Fundamentals of DR/DME

Introduction

Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME)

DR is caused by ongoing damage to the small blood vessels of the retina. The leakage of fluid into the retina may lead to swelling of the surrounding tissue, including the macula. DME is the build-up of fluid in a region of the macula. About half of all people with DR will develop DME. Although it is more likely to occur as DR worsens, DME can happen at any stage of the disease, according to the NEI.¹

The pathogenesis of DME is multifactorial and complex. Chronic hyperglycemia results in loss of pericytes, basement membrane thickening, and loss of tight junctions in capillary endothelium. This culminates in breakdown of blood-retinal barrier with increased vascular permeability, resulting in leakage of fluid, as shown in the illustration. The accumulation of edema causes loss of normal retinal architecture, indicated in the optical tomography coherence (OCT) image, which results in the loss of vision.²

DME Pathogenesis

An inflammatory cascade plays a key role in the pathogenesis of DME. This cascade involves multiple inflammatory cytokines including VEGF, which has inflammatory as well as angiogenic properties. Hyperglycemia activates inflammatory pathways that damage the retinal vasculature, leading to breakdown of the blood-retinal barrier, vascular leakage, and DME.³

DRCR.net Protocol I

In DME, the main treatment modalities include laser photocoagulation, intravitreal anti-VEGFs, and intravitreal corticosteroids or corticosteroid implants (0.19 mg fluocinolone acetonide and 0.7 mg dexamethasone).⁴ Anti-VEGF drugs have become first-line treatment for diabetic eye disease. Aflibercept, bevacizumab, and ranibizumab improve vision in eyes with center-involved DME, with the relative effect depending on baseline VA.⁵

The Protocol I study, a multicenter, randomized clinical trial, evaluated intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of DME. The main outcome measure was best-corrected visual acuity (BCVA) and safety at 1 year.⁶

Eyes were randomized to sham injection plus prompt laser (n=293); 0.5 mg ranibizumab plus prompt laser (n=187); 0.5 mg ranibizumab plus deferred (≥24 weeks) laser (n=188); or 4 mg triamcinolone plus prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.⁶

Visual Acuity

The 1-year mean change (±standard deviation) in the VA letter score from baseline was significantly greater in the ranibizumab plus prompt laser group (+9±11, P < .001) and ranibizumab plus deferred laser group (+9±12, P < .001) but not in the triamcinolone plus prompt laser group (+4±13, P=0.31) compared with the sham plus prompt laser group (+3±13). Reduction in mean central subfield thickness in the triamcinolone plus prompt laser group was similar to both ranibizumab groups and greater than in the sham plus prompt laser group.

In the subset of pseudophakic eyes at baseline (n = 273), VA improvement in the triamcinolone plus prompt laser group appeared comparable to that in the ranibizumab groups. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure (IOP) and cataract surgery were more frequent in the triamcinolone plus prompt laser group. Two-year VA outcomes were similar to 1-year outcomes.⁶

Pseudophakic Patients

Triamcinolone and laser also performed well among a specific group of patients in Protocol I.⁶

In the subset of pseudophakic eyes at baseline (n=273), VA improvement in the triamcinolone plus prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated IOP and cataract surgery were more frequent in the triamcinolone plus prompt laser group.⁶

DRCR.net Protocol I Subanalysis

Subanalysis was conducted to determine if factors may predict anti-VEGF treatment success or failure. Study eyes were differentiated into one of four categories based on whether they had at least a 20% reduction from baseline central subfield thickness at the 16-week visit.⁷ 

A total of 37 baseline demographic, systemic, ocular, optical coherence tomographic (OCT), and fundus photographic variables were assessed for association with change in visual acuity or central subfield thickness (CST) between baseline and 1 year in 361 eyes that were randomly assigned to intravitreal ranibizumab with prompt or deferred laser treatment within a trial of ranibizumab, triamcinolone acetonide, and laser treatment for center-involved diabetic macular edema. A categorical variable describing follow-up anatomic responses to therapy was added to the visual acuity outcome model.⁷

After adjusting for baseline VA, a larger VA treatment benefit was associated with younger age (P < .001), less severe DR on clinical examination (P =.003), and absence of surface wrinkling retinopathy (P < .001). The reduction in central subfield thickness (CST) during the first treatment year also predicted better VA outcomes (P < .001). After adjusting for baseline CST, the presence of hard exudates was associated with more favorable improvement on OCT scan (P = .004). Because only 11 eyes experienced vision loss and six eyes experienced an increase in CST, factors for poor outcomes could not be evaluated.

