Advances In The Treatment Of Diabetic Retinopathy
Advances in the Treatment ofDiabetic Retinopathy:Paradigm shifts in patient careand educationJuly 21, 2016
PresentersNeyal J. Ammary-Risch,M.P.H., MCHESDirector,National Eye HealthEducation Program (NEHEP),National Eye Institute (NEI)2Emily Y. Chew, M.D.Judy E. Kim, M.D.Deputy Director,Division of Epidemiologyand Clinical Applications,NEIProfessor of Ophthalmology,Medical College of Wisconsin,Vice-Chair, DRCR.net,Member, NEHEP PlanningCommittee
What is the National Eye Health Education Program(NEHEP)? NEHEP was established by theNational Eye Institute (NEI) of theNational Institutes of Health (NIH) toserve as an extension of activities invision research so science-basedinformation can be applied topreserving sight and preventingblindness. Goal: To ensure that vision is a publichealth priority through the translation ofeye and vision research into public andprofessional education programs.3
What is the Diabetic Retinopathy Clinical ResearchNetwork (DRCR.net)? Is a collaborative network dedicated to facilitating multicenterclinical research of diabetic retinopathy, diabetic macular edema,and associated conditions. Supports the identification, design, and implementation ofmulticenter clinical research initiatives focused on diabetesinduced retinal disorders. Emphasizes clinical trials; however, epidemiologic outcomes andother research may be supported as well.4
Diabetes in the United States 29.1 million Americans havediabetes—9.3 percent of the U.S.population. Of these, 8.1 million do not knowthat they have the disease. An estimated 86 million adultshave prediabetes. One out of four people withprediabetes do not know theyhave it. Diabetes is the 7th leading causeof death in the United States.5Source: CDC National Diabetes Statistics Report, 2014.
Diabetic RetinopathyDamage to the blood vessels in the retinadue to diabetes.6
Diabetic Retinopathy Prevalence and 0011,300,00014,600,000* Includes adults age 40 and older in the United States with diabetic retinopathy.7Source: https://nei.nih.gov/eyedata/diabetic
Projections for Diabetic Retinopathy by Ethnic Groupin 2030 and 2050 (in millions)8Source: https://nei.nih.gov/eyedata/diabetic
Emily Y. Chew, M.D.AN OVERVIEW OF DIABETICRETINOPATHY9
Early Treatment of Diabetic Retinopathy Study (ETDRS)Classification of Diabetic Retinopathy10
Diabetic RetinopathyFive pathologic processes: Formation of microaneurysms (outpouchings of the small vessels) Excessive vascular permeability (leakage) Vascular occlusions (closure of blood vessels) Proliferation of new vessels ( hemorrhage) Contraction of new blood vessels: Scarring, retinal detachment11
Classification of Diabetic RetinopathyNonproliferative: No apparent retinopathy (no abnormalities) Mild nonproliferative: Microaneurysms only Moderate nonproliferative: More than just microaneurysms but lessthan severe nonproliferative diabetic retinopathy (NPDR) Severe nonproliferative (the stage before new vessels develop,so-called proliferative diabetic retinopathy)12
Microaneurysm Formation Earliest clinical sign ofretinopathy Minimal impact onvision at this stageMicroaneurysm13
Excessive Vascular Permeability(leakage from blood vessels)Macular Edema (swelling of the center of the retina) With increasing number of microaneurysms Signs: Hard exudates Mainly lipids Yellow lesions Accompanies retinalHard exudatesedema or swellingDecreased vision: 20/6014
Excessive Vascular Permeability(leakage from blood vessels)Fluorescein Angiography (injection of dye)Center (macula)Normal15Macular edema
Vascular Occlusions (blockage of vessels)Representing Increasing Lack of OxygenVenous beadingHemorrhageAbnormal vessels (IRMA)Increasing hemorrhages16Venous abnormalities andabnormal vessels
Proliferation of New VesselsProliferative diabetic retinopathy (PDR): Early High-risk AdvancedNew vessels on the diskHemorrhageHigh-risk PDR17
Proliferation of New VesselsNew vesselsNew vessels inthe area of laserNeovascularization Elsewhere (NVE)18
Proliferation of New Vessels19New vessels on the discScar TissueAdvanced proliferativediabetic retinopathyContraction of scar tissue withnew vessels
Overview of Diabetic Retinopathy 20Clinical ClassificationGlobal Burden of Diabetic RetinopathyClinical Trials Prior to DRCR.netMedical Therapies
Global Burden of Diabetic Retinopathy (DR)35 studies 22,896 patientsAmong those with diabetes: 34.6% with any DR (93M)6.95% with proliferative DR (17M)6.81% with diabetic macular edema10.2% with vision-threatening DR (28M)21Source: Diabetes Care, March 2012. 35(3): 556–564.
