows: 1) pre-injection ocular irrigation with povidone-iodine (PI), 2) application of sterile lid speculum, 3) reduction in talking during injection, and 4) utilization of prophylactic antibiotics. A prospective clinical trial and retrospective studies have shown that application of PI in various concentrations and durations significantly decreases culture-positive endophthalmitis (Speaker & Menikoff, 1991, Friedman et al., 2013 and Shiamada et al., 2013). Sterile lid speculum, however, has not been shown to affect conjunctival flora (Friedman et al., 2013). Organisms that colonize

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the respiratory tract are common organisms that cause endophthalmitis and reduced talking or wearing a facemask has shown decreased rates of endophthalmitis (Lyall et al., 2012, McCannel, 2011, Moshfeghi et al., 2011, Schimel et al., 2011). Lastly, prophylactic antibiotics remains controversial as all evidence shows no affect on rates of endophthalmitis; in fact, some studies established increased antibiotic resistant organism with continued use of antibiotics (Storey et al., 2014, Cheung et al., 2012, Kim & Toma, 2011, Moss et al., 2009).

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Conclusion Anti-VEGF therapy and corticosteroids have provided alternative therapies in the management of DME, a previously crudely treated complication of diabetes. Identification of these modalities has, in isolation, proven to not only stabilize but also improve vision. In treatment naïve patients, anti-VEGF therapy has essentially replaced laser photocoagulation as the new standard of care. However, rescue or supplemental laser therapy was routinely utilized throughout all clinical trials. In patients affected with refractory DME, corticosteroids show promise in improving visual outcomes. As further studies refine the administration route, schedule, and relative efficacy, we may see permutations of anti-VEGF therapy, corticosteroids, and laser therapy as a multimodal approach in managing diabetic retinopathy.

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Acknowledgements 1) Funding/support: none 2) Financial disclosures: Alcon Laboratories (RPS), Genentech (RPS), Regeneron (RPS), Allergan (RPS), ThromboGenics (RPS), Shire (RPS)

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49. Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr, et al. Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six-year experience at a university referral center. Retina. 2011;31(4):662-668. doi: 10.1097/IAE.0b013e31821067c4 50. Moss JM, Sanislo SR, Ta CN. A Prospective Randomized Evaluation of Topical Gatifloxacin on Conjunctival Flora in Patients Undergoing Intravitreal Injections. Ophthalmology. 2009;116:1498-1501. doi:10.1016/j.ophtha.2009.02.024 51. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4)789-801. doi: 0.1016/j.ophtha.2011.12.03 52. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010;117(11):21462151. doi: 10.1016/j.ophtha.2010.08.016 53. Ohr Pharmaceuticals. Ohr Pharmaceutical Announces Successful End of Phase II Meeting with FDA on Squalamine Eye Drops (OHR-102 in Wet AMD). Accessed Oct 22nd, 2015. http://www.ohrpharmaceutical.com/media-center/pressreleases/detail/304/ohr-pharmaceutical-announces-successful-end-of-phase-ii 54. Pearson PA, Comstock TL, Ip M, et al. Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: A 3-Year Multicenter, Randomized, Controlled Clinical Trial. Ophthalmology. 2011;118(8):1580-1587. doi: 10.1016/j.ophtha.2011.02.048. 55. Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. 2012;130(8):872-979. doi:10.1001/archophthalmol.2012.393 56. Rangasamy S, McGuire PG, Franco NC, et al. Chemokine mediated monocyte trafficking into the retina: role of inflammation in alteration of blood-retinal barrier in diabetic retinopathy. PLoS One. 2014;9(10):e108508. doi: 10.1371/journal.pone.0108508 57. Rao VR, Prescott E, Shelke NB, et al. Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR). Invest Ophthalmol Vis Sci. 2010;51(10):5198-5204. doi: 10.1167/iovs.09-5144 58. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419–31. doi: 10.1056/NEJMoa054481 59. Saaddine JB, Honeycutt AA, Narayan KM, Zhang X, Klein R, Boyle JP. Projection of diabetic retinopathy and other major eye diseases among people with diabetes mellitus: United States, 2005–2050. Arch Ophthalmol. 2008;126(12):1740–1747. 60. Sarao V, Veritti D, Boscia F, et al. Intravitreal Steroids for the Treatment of Retinal Diseases. Scientific World Journal. 2014;989501. http://dx.doi.org/10.1155/2014/989501 61. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007; 99: 1232–1239. doi: 10.1093/jnci/djm086 62. Scheppke L, Aguilar E, Gariano RF, et al. Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits. J Clin Invest. 2008;118(6):2337-2346. doi: 10.1172/JCI33361 63. Scott IU, Danis RP, Bressler SB, Bressler NM, Browning DJ, Qin H, DRCR.net. Effect of Focal/Grid Photocoagulation on Visual Acuity and Retinal Thickening in Eyes with