Approximately 50% of the study eyes received early and consistent therapeutic benefits.  The remaining 50% received inconsistent, variable or were categorized as nonresponders.

Early Analysis of DRCR.net Protocol I

To determine whether early VA response to ranibizumab in DME is associated with long-term outcome, Gonzalez et al pooled data from the ranibizumab plus prompt and deferred laser treatment arms of the Protocol I study to explore the relationship between early (week 12) and late (weeks 52-156) VA response.  Response was measured by a mean change from baseline in BCVA and categorized improvement was defined as  <5, 5-9, or ≥10 ETDRS letters in BCVA.⁸

The results of this post hoc analysis of randomized controlled trial data revealed that ranibizumab plus or minus laser therapy resulted in similar rates of suboptimal and pronounced BCVA improvement at 12 weeks. Specifically, in the analysis population (340 eyes), <5-, 5- to 9-, and ≥10-letter BCVA improvements occurred in 39.7%, 23.2%, and 37.1% of eyes, respectively, at 12 weeks, and 34.2%, 16.5%, and 49.3% of eyes at 156 weeks. Within each early BCVA response category (<5, 5-9, and ≥10 letters of improvement at 12 weeks), mean CFB BCVA at 52-156 weeks varied by <5 letters from that at 12 weeks. CFB BCVA and <5-letter improvement at 12 weeks showed significant positive and negative association, respectively, with CFB BCVA and ≥10-letter improvement at 52 and 156 weeks. Similar relationships were demonstrated in eyes with baseline BCVA <69 letters, and associations remained significant after multivariate adjustment for potential confounders.⁸

Within each early BCVA response category (<5, 5-9, and ≥10 letters of improvement at 12 weeks), mean CFB BCVA at 52-156 weeks varied by <5 letters from that at 12 weeks.

Why the Difference in Response?

A genetic composition appears to play a role in how patient responds to anti-VEGF treatment.  Each individual’s VEGF polymorphisms, polymorphisms in aldose reductase, endothelial lipase, erythropoietin, serine-threonine kinase can increase the risk of DME. VEGF and VEGF receptor polymorphisms upregulate and downregulate gene products and transcription factors regulating anti-VEGF response. This may be a potential target for gene therapy.⁹

DRCR.net Protocol T

The primary outcome of the Protocol T study was the change in VA at 1 year with three pair-wise comparisons. All drug groups were managed with the same structure retreatment protocol.⁵

The study was conducted at 89 sites, over which 660 patients with DME were randomized to receive injections of 2-mg aflibercept (n = 224); 1.25-mg bevacizumab (n = 218); or 0.3-mg ranibizumab (n = 218). The drugs were administered as often as every 4 weeks. At the 24-week visit, regardless of VA and macular thickness, the researchers would withhold the injection if there had been no improvement or worsening after two consecutive injections. The investigators would resume treatment if the VA letter score or the retinal thickness worsened.¹⁰

The primary outcome compares all eyes in each of the three groups and shows that eyes in the aflibercept group gained an average of 13 letters versus 11 letters in the ranibizumab group and 10 letters in the bevacizumab group. These differences were significant when comparing aflibercept to either of the other two drugs.^5,10

Among eyes with better baseline vision, there was no difference between the three agents, with all three groups gaining an average of 8 letters in the first year.^5,10

When the initial VA letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40), which represented 51% of participants, the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P > .50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P < .001 for aflibercept vs. bevacizumab, P =.003 for aflibercept vs. ranibizumab, and P = .21 for ranibizumab vs. bevacizumab).⁵

There was an increasing relative difference across VA range not just dependent on pre-specified category (better or worse than 20/50). The worse the VA, the greater the treatment interaction on VA outcomes.¹⁰ For anatomic outcomes, all three drugs dry the retina, however, aflibercept is superior to both bevacizumab and ranibizumab while ranibizumab is superior to bevacizumab in reducing retinal thickness.²

