The Aspen Retinal Detachment Society (ARDS) meeting in Snowmass, Colorado, is always a haven of learning—a place where clinicians come together to discuss new data, therapeutics, and surgical approaches. During the 2023 meeting, held March 4-8, Charles C. Wykoff, MD, PhD; Susan B. Bressler, MD; and Zofia A. Nawrocka, MD, PhD, shared recent findings that have shifted the way we treat patients with diabetic retinopathy (DR) and diabetic macular edema (DME). Here, you can find a summary of their excellent lectures (Figure).
ARDS 2024 is just a few weeks away, set for March 2-6. Visit aspenretina.com to register, find lodging, and prep for another year of top-notch education!
- Timothy G. Murray, MD, MBA
ABOUT THE SPEAKERS
Charles C. Wykoff, MD, PhD
- Director of Research, Retina Consultants of Texas/Retina Consultants of America, Houston; Deputy Chair for Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston
- Editorial Advisory Board Member, Retina Today
Susan B. Bressler, MD
- Julia G. Levy, PhD, Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore
Zofia A. Nawrocka, MD, PhD
- Vitreoretinal Specialist, Ophthalmic Clinic, “Jasne Blonia,” Lodz, Poland
RETINAL NONPERFUSION IN DR
Dr. Wykoff began his lecture by outlining the evidence for retinal nonperfusion as a biomarker of DR progression. First, a RISE and RIDE post-hoc analysis showed that, over 3 years, the risk of progression to proliferative DR (PDR) was substantially lower in patients treated with monthly ranibizumab (Lucentis, Genentech/Roche) compared with sham.1 However, despite monthly injections, close to one in five patients still developed PDR. The only baseline factor that helped to predict progression was retinal nonperfusion. Second, the DRCR Protocol AA trial showed that greater baseline nonperfusion on fluorescein angiography was associated with a higher risk of disease worsening.2 Finally, a post-hoc analysis of the PANORAMA study found that retinal nonperfusion once again played a critical role in progression.3
The phase 2 RECOVERY trial studied nonperfusion changes in patients with PDR without DME, Dr. Wykoff said. Patients were treated with aflibercept (Eylea, Regeneron) either monthly or every 3 months, and the 1-year results showed relatively stable nonperfusion with monthly dosing and a 29% worsening with the extended dosing schedule.4
Dr. Wykoff then discussed reports of retinal reperfusion in the literature.5-7 In the RISE, RIDE, and VISTA studies, there was a steady increase of nonperfusion over time in eyes in the sham arm. In the group that received anti-VEGF therapy, the increase in nonperfusion appeared to be blunted.8,9
Dr. Wykoff explained that the best evidence we have of reperfusion is the concept of a leukostatic plug. According to the concept, in any hypoxic state, there is an upregulation of VEGF and other cytokines. A downstream effect is the upregulation of the ICAM-1 molecule, a receptor that endothelial cells express to attract white blood cells. White blood cell clumping can then block the blood vessel. Through VEGF inhibition, downstream expression of these molecules is modified, causing a reversal of the breakdown of this plug and improving flow.
Dr. Wykoff concluded his talk with a brief look at therapies in the pipeline working to address retinal reperfusion.
Figure. During ARDS 2023, Drs. Wykoff (left), Bressler (middle), and Nawrocka (right) share the latest data and treatment approaches for DME. Images courtesy of Kevin Caldwell Photography.
DME MANAGEMENT: STEP THERAPY
Dr. Bressler provided an update on first-line therapy for patients with DME. In DRCR Protocol T, aflibercept, bevacizumab (Avastin, Genentech/Roche), and ranibizumab were all effective in achieving visual improvement through 2 years in patients with center-involving DME (CI-DME).10 However, a subgroup analysis found that, at 1 year, aflibercept showed superiority for patients with a VA of 20/50 or worse and remained superior to bevacizumab but was statistically similar to ranibizumab at 2 years, Dr. Bressler explained.11 An area-under-the-curve analysis found that aflibercept remained superior to ranibizumab for patients with a presenting VA of 20/50 or worse. It’s reasonable to consider aflibercept as the first-line therapy for patients with CI-DME and a VA of 20/50 or worse, she said.
She then moved on to discuss Protocol AC, in which patients with CI-DME with a VA of 20/50 or worse were randomly assigned to either aflibercept monotherapy or bevacizumab and switched if necessary.12 Within 2 years, 70% of patients who started with bevacizumab had switched to aflibercept, Dr. Bressler noted. Although the net number of injections was similar between the two groups over 2 years, there is a cost savings when starting with bevacizumab, she said, adding that step therapy did not compromise long-term visual outcomes when using the Protocol AC criteria.