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Non-Center Involved Clinically Significant Diabetic Macular Edema. Retina. 2009;29(5):613-617. doi: 10.1097/IAE.0b013e3181a2c07a 64. Sfikakis PP, Grigoropoulous V, Emfietzoglou I, et al. Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebocontrolled, crossover, 32-week study. Diabetes Care. 2010;33(7):1523-1528. doi: 10.2337/dc09-2372 65. Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol. 2006;39(5):469-478. 66. Shimada H, Hattori T, Mori R, et al. Minimizing the endophthalmitis rate following intravitreal injections using 0.25% povidone-iodine irrigation and surgical mask. Graefes Arch Clin Exp Ophthalmol. 2013;251:1885-1890. doi: 10.1007/s00417-013-2274-y 67. Shoshani T, Faerman A, Mett I, et al. Identification of a Novel Hypoxia-Inducible Factor 1-Responsive Gene, RTP801, Involved in Apoptosis. Mol Cell Biol. 2002; 22(7):22832293. doi: 10.1128/MCB.22.7.2283-2293.2002 68. Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 2009;116(6):1142-1150. doi: 10.1016/j.ophtha.2009.01.011 69. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology. 1991;98(12):1769-1775. doi: http://dx.doi.org/10.1016/S01616420(91)32052-9 70. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol. 2008;92:667– 668. doi:10.1136/bjo.2007.134874 71. Storey P, Dollin M, Pitcher J, et al. The Role of Topical Antibiotic Prophylaxis to Prevent Endophthalmitis after Intravitreal Injection. Ophthalmology. 2014;121:283-289. doi: http://dx.doi.org/10.1016/j.ophtha.2013.08.037 72. Tunc M, Onder HI, Kaya M. Posterior sub-Tenon’s capsule triamcinolone injection combined with focal laser photocoagulation for diabetic macular edema. Ophthalmology. 2005;112(6):1086-1091. doi: http://dx.doi.org/10.1016/j.ophtha.2004.12.039 73. Van der Reis MI, La Heij EC, De Jong-Hesse Y, et al. Ringens PJ, Hendrikse F, Schouten JS. A Systematic Review of the Adverse Events of Intravitreal Anti-Vascular Endothelial Growth Factor Injections. Retina. 2011;31(8):1449-1469. doi: 10.1097/IAE.0b013e3182278ab4 74. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, et al. Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol.2008; 246(1):81-87.doi: 10.1007/s00417-007-0660-z 75. Yau JW, Rogers SL, Kawasaki R, et al., Global Prevalence and Major Risk Factors of Diabetic Retinopathy. Diabetes Care. 2012;35(3):556-564. doi: 10.2337/dc11-1909

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Figure Legends Figure 1. A representation of the three various types of anti-VEGF therapy and how they differ in development and mechanism of action. While ranibizumab and bevacizumab are both humanized monoclonal antibodies, ranibizumab has further affinity purification and decreased size. In contrast, aflibercept replicates two portions of the VEGF receptor attached to an antibody Fc region, effectively working as a “trap receptor”.

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Figure 2. Mean change in best-corrected visual acuity (BCVA) from baseline through 36 months in the RISE/RIDE clinical trials. These outcomes were evaluated by changes in Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Sham subjects that crossed over to the ranibizumab 0.5 mg at or after month 25 (n=190) are shown in the transition from the black to red triangles.

