The Early Treatment Diabetic Retinopathy Study (ETDRS) and resulting Diabetic Retinopathy Severity Scale (DRSS) were landmark National Eye Institute initiatives. The investigators classified diabetic retinopathy (DR) into 13 clinical levels based on clinical findings including hemorrhages, microaneurysms, venous beading, intraretinal microvascular abnormalities (IRMA), and neovascularization. The beauty of the scale is it allowed a physician to predict the risk of developing proliferative DR (PDR) from any given level over time. A 2-level change in the DRSS has been used by the FDA to determine whether a treatment is making a meaningful change.

The ranibizumab registration studies for diabetic macular edema (RISE/RIDE) were the first to show that a significant number of patients demonstrated a ≥2 step change in DRSS with anti-VEGF therapy, leading to approval of ranibizumab for the management of DR. This was followed by the Diabetic Retinopathy Clinical Research Retina Network (DRCR Retina Network) Protocol S and the Bayer/Regeneron CLARITY studies, which reported improved outcomes with anti-VEGF over panretinal photocoagulation (PRP) in patients with PDR, and more recently with PANORAMA and Protocol W in patients with nonproliferative DR (NPDR). In this issue, we explore the expanding use of anti-VEGF to manage DR.

Although these data exist, many physicians do not use anti-VEGF for DR. One reason physicians give is they are concerned about follow-up. In clinical studies, patients are usually not lost to follow-up, but if anti-VEGF is used in a clinical practice this can happen easily and frequently in this population of patients. This became acutely more evident in the spring and summer during the COVID-19 pandemic, when many diabetic patients feared coming to their visits and missed many injections. Many patients have shown up late in the summer only because of bleeds from recurrent neovascularization. Only time will tell what will happen to these patients.

Anti-VEGF is perfectly designed to reduce the clinical features that are the basis for the DRSS, namely neovascularization, IRMA, and retinal hemorrhages. This fact has led some to question whether the anti-VEGF agents are truly modifying the course of the DR or simply improving the signs but not the disease. If a patient truly has improved to, say, a level 35 (mild NPDR) from 53 (severe NPDR) with anti-VEGF injections then their chance of progressing to PDR over a year should have gone from 50% to between 5% and 10%. In reality, upon ceasing anti-VEGF, these patients progress considerably more rapidly than the ETDRS natural history studies would suggest.

This leaves us with a conundrum. The studies show better outcomes and fewer adverse events with anti-VEGF injections than with PRP for DR, but only if patients receive frequent injections. My patients will not come in for these injections. Hopefully, with longer acting anti-VEFG agents or maybe even anti-VEGF-producing gene therapy solutions, we can have the best of both worlds. RP