Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

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This article was reviewed by Carl W. Baker, MD

A post hoc analysis of data from Diabetic Retinopathy Clinical Research (DRCR) Retina Network Protocol V provides insight on outcomes when eyes with center-involved diabetic macular edema (CI-DME) and good visual acuity are managed with initial observation and treated with anti-VEGF therapy only if vision worsens.

The findings were reported in a paper published in 

 and reviewed by Carl W. Baker, MD, at the 

American Academy of Ophthalmology’s 2020 virtual meeting.

Aflibercept broadly effective for reducing DR severity in post-hoc analysis

Protocol V randomly assigned eyes with CI-DME and visual acuity (VA) 20/25 to initial management with intravitreal aflibercept (Eylea), focal grid laser, or observation. 

Eyes in the laser and observation arms were to receive aflibercept only if they had a decrease in VA meeting protocol-specified criteria.

At the end of the 2-year study, mean VA was 20/20 in the 3 randomly assigned arms. Among the 236 eyes initially randomly assigned to observation, two-thirds did not require anti-VEGF therapy. 

Within the latter subgroup, median VA at 2 years was also 20/20, and 31% had spontaneous resolution of their 

. Eyes in the observation group requiring aflibercept still achieved good vision at 2 years.

Analyses done to identify baseline characteristics associated with receipt of treatment for 

after initial observation identified 3 factors that related to DME severity in the study eye, retinopathy severity in the study eye, and need for treatment of DME in the fellow eye.

DME strategies directed by knowledge of mechanisms

“Based on the primary end point results from Protocol V that showed no difference in vision outcomes between eyes treated initially with aflibercept and those with treatment withheld until vision worsened, many clinicians and patients might choose initial observation for eyes with CI-DME and good visual acuity,” said Baker, who is in private practice at the Hilton Head Retina Institute in Hilton Head, South Carolina.


Baker added that the post hoc analysis provides more practical guidance for clinicians.

“The 3 risk-related baseline factors identified by this analysis—higher levels of retinopathy, DME requiring treatment in the fellow eye, and greater OCT [optical coherence tomography] thickness—are associated with a potential need for injections,” he pointed out. “It can be useful when clinicians are deciding what treatment strategy may be the best option for their DME patients with good vision.”

Follow-up in Protocol V for eyes in the observation arm began with visits at 8 and 16 weeks and continued at 16-week intervals unless VA declined. 

Treatment with aflibercept was initiated if electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) VA decreased by ≥10 letters from baseline at any visit or by 5 to 9 letters at two consecutive visits 4 weeks apart.

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For eyes showing a 5- to 9-letter loss at one visit that was not sustained at the follow-up visit, the follow-up interval was decreased to every 8 weeks if central subfield thickness (CST) worsened by ≥10% from the preceding visit or exceeded 400 µm. 

If the eye still did not meet the VA criteria for initiating aflibercept, the follow-up interval was doubled to the previous schedule if CST was stable or improved and halved again if the CST had worsened.

Baker reported that with following of this DRCR algorithm, two-thirds of the observation group never required injections over 2 years and the mean vision was the same as that of eyes that were initially treated with aflibercept.

“Even in the eyes that had worsening vision to the point of requiring aflibercept injections, the median visual acuity was 20/25 at the 2-year end point of the study,” Baker said. “These eyes required fewer injections over the 2-year course of the study than the group initially randomized to aflibercept.”

Post hoc analysis: Protocol V provides more practical DME guidance for clinicians


Baker added that it is not fair to compare VA in the subgroups of eyes in the observation group that did and did not receive aflibercept because the eyes that were treated needed to have vision loss to qualify for aflibercept.

An analysis to identify predictors of receiving aflibercept among eyes managed initially with observation looked at nine baseline variables, of which three were found to be significant. 

The strongest risk factor was having a nonstudy eye that was receiving or was planned to receive treatment for DME within 4 months of study enrollment.