She then discussed Protocol V, in which patients with CI-DME with a VA of 20/25 or better were randomly assigned to either anti-VEGF treatment, focal grid laser, or observation until vision loss occurred. Regardless of the strategy, 15% to 19% lost 1 or more lines of vision, Dr. Bressler explained. Within each treatment arm, about half of patients who lost vision lost between 5 and 9 letters. There was no difference between the treatment strategies, she emphasized. At the end of 2 years, 85% maintained a VA of 20/25 or better, regardless of treatment approach.
CHECK OUT OUR VIDEO COVERAGE OF ARDS 2023
VITRECTOMY FOR DME
Finally, Dr. Nawrocka discussed vitrectomy as a treatment option for patients with DME. She highlighted her study in which 44 eyes with treatment-naïve DME underwent vitrectomy and experienced an improvement in DME and visual acuity.13
She then discussed another study that reported that a subretinal injection of balanced salt solution (BSS) in DME led to a decrease in osmotic pressure and the viscosity of subretinal fluid.14 This can promote water transport from the subretinal space into the choroid and wash out cytokines and migratory cells. To further test this hypothesis, Nawrocki et al designed a study in which each patient’s better-seeing eye (n = 14) was treated with aflibercept and the worse-seeing eye underwent vitrectomy with ILM peeling and a subretinal injection of BSS. The team found that the central subfield thickness decreased similarly in each group, Dr. Nawrocka explained. The delta in visual acuity was similar in each group. A mean of 3 injections were performed over the course of 6 years in half of the vitrectomized eyes, suggesting that these eyes responded well to anti-VGEF treatment, Dr. Nawrocka added.
She concluded by emphasizing that the rate of visual acuity improvement is similar in eyes treated with anti-VEGF injection and those treated with vitrectomy. Performing vitrectomy decreases the possible number of required future anti-VEGF injections, may reduce the density of the superficial foveal avascular zone, and may have a protective effect on future DR complications.
1. Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015;122(2):367-374.
2. Silva PS, Marcus DM, Liu D, et al. Association of ultra-widefield fluorescein angiography–identified retinal nonperfusion and the risk of diabetic retinopathy worsening over time. JAMA Ophthalmol. 2022;140(10):936-945.
3. Brown DM, Wykoff CC, Boyer D, et al. Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathy: results from the PANORAMA randomized clinical trial. JAMA Ophthalmol. 2021;139(9):946-955.
4. Wykoff CC, Nittala MG, Zhou B, et al. Intravitreal aflibercept for retinal nonperfusion in proliferative diabetic retinopathy: outcomes from the randomized RECOVERY Trial. Ophthalmol Retina. 2019;3(12):1076-1086.
5. Chan GH. Natural history of diabetic retinopathy. Lancet. 1968;2(7564):391-393.
6. Levin AM, Rusu I, Orlin A, et al. Retinal reperfusion in diabetic retinopathy following treatment with anti-VEGF intravitreal injections. Clin Ophthalmol. 2017;11:193-200.
7. Sorour OA, Mehta N, Baumal CR, et al. Morphological changes in intraretinal microvascular abnormalities after anti-VEGF therapy visualized on optical coherence tomography angiography. Eye Vis (Lond). 2020;7:29.
8. Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014;121(9):1783-1789.
9. Wykoff CC, Shah C, Dhoot D, et al. Longitudinal retinal perfusion status in eyes with diabetic macular edema receiving intravitreal aflibercept or laser in VISTA study. Ophthalmology. 2019;126(8):1171-1180.
10. 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(13):1193-1203.
11. 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.
12. Jhaveri CD, Glassman AR, Ferris FL 3rd, et al. Aflibercept monotherapy or bevacizumab first for diabetic macular edema. N Engl J Med. 2022;387(8):692-703.
13. Michalewska Z, Stewart MW, Landers MB 3rd, Bednarski M, Adelman RA, Nawrocki J. Vitrectomy in the management of diabetic macular edema in treatment-naïve patients. Can J Ophthalmol. 2018;53(4):402-407.
14. Morizane Y, Kimura S, Hosokawa M, et al. Planned foveal detachment technique for the resolution of diffuse diabetic macular edema. Jpn J Ophthalmol. 2015;59(5):279-287.
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