Pam Harrison

September 05, 2013

TORONTO, Ontario — The severity of diabetic retinopathy is more likely to improve and progression to proliferative diabetic retinopathy is less likely to occur when diabetic macular edema is treated with monthly ranibizumab, new research shows.

At 36-month follow-up, vision and the severity of diabetic retinopathy were significantly more likely to have improved in patients treated with monthly ranibizumab than in those treated with a sham injection.

In addition, ranibizumab-treated patients were approximately 3-fold less likely to develop proliferative diabetic retinopathy than their sham counterparts.

The results were presented by Lloyd Clark, MD, from the Palmetto Retina Center in West Columbia, South Carolina, here at the 31st Annual Meeting of the American Society of Retina Specialists.

"It's difficult to extrapolate the data from these studies strictly to the real-world situation because patients in these trials received monthly injections of ranibizumab for 3 years, and that is a difficult regimen to follow in the clinic," Dr. Clark told Medscape Medical News.

"But the findings are very encouraging, in that they show that when used in combination with conventional modalities, [anti-VEGF] treatment can improve diabetic retinopathy in these patients," he added.

Phase 3 Studies

In the phase 3 RISE and RIDE trials, patients with diabetic macular edema were randomly assigned to ranibizumab — either 0.3 mg or 0.5 mg monthly — or sham injections. At baseline, best-corrected visual acuity ranged from 20/40 to 20/320, and central subfield thickness on optical coherence tomography was at least 275 µm. The primary end points of the trial were change in best-corrected visual acuity, change in the severity of diabetic retinopathy at month 24, and the effect of treatment on worsening diabetic retinopathy at month 24.

At month 24, patients who had previously received sham injections were crossed over to ranibizumab 0.5 mg monthly. "Ranibizumab improved vision in diabetic macular edema patients through 36 months," Dr. Clark observed. At month 24, mean change in best-corrected visual acuity, based on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, was 11.7 to 12.0 letters for the 2 ranibizumab groups, and was 2.5 letters for the sham injection group.

After crossover from sham injections to monthly ranibizumab, the mean change in best-corrected visual acuity remained relatively stable for the 2 ranibizumab groups and improved by a mean of 4.5 letters for the sham injection group.

The severity of diabetic retinopathy was also significantly more likely to improve with either dose of ranibizumab than with sham injection.

Table. Improvement in Diabetic Retinopathy on the ETDRS Scale

Treatment Group ≥2 Steps, % ≥3 Steps, %
Month 24    
0.3 mg 37.2 13.2
0.5 mg 35.9 14.5
Sham 5.4 1.3
Month 36    
0.3 mg 38.9 15
0.5 mg 39.3 13.2
Sham/0.5 mg crossover 23.8 3.3

 

"These data suggest that improvement in retinopathy occurs early in the course of ranibizumab therapy," Dr. Clark noted. The severity of diabetic retinopathy was also significantly less likely to worsen in patients treated with ranibizumab than in those treated with sham injections, he added.

At 36 months, 33.9% of eyes originally assigned to sham injections developed proliferative diabetic retinopathy, despite crossing over to monthly ranibizumab at month 24.

In contrast, only 12.8% of eyes treated with the 0.3 mg dose of ranibizumab and 15.1% of those treated with the 0.5 mg dose had evidence of proliferative disease at month 36. When sham eyes crossed over to active therapy, the rate of proliferative diabetic retinopathy did slow.

However, Dr. Clark noted, many of the eyes that worsened in the third year had developed proliferative disease by month 24, and they remained classified as proliferative diabetic retinopathy at the end of the trial.

Unique Opportunity

"Due to the size and duration of RISE and RIDE, we had a unique opportunity to understand risk factors for diabetic retinopathy progression," Dr. Clark explained.

In the sham group, at month 24, more severe diabetic retinopathy (hazard ratio [HR], 0.24) and the presence of subretinal fluid on optical coherence tomography at baseline (HR, 0.52) were strongly and significantly related to the risk of developing proliferative diabetic retinopathy.

In contrast, capillary loss in the macular grid at baseline was strongly and significantly related to the development of proliferative diabetic retinopathy in the ranibizumab groups, compared with no capillary loss (HR, 0.41). In the overall cohort, treatment with ranibizumab was the factor most significantly associated with a reduced risk for progression of diabetic retinopathy (P < .0001 for both doses).

"A small percent of eyes still progress to proliferative diabetic retinopathy, despite monthly ranibizumab," Dr. Clark said. "And while I don't think these numbers suggest a paradigm shift in our practice yet, they certainly demonstrate encouraging results from VEGF suppression in proliferative diabetic retinopathy."

"I think these results are absolutely fascinating," said Suber Huang, MD, professor of ophthalmology at Case Western Reserve University School of Medicine in Cleveland, who was asked by Medscape Medical News to comment on the findings. "Dr. Clark and his study group should be congratulated on their results."

RIDE and RISE were supported by Genentech. Dr. Clark reports a number of financial interests, including support from Genentech. Dr. Huang reports a number of financial interests, but none relevant to this study.

31st Annual Meeting of the American Society of Retina Specialists. Presented August 27, 2013.

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