Proliferative Diabetic Retinopathy: Should New Data Change Management?

American Academy of Ophthalmology (AAO) 2015

Charles C. Wykoff, MD, PhD


January 07, 2016

In This Article

Beyond Standard of Care

Diabetic retinopathy (DR) is a leading cause of vision loss around the world, and remains the most common cause of blindness among working-age people in the United States and many developed countries.[1] Largely mediated through pathologic retinal ischemia, DR leads to vision loss primarily through diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR).

PDR is defined by the development of neovascularization that originates from the retinal vasculature and aberrantly grows through the internal limiting membrane into the vitreous. Retinal neovascularization can either involve the optic disc (neovascularization of the disc) or more peripheral retina (neovascularization elsewhere). PDR typically leads to vision loss through rupture of the unstable, pathologic vessels, causing vitreous hemorrhage or retinal distortion and traction detachments due to concurrent proliferation of a fibrous scaffold along with the abnormal vessels.

Epidemiologic data gathered from over 1200 patients in the Wisconsin Epidemiologic Study of Diabetic Retinopathy suggested that, given a long enough duration of diabetes, approximately 60% of diabetics will develop PDR.[2] Such a transition to PDR significantly increases the risk for progressive vision loss, and without intervention, approximately one half of eyes will ultimately experience severe vision loss.[3] Currently, PDR results in 12,000-24,000 new cases of blindness each year in the United States.[4]

Validated through the Diabetic Retinopathy Study, panretinal photocoagulation (PRP) has been the standard treatment for PDR since the 1970s.[5] PRP is typically applied to the peripheral retina in the office setting and can be exceptionally effective at inducing regression of neovascularization and disease stabilization. Application of appropriate PRP reduces the risk for severe vision loss to approximately 4%.[6]

Despite its remarkable effectiveness in the treatment of PDR, PRP can have untoward effects, including peripheral visual field defects, night-vision loss, loss of contrast sensitivity, and loss of visual function. Furthermore, PRP itself can be ineffective in some eyes, with subsequent need for traditional vitrectomy surgical intervention in at least 5% of eyes despite appropriate laser treatment.[7]

Therefore, supplemental or alternative therapies for PDR could be of substantial clinical value. Pathologic overexpression of vascular endothelial growth factor (VEGF)-A[8] is a key driver of DR, DME, and PDR. Pharmaceutical agents that specifically inhibit VEGF, including ranibizumab, aflibercept, and bevacizumab, have revolutionized the management of DME, as well as other exudative retinal diseases, such as age-related macular degeneration and venous occlusive disease. These remarkably well-tolerated medications are administered in the clinic using a 30-gauge or smaller needle inserted through the pars plana directly into the vitreous cavity.

Multiple prospective, randomized trials focusing on the management of DME have demonstrated that anti-VEGF therapy can significantly blunt the progression of DR to PDR. For example, PDR events were reduced in the RIDE/RISE phase 3 trials at 2 years from approximately 34% with sham treatment to 11% with monthly ranibizumab treatment (either 0.3 mg or 0.5 mg).[9,10] Anti-VEGF treatments have the concurrent benefit of not only slowing progression to PDR but also improving the severity of DR in a substantial proportion of patients,[10,11] a clinical finding not observed with PRP alone.


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