When followed over time, about 75% of patients in the RIDE/RISE trials who had the highest risk of progression to proliferative diabetic retinopathy benefited from ranibizumab with “robust” regression of diabetic retinopathy severity levels.
Reviewed by Charles C. Wykoff, MD
Houston-Investigators in a follow-up RISE/RIDE analysis of patients who had the highest risk of progression to proliferative diabetic retinopathy saw “robust” regression of diabetic retinopathy in high percentages of patients treated with ranibizumab (Lucentis, Genentech) independent of their baseline characteristics, including macular non-perfusion.
Diabetic retinopathy is a global problem and the most common complication of diabetes that affects vision and causes blindness in working-age individuals. Its incidence rate is expected to nearly double from 2010 to 2050, making identification of effective treatments paramount, according to Charles C. Wykoff, MD.
The Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale quantifies retinopathy severity and population-based studies, including the Los Angeles Latino Eye Study, have demonstrated decrease in patients’ health-related quality of life when the severity of diabetic retinopathy worsens beyond the 43 level. At that level, patients have moderate non-proliferative diabetic retinopathy.
“It is at this level that difficulty in driving begins to increase and quality of life on the National Eye Institute Visual Function Questionnaire begins to drop,” said Dr. Wykoff, who is in private practice in Houston.
In the RIDE/RISE phase III trials in which patients with diabetic retinopathy and diabetic macular edema were randomly assigned sham injections or treatment with 0.3- or 0.5-mg doses of intravitreal ranibizumab, investigators found that time to proliferative diabetic retinopathy was significantly delayed in those treated with ranibizumab.
Both ranibizumab doses significantly (p <0.001) resulted in clinically meaningful diabetic retinopathy. Improvement compared with sham injections based on the pooled RIDE/RISE data (Ip et al. Ophthalmology. 2015;122:367-374).
Ranibizumab also was found to significantly (p < 0.05) decrease worsening of retinal non-perfusion compared with sham treatment (Campochiaro et al. Ophthalmology. 2014;121:1783-1789).
In light of these encouraging results, the RISE/RIDE investigators analyzed patients at high risk of progression to proliferative diabetic retinopathy in the near future-i.e., those who had moderately severe or severe non-proliferative diabetic retinopathy/ETDRS diabetic retinopathy severity, or levels 47/53 at baseline.
Investigators evaluated the effect of the baseline characteristics and macular non-perfusion on the outcomes in these patients in the RIDE/RISE trials.
To assess diabetic retinopathy, stereoscopic seven-field color fundus photographs were obtained at screening and months 3, 6, 12, 18, 24, and 36 and evaluated at the University of Wisconsin Fundus Photograph Reading Center. To assess macular nonperfusion, fluorescein angiograms were obtained at the same time points and analyzed by masked graders at the reading center to measure the area of the macular nonperfusion in the combined center, inner, and outer subfields of the images.
The levels of diabetic retinopathy at baseline were similar in the three treatment groups-i.e., sham and 0.3- and 0.5-mg ranibizumab were all similar.
Patients with diabetic retinopathy who benefited most from ranibizumab were those with baseline moderately severe or severe non-proliferative diabetic retinopathy (level 47/53), he noted.
“Importantly, 75% of patients treated with ranibizumab who had a diabetic retinopathy level of 47/53 at baseline had a two-step or greater improvement in diabetic retinopathy compared with sham treatment by month 12 and this was sustained through month 36,” Dr. Wykoff said.
In contrast to this improvement among ranibizumab-treated eyes, patients in the sham group representing the natural history of diabetic retinopathy with moderately severe and severe non-proliferative diabetic retinopathy at baseline were six times more likely to progress to proliferative diabetic retinopathy through 24 months, he said.
Analysis showed that baseline characteristics-including central foveal thickness (CFT), best-corrected visual acuity (BCVA), and duration of diabetes-were not predictive of two-step or greater improvements in patients with a diabetic retinopathy severity level of 47/53.
“In patients with the highest risk of non-proliferative diabetic retinopathy at baseline, a two-step or more diabetic retinopathy severity improvement was independent of these baseline characteristics, including baseline CFT, BCVA, and duration of diabetes,” Dr. Wykoff said.
Investigators also found no predictive value of subscale levels within diabetic retinopathy severity levels 47 and 53 in predicting aâ¯two-step or greater improvement in diabetic retinopathy severity at month 24 for patients with the highest-risk non-proliferative diabetic retinopathy at baseline.
Others question the study sought to answer were: Does macular non-perfusion impact the ability to achieve diabetic retinopathy improvements? How does macular non-perfusion change over time?
Data indicated that macular nonperfusion at baseline did not affect the two-step or greater improvements in diabetic retinopathy that occurred as the result of treatment with ranibizumab in patients with a baseline diabetic retinopathy level of 47/53.
The proportions of patients with macular non-perfusion increased in the sham-treated patients and remained stable in those treated with ranibizumab.
Conclusions reached by this study, according to Dr. Wykoff, were that the natural course of diabetic retinopathy is worsening over time with progressive decline in the patients’ health-related quality of life. Within this context, treatment with ranibizumab led to robust improvements in diabetic retinopathy severity scores in patients who were at the highest risk of progression to proliferative diabetic retinopathy independent of the baseline characteristics investigated including macular nonperfusion.
“Data looking at diabetic retinopathy severity levels over time in the highest-risk non- proliferative diabetic retinopathy eyes within RIDE/RISE show clinically relevant improvements with ranibizumab treatment in a large majority of patients,” Dr. Wykoff said. “Such disease-modifying effects of ranibizumab indicate a substantial role in diabetic retinopathy management beyond simple mitigation of diabetic macular edema.”
Charles C. Wykoff, MD
This article was adapted from Dr. Wykoff’s presentation at the 2016 meeting of the Association for Research in Vision and Ophthalmology. Dr. Wykoff is a consultant to Genentech.