Conference Update

Anti-VEGF for halting and reversing the progression of DR

2 months ago, OP Editor

Apart from identifying patients who are at increased risk of progression from non-proliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR), it is no less important to determine the optimal time to start treatment. For decades, panretinal photocoagulation (PRP) has been a standard of care for PDR,1,2 but recent investigations have revealed the potential benefits of an earlier intervention with the anti-vascular endothelial growth factor (anti-VEGF) agents. The findings were discussed at the American Society of Retina Specialists (ASRS) 2018 Annual Meeting.3,4

Threshold for initiating treatment for patients with DR

DR is characterized by distinct morphological abnormalities in the retinal microvasculature.5,6 Microaneurysms are typically found in the earliest stage of DR (mild NPDR), but there could be a gradual, progressive closure of retinal blood vessels leading to retinal ischemia as the disease progresses (moderate/severe NPDR).5,6 To compensate for the lack of circulation due to retinal ischemia, formation of new but fragile blood vessels may spread from the optic disc or from elsewhere in the retina (PDR).5,6 Left untreated, the disease could then present with high-risk characteristics that ultimately result in severe visual loss.5,6

“The core concept here is, what is your threshold for initiating treatment for patients with DR?” said Dr. Charles C. Wykoff of Retina Consultants of Houston, US. “Most of us can agree that patients with vision loss, diabetic macular edema (DME), and those with high-risk PDR warrant treatment, but there are many patients with DR that do not fit into those nice buckets. For example, what about NPDR without DME?”7 The phase 3 PANORAMA trial was designed to answer such question.

PANORAMA: A trial specifically designed for the moderate/severe NPDR population

PANORAMA randomized 402 patients with moderate/severe NPDR in a 1:1:1 ratio to receive sham, aflibercept 2mg every 8 weeks (q8w), or aflibercept 2mg every 16 weeks (q16w).3,8,9 These patients had a baseline Diabetic Retinopathy Severity Scale (DRSS) level of 47 or 53, indicating a high risk of progression to PDR over the next few years.3,8,9 The mean age of patients was 55.7 years, with almost all of them (91.5%) being type 2 diabetes patients.3,8,9 The mean baseline best corrected visual acuity (BCVA) was 82.4 ETDRS letters, whereas the mean central retinal thickness was 247.4µm.3,8,9 Three-quarter of patients had DRSS level 47 disease severity.3,8,9

The 24-week analysis of PANORAMA found a significantly higher proportion of patients with at least a 2-step improvement in DRSS from baseline in the aflibercept group versus sham group (58.4% vs. 6%; p<0.0001).3,9 Results of the two aflibercept groups were combined for the primary outcome analysis, but a separate analysis also found consistent benefits regardless of the dosing regimens (61.5% for q8w group; 55.2% q16w group; both p<0.0001 versus sham).3,9 Mean central retinal thickness was decreased by 19.4µm in the aflibercept groups and increased by 4.7µm in the sham group (p<0.0001).9 “Outcomes were very similar between the two aflibercept arms,” Dr. Wykoff said.7

No new safety signals were identified in the trial.3,8,9 One case of mild intraocular inflammation (IOI) was reported in the aflibercept groups (0.085% rate per injection), but this was consistent with the findings in previous clinical trials.8 “When you look at the portion of patients developing potentially vision threatening complications, there was a substantial difference between the arms,” Dr. Wykoff said. “[Patients who received sham], about 1 in 4 of them, or just over 25%, developed either PDR, defined as posterior segment neovascularization or anterior segment neovascularization, or developed center-involved DME over the course of just 6 months. That’s in comparison to about 4.5% in the combined aflibercept arms.”7

“This is the first time a therapy has demonstrated it can reverse disease progression in patients with moderately severe to severe NPDR without DME, in a trial specifically designed to study this population,” said Dr. George D. Yancopoulos, the President and Chief Scientific Officer of Regeneron. “We look forward to sharing one-year results later this year.”8

Post-hoc analysis of RIDE and RISE: A tantalizing glimpse of possible benefits with anti-VEGF

Indeed, the findings in PANORAMA deserve further investigation to establish the role of anti-VEGF for an early treatment of DR, but a post-hoc analysis of the RIDE and RISE trials may provide a tantalizing glimpse of the long-term visual benefits. RIDE and RISE were two identically designed phase 3 trials of ranibizumab in 759 patients with DR and DME.10 These patients were randomized in a 1:1:1 to receive monthly intravitreal injections of ranibizumab 0.3mg, ranibizumab 0.5mg, or sham.10 After 24 months, patients in the sham group crossed over to receive monthly injections of ranibizumab 0.5mg.10