DRCR.net Protocol U

Because some eyes have persistent DME following despite treatment with anti-VEGF treatment, this study was conducted to test the efficacy of subsequently adding intravitreal corticosteroids to the treatment regimen in an attempt to achieve better vision outcomes than continued anti-VEGF therapy alone.¹¹

The investigators compared continued intravitreal ranibizumab alone with ranibizumab plus an intravitreal 0.7 mg dexamethasone implant in eyes with persistent DME. The primary outcome was change in mean VA letter score at 24 weeks as measured by the electronic ETDRS. The principal secondary outcome was change in mean CST as measured with the use of OCT.¹¹

The phase 2, multicenter, randomized clinical trial included 129 eyes from 116 adults with diabetes. Eyes had persistent DME with VA of 20/32 to 20/320 after at least three anti-VEGF injections before a run-in phase, which included an additional three monthly 0.3-mg ranibizumab injections. Data analysis was according to intent to treat.

Of the 116 randomized patients, median age was 65 years. The mean (SD) improvement in VA from randomization was 2.7 (9.8) letters in the ranibizumab plus dexamethasone group (combination) and 3.0 (7.1) letters in the ranibizumab group, with the adjusted treatment group difference (combination minus ranibizumab) of –0.5 letters (95%CI, −3.6 to 2.5; 2-sided P = .73). Mean (SD) change in CST in the combination group was –110 μm compared with –62 μm for the ranibizumab group. Nineteen eyes (29%) in the combination group experienced increased IOP or initiated treatment with antihypertensive eyedrops compared with zero in the ranibizumab group.^11,12

The authors concluded that although its use is more likely to reduce retinal thickness and increase IOP, the addition of intravitreous dexamethasone to continued ranibizumab therapy does not improve VA at 24 weeks more than continued ranibizumab therapy alone among eyes with persistent DME following anti-VEGF therapy.  Of note, however, is that the investigators did not sort out phakic versus pseudophakic patients.

DR Progression: Mild NPDR to PDR

DR progresses in an orderly fashion from mild to more severe stages when there is not appropriate intervention, and the disease is divided into two broad categories: the less severe nonproliferative DR (NPDR) and the more severe proliferative diabetic retinopathy (PDR). Natural DR progression was first assessed and documented in detail in the landmark DR clinical trials (Early Treatment Diabetic Retinopathy Study [ETDRS] and Diabetes Control and Complications Trial  [DCCT]) in the 1980s and 1990s. The ETDRS scale divides DR into 13 levels ranging from absence of retinopathy to severe vitreous hemorrhage, can be used to describe overall retinopathy severity and change in severity over time.^13,14

The two most common vision-threatening complications (VTC) that may result from DR are DME and progression to PDR. Progression to PDR is heralded by the production of neovascularization (of the disc, elsewhere in the retina, or in the anterior segment on the iris), which is also promoted by vascular endothelial growth factor (VEGF) produced by ischemic retinal tissue. Neovascular fronds are prone to rupture, leading to vitreous hemorrhage and/or hyphema, and can also lead to tractional retinal detachment as well as neovascular glaucoma.¹⁵

As seen in these fundus photos, DR worsening is associated with the development of an increasing number of pathologic features. In the absence of DME or other VTCs, the transition from NDPR to PDR is significant, as in the past when only laser treatment was available, treatment was generally reserved for patients with PDR.  Two intravitreal anti-VEGF agents are FDA approved for regressing DR: aflibercept and ranibizumab.¹³

Patients with diabetes are also at higher risk for additional ocular complications. Compared with individuals without diabetes, patients with diabetes have a 40% increased risk of developing glaucoma and a 60% higher risk of developing cataracts.¹⁶

DRCR.net Protocol S: 2-Year outcomes

Panretinal photocoagulation (PRP) had been the standard treatment for PDR since the Diabetic Retinopathy Study demonstrated its benefit more than 40 years ago. In a 2014 survey, 98% of retina specialists reported using PRP for initial PDR management in the absence of DME.¹⁷

Protocol S was undertaken to evaluate the noninferiority of intravitreal ranibizumab compared with PRP for VA outcomes in patients with PDR. The primary outcome was mean VA change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included VA area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.¹⁷

The randomized clinical trial enrolled 305 adults with PDR, and both eyes were enrolled for 89 participants (1 eye to each study group) for a total of 394 study eyes. Individual eyes were randomly assigned to receive PRP treatment, completed in one to three visits (n = 203 eyes), or ranibizumab 0.5 mg at baseline and as frequently as every 4 weeks based on the retreatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME.