A total of 92 eyes were in this subgroup, and they had a 2.55-fold greater likelihood of needing aflibercept in the study eye compared with eyes that were not receiving binocular treatment for 

Research suggests course of diabetic eye disease influenced by genetic factors


Eyes with a baseline diabetic retinopathy severity score ≥ 47 (moderate severe nonproliferative diabetic retinopathy or worse) (n = 80) had a 2.22-fold increased risk of receiving aflibercept compared with eyes entering the study with less severe diabetic retinopathy (

An analysis of the impact of baseline CST showed that eyes with a Zeiss-Stratus equivalent ≥300 µm were approximately twice as likely as eyes with less thickening to need aflibercept (

Baseline factors not associated with receipt of aflibercept among the eyes initially managed with observation were gender, age, race/ethnicity, glycated hemoglobin A1C (HbA1c), and VA prior to 


Baker outlined several limitations of the analyses. He noted that because they were conducted post hoc and multiple characteristics were evaluated, some of the associations between baseline features and receipt of aflibercept could have been identified due to chance.

In addition, treatment decisions were guided by VA obtained from E-ETDRS testing following protocol refraction, which could differ from VA measurements taken in clinical settings. 

Finally, the analysis does not provide information on the group initially treated with laser.


Baker receives grants for clinical research from Regeneron Pharmaceuticals, Inc, and other companies marketing products for treatment of DME.


1. Glassman AR, Baker CW, Beaulieu WT, et al. Assessment of the DRCR Retina Network approach to management with initial observation for eyes with center-involved diabetic macular edema and good visual acuity: a secondary analysis of a randomized clinical trial. 

. 2020;138(4):341-349. doi:10.1001/jamaophthalmol.2019.6035

Articles

Protocol V delves into observation of disease.

Study targets strategies for CI-DME

This article was reviewed by Rishi P. Singh, MD



A retrospective cohort study characterizing presenting disease-related features, treatment, and outcomes of patients with 

 reinforces the existence of racial/ethnic and socioeconomic health care disparities in the US population.

The research, presented recently by Rishi P. Singh, MD, was conducted to understand how presenting visual acuity and 

severity differ among patients receiving anti-VEGF injections for DME and to characterize associations between socioeconomic factors and anti-VEGF injection utilization and visual acuity outcomes.

The analyses showed that Hispanic/Latino ethnicity and Medicaid insurance were associated with worse presenting visual acuity at diagnosis. 

Factors associated with receipt of a higher number of anti-VEGF injections over time were non-Hispanic ethnicity, private insurance status, and White race. Non-Hispanic ethnicity and private insurance status also correlated with better long-term visual acuity outcomes.

“Our study’s results are consistent with those of some previous studies, including an analysis of patients at Cole Eye Institute,” said Singh, a retina specialist at Cleveland Clinic Cole Eye Institute and an associate professor of ophthalmology at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Ohio. “While we think the natural history of DME is influenced by glycemic control, the time since diabetes diagnosis, and ophthalmic interventions, we are realizing from the accumulating research that it is far more complex. Rather, patient outcomes depend on multiple interrelated factors, including health care access, disease burden, and racial and social factors.”

Identification of the disparities provides a foundation for further research and efforts to rectify the issues.

 Disparities in care of retinal detachments

“We are hoping to improve physician understanding of the social determinants of health and barriers to care to develop appropriate treatment plans for at-risk populations,” Singh said. “In addition, we would like to expand our research to examine other factors as possible predictors of anti–VEGF injection utilization, including education, [hemoglobin] A1c level, smoking status, distance to clinic, and racial-ethnic biases in health care settings.”

Singh said investigators also recognize the need to characterize literacy among patient populations and with regard to ophthalmic interventions as a means to identify opportunities for improving access to regular anti-VEGF injections for at-risk populations.

Investigators for this retrospective cohort study searched the IRIS Registry to identify adults (aged > 18 years) with a diagnosis of treatment-naive DME receiving their first anti-VEGF injection.

A total of 203,673 patients met the eligibility criteria, with most (51%) residing in the southern United States. The patients had an average age of 60 years and were nearly equally represented by men and women. 

Approximately 50% of the population had diabetic retinopathy, and the largest proportion of patients with diabetic retinopathy had proliferative disease. Baseline visual acuity for the entire population was an Early Treatment Diabetic Retinopathy Study (or ETDRS) letter score of approximately 66.