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Table 1. A summarization of the major clinical trials involved in evaluating the safety and efficacy of anti-VEGF and corticosteroid therapy in the treatment of DME. Study Design Primary Outcome: Randomized and Treatment arm (n): Mean Drug Group Treatment Control Primary +/- SD (where available) Trial (n) Outcome ETDRS Letter Change Time from Baseline (letters) Point Phase II, Sham (49): -1.4±14.2 RESOLVE 12 IVR 0.3mg - 1mg 3q4 (102): (151) months 1+0.3±9.1 Laser (34): +5.1 Phase II, READ-2 IVR 0.5mg 3q8 (33): +7.7 24 (126) IVR 0.5mg 3q8 + Laser (34): month +6.8 Laser (110): +0.8±8.56 Phase III, IVR 0.5mg 3q4 (115): RESTORE +6.1±6.43 12 (345) months IVR 0.5mg 3q4 + Laser (118): +5.9±7.92 Sham 3q4 + Prompt Laser Ranibizumab (293): +3.0±13 (Lucentis) IVR 0.5mg 3q4 + Prompt DRCR.net Phase III, Laser (187): +9.0±11 Protocol I 60 IVR 0.5mg 3q4 + Deferred (854 eyes) months Laser (188): +9.0±12 Anti-VEGF Triamcinolone + Prompt agents Laser (186): +4.0±13

Bevacizumab (Avastin)

RISE (377)

Phase III, 24 months

Sham q4 (126): +2.6 IVR 0.3mg q4 (125): +12.5 IVR 0.5mg q4 (125): +11.9

RIDE (382)

Phase III, 24 months

Sham q4 (130): +2.3 IVR 0.3mg q4 (125): +10.9 IVR 0.5mg q4 (127): +12.0

BOLT (80)

Phase II, 24 months

DRCR.net et al. 2007 (121)

RCT 24 months

Laser q12 (28): -0.5±10.6 IVB 1.25mg q6 (37): +8.6±9.1 Laser (19): IVB 1.25mg 2q6 (22): IVB 2.5mg 2q6 (24): IVB 1.25mg + sham q6 (22): IVB 1.25mg 2q6+ laser q3 (22):

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DA VINCI (221)

Phase II, 12 months

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Aflibercept (Eylea)

Phase III, 52 weeks

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VIVD-DME and VISTADME (872)

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DRCR.net 2008 (840) Gillies et al 2011 (84 eyes) Gillies et al 2006 (69)

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Triamcinolone (TAc)

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Corticosteroids

FAME (956)

Dexamethosone (DEX)

Ozurdex MEAD (1048)

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Fluocinolone acetonide (FAc)

*% of total patients

VISTA: Laser (154): +0.2±12.5 IAI 2mg q4 (155): +12.5±9.5 IAI 2mg q8 (152): +10.7±8.2

Phase III, 24 months RCT, 24 months RCT, 24 months Phase III, 24 months Phase III, 36 months

VIVID: Laser (133): +1.2±10.6 IAI 2q4 (136): +10.5±9.5 IAI 2q8 (135): +10.7±9.3 Laser (330):+1±17 IV TAc 1mg (256): -2±18 IV TAc 4mg (254): -3 ± 22 Laser (42): -1.46 IV TAc + Laser (42): +0.76 Sham (35): -2.9 IV TAc 0.1ml (34): +3.1 Sham (185): +1.7 IV FAc 0.2ug/day (375): +4.4 IV FAc 0.5ug/day (393): Sham (350): +2±8 +5.4 DEX 0.35mg (343): +3.6±8.1 DEX 0.7mg (347): +3.5±8.4

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Anti-VEGF

Common ocular side effects:  Cataract formation requiring surgery  Transient and sustained intraocular pressure increase requiring medicinal or surgical treatment

Severe ocular side effects:  Endophthalmitis  Intraocular inflammation  Rhegmatogenous retinal detachment  Tractional retinal detachment

Severe ocular side effects:  Endophthalmitis  Rhegmatogenous retinal detachment  Pseudoendophthalmitis  Vitreous hemorrhage

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Common ocular side effects:  Transient intraocular pressure elevation  Subconjunctival hemorrhage  Pain

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Figure 2

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Highlights  Provide historical perspective in the management of diabetic macular edema  Summarize the major clinical trials in anti-VEGF therapy of diabetic macular edema  Review indications for corticosteroid use in diabetic macular edema  Describe the major side effects of intraocular anti-VEGF and corticosteroids  Elucidate the evolving role of anti-VEGF and corticosteroid therapy in diabetic macular edema  Evaluate the strengths and weaknesses of combinatorial therapy