Laird Harrison

August 17, 2017

BOSTON — Vascular endothelial growth-factor (VEGF) inhibitors do not necessarily stop the progression of diabetic retinopathy in people with macular edema, new research shows.

"We shouldn't forget that there are some people who aren't improved at all, and their level of retinopathy may worsen," said Susan Bressler, MD, from Johns Hopkins Medicine in Baltimore.

But, she told Medscape Medical News, among the VEGF inhibitors, aflibercept might be more effective for the proliferative form of the disease.

Previous research has shown that retinopathy is less likely to worsen and is more likely to improve after treatment with ranibizumab (Lucentis, Genentech) or aflibercept (Eylea, Regeneron) than after treatment with laser photocoagulation. The same appears true for bevacizumab (Avastin, Genentech), but the data available are not as strong.

Dr Bressler presented results from a preplanned secondary analysis of the Diabetic Retinopathy Clinical Research Network ( Protocol T trial, comparing the three drugs in patients with diabetic macular edema, here at the American Society of Retina Specialists 2017 Annual Meeting.

In their study, Dr Bressler and her colleagues assessed 650 eyes with center-involved diabetic macular edema and vision impairment (Snellen equivalent of 20/32 to 20/320). Patients were randomly assigned to one of three treatment regimens that followed the structured retreatment Protocol T protocol for 2 years: 174 patients received aflibercept 2 mg, 168 received ranibizumab 0.3 mg, and 153 received bevacizumab 1.25 mg up to every 4 weeks.

The team used clinical events and fundus photos to identify disease progression.

The clinical events consisted of panretinal photocoagulation, vitrectomy or injections for proliferative diabetic retinopathy, vitreous hemorrhage, retinal detachment, neovascularization of the iris, neovascularization of the angle, and neovascular glaucoma.

The fundus photo observations consisted of a worsening of two or more levels on the ETDRS retinopathy scale, progression from nonproliferative to proliferative diabetic retinopathy, and progression from low- to high-risk proliferative diabetic retinopathy or to advanced proliferative diabetic retinopathy.

The team defined improvement as the absence of these signs of worsening and improvement on annual fundus photos. If a patient had active proliferative diabetic retinopathy at baseline, it had to become inactive or nonproliferative. Other degrees of retinopathy had to improve by at least two levels.

Over the 2-year period, the cumulative probability of diabetic retinopathy worsening in the three groups was less than 10%, and there was no significant difference among the drugs.

This probability was slightly higher in the subgroup of patients with moderate to severe nonproliferative retinopathy, where about one-quarter of those with proliferative retinopathy at baseline progressed; again, though, there was no significant difference among the drugs.

Table 1. Progression of Diabetic Retinopathy at 2 Years

Stage of Retinopathy Aflibercept, % Ranibizumab, % Bevacizumab, %
  All 10 7 10
  Moderate to severe 18 7 13
Proliferative 17 18 26

Patients with severe disease were more likely to see improvement.

"This observation is consistent with other observations of Protocol T, in which we saw that the vision outcomes were superior in eyes with more severe disease, as reflected by a lower level of starting acuity or a thicker macula," Dr Bressler explained.

At 1 year, patients with nonproliferative retinopathy in the bevacizumab group were less likely to improve than those in the aflibercept group (P = .004) and those in the ranibizumab group (P = .01). However, at 2 years, these differences became nonsignificant.

Improvements were greatest in patients with proliferative disease. At 2 years, those in the aflibercept group were more likely to improve than those in the bevacizumab group (P = .01) and those in the ranibizumab group (P = .06). Rates of improvement were similar in the ranibizumab and bevacizumab groups.

This finding should be interpreted with caution, Dr Bressler noted, because the number of patients with proliferative disease was very small. At 2 years, there were only 27 patients in the aflibercept group, 24 in the ranibizumab group, and 33 in the bevacizumab group.

Table 2. Improvements in Diabetic Retinopathy at 2 Years

Stage of Retinopathy Aflibercept, % Ranibizumab, % Bevacizumab, %
  All 25 31 22
  Moderate to severe 51 54 50
Proliferative 70 38 30

The researchers were not able to determine whether improvement in retinopathy delays the loss of visual acuity or the need for other interventions. The team is planning to test that hypothesis in the new Protocol W trial, Dr Bressler reported.

In the meantime, the study findings "remind us to be diligent about monitoring these patients for progression of retinopathy, despite the fact that they're receiving regular anti-VEGF therapy for their diabetic macular edema," she explained.

There were some limitations to the study, she acknowledged. The follow-up period was short, the number of missed visits was high, and the number of annual visits without gradable photographs was high.

Patients with nonproliferative retinopathy in the bevacizumab group were slightly older than those in the other two treatment groups, and more patients in the aflibercept group had type 1 diabetes.

Patients with proliferative retinopathy in the ranibizumab group were more likely to have undergone panretinal photocoagulation than those in the other two treatment groups, and their retinopathy was more severe. Macular edema was more severe in the aflibercept group.

When asked by a member of the audience how these findings relate to findings from the previous Protocol I study, Dr Bressler reported that, in general, they are similar.

However, she explained, in Protocol I, after treatment with laser therapy and triamcinolone for 3 years, the rate of disease progression was highest in patients with nonproliferative retinopathy, whereas it was lowest in those with proliferative retinopathy.

But the data on patients treated with steroids and laser therapy were difficult to interpret, she added, because many of these patients had cataracts, and both cataracts and cataract surgery can affect retinopathy.

The overall picture is positive. "The take-away message is that anti-VEGF treatment works well to slow the progression and improve diabetic retinopathy," said session moderator Charles Wykoff, MD, PhD, from Retina Consultants of Houston.

This evidence of the effectiveness of VEGF inhibitors supports previous studies and amounts to "a big paradigm shift," he told Medscape Medical News. But, he added, there is still a role for steroids in this condition. "That's where the clinical touch comes in."

The study was funded by the National Institutes of Health, with contributions from Regeneron and Genentech (Roche). Dr Bressler reports receiving grant support from Jaeb Center, Bayer, Boehringer-Ingelheim, Novartis, Notal Vision, and Roche. Dr Wykoff reports relationships with Alcon Laboratories, Alimera Sciences, Allegro, Allergan, Alnylam Pharmaceuticals, Apellis Pharmaceutical, Aura, Bayer, Clearside Biomedical, DORC International, Genentech, Iconic Therapeutics, NEI, the National Institutes of Health, Novartis, OHR Pharmaceuticals, ONL Therapeutics, Ophthotech Corp, pSivida, Regeneron Pharmaceuticals, Roche, Santen, SciFluor Life Sciences, ThromboGenics, Tyrogenex, and Valeant.

American Society of Retina Specialists (ASRS) 2017 Annual Meeting. Presented August 13, 2017.

Follow Medscape Ophthalmology on Twitter @MedscapeEye and Laird Harrison @LairdH


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