Advances in the Management of Diabetic Retinopathy

Educational Objectives

The goal of this program is to improve outcomes of patients with diabetic retinopathy. After hearing and assimilating this program, the clinician will be better able to:

1. Devise a treatment plan for a patient with diabetic macular edema.

2. Apply the findings of clinical trials to the treatment of a patient with proliferative diabetic retinopathy.

3. Assess the risks and benefits of treatment with steroids in patients with different forms of diabetic retinopathy.

Summary

Diabetes: affects >30 million Americans; after 20 yr, almost all patients with type 1 diabetes, and ≈60% with type 2, have some diabetic retinopathy (DR); leading cause of vision loss in working-age adults; severity depends on disease duration, patient age, control of blood glucose and blood pressure (BP), and serum lipid levels; among patients with high-risk proliferative DR (PDR) or clinically significant diabetic macular edema (DME), 33% have not seen ophthalmologist in preceding 2 yr

DR as microvascular disease: damages blood vessels, causing leaks and ischemia; release of neovascular stimuli contributes to leaks and causes neovascularization (NV); vascular endothelium and pericytes damaged; cytokines released, including vascular endothelial growth factor (VEGF); inflammation contributes to DR (macrophages present in ocular tissue)

DCCT trial: researched benefit of intensive control of blood glucose; reducing glycated hemoglobin (HbA1c) important; rapidly lowering HbA1c can worsen existing DR; if patient has minimal background DR and no leaking microaneurysms near fovea, rapid decrease in HbA1c of little concern; patients with severe nonproliferative DR (NPDR) need close follow-up as blood glucose brought under control

UKPDS trial: lowering HbA1c by 1 point reduces need for laser therapy by ≈30%, independent of baseline HbA1c; trial highlighted importance of BP control; need for laser treatments decreased by 33% in patients with “tight” BP control (ie, 150/85 mm Hg); normalization of BP associated with ≈3-line gain in vision acuity (VA); American Diabetes Association recommends HbA1c <7% and BP of ≈130/80 mm Hg; daily exercise and dietary management also critical

Diabetic Retinopathy Clinical Research (DRCR) Network Protocol M: patients received usual care or intense personalized diabetes education; risk for blindness from untreated DR stressed; intervention produced no significant reduction in HbA1c; suggests that discussing glucose control not helpful (but still recommended)

Focal laser photocoagulation: in ETDRS, use of focal laser slowed vision loss; may help patients with hard exudates and thickening (if partially within 500 m of fovea); may also help patients with ring of exudate not involving fovea and few leaky microaneurysms; may benefit patients with leakage in ≥1 disc area near fovea; complications — damage to fovea; scotoma; growth of initially small laser burn, with increased encroachment into fovea; breakage of Bruch membrane, causing formation of choroidal neovascular membrane

Intravitreal triamcinolone for DME: unlike focal laser therapy, injections of triamcinolone (eg, Kenalog, Triesence, Trivaris) improved VA; in 6 wk, improvement seen in optical coherence tomography (OCT) images and VA; Protocol B — compared 2 doses of triamcinolone vs focal laser; at 4 mo, higher dose of triamcinolone (4 mg) most beneficial; benefit decreased over time because of cataract formation; by yr 3, VA similar to baseline; similar outcome seen with low dose, with fewer cataracts; after focal laser, VA stable or slightly improved; more cataracts seen with low-dose triamcinolone than with focal laser; by yr 3, ≈100% of patients in 4-mg group had cataracts, and many had increased intraocular pressure (IOP)

DRCR Protocol I: compared focal laser vs triamcinolone vs anti-VEGF agent ranibizumab (Lucentis); included 2 ranibizumab subgroups (one that started with ranibizumab, then added focal laser after 6 mo, if needed; in other group, ranibizumab and laser given upfront); improvement seen within 2 to 3 mo with ranibizumab; at yr 2, those treated with ranibizumab had 10-letter gain in VA; 2 to 3 letters gained by patients treated with triamcinolone or laser; in pseudophakic patients, outcomes similar for ranibizumab and triamcinolone; ranibizumab with deferred laser superior to ranibizumab plus laser upfront; anti-VEGF monotherapy now standard of care; for patients with center-involving DME, upfront laser not helpful (possibly harmful)

