Presentation on theme: "Emerging Trends In the Treatment of Diabetic Macular Edema"— Presentation transcript:
1 Emerging Trends In the Treatment of Diabetic Macular Edema University of MilanJune 2007Anthony Cavallerano, OD, FAAOVA Boston Health Care SystemNew England College of OptometryBoston, Massachusetts
2 Diagnosed Cases (Millions) Diabetes: 20.8 Million and Climbing14 million diagnosed million undiagnosedType 2 diabetes accounts for 90-95% of cases+60%12+17%8Diagnosed Cases (Millions)4198019902000Centers for Disease Control and Prevention
3 Risk Factors for Prediabetes Age45 years or olderYounger than 45, overweight, and have one or more of the following risk factors:Family history of diabetesLow HDL cholesterol and high triglyceridesHypertensionHistory of gestational diabetes or gave birth to a baby weighing more than 9 poundsMinority group backgroundAfrican AmericanAmerican Indian, Hispanic American/LatinoAsian American/Pacific Islander)
4 Scope of the ProblemTotal: 20.8 million children and adults % of the population -- have diabetes.10.3 million over age 60Diagnosed: 14.6 million peopleUndiagnosed: 6.2 million peoplePre-diabetes: 41 million people1.5 million new cases of diabetes were diagnosed in people aged 20 years or older in 2005.
5 Introduction Historical Background: Diabetic Macular Edema (DME) was unrecognized before invention of the ophthalmoscope (Helmholtz, 1851).Jaeger in 1856 was the first to describe a “roundish or oval yellow spots and extravasations which permeate part or the whole thickness of the retina” in a patient with positive urine glucose test for Diabetes Mellitus.That same year Von Graefe refuted any relationship of the eye findings to diabetes.
6 Introduction Historical Background (cont’d): In 1869 Noyes established a causal relationship between the changes described by Jaeger and Diabetes Mellitus (DM).In 1872 Nettleship confirmed this theory in his treaties on the issue (“Noyes’ glucosuric retinitis”).In 1875 Appolinaire in Paris reported these observations and described in addition, the accumulation of lipid in the retina which he designated “glucose induced amblyopia.”Diabetic Macular Edema (DME) was thereafter recognized as a clinical entity.
7 Diabetic Macular Edema (DME) Definition: Diabetic macular edemais retinal thickening caused by the accumulation of intraretinal fluid primarily in the inner and outer plexiform layers. It is believed to be a result of hyperpermeability of the retinal vasculature.Can be present with any level of diabetic retinopathy (DR).
8 Clinically Significant Macular Edema Retinal thickening at or within 500 µm from the center of the macula orHard exudates at or within 500 µm from the center of the macula if accompanied by thickening of the adjacent retina orA zone of retinal thickening, 1 disc area or larger in size, located 1 disc diameter or less from the center of the macula
9 Factors affecting DME Incidence of DME increases with Elevated levels of Hb A1CLevel of severity of DRDuration of DMElevated diastolic blood pressureGender (more frequent in females)Wisconsin Epidemiologic Study of DRKlein R et al. Ophthalmology 1998;105:
10 US Epidemiology : 5.8 million people are known to have DM in the USA 4 to 5 million Americans have DM that has not been diagnosed9% of diabetic population in US will have macular edemaOf these, 200,000 patients with “macular edema alone” are at risk of moderate visual loss (Aiello and Ferris, 1987).
11 Pathophysiology in Diabetic Macular edema Collection of intraretinal fluidNonperfusion of capillariesTraction on the maculaIntraretinal heme/ pre retinal hemeMacular hole formationCombinations of above
12 Clinical Characteristics A wide spectrumFocal LeakageDiffuse LeakageCombination of diffuse and focal leakage
13 Clinical Characteristics Focal leakage:usually limited to well defined areas of leakage, such as microaneurysms.F A will clearly show the source of leakageJalkh, A. Atlas of Fluorescein Angiography
14 Clinical Characteristics Diffuse leakage:widespread, poorly demarcated leakage believed to be related to the destruction of the inner blood retinal barrier.F A will show widened intercapillary spaces, with diffusely dilated bed, and diffuse leakage.? RPE dysfunction
15 Laser Treatment for CSME Focal: spots to areas of discrete leakageGrid: spots in areas of diffuse leakage“Focal-Grid”: combination of the above
16 Macular edema & laser rx ETDRS showed that in eyes with CSME, focal laser photocoagulation reduces the risk of moderate visual loss by 50% or more.It also reported an increase in the chance of improvement on the final BCVA.
17 Macular edema & laser rx Other studies confirmed the positive effect of laser rx (Patz et al 1973, Blankenship 1979, Olk 1985, and Lee 1991).However, in all the studies, 15%-24% of eyes experienced moderate visual loss despite focal laser rx.These eyes generally had diffuse diabetic macular edema (DDME) or poor macular perfusion.