All eyes received initial PRP; 98% received protocol-defined complete PRP. After completion of PRP, 92 eyes (45%) received additional PRP (median time from baseline to additional PRP was approximately 7 months. Only 12 eyes (6%) in the ranibizumab group received PRP; more than half of the eyes in the PRP group received ranibizumab for DME; thus, the protocol essentially tested ranibizumab for PDR vs PRP plus ranibizumab when needed for DME treatment.¹⁷

Among eyes with PDR, treatment with ranibizumab resulted in VA that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with PDR.¹⁷

Protocol S trial demonstrated that ranibizumab therapy for PDR is noninferior to PRP at 2 years for change in VA from baseline (5-letter noninferiority margin). Ranibizumab also provided several benefits over PRP through 2 years. The ranibizumab group showed superior gain in VA over the course of 2 years, decreased peripheral visual field loss, and fewer vitrectomies. In addition, ranibizumab-treated eyes were less likely to develop central-involved diabetic macular edema (CI-DME) causing vision impairment of 20/32 or worse.

The randomized clinical trial conducted at 55 US sites among 305 adults with PDR. Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. Study participants had type 1 or type  2 diabetes, at least 1 eye with PDR, no previous PRP, and a BCVA of 24 or higher (approximate 20/32 or better). In the ranibizumab group, study eyes received a 0.5-mg intravitreal injection at baseline and every 4 weeks through 12 weeks, and thereafter, retreatment was based on investigator assessment.  DME at baseline was present in 22% of the ranibizumab group and 23% of the PRP group. Baseline characteristics of the two groups appeared similar.¹⁷

The results showed that in patients treated with ranibizumab versus PRP had:

• superior mean BCVA over 2 years (AUC) and visual field outcomes;
• decreased occurrence of vitrectomy;
• decreased development of center-involved DME (CI-DME); and
• 47% of eyes with ranibizumab improved ≥2 steps.¹⁷

For a patient with relatively severe DR, such as the patient population with PDR in Protocol S, the improvement effect can be even greater. The 47% of patients who had a 2 or more-step reduction in severity by 2 years had a mean of 10 to 14 ranibizumab injections; as many as 59% of eyes with DME (vs 38% without) and 30% overall had a 3-step reduction in severity.¹⁷

Note: An eye with PRP cannot improve beyond level 60. It can be worse than 60 if active neovascularization is present but cannot be better than 60; therefore assessing improvement is not possible.

DRCR.net Protocol S Study: 5-Year Outcomes

The outcomes at 5 years reinforced the 2-year data for Protocol S: 46% of patients in anti-VEGF group had a 2 or more step improvement in PDR severity.

The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in VA letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95%CI, −2.3 to 3.5; P = .68); the mean VA was 20/25 (approximate Snellen equivalent) in both groups at 5 years.¹⁸

The mean (SD) change in cumulative visual field total point score was −330 (645) vs −527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively. Vision-impairing DME developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively. No statistically significant differences between groups in major systemic adverse event rates were identified.¹⁸

CLARITY Study

CLARITY, a phase 2b, randomized, controlled, single-masked, multicenter clinical trial, was conducted to determine the efficacy, safety and cost-effectiveness of intravitreal aflibercept in PDR and to investigate the impact on local oxygenation. Aflibercept is an inhibitor of VEGF-A, VEGF-B and PLGF.¹⁹

The study specifically was designed to determine the impact of repeated intravitreal aflibercept injections in the treatment and prevention of PDR. A total of 220 participants with treatment-naïve or treated but active retinal neovascularization (NV) in at least one eye were randomly allocated 1:1 to aflibercept injections or PRP for 52 weeks. The primary outcome is the change in BCVA in the study eye at 52 weeks. Secondary outcomes include changes from baseline in other visual functions, anatomical changes and cost-effectiveness. Ocular and nonocular adverse events will also be reported over 52 weeks.¹⁹

The results revealed that patients with PDR who were treated with intravitreal aflibercept had an improved outcome at 1 year compared with those treated with PRP standard care.

