A multimodal approach to diabetic macular edema

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Abstract

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.

Introduction

Diabetic retinopathy (DR) is the most common complication of diabetes, affecting one in three diabetics (Center of Disease Control National Center of Chronic Disease Prevention & Health Promotion Division of Diabetes Translation, 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, nd). 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.

Section snippets

Evolution of treatments

Historically, the treatment of DME was focused on vision stabilization. The 1985 landmark Early Treatment of Diabetic Retinopathy Study (ETDRS) 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

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).

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).

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

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.

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 circulation after intravitreal injection (Degenring & Jonas, 2004). Although many side effects have been reported, we present the more common and concerning side effects (Table 2).

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.

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 anti-VEGF antibodies. We will briefly highlight a few of the drugs that are currently in development.

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

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 DRCR.net 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

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 naive 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

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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    Conflicts of interest:

    Au: none.

    Singh: consulting fees: Alcon Laboratories, Genentech, Regeneron, Allergan, ThromboGenics, Shire; contract research: Genentech, Regeneron, ThromboGenics.

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