18 Diabetic Retinopathy Features Reduced retinal blood flow Closure of retinal capillaries and arteriolesIschemia/Cotton-wool spotsBreakdown of the blood/retinal barrier with increased vascular permeability of retinal capillariesIntraretinal microvascular abnormalities (IRMA) also found adjacent to areas of capillary closure70% of NVE occurs in same area as IRMAProliferation of new vessels and fibrous tissueContraction of vitreous and fibrous proliferation with VH and RD
19 Current Therapies for Microvascular Complications InterventionDemonstrated Efficacy to Delay or PreventRetinopathy Nephropathy NeuropathyGlucose Control+BP ControlACE Inhibitors?+LDL Control?AspirinNoSmoking Cessation
21 Case Studies - Patient EM 59-year-old African-American maleType 2 DM x 11 yrsLEE: 1.5 yrPt complaint “having trouble seeing”PMHx:Uncontrolled HTN+ proteinuriaLast HbA1c = 11.1%Meds: insulin, antihypertensive
22 Patient EM Cholesterol levels within normal limits Current Albumin/Creatine level = µg/mg (Normal: µg/mg)Triglycerides and LDL levels calculated but non- fasting
23 Case Study EM Exam Findings VA OD 20/30+ OS 20/30 Sensorimotor exam normalNo distortion with Amsler gridEarly NSC, PSC OU; early CC, vacuoles OSIOP 14mmHg OU
24 Case Study EMPlanLaser treatment for macular edema within one to two weeksControl of BP and BG
25 Case Study EM Treatment Focal laser treatment 4 month follow-up OD at 3 weeksOS at 7 weeks4 month follow-up
26 Case Study EMNotesHTN, renal disease and dyslipidemia can affect onset and progression of retinopathyCo-management with other health care providersLesions that may indicate nondiabetic etiologyVenous caliber abnormalitiesParapapillary cotton wool spots of similar onsetFlame-shaped hemorrhagesDiffuse retinal edemaWhite centered hemorrhages (Roth’s spots)
27 Case DG 35-year-old Caucasian male Type 1 DM 23 years VA: OD-20/30; OS-20/40Denies hypertension, renal disease, hypercholesterolemia/dyslipidemia
28 Patient DG Diagnosis: Plan: Moderate NPDR OU DME not CSME OD Clinically Significant Macular Edema OSPlan:FA to identify treatable lesions OSFocal laser photocoagulation OS
29 Clinical Characteristics Focal leakage:Well defined areas of leakage; e.g., microaneurysmsFFA will clearly show the source of leakageDiffuse leakage:Poorly demarcated widespread leakageDestruction of the inner blood retinal barrier.FFA will show widened intercapillary spaces, with diffusely dilated capillary bed, and diffuse leakage.RPE dysfunction
30 Macular Edema & Laser Treatment Focal: spots to areas of discrete leakageFocal Grid: spots in areas of diffuse leakageCombination of the above
31 Clinically Significant Macular Edema (CSME) Retinal thickening at or within 500 from the center of the maculaHard exudates at or within 500 from center of the macula with thickening of adjacent retinaAn area or areas of retinal thickening at least one disc area in size, at least part of which is within one disc diameter of the center of macula
32 Role of Hypertension in DME WESDR - diabetic patients with HTN had 3 x incidence of DME.UKPDS__rigorous BP control with ACE-inhibitor or -blocker reduced the risk of the two-step progression of DR significantly.
33 Role of Hypertension in DR Impairs retinal vascular autoregulationPromotes endothelial damage in retinal vasculatureIncreases expression of Vascular Endothelial Growth Factors (VEGF) and its receptors by vascular stretch of retinal endothelium
34 Role of Renal Disease in DME Gross proteinuria associated with 95% increased risk of DME (WESDR)Case reports of reduction of diabetic macular edema after dialysisType 1 patients with microalbuminuria have three-fold risk of PDR compared to those with normal levels
35 Role of Serum Lipids in DR Elevated serum lipids are associated with increased risk of retinal hard exudatesIncreased amounts of hard exudates are associated with increased risk of visual impairmentElevated lipids, most notably triglycerides, are a risk factor for development of high-risk PDRETDRS Report # 18 and 22
36 Role of Protein Kinase C Activation in the Retinal Vasculature Increases:Basement matrix protein synthesisActivation of leukocytesEndothelial cell activation and proliferationSmooth muscle cell contractionCytokine activation, TGF-, VEGF, endothelinAngiogenesisEndothelial permeability
37 Role of Vitreous in DMEVitreomacular traction is believed to be a contributor to the multifactorial etiology of DME.The role of the posterior hyaloid in a subset of eyes with diffuse macular edema has become increasingly recognised (Schepens et al, 1984).Nasrallah et al observed that a posterior hyaloid separation was more common in diabetic eyes without M.E than with M.E (55% v/s 20.0%).(Nasrallah et al, Ophthalmology vol 90: 1988)
38 Case CD 35-year-old Caucasian male Type 1 DM 10 years VA: OD-20/25; OS-20/20Amsler Grid: Normal OD and OS
39 Diagnosis OD Severe NPDR OD CSME OD HE < 500 microns from center of maculaTh < 500 microns from center of macula
40 Management MA with late leakage into fovea Lesions ring the foveal avascular zone and are < 500 microns from center and not amenable to laser photocoagulationNovel and evolving therapies for DME
41 Diabetic Retinopathy Clinical Research Network DRCR.net: Dedicated to multicenter clinical research ofdiabetic retinopathy, macular edema & associated disorders
42 DRCR Network Overview Funding: Objective: National Eye Institute-sponsored cooperative agreement initiated September 2002Objective:The development of a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions.
