While laser photocoagulation was long considered the standard treatment for diabetic macular edema (DME), evidence has led to a shift toward the use of anti-VEGF injections. A recent study set out to compare the efficacy and safety of the three available drugs, Eylea (aflibercept, Regeneron Pharmaceuticals), Avastin (bevacizumab, Genentech) and Lucentis (ranibizumab, Genentech)—and generated some interesting results that were recently published in The New England Journal of Medicine.¹ Generally considered to be comparable for most indications, the three agents were tested to identify potential agent-specific distinctions in patient response. 

Protocol T
Researchers from the Diabetic Retinopathy Clinical Research Network, through a randomized clinical trial called Protocol T funded by the National Institutes of Health, found that Eylea provided more visual improvement for study participants with initial visual acuity of 20/50 or worse—a mean improvement of 19 letters on the visual acuity score, compared to 12 for Avastin and 14 for Lucentis. The same was not the case for participants with visual acuity between 20/32 and 20/40, however, as all three groups showed similar improvement: an eight-letter gain on average for each of the three drugs.

Study in the Spotlight The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. DOI: 10.1056/NEJMoa1414264.

The study included 660 adults with either Type 1 or Type 2 diabetes, center-involved DME and at least one eye with visual acuity of 20/32 or worse. Participants were randomly chosen to receive Eylea, Avastin or Lucentis, and follow-up visits occurred roughly every four weeks. Over a one-year period, participants received a median of nine or 10 injections. For those with entering visual acuity of 20/40 or better, there was no difference in injections needed—a median of nine for each agent. However, when acuity was 20/50 or worse, the Eylea and Lucentis patients each required one fewer injection than those given Avastin (10 each for aflibercept and ranibizumab vs. 11 for bevacizumab).

An increase in the visual acuity letter score of five or more or a decrease in central subfield thickness of 10% or more was considered an improvement; a decrease in visual acuity letter score of five or more or increase in central subfield thickness of 10% or more was documented as worsening. Overall, all three medications showed improvement, although the relative effect depended on initial visual acuity.

DME in the US Given the increasing prevalence of diabetes in the United States, it’s no surprise eye care providers are seeing more and more patients with diabetes-related ocular complications such as diabetic macular edema (DME).1 Eye care professionals are important providers in the continuum of care, and not just for the treatment of the ocular complications diabetes can create. “We ODs and general ophthalmologists play a significant role in educating patients with diabetes, helping them to make wise decisions and be compliant,” says Dr. Karpecki. “We need to be well-informed about the disease, diagnose it early via new technologies that involve lens autofluorescence or early signs of diabetic retinopathy, and work closely with PCPs and retina specialists” to help patients successfully manage their blood glucose levels via education about compliance. “We also need to be looking closely for DME in all of our patients with a diagnosis of diabetes because more than half of all cases are not being diagnosed,” Dr. Karpecki adds. “Patients who are quickly identified and effectively treated will have a significant benefit” in reduced morbidity and faster recovery. Considering that DME affects approximately 750,000 people in the US and is considered the leading cause of blindness, it’s something everyone encounters in their practice.2 Eye care providers working to preserve their patient’s visual acuity for as long as possible have many treatment options to choose from—and new research, such as the Protocol T study, is going to help them make the best possible recommendations for each patient’s disease course. 1. CDC. Diabetes Public Health Resource. www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. 2. Varma R, Bressler NM, Doan QV, et al. Prevalence and risk factors for diabetic macular edema in the United States. JAMA Ophthalmol. 2014;132:1334-40.

Study participants whose DME did not improve were also given laser photocoagulation. Thirty-seven percent of the Eylea-treated participants had laser treatment at least once between 24 and 48 weeks, compared to 56% of the Avastin group and 46% of the Lucentis group. The researchers postulate this “probably reflects the greater proportion of aflibercept treated with resolution of central-subfield-involved diabetic macular edema.”

In addition to studying visual acuity measures, researchers noted all three drugs also decreased retinal thickness, but more so for the Eylea and Lucentis groups than the Avastin group. Similar to the visual acuity measures, the treatment effect varied according to initial visual acuity.

Finally, the study took a closer look at the safety of these drugs and found that rates of serious adverse events, hospitalization and pre-specified systemic adverse events were similar for all three drugs. While a post hoc analysis revealed that more patients treated with Eylea reported adverse cardiovascular events than patients treated with Avastin and Lucentis, the authors postulate the differences could be due to chance, given the lack of corroboration in other studies.

Clinical Implications
The study authors concluded that Eylea, Avastin and Lucentis were all effective and relatively safe treatments for DME. All three were similarly effective for those with mild initial visual acuity, but Eylea was more effective for those with worse levels of acuity. Clinicians “should consider the eligibility criteria for this study, such as visual acuity, retinal thickness, and prior treatment for diabetic macular edema” when applying the results of this study to their clinical practice, the study authors conclude.¹ 

Optometrists comanaging DME patients “should try to work with retina specialists that have a good understanding of the role of all three drugs related to DME,” Paul M. Karpecki, OD, recommends. “A patient who has DME and vision worse than 20/50 should likely be receiving Eylea if an anti-VEGF is the treatment of choice,” he says. Earlier studies have indicated approximately 75% of DME patients present with visual acuity of 20/40 or better.² In such patients, the choice of therapy will often be more about price and availability, as Avastin costs about $50 per dose compared to $1,200 for Lucentis and $1,950 for Eylea.³ As such, many ophthalmologists may continue to favor off-label Avastin to ease the financial burden of treatment. Rebates and other patient-support efforts can also help reduce costs, Dr. Karpecki says.

The plan is to continue follow-up through two years of treatment to learn more about the efficacy and safety of these three drugs, the researchers said in a National Eye Institute release. As it stands, this study presents a new opportunity for ODs to offer patients better guidance on the treatment options available to them.

For optometrists, the study underscores the need for education (of patients) and engagement (with retina specialists). Inform patients of the latest findings and explain that retina specialists have various options—even focal laser if the leakage is not close to the macula—and certainly a new understanding of anti-VEGF choices as a result of the Protocol T results, says Dr. Karpecki.

 “And when we notice DME—usually diagnosed as exudates or hemorrhages within a disc diameter of the macula, or via OCT if a practice has one—we know there are very effective treatments and therapy should be recommended,” Dr. Karpecki says.

1. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. DOI: 10.1056/NEJMoa1414264.
2. Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema—relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Arch Ophthalmol. 1995;113:1144-55.
3. Martin DF, Maguire MG. Treatment choice for diabetic macular edema. N Engl J Med. 2015 Feb 18. DOI: 10.1056/NEJMe1500351.