Emerging Therapies in Diabetic Retinopathy

San Francisco—Diabetic retinopathy, a term used for all abnormalities of the small blood vessels of the retina caused by diabetes, is estimated to be the most frequent cause of new cases of blindness among adults 20 to 74 years of age. All individuals with type 1 or type 2 diabetes are at risk for diabetic retinopathy.

Diabetic retinopathy is classified into 2 types: (1) nonproliferative diabetic retinopathy is the early stage of the disease, in which symptoms are mild or nonexistent; and (2) proliferative diabetic retinopathy is the more advanced form of the disease that is characterized by the growth of new blood vessels on the retina and posterior surface of the vitreous. Symptoms of diabetic retinopathy include seeing spots or floaters in the field of vision, blurred vision, having a dark or empty spot in the center of vision, and difficulty seeing well at night. The major causes of visual loss from diabetic retinopathy are attributed to diabetic macular edema, proliferative diabetic retinopathy, cataracts, and glaucoma. Guidelines recommend that diabetes patients have a comprehensive dilated eye examination once a year.

Researchers discussed the latest efforts to combat this eye disease during a symposium at the ADA meeting. Michael D. Abràmoff, MD, PhD, professor, opthalmology, University of Iowa, reported on his efforts to use computer programs to screen for diabetic retinopathy in the primary care setting. The technology, which is under review with the FDA, uses algorithms to analyze digital images of the retina, looking for lesions, hemorrhaging, microaneurysms, and other signs of retinopathy.

He said the goal is to use the technology to ensure more annual screenings occur. Early detection of diabetic retinopathy can prevent vision loss, but only about 50% of people with diabetes make it to an eye care provider for an annual screening. Barriers to screening include an insufficient number of ophthalmologists, lack of access to care, and cost, according to Dr. Abràmoff.

“Screening for diabetic retinopathy in primary care is now within reach through automated analysis of images,” he said. “If the technology is FDA approved, success will hinge on how this is integrated into the primary care workflow and accepted by ophthalmologists.”

Lee M. Jampol, MD, professor, ophthalmology, Feinberg School of Medicine, Northwestern University, provided an update from the Diabetic Retinopathy Clinical Research Network (www.drcr.net), which he chairs. Funded by the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, the Web site is dedicated to multicenter clinical research of diabetic retinopathy, macular edema, and associated conditions. The research network has about 120 active sites.

Dr. Jampol highlighted 3 of the network’s trials. Protocol I, which is now closed with 5 years of follow-up, compared laser treatment to ranibizumab, a vascular endothelial growth factor A (VEGF-A) antagonist, in the treatment of diabetic retinopathy. The study included 691 patients at 52 sites. Three-year results showed that fewer injections were needed in years 2 and 3 to sustain visual acuity gains observed in year 1. However, more injections were needed in the ranibizumab plus deferred laser group, he reported.

“Initiating anti-VEGF treatments as the initial strategy should be the gold standard of diabetic macular edema. Subsequent laser can be given, but its value needs further research,” said Dr. Jampol.

Two other studies, Protocol S and Protocol T, are near completion. Protocol S compares the effectiveness of anti-VEGF injections with pan-retinal photocoagulation, which for 40 years has been the treatment of choice and has been highly effective in proliferative diabetic retinopathy. Two-year results will be available in December 2014. Protocol T, the largest trial conducted by the network, compares the safety and efficacy of 3 anti-VEGF drugs—ranibizumab, bevacizumab, and aflibercept—in the treatment of diabetic macular disease. One-year results are slated for publication in January 2015, he said.

Protocol S and Protocol T “may well change the management of proliferative diabetic retinopathy,” concluded Dr. Jampol.

Meanwhile, other researchers are attempting to identify a genetic explanation for diabetic retinopathy, but that has proven challenging, said Lucia Sobrin, MD, MPh, associate professor, department of ophthalmology, Harvard Medical School.

Diabetic retinopathy is significantly influenced by duration of diabetes and glycemic control but also has underlying genetic risks factors, she said, noting that studies have found that relatives of patients with diabetic retinopathy have as high as a 3-fold risk of diabetic retinopathy.

Dr. Sobrin discussed 2 gene studies in diabetic retinopathy. In candidate-gene association studies, the genes most widely studied in diabetic retinopathy include VEGF, aldose reductase, receptor for advanced glycation end-products, and genes in the renin-angiotensin system. While there have been many candidate-gene association studies, Dr. Sobrin said the findings of these studies had multiple issues, including inconsistent citing, incorrect hypotheses of what genes are involved, lack of comprehensive coverage of gene variation, and insufficient sample size as reasons for the inconsistent outcomes.

She said the field has moved toward genome-wide association studies (GWAS). Compared with candidate-gene association studies, GWAS give an unbiased sampling of the genome and high-density sampling of the genome. Furthermore, GWAS have proven successful with type 2 diabetes and age-related macular degeneration. She said that initial results from GWAS are promising.

“Based on our experience with other diseases, the future success of GWAS will rely on large collaborative efforts or consortia,” she said. They will need to address the following factors:

     • Retinopathy phenotype harmonization
     • Covariate data harmonization
     • Rigorously defined case and control to maximize ability to find associations
     • Appropriately accounted for duration of disease and glycemic control
     • Inclusion of multiple ethnicities

“Larger collaborative efforts will eventually be necessary to completely uncover the genetic architecture of diabetic retinopathy,” said Dr. Sobrin.—Eileen Koutnik-Fotopoulos