Diabetic Retinopathy

1. Dr. Raymond R. Maeda

2.  Students will be able to. . .
◦ Describe the demographics of those individuals who
have diabetes
◦ Identify patients at risk for diabetes
◦ Differentiate the different types of diabetes
◦ Recognize the criteria for diagnosing diabetes
◦ Construct a case history for their patient who has
diabetes
◦ Identify the relevant studies in regards to diabetes and
diabetic retinopathy
◦ Recognize the impact diabetes has on the organs in the
human body

3. ◦ Recognize all of the ocular complications related to
diabetes
◦ Be able to distinguish the different classifications for
diabetic retinopathy and the appropriate treatment
◦ Explain the etiology of the different classifications
diabetic retinopathy
◦ Be familiar with future possible treatments of diabetic
retinopathy

4.  Diabetes is a group of diseases marked by high
levels of blood glucose resulting from defects in
insulin production, insulin action, or both.
 1.7 million new cases
in 2012
 4% of the US has some
level of diabetic retinopathy
retinopathy

5.  EVERY 24 HOURS there
are :
◦ 4,100 new cases of diabetes
◦ 810 deaths due to diabetes
◦ 230 amputations
◦ 120 kidney failures
◦ 55 new cases of blindness

6. 29 million people (9.3%)
Total Cost = 245 Billion
Dollars
 Direct Medical Costs
◦ 176 Billion Dollars
◦ (medical expenses)
 Indirect Medical Costs
◦ 69 Billion Dollars
◦ (disability, work loss,
premature death)

7.  Non-Hispanic Whites 7.6
 Asian Americans 9.0
 Hispanics 12.8
 Non-Hispanic Blacks 13.2
 American Indians/Alaska Natives 15.9
 *2010-2012

8.  Type II DM appears to be rising parallel with
global trends towards obesity.
 Weight gain of 10-15 pounds can increase the risk
of DM by 50%.
◦ Especially in women
◦ Seeing prevalence of metabolic
syndrome also rise in women.
 65% of Americans are over-
weight or obese

9.  Type I – bodies immune system destroys pancreatic
beta cells
 Type II – begins as insulin resistance and then gradually
the pancreas loses its’ ability to produce insulin.
 Gestational
◦ Form of glucose intolerance during the 2nd
or 3rd
trimester
◦ 5-10% dx’d with DM
◦ 50% chance of development of DM in 5-10 years

11.  Associated with obesity, older age, family hx,
impaired glucose metabolism, physical inactivity,
and race/ethnicity
 African Americans, Hispanics, Native Americans,
*Asian Americans, and Pacific Islanders
 Seeing it more frequently dx’d in children

13.  Recent studies are demonstrating the need for
ethnic-specific guidelines
◦ A1C measures higher in South Asians than White
Europeans (*looked at data from 6040 people aged 40 –
75 between 2005-2009 included 1352 South Asians and
4688 white Europeans) Diabetes Care
◦ A1C level that was associated with an increased
prevalence of retinopathy was significantly lower in blacks
than in whites Annals of Internal Medicine

14.  National Health and Nutrition Examination Survey
(NHANES) (Dr. May in 2012)
◦ Performed recent analysis on five 2-year cycles looking at
prevalence of prediabetes and diabetes in American teens.
◦ IT HAS MORE THAN DOUBLED BETWEEN 1999
AND 2008 – 9% TO 23%
◦ 26% OF THE OVERWEIGHT AND OBESE
ADOLESCENTS WERE PRE-
HYPERTENSIVE/HYPERTENSIVE AND HAD
BORDERLINE/HIGH LDL-C.

15.  This is a multicenter study funded by CDC and NIH to
examine diabetes among young children and
adolescents.
◦ From 2008-2009, an estimated 18,436 people younger than
20yo (US) were newly diagnosed with Type I diabetes and 5,089
were newly diagnosed with Type II diabetes.
◦ Non-Hispanic White children and adolescents had the highest
rate of new cases of Type I
◦ The rate of Type II DM was greater among people 10-19 yo than
in younger children, with highest rates in minority populations

16.  2009-2012: based on fasting glucose or A1C,
37% of U.S. adults 20yo and older had pre-
diabetes (51% of those 65 and older).
 86 million Americans!!