A total of 232 participants (116 per group) were recruited; 221 participants (112 in aflibercept group; 109 in PRP group) contributed to the modified intention-to-treat model, and 210 participants (104 in aflibercept group; 106 in PRP group) within per protocol. Aflibercept was noninferior and superior to PRP in both the modified intention-to-treat population (mean best corrected visual acuity difference 3·9 letters and the per-protocol population. The 95% CI adjusted difference between groups was more than the prespecified acceptable margin of –5 letters at both 12 weeks and 52 weeks. The investigators noted no safety concerns.²⁵

CLARITY study is the first of its kind in two respects. It’s the first randomized controlled trial of intravitreal aflibercept in PDR and the results provide substantial evidence that the visual outcome of active PDR at 1 year with aflibercept therapy is superior to PRP.  This is also the first to show a superior VA outcome with an anti-VEGF agent in eyes with PDR with no baseline macular edema (P=.007) compared with PRP therapy. Of particular note is that this effect was achieved with four aflibercept injections irrespective of the PDR risk status and previous PRP treatment history. There was a lower chance of vitreous hemorrhage with aflibercept compared with PRP and supplemental PRP was rarely required with aflibercept (2%).²⁵

The authors concluded that this is evidence that aflibercept can be adopted as an alternative to PRP in the first year of therapy.²⁵

PANORAMA

1-year results from the phase 3 PANORAMA trial confirmed early results that patients with moderately severe and severe nonproliferative PDR (NPDR) are at high risk of rapidly progressing to vision-threatening complications (VTC), defined as PDR/anterior segment neovascularization or center involved (CI)-DME . In untreated patients with severe NPDR, >40% of patients developed these events at 1 year. Intravitreal aflibercept treatment prevented approximately 74% of these complications.^20,21

PANORAMA is an ongoing, pivotal, double-masked, randomized, 2-year trial that enrolled 402 patients and is designed to investigate aflibercept for the improvement of moderately severe to severe NPDR (DRSS level 47 and 53) in patients without DME compared to sham injections.^{20, 21}

Patients were administered 2 mg aflibercept at either every 8 weeks (q8) or every 16 weeks (q16) versus sham. Eighty percent of patients in the q8 group (N = 134) had at least a 2‑step improvement on DRSS score from baseline (P < .0001) at one year. Sixty-five percent of patients in the q16 group had a (N = 135) had at least a 2‑step improvement on DRSS score from baseline (P < .0001) at one year. Fifteen percent of patients receiving sham injection had at least a 2‑step improvement on DRSS score from baseline.^20,21

The proportion of patients developing a VTC or CI-DME through week 52 was also significant. Forty-one percent of patients in the sham group developed a VTC, compared with 11% in the q8 and 10% in the q16 group.

In this study, the number needed to treat was three patients in order to prevent one prespecified vision-threatening complication or CI-DME event.

“PANORAMA provides high-quality data to inform treatment of NPDR without DME, as it is the first prospective trial involving these high-risk patients since the landmark ETDRS trial of the 1980s, when laser was the only treatment option,” said Dr. Wykoff, who presented the 52-week results of the study for the first time at the Angiogenesis, Exudation, and Degeneration 2019 symposium in February. “Without treatment, a large percentage of patients in the trial developed proliferative disease and CI-DME in the first year.”

DRCR.net Protocol W

DRCR.net Protocol W is an ongoing study examining the safety and efficacy of prompt anti-VEGF versus observation in eyes presenting with severe NPDR and no CI-DME for prevention of VTCs.²²

In particular, the study will assess the proportion of eyes that develop PDR/PDR-related outcomes or CI-DME causing VA loss at 2 years. If there is a clinically important difference identified among the treatment groups for the primary outcome at 2 years, the study will also evaluate whether increased chance of prevention of PDR/DME with anti-VEGF at 2 years results in long-term beneficial visual outcomes at 4 years.