Global Burden of Diabetic Retinopathy35 studies 22,896 patientsAmong those with diabetes, increased risk of diabetic retinopathy: Longer duration of diabetes Poorer glycemic control Poorer blood pressure control Poorer control of blood cholesterol levels22Source: Diabetes Care, March 2012. 35(3): 556–564.
Diabetic RetinopathyNational Institutes of Health-supported Clinical RSeverePDRDCCT / UKPDSETDRSDRSACCORD23NPDR: Nonproliferative diabetic retinopathyPDR: Proliferative diabetic retinopathyDRVS
Treatments for Diabetic RetinopathyStandard therapies: Laser photocoagulation Surgical intervention (vitrectomy) Medical therapies delivered into the eye (intravitreal injections) Systemic medical therapies involving blood sugar, blood pressure,and cholesterol control24
Rates of Severe Vision Loss (SVL)* inDiabetic Retinopathy Study (DRS 1971–1976)Laser reduced the rateof SVL by 50% (twotypes of lasers: Argonand Xenon).Event Rate (%)4030ControlEyes20Argon TreatedArgonTreated10Xenon Treated00123YearsLaser burns*SVL: 5/200 on two visits 4 months apart254
Laser Photocoagulation forProliferative Diabetic RetinopathyImmediately after laser26Images courtesy of Dr. Harry Flynn1 year later
Success of Laser Treatment for Diabetic Retinopathy(risk of SVL* reduced by 95%)Event Rate %5040DRSUntreated Eye302010ETDRS EyesETDRS Patient0027* SVL: 5/200 on two visits 4 months apart24Years6810
Focal Laser Photocoagulation in theEarly Treatment Diabetic Retinopathy Study(ETDRS 1980–1989)Focal laser photocoagulationreduced the risk of moderatevision loss (going from 20/20to 20/40) in eyes withmacular edema by 50%.4030Control Eyes20Focal Argon10Argon Treated012YearsFocal laserStandard care until the onset of anti-VEGF* therapies28* VEGF: Vascular endothelial growth factor3
Focal Laser Photocoagulation forDiabetic Macular EdemaLaser burnHard exudatePrior to laserImmediately after laserStandard care until the onsetof anti-VEGF* therapies4 months after laser29* VEGF: Vascular endothelial growth factor
Surgical Intervention:Pars Plana Vitrectomy30
Vitrectomy for Vitreous Hemorrhage and TractionAssociated with Proliferative Diabetic RetinopathyTraction from scarringHemorrhageBefore surgery (vitrectomy)31Images courtesy of Dr. Harry FlynnAfter surgery (vitrectomy)
Vitrectomy for Vitreous Hemorrhage Associated withProliferative Diabetic RetinopathyHemorrhageBefore surgery (vitrectomy)32Images courtesy of Dr. Harry FlynnAfter surgery (vitrectomy)
Vitrectomy for Severe Scarring of ProliferativeDiabetic RetinopathyScarring from proliferativediabetic retinopathyBefore surgery (vitrectomy)33Images courtesy of Dr. Harry FlynnAfter surgery (vitrectomy)
Medical Management RecommendationsIntensive medical control: Blood glucose Blood pressure Blood lipids34
Diabetes Control and Complications Trial (DCCT 1983–1989) in Type 1 Diabetes Study of Glycemic ControlDCCT PatientsN 1,441SubgroupPrimary Prevention(no retinopathy at baseline)Secondary Intervention(has retinopathy at ic ControlN 34835ConventionalGlycemic ControlN 378IntensiveGlycemic ControlN 363ConventionalGlycemic ControlN 352
DCCT Study Design Study QuestionPrimary Prevention Will intensive insulin therapy prevent the development andsubsequent progression of retinopathy?Secondary Prevention Will intensive insulin therapy prevent the progressionof retinopathy?36
Diabetes Control and Complications TrialHemoglobin A1C (a measure of glucose rs34
DCCT Results Primary Intervention – (no retinopathy)Development and Three-Step Progression of DiabeticRetinopathy Along the ETDRS Severity ScalePercentage with 810
DCCT Results Secondary Intervention – (has retinopathy)Three-Step Progression of Diabetic Retinopathy Along theETDRS Severity ScalePercentage with 810