Identifying gaps in anti-VEGF treatment among minorities with DME

Study results showed a stronger correlation between diabetic retinopathy severity and Black/African American patients vs White patients, Hispanic/Latino patients vs non-Hispanic/non-Latino patients, and patients with Medicaid vs those with private insurance.

Factors associated with better visual acuity at presentation included younger age and male gender. 

Again, there were statistically significant differences favoring White patients vs Black/African-American patients, non-Hispanic/non-Latino patients vs Hispanic/Latino patients, patients with private insurance vs those with Medicaid, and patients with Medicare coverage versus those with Medicaid.

Analyses comparing patients with mild nonproliferative diabetic retinopathy to those with either severe nonproliferative disease or proliferative disease showed that patients having a worse level of diabetic retinopathy also had worse visual acuity at presentation. 


Visual acuity at presentation among non-Hispanic patients was similar across all geographic regions, defined as Midwest, Northeast, South, and West. 

However, geographic disparity in visual acuity at presentation was noted among Hispanic patients and patients with Medicaid as their primary insurance.

“In particular, our study showed that visual acuity at presentation was lower among Hispanics and those living in the Sunbelt states, where diabetes prevalence is very high,” Singh said.

Analyses of anti–VEGF injection utilization showed that patients received about 3.8 injections during the first year after diagnosis. 

Differences in anti–VEGF injection utilization showed higher utilization among White non-Hispanic patients versus White Hispanic patients, Medicare and private insurance patients versus Medicaid patients, and patients with less severe versus more severe retinopathy.

The study also evaluated factors associated with differences in visual acuity during 5 years of follow-up. These analyses showed that compared with White patients, Black patients had worse visual acuity at baseline and throughout the duration of follow-up. 

Identifying biomarkers to predict diabetic retinopathy progression

Disparity also existed between Hispanic and non-Hispanic patients, with Hispanic patients presenting with and maintaining worse visual acuity throughout the study, and the difference between Hispanic and non-Hispanic patients was even greater than the disparity between Black patients and White patients. 

Patients with more severe diabetic retinopathy at baseline also maintained worse vision throughout follow-up compared with those less severely affected. 

An analysis with patients stratified by insurance status showed all groups maintained the same mean visual acuity throughout follow-up. 

The best average visual acuity was found among private insurance patients, followed by those with Medicare coverage; those with Medicaid had the worst visual acuity.

Interestingly, however, when patients were stratified by race/ethnicity and insurance status, Hispanic patients with private insurance had worse visual acuity at presentation and at 5 years than non-Hispanic Medicaid patients, Singh concluded. 


This article is based on Singh’s presentation at the American Academy of Ophthalmology 2020 virtual annual meeting. Singh is a consultant to companies that market treatments for DME and diabetic retinopathy.

Study highlights role of demographic and socioeconomic characteristics in treatment.

Investigators uncover health care disparities among US patients

This article was reviewed by Dante J. Pieramici, MD

After 1 to 2 years of follow-up in a phase 1/2a dose-escalation study, RGX-314 subretinal gene therapy (ReGenX Bio) for neovascular 

continues to be generally well-tolerated and is demonstrating a durable treatment effect with stable to improved visual acuity and retinal thickness as well as meaningful reductions in anti-VEGF injection burden, according to Dante J. Pieramici, MD.

RGX-314 uses a novel adeno-associated viral vector (AAV8) to deliver a gene for an anti-VEGF monoclonal antibody fragment to achieve sustained protein production by retinal cells, said Pieramici, a retina specialist in private practice, California Retina Consultants, Santa Barbara, California.

“A pivotal trial of subretinal RGX-314 gene therapy for neovascular AMD will be starting in 2021,” he said. “A phase 2 clinical trial (AAVIATE) is exploring RGX-314 delivered via a suprachoroidal route as treatment for neovascular AMD. A phase 2 study is investigating suprachoroidal RGX-314 as treatment for diabetic retinopathy without center involved- diabetic macular edema.”

ADVM-022 offers sustained anatomic improvements in wet AMD

The phase 1/2a trial of subretinal RGX-314 for neovascular AMD enrolled 42 patients across 5 dose cohorts (3 x 109 to 2.5 x 1011 GC/eye). 

