Drug slows diabetic retinopathy progression, but delays may limit effect

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The natural history of diabetic retinopathy is modified by long-term treatment with intravitreal ranibizumab, relates one ophthalmologist.

Dr. Ip

By Lynda Charters; Reviewed by Michael S. Ip, MD

Madison, WI-The natural history of diabetic retinopathy changes with long-term intravitreal ranibizumab (Lucentis, Genentech) treatment in some eyes with diabetic macular edema (DME). The severity of the diabetic retinopathy regressed more in these eyes compared with sham-treated eyes,

In addition, there was a lower likelihood of progression of the severity of diabetic retinopathy, according to the 36-month results of the RISE and RIDE phase III clinical trials.

The clinical unknowns investigators sought to address in these trials that evaluated the severity of diabetic retinopathy with ranibizumab treatment were:

·      the long-term effects on the regression of diabetic retinopathy

·      the long-term effects of ranibizumab on stopping the progression of diabetic retinopathy severity

·      the baseline factors associated with development of proliferative diabetic retinopathy in patients with DME

In these clinical trials, patients were randomly assigned to sham treatment or either 0.3 mg- or 0.5-mg ranibizumab, according to Michael S. Ip, MD.

The treated patients received monthly injections to month 24. At that time, the treated patients continued treatment and those in the sham group crossed over to monthly 0.5-mg ranibizumab injections for the next 12 months.

Investigators evaluated severity of diabetic retinopathy based on fundus photographs obtained at baseline and at 3, 6, 12, 18, 24, 30, and 36 months after ranibizumab treatment. Outcomes were two or greater and three or greater step changes (improvements) compared with baseline on the ETDRS severity scale.

Dr. Ip recapped that the severity of diabetic retinopathy was significantly more likely to improve in eyes treated with ranibizumab.

“At 24 months, there were more two or more and three or more step improvements in diabetic retinopathy severity in the treated groups compared with the sham group,” he said.

Specifically, regarding the two or more step changes, 37.2% and 35.9% of patients treated with 0.3 and 0.5 mg of ranibizumab had improvements in diabetic retinopathy severity. Regarding three or more step changes, the respective values were 13.2% and 14.5%.

Risk of progression over time

“These improvements were maintained to month 36,” Dr. Ip said. “In the original sham group that received 0.5-mg ranibizumab injections after cross-over, there was some improvement in the retinopathy, although it did not reach the level of improvement seen in the patients initially treated with ranibizumab.”

At 36 months, regarding the two-step changes in the ranibizumab groups, 38.9% and 39.3%, respectively, of patients in the 0.3- and the 0.5-mg ranibizumab groups had improvements in the diabetic retinopathy severity. Regarding the three-step changes, the respective values were 15.0% and 13.2%.

Investigators found that the severity of diabetic retinopathy is significantly less likely to worsen in eyes treated with ranibizumab compared with the sham group.

There was also a slight reduction in progression in the sham-treated eyes that crossed over to active treatment. The halting of the progression in diabetic retinopathy that was seen at 24 months continued to 36 months.

In the ranibizumab-treated groups, the baseline characteristic that may predict development of proliferative diabetic retinopathy was-based on multiple covariate analysis-only capillary loss within the ETDRS grid. In the sham group, the severity of the diabetic retinopathy and the presence or absence of subretinal fluid were associated with proliferative diabetic retinopathy.

“Ranibizumab-treated eyes with DME had greater regression of diabetic retinopathy severity compared with the sham-treated eyes at 24 months that continued to 36 months,” Dr. Ip said.

“These eyes were less likely to have progression of severity of diabetic retinopathy compared with sham-treated eyes at 24 months and the sham-treated eyes that crossed over to ranibizumab treatment at 36 months,” he said. “At 36 months, the risk of development of proliferative diabetic retinopathy was about three-fold greater in the sham-treated eyes compared with the ranibizumab-treated eyes.”

Results suggested that delaying ranibizumab treatment may result in a reduced chance to improve the severity of the diabetic retinopathy, he noted. However, it is unknown if delaying ranibizumab by less than 2 years would result in a similar loss of benefit.

“We speculated that the longer the delay, the greater the loss of effect of ranibizumab on the severity of diabetic retinopathy,” Dr. Ip said.

Though the results were derived from large, randomized trials, the findings were derived from secondary and exploratory analyses, he cautioned. Investigators do not recommend using ranibizumab specifically or primarily to treat diabetic retinopathy severity. Panretinal photocoagulation remains the primary treatment for advanced diabetic retinopathy.

Regarding the finding that capillary loss was the factor in the ranibizumab-treated eyes that predicted the risk of progression to proliferative diabetic retinopathy assessing patients for capillary loss may be important to identify susceptible patients.

Identification of other pathophysiologic mechanisms should be addressed in future trials, considering that some eyes still develop proliferative diabetic retinopathy despite administration of chronic anti-vascular endothelial growth factor therapies, which suggested that other mechanisms may be involved.

Michael S. Ip, MD

E: msip@wisc.edu

Dr. Ip is a consultant to Genentech.

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