Protocol T: compared aflibercept (Eylea), bevacizumab, and ranibizumab; baseline VAs 20/32 to 20/320; VA in clinic poorer than in clinical trial, where optimally refracted (eg, 20/32-20/40 vs 20/50-20/60); generally, good outcomes seen with all 3 drugs; for patients with VA of ≤20/50 in trial (20/60-20/70 in clinic), bevacizumab least effective, ranibizumab intermediate, and aflibercept most effective; at 2 yr, difference between ranibizumab and aflibercept narrowed; bevacizumab most cost-effective and produced 2.5 lines of improvement at yr 2; aflibercept produced 1 additional line of improvement but most expensive; cost of ranibizumab intermediate, and VAs approximately same as those with aflibercept; bevacizumab often chosen for patients with relatively good VA, and aflibercept if VA poorer

Duration of treatments: in yr 1, many injections (≈8) needed; by yr 2, most patients only need ≈2 injections (some patients need more, but <8); by yr 3, usually one injection; by yr 4 and 5, most require no injections; injections seem to have benefits beyond treating DME; example — patient with DME and high-risk PDR; received ranibizumab 1 time/mo for 2 yr; after 2 yr, intraretinal hemorrhages cleared, along with DME and vitreous hemorrhage (VH); initially graded as high-risk PDR, or DR Severity Scale (DRSS) score of 71; after 2 yr, NPDR rated as mild (DRSS score of 35); in patients with moderate or severe NPDR, or PDR, ranibizumab best for slowing worsening of DR, compared with laser or triamcinolone

Panorama trial: patients with moderate to severe NPDR or PDR given 3 or 6 aflibercept injections per year; among controls, ≈15% showed 2-step improvement in DRSS score; 2-step improvement seen in 65% of patients with 3 injections per year and 80% of those with 6 per year; rate of vision-threatening events (DME or high-risk PDR) ≈40%/yr in controls; with injections, risk 10%; shows that aflibercept treats underlying DR, as well as DME and NV; advisability of giving injections every 3 mo to all patients with moderate or severe NPDR (even if HbA1c <7%) undetermined

Protocol V: many patients with DME have good VA (eg, 20/20-20/30 in clinic), so trial needed to determine how best to treat them; patients randomized to aflibercept (initially given monthly, then as needed) vs focal laser vs observation; patients in latter groups treated with aflibercept if VA decreased ≥2 lines; at 2 yr, VA of 20/20 maintained in most patients, independent of group; observation likely safe for patients with central DME but good VA; treatment can be given if VA eventually declines

Steroids: cause cataracts and elevated IOP; fluocinolone intravitreal implant beneficial in patients with severe chronic DME; steroids may reduce frequency of anti-VEGF injections in patients with moderate DME; in Protocol U, dexamethasone implant improved appearance on OCT but not VA; most clinicians start with anti-VEGF, and may then add steroids in patients with poor vision or substantial DME

Panretinal photocoagulation (PRP): original goal treatment of entire peripheral fundus; effects of PRP — decrease in growth factors; thinning of ischemic retina, which may promote greater diffusion of oxygen in choroid into vitreous; irritating or damaging retinal pigment epithelium (RPE), which may improve its function upon regrowth; eliminating dying retinal cells may halt release of growth factors; abolishes existing NV, prevents new NV, and reduces VH; risk for severe vision loss reduced by 50%; complications — some discomfort; decrease in peripheral or night vision; worsening of DME; NV occurs at junction of perfused and nonperfused retina; PRP usually started outside arcade and moved far outward; low-cost and long-lasting treatment

Protocol S: PRP vs ranibizumab in patients with any grade of PDR; in ranibizumab group, patients without DME received ≈10 injections within 2 yr; those with DME received ≈14; in PRP group, ≈50% of patients needed second PRP treatment; visual outcome slightly better in ranibizumab group; DME more common in PRP group than in ranibizumab group (28% vs 9%); fewer vitrectomies needed with ranibizumab than with PRP (4% vs 15%); at 2 yr, visual fields (VFs) nearly unchanged in ranibizumab group but much worse in PRP group; yr 5 — findings less clear, but VAs still ≈20/25 in both groups; ≈20 injections per patient in ranibizumab group, vs 5 per patient with PRP; no need for ongoing treatment in ≈40% of patients; VFs no longer significantly better in ranibizumab group, but fewer vitrectomies needed; conclusion — no definitive advantage for PRP or anti-VEGF in patients with PDR

