Featured, In the News / Politics:

Seeing is Believing: A Look at VEGF Inhibitors for Diabetic Macular Edema

By: Svetlana Akbasheva, Staff Editor, PharmD Candidate c/o 2016

Diabetes is one of the biggest health problems in the United States, with the 2014 National Diabetes Statistics Report stating that 9.3% of the population, or over 29 million people, has the disease.1 One of the major complications of uncontrolled diabetes mellitus is diabetic retinopathy, which results when consistently high blood glucose levels cause damage to the blood vessels of the eye.2 The first manifestations of diabetic retinopathy are microaneurysms, or small swollen areas in the blood vessels of the retina. These blood vessels gradually become blocked, which begins depriving the retina of oxygen and nutrients. In response, the retina sends out signals for more blood vessels to grow. However, these new vessels are very fragile and problems arise if the vessels begin to leak, covering the eye with blood and resulting in the loss of vision.2

It is estimated that approximately 28.5% of patients with diabetes go on to develop eye problems.1 One of the common manifestations of this retinopathy is diabetic macular edema (DME). The macula is the part of the eye that is responsible for sharp, central vision. Macular edema occurs when fluid from ruptured blood vessels leaks into this part of the eye, causing swelling and blurry vision.2 DME can arise at any stage of diabetic retinopathy but is more common with severe disease.2

In the 1980s, the standard treatment for DME was laser eye therapy, but in recent years that has given way to intravitreal injection therapy using medications that block vascular endothelial growth factor (VEGF).3 The VEGF family is responsible for the proliferation and permeability of blood vessels and thus is a big player in the pathology of DME.3,4 The three VEGF inhibitors currently in use for DME are aflibercept (Eylea®), ranibizumab (Lucentis®), and off-label bevacizumab (Avastin®). 3 Aflibercept is a recombinant protein,4 while ranibizumab and bevacizumab are monoclonal antibodies.5,6

A recent multicenter, randomized, long-term trial conducted by the Diabetic Retinopathy Clinical Research Network put these three therapies head to head for the first time to determine which, if any, was superior in treating DME.3 Visual-acuity scores were used to assess the severity of retinopathy; these scores range from 0 to 100, with a higher score indicating better vision and a score of 85 corresponding with a Snellen score of 20/20.

Patients included in the study were over 18 years old with type I or II diabetes and at least one eye with a visual acuity score between 24 and 78 as a result of clinical DME. Patients were excluded if they had received any VEGF inhibitor therapy in the past year. Block randomization was used to assign 660 patients to one of the three therapies in a 1:1:1 ratio. If patients had macular edema in both eyes, the non-study eye received the same treatment as the study eye. Investigators and study coordinators were the only people who were aware of the drug assignments; participants and personnel in charge of measuring outcomes were blinded.

Study drugs were administered every four weeks, at doses of aflibercept 2.0 mg, ranibizumab 0.3 mg, and bevacizumab 1.25 mg. Patients were eligible to receive laser photocoagulation therapy in addition to their anti-VEGF therapy after 24 weeks of treatment if their DME did not improve. The primary endpoint of the study was the mean change in visual-acuity scores after one year of therapy.3

The analysis of the primary endpoint was performed using the intent-to-treat population. Excluding deaths, 96% of participants completed the first year of the study. At the one-year mark, the mean improvement in the visual-acuity score from baseline was greatest in the aflibercept group, significantly better than bevacizumab (13.3 vs. 9.7, p<0.001) and ranibizumab (13.3 vs. 11.2, p=0.03).3

The investigators then further assessed these results by comparing the efficacy of the treatments depending on the baseline vision of the participants. For participants with baseline visual-acuity scores of 69 to 78 (Snellen equivalent 20/32 to 20/40), there was no significant difference in the mean improvement from baseline between the three drugs. However, in participants with baseline visual-acuity scores of less than 69 (Snellen equivalent 20/50 or worse), aflibercept was associated with significantly better vision at one year compared to both ranibizumab and bevacizumab, with a mean visual-acuity score improvement of 18.9 +/- 11.5 versus 14.2 +/- 10.6 for ranibizumab (difference 4.7, p=0.003) and 11.8 +/- 12.0 for bevacizumab (difference 6.5, p<0.001). Ocular and systemic adverse effects were comparable among the three groups, with one of the most common being intraocular pressure elevation.3

The results of this study are significant because the three VEGF inhibitors currently in use for DME differ considerably in their cost profiles. According to Medicare data, the cost of a single dose of medication is $1950 for aflibercept, $1200 for ranibizumab, and $50 for bevacizumab.3 However, a complication with bevacizumab is that it must be repackaged into aliquots of 1/500th of the systemic chemotherapy dose to be used for intravitreal injection, which makes sterility, purity, and potency testing an additional requirement before use.3 In terms of clinical practice, the results of the current study suggest that it may be more cost-effective to use intravitreal ranibizumab or bevacizumab in DME patients with baseline visual-acuity scores above 69, and reserve the more expensive aflibercept for use in patients with baseline scores of less than 69.3



  1. 2014 National Diabetes Statistics Report. Centers for Disease Control and Prevention. http://www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html. Published 10/24/2014. Last Updated 10/24/2014. Access date 2/4/15
  2. Facts about diabetic eye disease. National Eye Institute. https://www.nei.nih.gov/health/diabetic/retinopathy. Last Updated 06/01/2012. Access date 2/4/15
  3. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-203.
  4. Eylea (aflibercept) [package insert]. Tarrytown, NY; Regeneron Pharmaceuticals, Inc.; Revised 03/2015.
  5. Lucentis (ranibizumab) [package insert]. South San Francisco, CA; Genentech, Inc.; Revised 02/2015.
  6. Avastin (bevacizumab) [package insert]. South San Francisco, CA; Genentech, Inc.; Revised 11/2014.

[pubmed_related keyword1=”diabetic” keyword2=”macular” keyword3=”edema”]

Published by Rho Chi Post
Both comments and trackbacks are currently closed.