CHICAGO, Illinois — Ranibizumab is effective in reducing the severity of diabetic retinopathy, according to an analysis of the RIDE and RISE randomized trial populations, researchers reported here at the American Academy of Ophthalmology 2012 Annual Meeting.
The studies also showed that continuous treatment up to 36 months provided sustained benefits.
"Our data suggest that a delay in administering ranibizumab therapy results in a reduction in the chance to improve the level of diabetic retinopathy severity," said Michael S. Ip, MD, from the Department of Ophthalmology at the University of Wisconsin Medical School in Madison, who presented the findings.
About one quarter of people with diabetes who are 40 years and older have diabetic retinopathy. One third of people who have had diabetes for more than 20 years develop diabetic macular edema (DME). Macular laser for DME reduces the risk for vision loss by about 50%, but few patients experience vision improvement, explained Leonard Feiner, MD, PhD, from Retina Associates of New Jersey in Teaneck, who presented 36-month follow-up data from the studies.
RIDE and RISE compared the benefit of ranibizumab 0.5 mg and 0.3 mg with sham injections in 759 patients screened for DME. Patients received monthly intravitreal or sham injections and, if necessary, macular laser for 24 months. In the 12 months between the 24- and 36-month end points, patients in the sham group could cross over to ranibizumab 0.5 mg.
The analysis was designed to determine whether the benefits seen at 24 months were maintained at 36 months, and to provide an in-depth look at the potential benefit of ranibizumab to protect against worsening diabetic retinopathy.
The primary outcome was a gain from baseline of at least 15 ETDRS (Early Treatment Diabetic Retinopathy Study) letters in best-corrected visual acuity (BCVA).
Benefit Maintained Beyond 2 Years
Patients originally assigned to ranibizumab maintained significant gains for a year beyond the primary end point of 24 months, without signs of additional ocular toxicity. With delayed treatment (i.e., the crossover group), BCVA gains were less robust, Dr. Ip reported.
In a separate presentation, Dr. Feiner reported that the improvements from the 24-month analysis were sustained in patients who had received previous DME treatment and in those who had not, in patients with baseline glycated hemoglobin levels above 8% and in those with levels 8% and below, and in patients with central foveal thickness of at least 450 µm and in those with thickness below 450 µm. Pooled analysis of fluorescein angiography leakage over time showed no disc areas of leakage at month 36 in 42.8% of the ranibizumab 0.5 mg group, in 30.1% of the ranibizumab 0.3 mg group, and in 22.0% of the sham group.
Ongoing treatment not only resulted in good DME control, it also provided significant reductions in diabetic retinopathy progression, improving the retinopathy scale in many patients — by 2 steps in 35% of the population and by 3 steps in 10% of the study population, Dr. Ip reported.
"From the 24-month analysis, we had strong evidence that ranibizumab prevents further worsening of diabetic retinopathy severity and actually improves the degree of severity for many patients. Since these were secondary analyses, we did not recommend using ranibizumab to specifically and primarily treat diabetic retinopathy severity at that time," Dr. Ip said.
The current analysis provides support for the use of ranibizumab to deter severity.
"Patients who continued to receive ranibizumab monthly between 24 and 36 months had a maintenance in the regression of diabetic retinopathy severity they achieved at month 24. In contrast, patients in the sham group, despite receiving the drug between months 24 and 36, did not have a change in their immediate retinopathy level," he said.
This benefit was paralleled in the visual acuity results. In the pooled RISE and RIDE populations, the mean change in BCVA at 36 months was 12.4 letters with ranibizumab 0.3 mg, 11.2 letters with ranibizumab 0.5 mg, and 4.5 letters with sham injection, Dr. Ip reported.
"Patients maintained vision with continuous therapy to month 36. Patients who started ranibizumab at month 24, however, only had a modest change in visual acuity," he explained. Mean change in BCVA in the sham group was 2.5 letters at 24 months and 4.5 letters at 36 months.
Dr. Ip said the data suggest that a delay in treatment is detrimental to patients, although it is not known whether a delay of less than 2 years will result in a similar loss of benefit on the level of diabetic retinopathy severity, he added.
Direction for Future Research
Who would have thought a few years ago that we would have a class of drug that is not only effective at treating DME, but actually improves diabetic retinopathy beyond just slowing progression? That is what we are seeing here," said Carl D. Regillo, MD, director of the retina service at the Wills Eye Institute and professor of ophthalmology at Thomas Jefferson University School of Medicine in Philadelphia, Pennsylvania.
"That said, in the trials, patients are treated monthly.... The question is whether we will short-change our ability to improve diabetic retinopathy to this extent if we cut back on the drug too quickly," he noted.
He questioned whether a full 36 months of treatment is necessary to achieve the improvements shown in RISE and RIDE.
"I have asked myself this question as well.... That analysis would be interesting," Dr. Ip responded.
They both note that the level of retinopathy severity is a predictor of long-term vision loss. "They go hand in hand," Dr. Regillo said. "The lower the level of diabetic retinopathy, the less likely you are to have DME. It's disease-altering, but whether the change is permanent or not when the patient goes off the drug has yet to be answered," he noted.
Dr. Ip, Dr. Feiner, and Dr. Regillo all report receiving consultant or speaker's fees and/or grant support from Genentech.
American Academy of Ophthalmology (AAO) 2012 Annual Meeting. Abstract PA053 and PA054. Presented November 12, 2012.
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