DCCT Summary (for Type 1 diabetes)Results of intensive therapy: Reduction in retinopathy Clinically important retinopathy (34%–76%) Photocoagulation (34%) First appearance of retinopathy (27%)40
DCCT SummaryResults of intensive therapy: Reduction in other 2o complications: Kidney function‒ Microalbuminuria (35%)‒ Clinical albuminuria (45%) Neuropathy‒ Clinical neuropathy (60%)41
EDIC/DCCT StudyEpidemiology of Diabetes Intervention & Complications Study Extension of the DCCT study after the clinical trial was finished Natural history study of DCCT patients Beneficial effects persist for an additional 4–25 years42
UK Prospective Diabetes Study(Type 2 diabetes 1977–1994; N 3,867)Summary: Glycemic and Blood Pressure ControlIntensive Glycemic Control Reduced microvascular complications by 12% Reduced progression of retinopathy by 25%Intensive Blood Pressure Control (140 vs. 180 mmHg) Reduced microvascular complications by 37% Reduced progression of retinopathy by 34% Reduced moderate vision loss by 47%43Source: Lancet, 2007. 17; 370: 1687–1697.
Legacy Effect (metabolic memory) in UKPDS 10 YearsAfter the UKPDS Clinical Trial StoppedType 2Diabetes*IntensiveGlycemicControlUKPDS(UK Prospective Diabetes Study)Outcome: Self-reports of vitreous hemorrhageretinal photocoagulation, or renal failureContinued to be reduced significantly by 24% in thosepreviously assigned to tight glycemic control vs. standardglycemic control* Newly diagnosed (within the past year)44Source: New England Journal of Medicine, 2008. 359: 1577–1589.
Actions to Control Cardiovascular Risk in Diabetes(ACCORD) Eye Study (Type 2 diabetes 2003–2009)Three medical therapies (n 10,251): Intensive glycemic control A1C 6% vs. 7.0%–7.9% Treatment to increase high-density lipoprotein cholesteroland lower triglycerides using Fenofibrate 200 mg plus statinvs. placebo statin Intensive blood pressure control SBP 120 mmHg vs. SBP 140 mmHg45
ACCORD Median A1C and Interquartile Ranges46The mean difference during the trial was 1.1%.
ACCORD Eye Study Design (n 2,856)Baseline and Year 4 comprehensive eye exams: Visual acuity measurements Fundus photography of seven standard stereoscopic fields Central grading of the fundus photographsusing the Early Treatment DiabeticRetinopathy Study (ETDRS) classificationof diabetic retinopathyF147Source: American Journal of Cardiology, 2007. 99(12A): 103i-111i.F2
Primary Analysis – DR ProgressionEffectOdds Ratio95% CIP-valueGlycemia0.67(0.51, 0.87)0.0025Lipid(Fenofibrate)0.60(0.42, 0.87)0.0056BloodPressure1.23(0.84, 1.79)0.29Odds ratio 1 (and 95% CI not including 1) means that the treatment was beneficial.48Source: New England Journal of Medicine, 2010. 363(3): 233-244.
ACCORD Eye Study Conclusions Intensive glycemic control and combination of Fenofibrate andSimvastatin reduced the proportion whose retinopathy progressedby about one-third. No effect on visual acuity. No statistically significant effect of intensive blood pressure control.49
ACCORDION Eye Study RetinopathyThree-Step Progression of Diabetic Retinopathy at 8YearsEffectOdds Ratio95% CIP-valueGlycemia0.42(0.28, 0.63) 0.0001Lipid1.13(0.71, 1.79)0.60BP1.21(0.61, 2.40)0.59Odds ratio 1 (and 95% CI not including 1) means that the treatment was beneficial.50
ACCORDION Eye Study Conclusions Intensive glycemic control continued to demonstrate beneficialeffects 4 years following cessation of the randomized trial. Effects were consistent across subgroups. Fenofibrate and Simvastatin showed no beneficial effect afterstopping Fenofibrate. No statistically significant effect of intensive blood pressurecontrol.51
Summary We have highly effective therapies from evidence-based studies. The medical therapies are very powerful and durable. The treatments using the standard laser have reduced the risk ofsevere vision loss. Laser treatment remains an important part of therapy.52Source: Lancet, 2007. 17; 370: 1687–1697.