In the post-hoc analysis, DR outcomes (a prespecified secondary endpoint of RIDE and RISE) were assessed through month 36 by baseline DR severity level.4,10 The number of patients were distributed evenly among the mild/moderate NPDR (DRSS level of 35 or 43), moderate/severe NPDR (DRSS level of 47 or 53), and PDR (DRSS level of 60 to 75) groups.4,10 Baseline distribution of DR severity levels was also similar across the treatment groups, thus allowing a comparison of DR outcomes by baseline DR severity.4,10

In each of the baseline DR severity groups, ranibizumab produced significant DR improvements when compared to sham.4,10 At month 24, the proportion of patients with 2-step or more improvement in DRSS from baseline ranged between 10.3% to 15.8% (mild/moderate NPDR) and 31% to 36.4% (PDR).4,10 The greatest benefit, however, was observed in patients with moderate/severe NPDR at baseline (Figure 1).4,10



Furthermore, ranibizumab treatment remarkably delayed the time to a new proliferative event in patients with moderate/severe NPDR (Figure 2).4,10 The probability of these patients to experience a proliferative event by month 36 was reduced to almost one-third when compared to sham (log-rank analysis: ranibizumab 0.3mg vs. sham, p=0.0004; ranibizumab 0.5mg vs. sham, p=0.0018).4,10




Dr. Michael J. Elman of Elman Retina Group in Glen Burnie, Maryland, US, summarized the findings of the post-hoc analysis. “The sweet spot, that the improvement in visual acuity… when you have moderate to severe NPDR, 80% of those patients will improve [with ranibizumab]. Not stopping the disease, but actually reversing the disease,” he said.11

Dr. Elman also argued that perhaps it is time to consider an earlier treatment of DR with the anti-VEGF.11 Nearly 40 years ago, the Diabetic Retinopathy Study (DRS) has demonstrated the benefits of panretinal photocoagulation (PRP) for treating PDR.12 However, ophthalmologists would have to weigh the risk and benefits of using PRP for NPDR cases. “Why? Because they were concerned about the side effects of PRP… but we don’t have those side effects with intravitreal ranibizumab,” Dr. Elman said.11 At the very least, he suggested that the findings from the post-hoc analysis of RIDE and RISE would make a compelling case of treating one eye with the anti-VEGF.9

Evolving treatment paradigm for DR

It is important, again, to note that the retrospective, post-hoc nature of analysis (RIDE and RISE) requires the findings to be interpreted carefully. Only time will tell whether similar and consistent benefits are going to be seen in PANORAMA with a longer follow-up. A thorough investigation remains crucial to determine the optimal use of anti-VEGF in the early treatment of DR.



  1. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology. 1981;88(7):583–600.
  2. 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.
  3. Wykoff CC. Intravitreal aflibercept for moderately severe to severe nonproliferative diabetic retinopathy (NPDR): The phase III PANORAMA Study. American Society of Retina Specialists (ASRS) 2018 Annual Meeting. July 20-25, 2018; Vancouver, Canada.
  4. Elman MJ. To treat or not to treat: Are we sacrificing treatment outcomes by allowing diabetic retinopathy (DR) to enter the proliferative stage? American Society of Retina Specialists (ASRS) 2018 Annual Meeting. July 20-25, 2018; Vancouver, Canada.
  5. Yam JC, Kwok AK. Update on the treatment of diabetic retinopathy. Hong Kong Med J. 2007;13(1):46-60.
  6. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015;2:17.
  7. VIDEO: Eylea improves nonproliferative diabetic retinopathy in phase 3 study. Healio. 2018 (Accessed August 13, 2018, at
  8. EYLEA (aflibercept) Injection Demonstrates Positive Topline Results in Phase 3 Non-Proliferative Diabetic Retinopathy Trial. PR Newswire. 2018 (Accessed August 21, 2018, at
  9. Benefits with Early Treatment of Diabetic Retinopathy. Medpagetoday. 2018 (Accessed August 21, 2018, at
  10. Wykoff CC, Eichenbaum DA, Roth DB, et al. Ranibizumab Induces Regression of Diabetic Retinopathy in Most Patients at High Risk of Progression to Proliferative Diabetic Retinopathy. Opthalmol Ret. 2018 [Epub ahead of print].
  11. VIDEO: Seeking the ‘sweet spot’ for treating diabetic retinopathy. Healio. 2018 (Accessed August 13, 2018, at
  12. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology. 1981;88(7):583–600.


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