Emerging Trends In the Treatment of Diabetic Macular Edema

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Emerging Trends In the Treatment of Diabetic
Macular Edema
University of Milan June 2007

• Anthony Cavallerano, OD, FAAO
• VA Boston Health Care System
• New England College of Optometry
• Boston, Massachusetts
• Anthony.cavallerano_at_va.gov

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Diabetes 20.8 Million and Climbing

• 14 million diagnosed 6.8 million undiagnosed
• Type 2 diabetes accounts for 90-95 of cases

60
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17
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Diagnosed Cases (Millions)
4
0
1980
1990
2000
Centers for Disease Control and Prevention. 2003.
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Risk Factors for Prediabetes

• Age
• 45 years or older
• Younger than 45, overweight, and have one or more
  of the following risk factors
• Family history of diabetes
• Low HDL cholesterol and high triglycerides
• Hypertension
• History of gestational diabetes or gave birth to
  a baby weighing more than 9 pounds
• Minority group background
• African American
• American Indian, Hispanic American/Latino
• Asian American/Pacific Islander)

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Scope of the Problem

• Total 20.8 million children and adults -- 7.0
  of the population -- have diabetes.
• 10.3 million over age 60
• Diagnosed 14.6 million people
• Undiagnosed 6.2 million people
• Pre-diabetes 41 million people
• 1.5 million new cases of diabetes were diagnosed
  in people aged 20 years or older in 2005.

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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.

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Introduction

• Historical Background (contd)
• 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.

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Diabetic Macular Edema (DME)

• Definition Diabetic macular edema
• is 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).

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Clinically Significant Macular Edema

• Retinal thickening at or within 500 µm from the
  center of the macula or
• Hard exudates at or within 500 µm from the center
  of the macula if accompanied by thickening of the
  adjacent retina or
• A zone of retinal thickening, 1 disc area or
  larger in size, located 1 disc diameter or less
  from the center of the macula

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Factors affecting DME

• Incidence of DME increases with
• Elevated levels of Hb A1C
• Level of severity of DR
• Duration of DM
• Elevated diastolic blood pressure
• Gender (more frequent in females)
• Wisconsin Epidemiologic Study of DR
• Klein R et al. Ophthalmology 19981051801-1815

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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 diagnosed
• 9 of diabetic population in US will have macular
  edema
• Of these, 200,000 patients with macular edema
  alone are at risk of moderate visual loss
  (Aiello and Ferris, 1987).

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Pathophysiology in Diabetic Macular edema

• Collection of intraretinal fluid
• Nonperfusion of capillaries
• Traction on the macula
• Intraretinal heme/ pre retinal heme
• Macular hole formation
• Combinations of above

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Clinical Characteristics

• A wide spectrum
• Focal Leakage
• Diffuse Leakage
• Combination of diffuse and focal leakage

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Clinical Characteristics

• Focal leakage
• usually limited to well defined areas of leakage,
  such as microaneurysms.
• F A will clearly show the source of leakage

Jalkh, A. Atlas of Fluorescein Angiography
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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

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Laser Treatment for CSME

• Focal 50-100 ? spots to areas of discrete
  leakage
• Grid 100-200 ? spots in areas of diffuse leakage
• Focal-Grid combination of the above

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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.

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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.

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Diabetic Retinopathy
Features

• Reduced retinal blood flow
• Closure of retinal capillaries and arterioles
• Ischemia/Cotton-wool spots
• Breakdown of the blood/retinal barrier with
  increased vascular permeability of retinal
  capillaries
• Intraretinal microvascular abnormalities (IRMA)
  also found adjacent to areas of capillary closure
• 70 of NVE occurs in same area as IRMA
• Proliferation of new vessels and fibrous tissue
• Contraction of vitreous and fibrous proliferation
  with VH and RD

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Current Therapies for Microvascular Complications
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Case Study EM
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Case Studies - Patient EM

• 59-year-old African-American male
• Type 2 DM x 11 yrs
• LEE 1.5 yr
• Pt complaint having trouble seeing
• PMHx
• Uncontrolled HTN
• proteinuria
• Last HbA1c 11.1
• Meds insulin, antihypertensive

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Patient EM

• Cholesterol levels within normal limits
• Current Albumin/Creatine level 231.6 µg/mg
  (Normal 0 - 20 µg/mg)
• Triglycerides and LDL levels calculated but non-
  fasting

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Case Study EM

• Exam Findings
• VA OD 20/30 OS 20/30
• Sensorimotor exam normal
• No distortion with Amsler grid
• Early NSC, PSC OU early CC, vacuoles OS
• IOP 14mmHg OU

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Case Study EM

• Plan
• Laser treatment for macular edema within one to
  two weeks
• Control of BP and BG

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Case Study EM

• Treatment
• Focal laser treatment
• OD at 3 weeks
• OS at 7 weeks
• 4 month follow-up

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Case Study EM

• Notes
• HTN, renal disease and dyslipidemia can affect
  onset and progression of retinopathy
• Co-management with other health care providers
• Lesions that may indicate nondiabetic etiology
• Venous caliber abnormalities
• Parapapillary cotton wool spots of similar onset
• Flame-shaped hemorrhages
• Diffuse retinal edema
• White centered hemorrhages (Roths spots)

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Case DG

• 35-year-old Caucasian male
• Type 1 DM 23 years
• VA OD-20/30 OS-20/40
• Denies hypertension, renal disease,
  hypercholesterolemia/dyslipidemia