Lost to Follow Up

There have been significant concerns about what happens to PDR patients who are treated with intravitreal anti-VEGF injections and are lost to follow-up. A 2019 study by Obeid et al showed that patients with PDR who were treated with PRP and were lost to follow-up had better vision than those who were treated with anti-VEGF and were lost to follow-up. Moreover, there were significantly greater number of eyes with tractional retinal detachments (TRDs) in the intravitreal injection group compared with PRP group. There was also significantly greater incidence of neovascularization of the iris (NVI) in the intravitreal injection arm compared with PRP arm.²³

Seventy-six eyes of 59 patients were included in the study, of which 30 received intravitreal injections with anti-VEGF and 46 received PRP. In the anti-VEGF group, mean VA worsened significantly when comparing the visit before being lost to follow-up with the return visit as well as with the final visit. In the PRP group, mean VA worsened significantly when comparing the visit before being lost to follow-up with the return visit. However, no significant difference was observed at the final visit. There was a significantly greater number of eyes with TDR in the intravitreal injections group compared with the PRP group at the final visit (10 vs. 1, respectively; P = .005). There was a significantly greater incidence of NVI in the intravitreal injection arm compared with the PRP arm at the final visit  (4 vs. 0, respectively; P = .02).²³

Given the potential sequelae of being lost to follow-up, the authors concluded that retina specialists must consider carefully the choice of treatment for patients with PDR.²³

Treatment Interruptions

In addition to the data from Obeid et al, Wubben and colleagues also illustrated in a retrospective, multicenter case series that patients with DR who are treated exclusively with anti-VEGFs and have an interruption in treatment may experience marked progression of disease with potentially devastating visual consequences.²⁴

This study examined 13 eyes of 12 patients who received anti-VEGF agents for for PDR with DME (7 eyes); PDR without DME (3 eyes); and moderate to severe NPDR with DME (3 eyes). Eight eyes had VA of 20/80 or better before treatment interruption. The median duration of treatment hiatus was 12 months. The following reasons for noncompliance were identified as: illness (31%); noncompliance (31%); and  financial issues (15%).²⁴

The complications observed included nine cases of vitreous hemorrhage, five cases of neovascular glaucoma, and four cases of TRD; 77% of eyes lost more than 3 lines of vision and 46% had final VA less than hand motions.²⁴

The results of these studies show that although patients with diabetes are subject to significant lapses in follow-up because of illness, financial hardship, or noncompliance, these patients, especially those with PDR, who are managed with anti-VEGF therapy alone, can result in irreversible blindness as a result of unintentional treatment interruptions.

Case 1: Patient with CI-DME and Good VA

-This 56-year-old black woman with type 2 noninsulin dependent diabetes presented with VA of 20/25 in her left eye.

-Her diabetes was well controlled and she had NPDR.

-She was injected multiple times with both bevacizumab and aflibercept in the span of 3 years and did not require injections in the last year.

-She was able to maintain good VA.

Case 2: Patient with CI-DME and Good VA

-This is a 46-year-old type 2 noninsulin dependent diabetic black man who presented with the BCVA of 20/20 in his right eye. The presenting CST on OCT was 416 μm.

-He was noted to have mild NPDR and his hemoglobin A1C was 6.1%

-Patient had some moderate DR and macular exudates.

-Patient had some moderate DR and macular exudates.

-He was observed.

-At 2-year follow-up, his VA was 20/25 with CST of 420 μm. His glycemic control remained good with hemoglobin A1C of 6.0%. At 2 years, he was documented to have moderate NPDR. According to Protocol V (which was a 2-year study), he was doing as expected with preserved vision and slight worsening of DR.

-The exudates were very centrally located.

-Despite initiation of injections and some improvement in vision, his vision ended up 20/30 at the last follow-up.

This case highlights important two important points. First, the results of the trials should always be interpreted in a context of individual patients and take in consideration multiple other factors such as other retinal pathologies, systemic comorbidities, demographic characteristics, compliance with follow-up, and response to treatment. The presence of exudates in the current case contributed to decreased vision. Second, the clinical trials usually last 2 years. There are some long-term follow-up trials but they have inherent selection retention biases. If this patient were a study patient in Protocol V, he would be in the group that did well on observation alone. However, diabetes is a life-long disease and DR requires life-long follow-up and treatment.