43 DRCR Network Sites DRCR.net >150 sites overall >90 community >450 total PIs>1000 study personnel40 States
44 DRCR CURRENTLY RECRUITING STUDIES Randomized trial comparing intravitreal triamcinolone acetonide and laser photocoagulation for DMEEvaluation of vitrectomy for DMEObservational study of development of DME following scatter laser photocoagulationSubclinical DME study
45 A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for Diabetic Macular EdemaTo determine whether intravitreal triamcinolone acetonide injections at doses of 1mg or 4mg produce greater benefit, with an acceptable safety profile, than macular laser photocoagulation in the treatment of diabetic macular edema.To compare the efficacy and safety of the 1mg and 4mg triamcinolone acetonide doses
46 Study Design Phase 3, multicenter, randomized clinical trial Randomization to one of three treatment groups:Standard of care group: conventional treatment consisting of modified ETDRS photocoagulationIntravitreal injection of 1mg of triamcinolone acetonideIntravitreal injection of 4mg of triamcinolone acetonideDuration of follow-up: Three yearsInjection volume always = 0.05ml
48 Formulation and Packaging Preservative & endotoxin freeIsotonic and pH BalancedSingle-unit DosingAllerganSterile, prefilled (0.05ml), single-dose, ready-to-use syringe with attached 27-gauge needle.Shelf-stable and requires no shaking to re-suspend.Homogeneous, white suspension, easily delivered.
49 Clinical Experience >75 active sites in >20 states >40 sites with pending certificationFirst patient 7/14/04>300 patients enrolled
50 Evaluation of Vitrectomy for Diabetic Macular Edema To provide information on the following outcomes in eyes with DME that undergo vitrectomy: visual acuity, retinal thickening, resolution of traction (if present), surgical complications.To identify subgroups in which there appears to be a benefit of vitrectomy and subgroups in which vitrectomy does not appear to be beneficial.
51 Subclinical Diabetic Macular Edema Study Primary Objective: To determine the incidence of progression of subclinical diabetic macular edema (DME)Subclinical DME—no edema involving the center of the fovea as determined by biomicroscopy but with center point thickness on OCT of at least 200 microns but less than or equal to 299 micronsProgression—increase in center point thickness of at least 50 microns to > 300 micronsSecondary Objectives:To evaluate factors predictive of the presence of subclinical macular edemaTo determine indicators of risk for progression of subclinical DME
52 STUDIES IN FOLLOW-UP PHASE Pilot study of laser photocoagulation for diabetic macular edemaPilot study of peribulbar triamcinolone acetonide for diabetic macular edema
53 Pilot study of laser photocoagulation for diabetic macular edema Compare laser treatment as we now use it (called “standard method”) with a similar laser treatment that is milder in intensity, but more extensive in number (called “mild macular grid” method)
54 Pilot study of peribulbar triamcinolone acetonide for diabetic macular edema To estimate the incidence of improvement of DME following a posterior peribulbar 40 mg triamcinolone acetonide injection compared with laser.To estimate the incidence of improvement of DME following an anterior peribulbar 20 mg triamcinolone acetonide injection compared with laser.To estimate the incidence of intraocular pressure elevation and other complications with each type of injection.To provide preliminary data comparing the incidence of improvement of DME with a peribulbar triamcinolone alone versus peribulbar triamcinolone followed by laser photocoagulation.
55 UPCOMING STUDIESA Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Avastin200 patient, phase 2 randomized, multi-center clinical trial.Provide preliminary data on the dose and dose interval related effects of intravitreally adminstered Avastin on retinal thickness and visual acuity in subjects with Diabetic Macular (DME) to aid in planning a phase 3 trial.Provide preliminary data on the safety of intravitreally administered Avastin in subjects with DME.
56 COMPLETED STUDIESTemporal Variation in OCT Measurements of Retinal Thickening in Diabetic Macular EdemaDetermine the proportion of eyes that demonstrate a potentially meaningful change in central retinal thickening measured on OCT throughout the day.Establish the time course of change for the eyes that experience diurnal change in central retinal thickening.Evaluate intra-observer and inter-observer variability on OCT measurements.
57 Eye Research Determine basic mechanisms of disease Identify potential therapeutic targetsDevelop specific novel therapiesEvaluate at subcellular, cellular & organism levelRigorous clinical trialsOpportunity to make today’s standard-of-care obsolete tomorrow
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