17.  Impaired fasting glucose (IFG)
◦ Fasting glucose is 100 – 125mg/dL
 Impaired glucose tolerance (IGT)
◦ Glucose level is 140 – 199mg/dl after a 2hr oral glucose tolerance
test
 Approximately 86 million adults have pre-diabetes
◦ 33% will convert to DM if there is no intervention in 10 yr.s
 Progression to DM can be prevented/delayed

18.  A large prevention study of people at high risk for
DM
◦ Showed that lifestyle intervention to lose weight and
physical activity reduced the development of Type II DM
by 60% (3 yr period)
 Metformin intervention reduced the risk by 30%
and was most effective in younger pt’s (25-44yo)
and in adults with a BMI > 35

19.  The Diabetes Control and Complications Trial DCCT
◦ Demonstrated benefits of intensive blood glucose control in patients with
Type I DM in regards to development and progression of diabetic
retinopathy.
 The United Kingdom Prospective Diabetes Study (UKPDS)
◦ Showed a 21% reduction in risk for progression of diabetic retinopathy
over a 12 year period for the intensive glycemic control group
 Other studies. .
◦ ACCORD (Action to Control Cardiovascular Risk in Diabetes),
ADVANCE (Action in Diabetes and Vascular Disease, VADT (Veterans
Affairs Diabetes Trial)

20.  The Wisconsin Epidemiologic Study of Diabetic
Retinopathy (WESDR)
◦ Is an ongoing epidemiologic study on the progression of
diabetic retinopathy.
 Looked at fundus photos, A1C and VA’s
◦ Significant conclusions:
 Severity of diabetic retinopathy is related to the duration of the
disease.
 After 20 years nearly 99% of Type I and 60% of Type II DM
pt’s had some degree of diabetic retinopathy.
*data was limited to primarily to white populations of northern
European descent.

21.  Early Treatment Diabetic Retinopathy Study (ETDRS)
◦ A prospective, randomized clinical trial evaluating
photocoagulation of pt’s with diabetes.
◦ Provided the definition for clinically significant macular edema**
◦ Demonstrated benefit of focal or grid laser in maintaining vision
◦ Early scatter photocoagulation not indicated in mild/moderate DR
and resulted in a small reduction for the risk of severe vision loss.
◦ Aspirin therapy had no impact on DR progression, risk of vitreous
hemorrhage, VA loss but did reduce risk of CA morbidity and
mortality.

23.  Periodontal (gum) disease is more common in
people with DM
 There is a clear relationship of the degree of
hyperglycemia and severity of periodontitis.
 Adults with poorly controlled DM (A1C > 9%) were
3x’s more likely to have severe
periodontal disease

24.  About 60-70% of people with diabetes have mild
to severe forms of nervous system damage.
◦ Impaired sensation or pain in feet or hands
◦ Slowed digestion
◦ Carpal tunnel
◦ Erectile dysfunction
 30% of diabetics over 40 years old
have impaired sensation in their feet.

25.  Foot ulcers are a common
occurrence (15%)
 50% will develop infection or have other
complications
 25% will have an amputation
 DM is the leading cause of lower-limb amputations

26.  Diabetes is the leading cause of kidney failure
◦ Accounts for close to 50% of all new cases of kidney
failure
 No sx’s until almost all function is gone
 Tx: ACE inhibitors, low protein
diet, dialysis
 ~200,000 people on dialysis due to
ESRD

27.  Diabetes is the major cause of heart disease and
stroke
 Adults with DM have heart disease rates 2-4
times higher than adults without DM.
 Risk for stroke is 2-4 times higher among
people with DM

28.  Diabetes is the 7th
leading cause of death in the
U.S.
◦ Risk for death is twice that of people of similar age
without DM
 Leading cause of kidney failure, non-traumatic
lower limb amputation and new cases of blindness
among adults in U.S.

