High levels of vascular endothelial growth factor (VEGF), as well as glucotoxicity or other causes, may hasten progression of retinal nonperfusion (RNP) in diabetic macular edema (DME), according to a retrospective analysis published online April 25 in Ophthalmology. The findings suggest that monthly injections of ranibizumab to lower VEGF may not completely prevent retinal capillary closure in DME.
"Despite the clinically significant benefits seen with intraocular injections of ranibizumab in patients with DME and [retinal vein occlusion], many retina specialists have voiced concerns that the neutralization of VEGF, a survival factor for endothelial cells, could damage retinal vessels and worsen RNP," write Peter A. Campochiaro, MD, from the Wilmer Eye Institute, Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues. "In fact, several case reports have suggested that a single injection of an anti-VEGF agent can cause acute worsening of retinal ischemia."
Therefore, the authors assessed the effect of monthly ranibizumab injection on posterior RNP in patients with DME. The investigators performed an unplanned retrospective analysis of data from 666 patients with DME who had participated in 2 randomized, phase 3, sham injection–controlled, double-masked, multicenter clinical trials (Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus [RISE] and Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus [RIDE]).
The main study outcome was the percentage of patients with no posterior RNP, as determined by an independent reading center that measured the area of RNP on fluorescein angiograms performed on patients enrolled in the trials.
"Although this is not a primary analysis, this exploratory analysis is both interesting and important," Emily Y. Chew, MD, deputy director of the Division of Epidemiology and Clinical Applications and chief of clinical trials, National Eye Institute/National Institutes of Health, Bethesda, Maryland, told Medscape Medical News when asked for independent comment. "There have been data that suggest progression of diabetic retinopathy is reduced by anti-VEGF therapy, [which] could be the mechanism of action for preventing further progression. The development of RNP is a sign of progression of diabetic retinopathy."
Anti-VEGF Linked to Less RNP
In the sham injection control group, the percentage of patients with no posterior RNP decreased from baseline to month 24. In contrast, both ranibizumab groups maintained a relatively stable percentage of patients with no posterior RNP. The differences between the sham and ranibizumab groups declined after month 24, when the sham group crossed over to receive monthly injections of ranibizumab 0.5 mg.
Noting that the data come from randomized trials, Dr. Chew said, "it is more likely to consider the anti-VEGF therapy as a plausible cause for the decrease in nonperfusion. Furthermore, similar findings are seen in other retinal vaso-occlusive diseases such as the vein occlusions. Such data help to support this notion that anti-VEGF therapy may in fact reduce the risk of development of RNP."
In all 3 groups, the percentage of patients with an increase in posterior RNP from baseline increased over time, but this occurred at a faster rate in the sham group. For the ranibizumab 0.5-mg group compared with the sham group, there were significant differences at every point between months 3 (9.6% vs 18.5%; P = .016) and 24 (16.1% vs. 37.6%; P < .0001). For ranibizumab 0.3 mg vs sham, there were significant differences at every point between months 6 (12.3% vs 23.0%; P = .013) and 24 (15.0% vs 37.6%; P < .0001).
When patients in the sham group started receiving ranibizumab at month 24, there was a decline from baseline to months 30 and 36 in the percentage of patients with an increase in posterior RNP, whereas the 2 ranibizumab groups continued their gradual rise.
"Just as high VEGF levels contribute to progression of [RNP] in retinal vein occlusion, the same is true in patients with DME, suggesting that regardless of the underlying disease process, high levels of VEGF can cause closure of retinal vessels," the study authors write. "However, our data also suggest that VEGF-induced worsening of retinal perfusion in DME is superimposed on another cause of more gradually worsening perfusion, possibly glucotoxicity. Thus, monthly injections of ranibizumab can slow, but not completely prevent, retinal capillary closure in patients with DME."
Limitations of this study include unplanned retrospective analyses and measurement of RNP in Early Treatment Diabetic Retinopathy Study fields 1 through 3, which constitutes the posterior pole of the eye. Generalizability to the entire retina may therefore be limited.
"Monthly injections of ranibizumab suppress macular edema, progression of RNP, and progression of retinopathy in diabetic patients," the study authors conclude. "This suggests that sustained neutralization of VEGF may remedy several aspects of the disease and minimize worsening of diabetic retinopathy. Therefore, sustained delivery of a VEGF antagonist should be explored as a comprehensive approach to treatment of diabetic retinopathy."
Other Treatments Needed
Dr. Chew noted that the idea that VEGF is not the only reason for progression of DME is not particularly novel, but that it is good to have evidence to support this concept. This may account for the fact that 30% to 50% persons with DME still have edema after reasonable anti-VEGF therapy.
"Further investigations may lead to discovery of other targets to assess, with the goal of developing other beneficial therapies that might be synergistic with the anti-VEGF therapy for the treatment of DME," Dr. Chew said. "Corticosteroids have a broad spectrum of action, and previous studies have indicated beneficial effects, suggesting that other factors are in play. Of course, the use of corticosteroids needs to be balanced with its potential adverse side effects."
Genentech Inc supported this study and employs 3 of the study authors. Some of the other study authors reported various financial disclosures involving Applied Genetic Technologies Corporation, Advanced Cell Technology, Genentech, Regeneron, Genzyme, Allergan, Oxford BioMedica, Molecular Partners, Aerpio, and/or Bayer Alimera. Full conflict-of-interest information is available in the article. Dr. Chew has disclosed no relevant financial relationships.
Ophthalmology. Published online April 25, 2014. Abstract
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Cite this: VEGF Blockade May Slow, but Not Halt, Progression in DME - Medscape - May 06, 2014.