Patients eligible for the study previously were treated with anti-VEGF agents and showed a response and most required very frequent injections to maintain disease control.

After undergoing vitrectomy and subretinal injection of RGX-314, patients were followed every 4 weeks. 

They were eligible to receive an anti-VEGF injection at the discretion of the investigator if they had increased, new or persistent choroidal neovascularization-related fluid, vision loss greater than or equal to 5 letters associated with fluid, or new ocular hemorrhage.

The baseline characteristics of the patients in the 5 dose cohorts were similar. Mean age was 80 years, mean BCVA was 55.7 ETDRS letters, mean central retinal thickness (CRT) was 399.1 µm, and patients had received an average of approximately 33 previous anti-VEGF injections for an annualized rate of approximately 9.6. Approximately 43% of patients had neutralizing antibodies to AAV8.

Novel gene therapy/medical device combo sheds light on retina in RP

Giving an update on the phase 1/2a study results, Pieramici presented data from follow-up to 2 years in the first 3 dose cohorts and from 1 year in the 2 highest dose cohorts. 

The primary endpoint of the study is focused on safety, and so far there had been only a single serious adverse event that was considered possibly drug-related. 

The event occurred in a patient in the highest dose cohort who developed increase of existing retinal pigmentary changes involving the macula and a significant decrease in vision.

Retinal pigmentary changes represented the most common ocular adverse event recorded in the study (76%). Most (70%) were mild and only 1 was severe. Mild postop inflammation developed in approximately one-third of patients and resolved within days to weeks.


Mean BCVA and mean CRT in the first 3 dose cohorts were relatively stable throughout the first year of follow-up. The mean annualized number of injections was unchanged in the first 2 dose cohorts but decreased to just 2.2 in cohort 3. 

Collaboration to focus on biologicals for the treatment of retinal diseases


During the second year, BCVA in the 2 lowest dose cohorts remained relatively stable. However, BCVA improved in the third dose cohort (+14 letters from baseline) with receipt of a mean of 2.8 annualized injections.

“The mean annualized injection burden in cohort 3 was reduced by 68% during the first year following RGX-314 administration and by more than 60% during year 2,” Pieramici explained.

In the 2 highest dose cohorts, mean BCVA was relatively stable during the year of available follow-up, and mean CRT showed a modest decrease at 1 month and remained stable thereafter. 

Mean change from baseline CRT was +61 µm in cohort 4 and -79 µm in cohort 5. BCVA was stable in cohort 4 but improved modestly in cohort 5, which had an 84% reduction in mean annualized anti-VEGF injection burden.

Considerations when using anti-VEGF for treating AMD

RGX-314 protein levels measured in aqueous samples showed a dose-dependent response across the five dose cohorts (range 2.2 ng/mL to 457.5 ng/mL) and remained relatively stable during 2 years of follow-up in cohort 3 and during the year of follow-up available for cohorts 4 and 5. 

Baseline serum neutralizing antibodies to AAV8 did not affect RGX-314 protein production, Pieramici concluded. 


This article is based on Pieramici’s presentation at the American Academy of Ophthalmology’s virtual 2020 annual meeting. Pieramici is a consultant for and receives research funding from ReGenX Bio.

Option demonstrates stable to improved visual acuity and retinal thickness.

Novel gene therapy for neovascular AMD showing efficacy, safety 


Use of a systematic, comprehensive approach to assess candidacy for refractive surgery can optimize surgical success and patient satisfaction, according to George O. Waring IV, MD, FACS.

“Whether undergoing a cornea- or lens-based procedure, patients should be generally healthy, and surgeons need to have a good understanding of the individual’s vision needs and goals,” said Waring, who is the founder and medical director of the Waring Vision Institute in Mount Pleasant, South Carolina, and also an adjunct assistant professor of bioengineering at Clemson University in South Carolina.

Visual outcomes of small-aperture IOL implant in post-laser refractive eyes

“In addition, a complete ocular examination is needed,” he said. “Advanced diagnostics can aid in decisions about candidacy and procedure selection, and more tools that show great promise for guiding surgical decisions are in development.”


Information that includes patient age, refractive error, lens opacity, dry eye status, and overall ocular health provides the foundation for determining whether a patient is a candidate for refractive surgery and the best surgical option that will direct the preoperative work-up.

