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Invited Commentary
March 2018

Anti–Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema: Does Flavor Matter?

Author Affiliations
  • 1Washington University School of Medicine, St Louis, Missouri
JAMA Ophthalmol. 2018;136(3):269-270. doi:10.1001/jamaophthalmol.2017.6559

Macular edema is the most common cause of vision loss in diabetes.1 Intravitreal vascular endothelial growth factor (VEGF)–targeted therapy for diabetic macular edema (DME) leads to sustained visual and anatomic gains in well-designed randomized clinical trials.2 Despite these advances, persistent DME (pDME) at 24 weeks after anti-VEGF therapy and chronic, persistent DME (cpDME) at 2 years after initiation of treatment is a significant problem. An exploratory analysis by the Diabetic Retinopathy Clinical Research Network demonstrated cpDME in 40% of participants at 3 years after anti-VEGF therapy with ranibizumab despite adherence to DRCR-retreatment protocols. The study also showed that despite persistent edema, visual outcomes were excellent in most patients.3,4

There are 3 intravitreal anti-VEGF agents that are widely used for treating DME: aflibercept, bevacizumab, and ranibizumab. In 2015, the Diabetic Retinopathy Clinical Research Network published the 2-year comparative effectiveness of these agents for the treatment of DME (protocol T) including an assessment of injection frequency.2 The accompanying study published in this issue of JAMA Ophthalmology5 is a post hoc analysis of anatomic (pDME and cpDME) and visual outcomes (≥10 letter change in visual acuity) in participants randomized to 1 of 3 anti-VEGF agents. At week 12, after 3 monthly injections, DME was present in 50.8% of aflibercept-treated eyes, 72.9% of bevacizumab-treated eyes, and 53.2% of ranibizumab-treated eyes. At week 24, a significantly higher proportion of eyes treated with bevacizumab (65.6%) had pDME compared with those treated with aflibercept (31.6%) or ranibizumab (41.5%). Most improvement in visual acuity in eyes with pDME was noted in the first 24 weeks of the study. In comparing eyes without DME with eyes with pDME at 24 weeks, change in mean visual acuity was significantly higher in eyes without DME in the aflibercept and ranibizumab groups, but not in the bevacizumab group. The cumulative probability that eyes with pDME at 24 weeks demonstrated cpDME at 2 years was significantly lower with aflibercept (44.2%) when compared with bevacizumab (68.2%) but not with ranibizumab (54.5%). There were no significant differences between the 3 groups in the median number of injections associated with presence of cpDME. The proportion of eyes gaining at least 10 letters of visual acuity from baseline at 2 years in eyes with or without cpDME was not significantly different in all groups and, most notably, at least 10 letters of vision loss was rare across the entire study cohort.

The important take-home message is that in eyes treated with anti-VEGF for DME, there is continued improvement in visual acuity and increasing resolution of DME from week 12 to 24 of therapy. In addition, anti-VEGF therapy leads to meaningful gains in vision and a low risk of vision loss through 2 years of therapy. When eyes with pDME at 24 weeks were followed up to 2 years, there were no significant differences in visual acuity change between eyes with or without cpDME in the aflibercept or bevacizumab groups, but eyes with cpDME in the ranibizumab group were slightly worse than eyes without edema. Aflibercept and ranibizumab were significantly better than bevacizumab at preventing pDME at 24 weeks. In addition, eyes randomized to aflibercept were more likely to have resolution of DME at 2 years compared with bevacizumab.

So, does the flavor of anti-VEGF in DME matter? Perhaps the most clinically relevant conclusion of this analysis is that anti-VEGF therapy for DME is associated with robust and sustained visual and anatomic improvements, irrespective of the specific anti-VEGF agent chosen. A more granular analysis suggests that aflibercept may be better than bevacizumab at improving anatomic outcomes at 24 weeks and 2 years. Although a higher proportion of eyes treated with ranibizumab had pDME at 24 weeks compared with aflibercept, the study may not be powered to detect small differences between these subgroups.

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Article Information

Corresponding Author: Rajendra S. Apte, MD, PhD, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8096, PO Box 8096, St Louis, MO 63110 (apte@wustl.edu).

Published Online: February 1, 2018. doi:10.1001/jamaophthalmol.2017.6559

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

References
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Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.  N Engl J Med. 2015;372(13):1193-1203.PubMedGoogle ScholarCrossref
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Apte  RS.  What is chronic or persistent diabetic macular edema and how should it be treated?  JAMA Ophthalmol. 2016;134(3):285-286.PubMedGoogle ScholarCrossref
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Bressler  SB, Ayala  AR, Bressler  NM,  et al; Diabetic Retinopathy Clinical Research Network.  Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment.  JAMA Ophthalmol. 2016;134(3):278-285.PubMedGoogle ScholarCrossref
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Bressler  NM, Beaulieu  WT, Glassman  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Persistent macular thickening following intravitreous aflibercept, bevacizumab, or ranibizumab for central-involved diabetic macular edema with vision impairment: a secondary analysis of a randomized clinical trial [published online February 1, 2018].  JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2017.6565Google Scholar
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