resize_shutterstock_198850808Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standard of care for DME has been macular laser photocoagulation, which has been shown to stabilize vision and reduce the rate of further vision loss by 50%; however, macular laser leads to significant vision recovery in only 15% of treated patients. Mechanisms contributing to the microvascular damage in DR and DME include the direct toxic effects of hyperglycemia, sustained alterations in cell signaling pathways, and chronic microvascular inflammation with leukocyte-mediated injury. Chronic retinal microvascular damage results in elevation of intraocular levels of vascular endothelial growth factor A (VEGF), a potent, diffusible, endothelial-specific mitogen that mediates many important physiologic processes, including but not limited to the development and permeability of the vasculature. The identification of VEGF as an important pathophysiologic mediator of DME suggested that anti-VEGF therapy delivered to the eye might lead to improved visual outcomes in this disease. To date, four different inhibitors of VEGF, each administered by intraocular injection, have been tested in prospective, randomized phase II or phase III clinical trials in patients with DME. The results from these trials demonstrate that treatment with anti-VEGF agents results in substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoid the ocular side effects associated with laser treatment. Thus, anti-VEGF therapy has become the preferred treatment option for the management of DME in many patients1.

Diabetic macular edema (DME) is an advanced, vision-limiting manifestation of diabetic retinopathy (DR) in which swelling of the central retina causes loss of central vision. The Wisconsin Epidemiologic Study found that the prevalence of DME increases from 0−3% in recently diagnosed individuals to 28−29% in those living with type 1 or 2 diabetes for at least 20 years. The long-term incidence of DME (over a 10-year period) in the Wisconsin study was highest (25.4%) in older-onset patients (diagnosed with diabetes at ≥30 years of age) with type 2 diabetes that required insulin and lowest (13.9%) in older-onset patients with type 2 diabetes who did not take insulin 1,3.

The Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol T, which is a comparison of the anti–vascular endothelial growth factor (VEGF) agents aflibercept (Eylea®), bevacizumab (Avastin®), and ranibizumab (Lucentis®) for treatment of center-involving diabetic macular edema (DME) with vision loss has prompted discussions at conferences and requests by peer-reviewed and non–peer-reviewed journals for post hoc analyses, 2,3. At 1 and 2 years post therapy the mean visual acuity (VA) improvement with all 3 agents was similar for eyes with VAs of 20/32 to 20/40 at randomization. For a baseline VA of 20/50 or worse, aflibercept produced a greater improvement in mean VA than the other agents at 1 year. Improvement in VA at the 2-year time point with aflibercept remained statistically superior to bevacizumab but not ranibizumab.

Recently a trial was undertaken to assess subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab (Lucentis®)3. The investigators performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness ≥250 μm on time domain optical coherence tomography) through the 24-week visit. They administered four monthly intravitreous injections of ranibizumab and then as needed per protocol as the intervention to improve visual acuity. The investigators concluded that the data suggested that less than half of eyes treated for DME with intravitreous ranibizumab had persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (≥2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists3.

Notably, an efficacy post hoc analyses of a randomized clinical trial of VEGF inhibitor comparative effectiveness trial for DME was undertaken by investigators to assess the impact VEGF inhibitors used to treat DME in recent comparative trials4,5. Post hoc analyses performed from May 3, 2016, to June 21, 2016, of a randomized clinical trial performed from August 22, 2012, to September 23, 2015, of 660 participants comparing 3 anti-VEGF treatments in eyes with center-involved DME causing vision impairment. They were looking for changes in visual acuity (VA) area under the curve and change in central subfield thickness (CST) within subgroups based on whether an eye received laser treatment for DME during the study. Although their design involved a post hoc analyses and the authors state these types of reviews should be viewed with caution given the potential for bias, they concluded that in eyes with a VA of 20/50 or worse, aflibercept (Eylea®) has the greatest improvement in VA over 2 years over bevacizumab (Avastin®) and ranibizumab (Lucentis®) . Focal/grid laser treatment, ceiling and floor effects, or both may account for mean thickness reductions noted only in bevacizumab-treated eyes between 1 and 2 years4,5.

It is clear that the science and the data on the long-term effectiveness of VEGF inhibitors to treat DME is an evolving science. Readers of this blog are highly encouraged to review in their entirety the links and references provided below. Additionally, it is recommended that for interested parties seeking to learn more on this topic that references, trial and data readily available in the public domain be reviewed thoroughly.

Links/References:

  1. Ther Adv Endocrinol Metab. 2013 Dec; 4(6): 151–169
  2. https://www.ncbi.nlm.nih.gov/pubmed/26746868
  3. JAMA Ophthalmol. 2016 Mar;134(3):278-85.
  4. http://www.medscape.com/viewarticle/870046
  5. http://jamanetwork.com/journals/jamaophthalmology/article-abstract/2556184