“In our practice, laser vision correction is more strongly considered for a younger patient who still has good accommodative ability, whereas a refractive lens exchange may be preferable for an older individual,” Waring explained.

Other considerations include the patient’s desire for good uncorrected vision at different distances and the importance of good stereopsis, both of which can take into account the individual’s occupation, hobbies, and recreational activities. 

Dispelling myths about refractive lens exchange

A history of previous ocular surgery, ocular pathologies, and previous use of contact lens monovision are other issues reviewed in the preoperative screening evaluation.


Components of the eye examination include current spectacle prescription; determination of monocular and binocular uncorrected vision acuity and near, best corrected visual acuity; and a surgical manifest refraction, including a cycloplegic refraction. 

Ocular dominance is also checked, including optical ocular dominance if the motor is equivocal, Waring said.


Diagnostic technologies are used to screen for corneal pathology that would determine patient candidacy for different procedures as well as for surgical planning.

“Historically, Placido-based topography has been the gold standard for evaluating patient candidacy for corneal refractive surgery, but elevation-based tomography has come into the mainstream and we have been studying in vivo assessments of corneal biomechanics in our center,” Waring said.

With Placido-based topographers, findings of asymmetric bow ties, inferior steepening, or skewed radial axis may be indicative of a patient who has an abnormal cornea and may not be a candidate for LASIK or potentially any corneal refractive surgery, depending on a multifactorial clinical presentation and severity.

9 best practices in refractive-cataract surgery planning

Using tomography, surgeons should check for a normal topographic pattern on the sagittal curvature map, normal thickness on the pachymetry map, anterior float less than 8 μm, and posterior elevation less than 18 μm to aid in screening patients as appropriate for LASIK. Other indices also provide useful information. 

For example, a Belin-Ambrósio enhanced ectasia display value of less than 1.4 or a maximum Ambrósio relational thickness result of more than 400 are favorable factors for candidacy.


Wavefront aberrometry is used in the preoperative evaluation of refractive surgery candidates to understand higher–order aberrations and for planning wavefront-guided laser vision–correction procedures, whereas biometry is needed in cases involving refractive lens exchange.

Ray tracing technologies that separate internal (lenticular) and external (cornea) optical aberrations can also be helpful for guiding surgical decisions. 

As an example, Waring cited data from an eye exhibiting higher internal optical aberrations that indicated suitability for a refractive lens exchange procedure.

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Anterior segment optical coherence tomography can provide information on pachymetry, epithelial thickness maps, anterior and, posterior keratometry, lens density, biometry, and in some cases, macular imaging. Lens imaging is also possible using Scheimpflug-based devices or double-pass wavefront technology.


Waring noted that evaluation of corneal biomechanics will be coming into the clinic as a technique to screen for corneal ectasia and ectasia risk in laser vision–correction patients. 

Early experience in Warning’s institute indicates that the tomographic and biomechanical index—a metric developed by Renato Ambrósio, MD, that combines Scheimpflug-based corneal tomography and biomechanical evaluation—is very helpful. 

The color-coded result identifies eyes that might be considered appropriate candidates for LASIK versus a surface ablation procedure, implantable contact lens, or refractive lens exchange.

Finite element modeling developed by William J. Dupps Jr, MD, is also an exciting development for identifying eyes at risk for ectasia after laser vision correction, Waring said.

Researchers targeting risk factors for ectasia after LASIK procedure

“Our experience with both of these technologies [has] been very positive,” he added.

The modeling incorporates information from sets of preoperative and postoperative cornea strain maps, which are generated from Scheimpflug tomography, to predict risk. 

In clinical practice, the preoperative strain map of a surgical candidate is compared with the database to see how the features of the cornea match with those of an eye that went on to develop postoperative ectasia. 


This article is based on Waring’s presentation at the American Academy of Ophthalmology’s 2020 virtual annual meeting. Waring is a consultant to Oculus, Reichert, and Visiometrics; receives lecture fees from Oculus; and owns equity in Visiometrics.

Physicians should consider basing decisions on findings from comprehensive consultation and examination.


Cheryl Guttman Krader, BS, Pharm

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Study targets strategies for CI-DME