Judy E. Kim, M.D.MANAGEMENT OF DIABETIC MACULAR EDEMA ANDPROLIFERATIVE DIABETIC RETINOPATHY:Findings from DRCR.net Trials and Paradigm Shift53
Objectives Review findings from DRCR.net clinical trials for diabetic macularedema and proliferative diabetic retinopathy: Protocol I Protocol T Protocol S Discuss paradigm change in management ofdiabetic retinopathy.54
Laser Photocoagulation Diabetic Retinopathy Study for PDR(1971–1976) Early Treatment Diabetic RetinopathyStudy for Diabetic Macular Edema(DME) (1980–1989)55
Optical Coherence Tomography (OCT)OCT image showing macular edema withfluid in the retina and under the retina56
Vascular Endothelial Growth Factor (VEGF) Elevated in active PDR Overexpression is associated with DME A central mediator of angiogenesis andvascular permeability A target for therapy57
Anti-VEGF izumab(Lucentis)VEGF58* Use of Avastin in the eye is off-label.
Laser Photocoagulation59
Intravitreal Injection of Anti-VEGF Agents60
Diabetic Retinopathy Clinical Research Network(DRCR.net) A collaborative network to facilitate multicenter clinical researchon diabetic retinopathy, diabetic macular edema, and associatedconditions61
DRCR.net Protocol IIntravitreal Ranibizumab or Triamcinolone Acetonide in Combinationwith Laser Photocoagulation for DMESham Prompt Laser62Ranibizumab(Lucentis)0.5 mg Prompt LaserRanibizumab(Lucentis)0.5 mg Deferred LaserTriamcinolone4 mg Prompt Laser
Protocol I63ObjectiveTo evaluate the safety and efficacy of intravitreal anti-VEGFtreatment in combination with immediate or deferredfocal/grid laser photocoagulation and intravitrealcorticosteroids in combination with focal/grid laser comparedwith focal/grid laser alone in eyes with center-involved DME.MajorEligibilityCriteriaDiabetic macular edema involving the center of the macula(optical coherence tomography central subfield thickness 250microns) responsible for visual acuity of 20/32 or worse.ProtocolStatusTotal enrolled (3/07–12/08): 691 subjects/854 eyes at 52sites
Change in Visual Acuity from Baseline (letter score)Mean Change in Visual Acuity (VA) at Follow-up VisitsSham Prompt LaserRanibizumab Prompt LaserRanibizumab Deferred LaserTriamcinolone Prompt Laser1110987N 626 (52 weeks)N 600 (68 weeks)N 600 (84 weeks)N 628 (104 weeks)65432100 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104Visit WeekP-values for difference in mean change in VA from sham prompt laser at the 104-week visit: Ranibizumab promptlaser 0.03; Ranibizumab deferred laser 0.001; and triamcinolone prompt laser 0.35.64
Change in Visual Acuity from Baseline (letter score)Mean Change in Visual Acuity (VA) at Follow-up VisitsSham Prompt LaserRanibizumab Prompt LaserRanibizumab Deferred LaserTriamcinolone Prompt Laser1110987N 626 (52 weeks)N 600 (68 weeks)N 600 (84 weeks)N 628 (104 weeks)65432100 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104Visit WeekP-values for difference in mean change in VA from sham prompt laser at the 104-week visit: Ranibizumab promptlaser 0.03; Ranibizumab deferred laser 0.001; and triamcinolone prompt laser 0.35.65
Mean Change in Visual Acuity Through5-year Follow-up in the Lucentis Groups 9.8P 0.09 7.266Source: Ophthalmology, 2015. 122: 375–381.
