Sabin Dang, MD and Chirag P. Shah, MD, MPH

Diabetic retinopathy is responsible for a significant amount of visual morbidity worldwide. Chronic insult to the retinal microcirculation induced by hyperglycemia can result in multiple pathologic processes that cause vision loss.¹ Among the most severe sequelae of this process is retinal neovascularization, the key feature of proliferative diabetic retinopathy (PDR) (Figure 10-1). Recent epidemiologic studies conducted in the United States have shown nearly 1.5% of Americans diagnosed with diabetes will progress to PDR.²

Patients with PDR develop new blood vessels that are derived from the existing retinal vasculature. These vessels are created in response to the hypoxic conditions of diabetic retinopathy; they do not follow normal vessel orientation and instead invade the vitreous cavity. In patients with PDR, there is significant risk of permanent vision loss without treatment. Neovascularization can lead to vitreous hemorrhage, tractional retinal detachment (TRD), and neovascular glaucoma.

Initial treatment of PDR was historically focused on the endocrine system, with pituitary ablation as the mainstay of treatment.³ This procedure had significant morbidity and mortality associated with it and was quickly abandoned after the introduction of panretinal photocoagulation (PRP). Peripheral retinal laser destroys hypoxic retina, thus decreasing the metabolic requirements of the peripheral retina and allowing for more oxygenation of remaining tissue and reducing neovascular growth factors. This treatment reduces the risk of severe vision loss by 50% to 60%.⁴ The advent of anti-vascular endothelial growth factor (VEGF) medications, however, has created new opportunities to treat PDR with a nondestructive treatment. This chapter reviews the evidence for anti-VEGF medications in the management of PDR and its associated complications.

Much work has been performed to help understand the relationship between retinal ischemia and the development of neovascularization. In 1948, Michaelson proposed the presence of factor X, a hypothetical substance that diffused through ocular tissue in response to hypoxic states.5 Forty years later, work by Senger et al⁶ identified a glycoprotein candidate for factor X, a molecule that they named vascular permeability factor. Additional research by Jakeman et al⁷ and Thieme et al⁸ further characterized this glycoprotein into what is now known as VEGF.⁸

Since the discovery of VEGF, significant research has been conducted to establish its role in the development of neovascularization in diabetic retinopathy. Both in human and animal models, high levels of VEGF in the vitreous have been associated with PDR.^9–11 Injection of laboratory-derived VEGF into eyes of primates resulted in the creation of retinopathy similar to that seen in ischemic retinal disease. Furthermore, inhibition of VEGF in animal mouse models inhibited the development of retinal neovascularization. In humans, treatment of PDR with PRP has been shown to decrease intraocular VEGF levels.² This body of research strongly supported the role of VEGF as a key mediator in the development of diabetic retinopathy, and has led to numerous clinical trials evaluating treatment with anti-VEGF agents for the full spectrum of diabetic disease.

Given the strong association of VEGF and retinal vascular disease, questions arose regarding whether genetic variations could account for variability in retinal disease severity. Work in this area led to the discovery of several VEGF gene polymorphisms and their role in the development of retinal neovascularization. Ray et al¹² examined the VEGF₄₆₀ genotype in patients with diabetes with and without PDR and found increased rates of PDR in patients who carried the VEGF₄₆₀ allele. This research has interesting implications regarding the use of genetic screening to stratify patients and their risk for development of PDR. However, the clinical utility of such genetic screening has not yet been established.

Traditionally, PRP has been the main treatment choice for PDR used by retina physicians, with 98% reporting the use of laser for primary treatment.13 While highly successful at reducing the risk of severe vision loss, PRP does have significant drawbacks. The application of PRP can induce or exacerbate diabetic macular edema, resulting in further vision loss. Additionally, ablation of the peripheral retina can lead to decreased contrast sensitivity, visual field loss, and decreased night vision.¹⁴

The observation of decreased proliferative retinopathy in patients receiving anti-VEGF treatments for diabetic macular edema led to multiple clinical trials. Arevalo et al¹⁵ evaluated the effectiveness of bevacizumab (Avastin) on retinal neovascularization using dosages of 2.5 mg/0.1 mL and 1.25 mg/0.05 mg in patients with prior PRP as well as treatment-naïve eyes. Bevacizumab significantly improved vision and decreased retinal neovascularization, with similar effects between the PRP and treatment-naïve groups.

A randomized, controlled trial coordinated by the Diabetic Retinopathy Clinical Research Network (DRCR.net) aimed to evaluate the effectiveness of ranibizumab (Lucentis) relative to PRP. In this study, identified as Protocol S, patients were randomized to ranibizumab 0.5 mg/0.05 mL intravitreal injection monthly for 3 months. At 4 months, patients were reevaluated, and were followed monthly without further injections if neovascularization had completely resolved. If any neovascularization was still present, additional injections were given at months 4 and 5. Beginning month 6 of the treatment protocol, injections were performed as needed, ceasing further treatments if retinal neovascularization had completely resolved or if no improvement was noted after two consecutive injections. Any patient who developed progressive retinopathy despite monthly injections was allowed to receive PRP. Review of the data at 2 years demonstrated that monthly ranibizumab was noninferior to PRP for the primary treatment of PDR (Figure 10-2). Subanalysis revealed a clear benefit of ranibizumab treatment in regard to retention of peripheral visual field.¹⁶

One concern regarding the use of anti-VEGF agents as primary treatment for PDR has been reports of the “crunch” phenomenon, where existing fibrovascular membranes from PDR undergo contraction after anti-VEGF treatment and cause TRDs. However, no patients were reported to have this phenomenon within the DRCR.net Protocol S trial.¹⁶ In comparision, a case series by Arevalo et al ¹⁵ found post-bevacizumab tractional detachments occurred in 5.2% of patients with severe PDR. This effect was seen on average 2 weeks after injection of bevacizumab, and thus was attributed to the administration of the anti-VEGF agent. Of note, in their case series, none of the eyes reported were treatment-naïve and all had refractory disease despite PRP, as well as poorly controlled hyperglycemia.

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