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Patient DG

• Diagnosis
• Moderate NPDR OU
• DME not CSME OD
• Clinically Significant Macular Edema OS
• Plan
• FA to identify treatable lesions OS
• Focal laser photocoagulation OS

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Clinical Characteristics

• Focal leakage
• Well defined areas of leakage e.g.,
  microaneurysms
• FFA will clearly show the source of leakage
• Diffuse leakage
• Poorly demarcated widespread leakage
• Destruction of the inner blood retinal barrier.
• FFA will show widened intercapillary spaces,
  with diffusely dilated capillary bed, and diffuse
  leakage.
• RPE dysfunction

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Macular Edema Laser Treatment

• Focal 50-100 ? spots to areas of discrete
  leakage
• Focal Grid 100-200 ? spots in areas of diffuse
  leakage
• Combination of the above

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Clinically Significant Macular Edema (CSME)

• Retinal thickening at or within 500 ? from the
  center of the macula
• Hard exudates at or within 500 ? from center of
  the macula with thickening of adjacent retina
• An 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

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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.

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Role of Hypertension in DR

• Impairs retinal vascular autoregulation
• Promotes endothelial damage in retinal
  vasculature
• Increases expression of Vascular Endothelial
  Growth Factors (VEGF) and its receptors by
  vascular stretch of retinal endothelium

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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 dialysis
• Type 1 patients with microalbuminuria have
  three-fold risk of PDR compared to those with
  normal levels

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Role of Serum Lipids in DR

• Elevated serum lipids are associated with
  increased risk of retinal hard exudates
• Increased amounts of hard exudates are associated
  with increased risk of visual impairment
• Elevated lipids, most notably triglycerides, are
  a risk factor for development of high-risk PDR

ETDRS Report 18 and 22
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Role of Protein Kinase C Activation in the
Retinal Vasculature

• Increases
• Basement matrix protein synthesis
• Activation of leukocytes
• Endothelial cell activation and proliferation
• Smooth muscle cell contraction
• Cytokine activation, TGF-?, VEGF, endothelin
• Angiogenesis
• Endothelial permeability

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Role of Vitreous in DME

• Vitreomacular 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)
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Case CD

• 35-year-old Caucasian male
• Type 1 DM 10 years
• VA OD-20/25 OS-20/20
• Amsler Grid Normal OD and OS

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Diagnosis OD

• Severe NPDR OD
• CSME OD
• HE lt 500 microns from center of macula
• Th lt 500 microns from center of macula

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Management

• MA with late leakage into fovea
• Lesions ring the foveal avascular zone and are lt
  500 microns from center and not amenable to laser
  photocoagulation
• Novel and evolving therapies for DME

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Diabetic Retinopathy Clinical Research Network

• DRCR.net Dedicated to multicenter clinical
  research of
• diabetic retinopathy, macular edema associated
  disorders

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DRCR Network Overview

• Funding
• National Eye Institute-sponsored cooperative
  agreement initiated September 2002
• Objective
• The development of a collaborative network to
  facilitate multicenter clinical research on
  diabetic retinopathy, diabetic macular edema and
  associated conditions.

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DRCR Network Sites
DRCR.net gt150 sites overall gt90
community gt450 total PIs gt1000 study personnel
40 States www.DRCR.net
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DRCRCURRENTLY RECRUITING STUDIES

• Randomized trial comparing intravitreal
  triamcinolone acetonide and laser
  photocoagulation for DME
• Evaluation of vitrectomy for DME
• Observational study of development of DME
  following scatter laser photocoagulation
• Subclinical DME study

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A Randomized Trial Comparing Intravitreal
Triamcinolone Acetonide and Laser
Photocoagulation for Diabetic Macular Edema

• To 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

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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 photocoagulation
• Intravitreal injection of 1mg of triamcinolone
  acetonide
• Intravitreal injection of 4mg of triamcinolone
  acetonide

• Duration of follow-up Three years
• Injection volume always 0.05ml

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Intraocular FormulationComparison with
Kenalog-40
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Formulation and Packaging
Preservative endotoxin free Isotonic and pH
Balanced Single-unit Dosing

• Allergan
• Sterile, 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.

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Clinical Experience

• gt75 active sites in gt20 states
• gt40 sites with pending certification
• First patient 7/14/04
• gt300 patients enrolled

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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.

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Subclinical Diabetic Macular Edema Study

• Primary Objective To determine the incidence of
  progression of subclinical diabetic macular edema
  (DME)
• Subclinical DMEno 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 microns
• Progressionincrease in center point thickness of
  at least 50 microns to gt 300 microns
• Secondary Objectives
• To evaluate factors predictive of the presence of
  subclinical macular edema
• To determine indicators of risk for progression
  of subclinical DME

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STUDIES IN FOLLOW-UP PHASE

• Pilot study of laser photocoagulation for
  diabetic macular edema
• Pilot study of peribulbar triamcinolone acetonide
  for diabetic macular edema

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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)

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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.
  

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UPCOMING STUDIES

• A Phase 2 Evaluation of Anti-VEGF Therapy for
  Diabetic Macular Edema Avastin
• 200 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.

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COMPLETED STUDIES

• Temporal Variation in OCT Measurements of Retinal
  Thickening in Diabetic Macular Edema
• Determine 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.

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Eye Research

• Determine basic mechanisms of disease
• Identify potential therapeutic targets
• Develop specific novel therapies
• Evaluate at subcellular, cellular organism
  level
• Rigorous clinical trials
• Opportunity to make todays standard-of-care
  obsolete tomorrow