Conclusion

In this evolving area of retinal disease treatment, it is imperative that vitreoretinal specialists be aware of the latest in clinical trial results, combined with real-world advice from well-known experts, and apply them to clinical practice.

1. NEI Facts about macular edema. https://nei.nih.gov/health/macular-edema/fact_sheet.
2. Shin ES, Sorenson CM, P Sheibani N. Diabetes and Retinal Vascular Dysfunction. J Ophthalmic Vis Res. 2014;9(3):362–373.
3. Zhang W, Liu H, Al-Shabrawey M, et al. Inflammation and diabetic retinal microvascular complications. J Cardiovasc Dis Res. 2011;2(2):96-103.
4. Bailey C, Chakravarthy U, Lotery A, et al. Real-world experience with 0.2 μg/day fluocinolone acetonide intravitreal implant (ILUVIEN) in the United Kingdom. Eye (Lond). 2017; 31(12):1707-1715.
5. Diabetic Retinopathy Clinical Research Network; Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015; 372:1193-1203.
6. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077.
7. Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012;130:1153-1161.
8. Gonzalez VH, Campbell J, Holekamp NM, et al. Early and long-term responses to anti-vascular endothelial growth factor therapy in diabetic macular edema: analysis of Protocol I data. Am J Ophthalmol. 2016 ;172:72-79.
9. Shah SU and Maturi RK. Therapeutic options in refractory diabetic macular edema. Drugs. 2017;77(5):481-492.
10. The Diabetic Retinopathy Clinical Research Network; Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359.
11. Maturi RK, Glassman AR, Liu D, et al.  Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: A DRCR network phase 2 randomized clinical trial. Ophthalmol. 2018;136(1):29-38.
12. DRCR.net. Powerpoint slides. 2015. Retrieved from http://drcrnet.jaeb.org/Studies.aspx?RecID=234.
13. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy. Ophthalmology. 1991;98(5 Suppl):823-833.
14. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015;2:17.
15. NEI Diabetic retinopathy defined. https://www.nei.nih.gov/eyedata/diabetic. Accessed August 9, 2019.
16. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):997-986.
17. Writing Committee for the Diabetic Retinopathy Clinical Research Network; Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial.  JAMA. 2015;314(20):2137-2146.
18. Gross JG, Glassman AR, Liu Dat al. Five year outcomes of pan retinal photocoagulation vs intravitreous ranibizumab for proliferatvive diabetic retinopathy: a randomized clinical trial. JAMA Ophthalmol. 2018;136(10):1138-1148
19. Sivaprasad S, Prevost AT, Bainbridge J, et al. Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): a multicentre phase IIb randomised active-controlled clinical trial. BMJ Open. 2015;5(9):e008405.
20. Wykoff CC. Intravitreal aflibercept for moderately severe to severe non-proliferative diabetic retinopathy (NPDR) The phase 3 PANORAMA Study. Presented at: Angiogenesis, Exudation, and Degeneration 2019 Symposium; February 9, 2019; Miami, Florida.
21. Eyewire News. One-year results from phase 3 Eylea trial in diabetic retinopathy presented. Updated February 11, 2019. Accessed October 8, 2019.
22. ClinicalTrials.gov. Intravitreous anti-vascular endothelial growth factor treatment for prevention of vision threatening diabetic retinopathy in eyes at high risk. ClinicalTrials.gov Identifier: NCT02634333. https://clinicaltrials.gov/ct2/show/NCT02634333.  Updated September 23, 2019. Accessed October 28, 2019.
23. Obeid A, Su D, Patel SN, et al. Outcomes of eyes lost to follow-up with proliferative diabetic retinopathy that received panretinal photocoagulation versus intravitreal anti-vascular endothelial growth factor. Ophthalmology. 2019;126(3):407-413.
24. Wubben TJ, Johnson MW; Anti-VEGF Treatment Interruption Study Group. Anti-vascular endothelial growth factor therapy for diabetic retinopathy: consequences of inadvertent treatment interruptions. Am J Ophthalmol. 2019;204:13-18
25. 25. Sivaprasad S, Prevost AT, Vasconcelos JC, et al. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial.Lancet. 2017;389(10085):2193-2203.