“Ultra-responsive” patients in Protocol S: example — after 1 yr (7 injections), patients improved from high-risk PDR to mild NPDR (6 steps on DRSS); in yr 2, 4 injections given and response maintained; of patients treated with ranibizumab, ≈50% had 2-step improvement; data reviewed to determine how many eyes ultra-responsive (4 steps better); grade ≥71 is high-risk PDR; data from patients with grades of ≈60 included; ≈30% of patients 4 steps better at 1 and 2 yr; VH and well-controlled HbA1c only background factors predictive of 4-step gain; same numbers of injections (≈7 in yr 1, and ≈4 in yr 2) given to ultra-responders and others; no rescue treatment required for ultra-responders

Continuing role for PRP: failure of patients to return for anti-VEGF treatment problematic; in Protocol S, ≈33% of patients did not return; post hoc study — 30 eyes included from patients in anti-VEGF group who had ≈6 injections, then lapsed for ≈1 yr; upon patients’ return, vitrectomy needed for tractional retinal detachment in ≈20% of eyes; no such vitrectomies needed in PRP group for patients who lapsed (≈15 mo); conclusion — among patients lost to follow-up, outcomes poorer if treated with anti-VEGF group than with PRP; because predicting who will lapse not possible, merits of PRP vs anti-VEGF vs combination therapy should be considered

Take-home points: good treatments exist for PDR; anti-VEGF monotherapy recommended for patients with PDR and DME; excellent response to anti-VEGF alone possible but not predictable; sustained anti-VEGF delivery may be best but so far unproven; perform PRP if patient at risk for not returning, particularly if patient has already lapsed

Surgery: useful for vitreal hemorrhage or retinal detachment; aim is to relieve traction, cauterize NV, and apply PRP; removing layer of vitreous from retinal surface critical; vitrectomy helps slow course of DR and maintain VA

Micropulse laser: does not cause visible burns; uses rapid “not-hot” burns to stimulate RPE; safe to apply over fovea; more data needed to identify appropriate candidates; may benefit patients with central serous retinopathy

Readings

Aiello LP et al: assessing the effect of personalized diabetes risk assessments during ophthalmologic visits on glycemic control: a randomized clinical trial. JAMA Ophthalmol 2015 Aug;133(8):888-96; Baker CW et al: Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA 2019 May 21;321(19):1880-94; Bressler SB et al: Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. Am J Ophthalmol 2016 Apr;164:57-68; Brown DM et al: Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013 Oct;120(10):2013-22; Diabetic Retinopathy Clinical Research Network (DRCR.net) et al: Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009 Mar;127(3):245-51; Elman MJ et al: Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology 2015 Feb;122(2):375-81; Gross JG et al: Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA Ophthalmol 2018 Oct 1;136(10):1138-48; Keen H: The Diabetes Control and Complications Trial (DCCT). Health Trends 1994;26(2):41-3; Matthews DR et al: Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol 2004 Nov;122(11):1631-40; Obeid A 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 Mar;126(3):407-13; Scott IU et al: Effect of focal/grid photocoagulation on visual acuity and retinal thickening in eyes with non-center-involved diabetic macular edema. Retina 2009 May;29(5):613-7; Sivaprasad S 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 Jun 3;389(10085):2193-2203; Vujosevic S et al: Subthreshold laser therapy for diabetic macular edema: metabolic and safety issues. Curr Med Chem 2013;20(26):3267-71; Wells JA et al: Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 2016 Jun;123(6):1351-9.

Disclosures

For this program, the following has been disclosed: Dr. Garg receives research support from Genentech. The planning committee reported nothing to disclose. In his lecture, Dr. Garg presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Garg spoke at the 18th Annual Downeast Ophthalmology Symposium, held September 20-22, 2019, in Bar Harbor, ME, and presented by the Maine Society of Eye Physicians and Surgeons. For information on upcoming CME activities from this sponsor, please visit maineeyemds.com. The Audio Digest Foundation thanks the speakers and sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

OP580301

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.