Drug slows diabetic retinopathy, but delays may limit its effect

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

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 DR 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 DR 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 DR 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 mg and 0.5 mg of ranibizumab had improvements in DR severity. Regarding three or more step changes, the respective values were 13.2% and 14.5%.

Progression over time

"These improvements were maintained to month 36," Dr Ip continued. "In the original sham group that received 0.5 mg ranibizumab injections after crossover, 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 DR severity. Regarding the three-step changes, the respective values were 15.0% and 13.2%.

Investigators found that the severity of DR 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 DR that was seen at 24 months continued to 36 months.

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

"Ranibizumab-treated eyes with DME had greater regression of DR 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 DR compared with sham-treated eyes at 24 months and the sham-treated eyes that crossed over to ranibizumab treatment at 36 months," he added. "At 36 months, the risk of development of proliferative DR was about threefold greater in the sham-treated eyes compared with the ranibizumab-treated eyes."

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

"We speculated that the longer the delay, the greater the loss of effect of ranibizumab on the severity of DR," Dr Ip said.

Though 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 DR severity. Panretinal photocoagulation remains the primary treatment for advanced DR.

Regarding the finding that capillary loss was the factor in the ranibizumab-treated eyes that predicted the risk of progression to proliferative DR, 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 DR despite administration of chronic anti-vascular endothelial growth factor therapies, which suggested that other mechanisms may be involved.