Transcript Diabetes “Detection” and “Care and Study” Demonstration

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
[email protected]
Diabetes: 20.8 Million and Climbing
• 14 million diagnosed + 6.8 million undiagnosed
• Type 2 diabetes accounts for 90-95% of cases
+60%
(Millions)
Diagnosed Cases
12
+17%
8
4
0
1980
1990
Centers for Disease Control and Prevention. 2003.
2000
Risk Factors for Prediabetes
• Age
– 45 years or older
– Younger than 45, overweight, and have
one or more of the following risk factors:
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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)
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.
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.
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.
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).
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
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 1998;105:1801-1815
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).
Pathophysiology in Diabetic Macular edema
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Collection of intraretinal fluid
Nonperfusion of capillaries
Traction on the macula
Intraretinal heme/ pre retinal heme
Macular hole formation
Combinations of above
Clinical Characteristics
• A wide spectrum
– Focal Leakage
– Diffuse Leakage
– Combination of diffuse and focal leakage
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
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
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
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.
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.
Diabetic Retinopathy
Features
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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
Current Therapies for
Microvascular Complications
Intervention
Glucose Control
Demonstrated Efficacy to Delay or Prevent
Retinopathy Nephropathy
Neuropathy
LDL Control
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+
?+
?
Aspirin
No
BP Control
ACE Inhibitors
Smoking Cessation
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+
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+
?
?
?
Case Study EM
Case Studies - Patient EM
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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
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
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
Case Study EM
Plan
• Laser treatment for macular edema within
one to two weeks
• Control of BP and BG
Case Study EM
Treatment
• Focal laser treatment
– OD at 3 weeks
– OS at 7 weeks
• 4 month follow-up
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
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Venous caliber abnormalities
Parapapillary cotton wool spots of similar onset
Flame-shaped hemorrhages
Diffuse retinal edema
White centered hemorrhages (Roth’s spots)
Case DG
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35-year-old Caucasian male
Type 1 DM 23 years
VA: OD-20/30; OS-20/40
Denies hypertension, renal disease,
hypercholesterolemia/dyslipidemia
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
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
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
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
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.
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
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
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 highrisk PDR
ETDRS Report # 18 and 22
Role of Protein Kinase C
Activation in the Retinal
Vasculature
Increases:
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Basement matrix protein synthesis
Activation of leukocytes
Endothelial cell activation and proliferation
Smooth muscle cell contraction
Cytokine activation, TGF-, VEGF, endothelin
Angiogenesis
Endothelial permeability
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)
Case CD
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35-year-old Caucasian male
Type 1 DM 10 years
VA: OD-20/25; OS-20/20
Amsler Grid: Normal OD and OS
Diagnosis OD
• Severe NPDR OD
• CSME OD
– HE < 500 microns from center of macula
– Th < 500 microns from center of macula
Management
• MA with late leakage into fovea
• Lesions ring the foveal avascular zone
and are < 500 microns from center and
not amenable to laser photocoagulation
• Novel and evolving therapies for DME
Diabetic Retinopathy Clinical Research Network
DRCR.net: Dedicated to multicenter clinical research of
diabetic retinopathy, macular edema & associated disorders
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.
DRCR Network Sites
DRCR.net
>150 sites overall
>90 community
>450 total PIs
>1000 study
personnel
40 States
www.DRCR.net
DRCR
CURRENTLY 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
A Randomized Trial Comparing Intravitreal
Triamcinolone Acetonide and Laser
Photocoagulation for Diabetic Macular Edema
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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
Study Design
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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
Intraocular Formulation
®
Comparison with Kenalog -40
Ingredient
Allergan Form
Kenalog® -40
2 and 8%
4%
Benzyl Alcohol
-
0.99%
Polysorbate 80
-
0.04%
To Isotonicity
To Isotonicity
0.34%
-
to pH 7.3
to pH 5.0 -7.5
Triamcinolone Acetonide
Sodium Chloride
Sodium Phosphate
Sodium Hydroxide/
Hydrochloric Acid
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 27gauge needle.
• Shelf-stable and requires
no shaking to re-suspend.
• Homogeneous, white
suspension, easily
delivered.
Clinical Experience
• >75 active sites in >20 states
• >40 sites with pending certification
• First patient 7/14/04
• >300 patients enrolled
Evaluation of Vitrectomy for
Diabetic Macular Edema
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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.
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 microns
– Progression—increase in center point thickness of at least 50
microns to > 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
STUDIES IN FOLLOW-UP PHASE
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Pilot study of laser photocoagulation for
diabetic macular edema
Pilot study of peribulbar triamcinolone
acetonide for diabetic macular edema
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)
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.
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.
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.
Eye Research
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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 today’s standard-of-care
obsolete tomorrow