January 03, 2019
4 min read

Anti-VEGF injections may play increasing role in treatment of diabetic retinopathy

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Patients with diabetic macular edema and moderately severe to severe nonproliferative diabetic retinopathy, as determined on the ETDRS Diabetic Retinopathy Severity Scale, greatly benefit from intravitreal anti-VEGF injection with ranibizumab, with more robust results than in patients with less or more severe diabetic retinopathy, according to a study.

“If untreated, these patients have a substantial risk of progressing to PDR,” Charles C. Wykoff, MD, told Ocular Surgery News.

The study was a post hoc analysis of the phase 3 RIDE and RISE clinical trials, in which the safety and efficacy of two different dosages of Lucentis (ranibizumab, Genentech) were assessed in 759 patients with DR and DME. The aim of the analysis was to examine the outcomes of patients at highest risk for progressing to PDR (identified as ETDRS DRSS level 47/53) and compare them with the outcomes of patients with proliferative disease and patients with more mild forms of DR.

The question was, “How responsive are these patients to anti-VEGF injections compared to the other patient populations?” Wykoff said.

Charles C. Wykoff

Two-step improvement

At 12 months, approximately 75% of the ranibizumab-treated patients in the 47/53 group showed a two-step or more DR improvement compared with 2.3% of sham-treated patients. Significant improvement was seen at 3 months and was maintained through 36 months, with approximately 80% of the group having achieved two steps or more of DR severity improvement. Diabetic retinopathy worsening was consistently and significantly lower in ranibizumab-treated patients compared with sham-treated patients. The probability of experiencing a new proliferative event by month 36 was reduced by three times compared with sham.

“DR severity improvements were substantially higher than achieved among patients with more advanced retinopathy as well as patients with less advanced retinopathy. This indicates that clinically DRSS levels 47 and 53 might be a group of patients to consider pharmacotherapy for DR. In this data set, patients with proliferative disease appeared to have a less robust response to pharmacotherapy, representing a possible reason to consider initiating dosing before patients transition to proliferative disease,” Wykoff said.

Proliferative diabetic retinopathy and center-involved DME with visual loss have conventionally been the thresholds for initiating interventional, ocular-specific treatment. This analysis supports considering a change to this paradigm and supports the notion that earlier treatment be considered among high-risk patients.

“The key new finding is that this higher-risk NPDR patient population appears to be remarkably sensitive to the benefit of anti-VEGF dosing, supporting the management strategy of considering earlier intervention,” Wykoff said. “The low rates of DR worsening indicate that anti-VEGF treatment at this stage significantly reduces the chance of progression to PDR.”


Two ongoing studies, the PANORAMA and the DRCR.net Protocol W, are investigating the benefits of initiating anti-VEGF treatment in this 47/53 high-risk population.

“These trials are studying a critical population because, unlike in the RISE and RIDE trials, patients have good vision and no center-involved DME at baseline,” he said.

Growing role of pharmacotherapy

For a long time, panretinal photocoagulation (PRP) has been the standard treatment for proliferative diabetic retinopathy or even severe nonproliferative diabetic retinopathy.

“I am definitely not suggesting that laser for PDR should be abandoned. To the contrary, in my clinical practice PRP still plays a key role in managing many eyes with PDR. But our findings, together with those of many other studies, show that there is a growing role of pharmacotherapy in the management of DR,” Wykoff said.

The DRCR.net Protocol S directly compared PRP and ranibizumab dosing in patients with proliferative diabetic retinopathy. In the ranibizumab 0.5 mg group, 47% of patients experienced two steps or more of DR improvement at 24 months.

“Protocol S showed that PRP can be a durable treatment: 49% of patients in the PRP arm needed a single PRP session with subsequent control of their proliferative disease through 5 years. From a functional perspective, 5-year data suggest that much of the initial visual advantage seen in the anti-VEGF arm through the first 2 years was lost by the end of 5 years. Visual acuity outcomes through the fourth and fifth years of the trial were essentially superimposable between the two arms. Also, while there remained a statistically significant greater loss of visual field in the PRP arm compared to the anti-VEGF arm at the end of year 5, this difference was less marked than the difference seen at the end of year 2,” Wykoff said.

All things considered, with the durability of PRP vs. the earlier advantage and the nondestructive nature of anti-VEGF, both options should remain in the armamentarium of clinicians, often to be used in combination and according to the stage of the disease.

“I think that the choice to treat and how to treat is an individualized choice. With anti-VEGF medications in our armamentarium, I think more physicians are considering treating eyes at high risk of progression to PDR, especially in settings in which the fellow eye has already lost vision due to DME or PDR. If these patients are observed, they need careful clinical follow-up, as we know that they have a high risk of disease progression,” Wykoff said.

The exploratory post hoc analysis of the RIDE and RISE trials, which focused specifically on those patients, provided additional evidence to support intervention at this stage to prevent progressive vision loss and development of PDR. – by Michela Cimberle

Disclosure: Wykoff reports he is a consultant for Alcon, Alimera, Allergan, Genentech, Notal Vision, Regeneron and Santen.