Median Number of Injections Prior to 5 YearLucentis Prompt Laser(N 124)Lucentis Deferred Laser(N 111)Median no. (range) of injectionsin Year 18 (7–11)9 (6–11)Median no. in Year 22 (0–5)3 (1–6)Median no. in Year 31 (0–4)2 (0–5)Median no. in Year 40 (0–3)1 (0–4)Median no. in Year 50 (0–3)0 (0–3)13 (9–24)17 (11–27)Median no. (range) of injectionsbefore the 5-year visit67
What has been learned from Protocol I for diabeticmacular edema treatment? Intravitreal Lucentis with or deferred laser is more effective inincreasing vision compared with laser in eyes with DMEinvolving the central macula. Visual benefit from intravitreal Lucentis was maintainedfor up to 5 years of follow-up despite the decreasing number ofinjections needed. Intravitreal anti-VEGF (Lucentis) therapy should be consideredfor patients with DME and decreased visual acuity.68
DRCR.net Protocol TComparative Effectiveness Study of Intravitreal Aflibercept,Bevacizumab, and Ranibizumab for DME69Sources: New England Journal of Medicine, 2015. 26; 372(13): 1193–1203.Ophthalmology, June 2016. 123(6): 1351–1359.
Background Eylea and Lucentis: FDA approved for DME. Avastin: Not FDA approved for intraocular use. Repackaged into aliquots 1/500 of systemic dose incancer treatments. Medicare allowable charges vary.70
Protocol TObjective and Treatment ArmsTo compare the efficacy and safety of intravitrealAflibercept, Bevacizumab, and Ranibizumab when given to treatcenter-involved DME in eyes with visual acuity of 20/32 to 20/320.2.0 mg/0.05mLAflibercept(Eylea)1.25 mg/0.05mLBevacizumab(Avastin)0.3 mg/0.05mLRanibizumab(Lucentis)660 eyes from 89 sites were equally randomized to each group71
Follow-up ScheduleBaseline to1 Year Visits every 4 weeksPrimary outcome at 1 year1 Year to 2 Years Visits every 4 to 16 weeksDepends on disease status and treatment Injection every 4 weeks until stable. Starting at the 6-month visit, laser treatment was administeredif DME persisted and was not improving.72
Comparison of Anti-VEGF for DME: Number of InjectionsEyleaAvastinLucentisGlobalP-valueNo. of Injections: MedianYear 1910100.045†Year 25660.32Over 2Years1516150.08† Pairwise comparisons (adjusted for multiple comparisons): Eylea-Avastin: P 0.045, Eylea-Lucentis: P 0.19,Avastin-Lucentis: P 0.22.73
Comparison of Three Anti-VEGF for DME:The Need for Laser TreatmentEyleaAvastinLucentisGlobalP-valueAt least one focal/grid laser74Year 137%56%46% 0.001Year 220%31%27%0.046Over 2Years41%64%52% 0.001
What did we learn from Protocol Tfor diabetic macular edema? At 2 years: Vision gains were seen with all three drugs.75
What did we learn from Protocol Tfor diabetic macular edema? At 2 years: When initial vision loss is mild (20/32 to 20/40),there is little difference between the three drugs.76
What did we learn from Protocol Tfor diabetic macular edema? At 2 years: When initial vision loss is greater (20/50 or worse),Eylea and Lucentis are more effective.77
What did we learn from Protocol Tfor diabetic macular edema? Anti-VEGF agents (Avastin, Eylea, Lucentis) with or withoutdeferred laser are effective in improving vision in eyes withcentral DME with vision loss. Depending on the initial visual acuity, different anti-VEGFagents may be considered.78
DRCR.net Protocol SPrompt panretinal photocoagulation vs. intravitreal Ranibizumabwith deferred panretinal photocoagulation for proliferativediabetic retinopathy79Source: Journal of the American Medical Association, 2015. 314(20): 2137–2146.
Background Current treatment for PDR is panretinal photocoagulation (PRP): Inherently destructive Adverse effects on visual function Some eyes with PDR that have DME
clinical research of diabetic retinopathy, diabetic macular edema, and associated conditions. Supports the identification, design, and implementation of multicenter clinical research initiatives focused on diabetes-induced retinal disorders. Emphasizes clin
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