29.  Every 1 point drop in A1C can reduce
microvascular complications (eye, kidney nerve
disease) by 40%.
 BP control can reduce the risk of heart disease
and stroke by up to 50%

30.  Controlling LDL’s can reduce cardiovascular
complications by 20-50%
 Foot care programs (risk assessment) can reduce
amputation rates by 45 – 85%
 Detecting and treating early diabetic kidney
disease by lowering BP can reduce decline in
kidney function by 30 – 70%

31. Refractive changes

Refractive shift

 Due to increased glucose
levels in the lens
 21% also demonstrate
transient “paralysis” of
accommodation

32. Dry Eyes
 Reduced corneal sensitivity
◦ Reduce reflex tearing
 Goblet cell density
◦ Produce mucin (stability)
 Affect on lacrimal gland
◦ Correlated to length of DM
 Tear Protein Patterns
◦ Lactoferrin, slgA, albumin,
lipocalin and lysozyme

33. “Snowflake” cataract
 Common in uncontrolled
Type I diabetic patients
 Sorbitol accumulates in
the lens fibers. Water
enters to correct the
osmotic imbalance
 Lens fibers swell / rupture

34. Posterior Subcapsular
Cataract
 Earlier onset of age-
related cataracts
 Due to binding of sugars
to lens proteins
 Osmotic imbalance can
also increase cortical
changes

35. Glaucoma
 LALES found 40% higher
prevalence in Type II
diabetic Latino pt’s
 Neovascular glc
◦ VEGF-induced
neovascularization of the iris
and angle
 Normotensive glc

36. Sixth Nerve Palsy 50%
 Sudden onset
 Transient
 Absence of other
neurologic involvement
 Resolves in 3-6 months.

37. CN III Palsy (45%) CN IV Palsy (5%)

38. Diabetic Papillopathy
 Can be unilateral or
bilateral
 Minimal affect on VA
 Resolved in 2-10 months
 If bilateral, need to r/o
papilledema (imaging or
LP)

39.  What is a “typical” chief complaint from a diabetic
patient?
 Questions to ask:
◦ Type of DM
◦ Duration of DM
◦ Blood sugars (Fasting / Post-prandial)
◦ A1C
◦ Medications (compliance)
◦ Who do they see / How often

40.  Does the pt smoke (increase progression)/ drink
(excess = non-compliance)
 Metabolic Syndrome (any 3 of the following):
◦ Central Obesity (waist): > 40” – Men / > 35” Women
◦ Triglycerides > 150mg/dl
◦ HDL Cholesterol: <40mg/dl – Men
<50mg/dl - Women
◦ Blood Pressure: > 130 / 85
◦ FBS > 100mg/dl
◦ Pt’s being treated dyslipidemia,
◦ HTN or DM

41.  Airlie House Grading System
◦ Developed in 1969
◦ With this grading system, seven-field stereoscopic
photographs are taken and the various lesions of diabetic
retinopathy are graded according to standardized
examples.
◦ Used in 2 landmark studies: The Diabetic Retinopathy
Study (DRS) and the Early Treatment Diabetic
Retinopathy Study (ETDRS).

42.  ETDRS (1981) – based on the modified Airlie House
classification of diabetic retinopathy.
◦ Gold Standard but not practical in everyday use.
◦ Consists of 30-degree stereoscopic photography of seven
standard fields on color film
 ETDRS (1991) – Annual meeting of the AAO
◦ Divided up retinopathy into NPDR and PDR
◦ Separate category for diabetic macular edema
 Circinate Diffuse
 Ischaemic Mixed

43.  International Clinical Diabetic Retinopathy (DR)
Disease Severity Scale
◦ In 2001 AAO decided a classification needed to be
evidence based and incorporate data found in excellent
clinical trials (ETDRS, WESDR. . etc)
◦ In 2003 the scale was completed
 Five Scales with increasing severity of retinopathy
 Also developed a grading scale for DME
◦ First determine if there is retinal thickening or not
◦ Second determine level of severity (mild, moderate or
severe).

45.  Non-Proliferative Diabetic Retinopathy (NPDR)
◦ Mild
◦ Moderate
◦ Severe
◦ Very Severe
 Proliferative
◦ High risk
◦ Low risk

46.  Also known as background diabetic retinopathy in
the internal medicine literature.
 For non-ophthalmic physicians and patients this
may imply non-progressive condition we all know
this is far from the truth.
 Diabetic retinopathy is a progressive disease.

47. Microaneurysms
 Pathologic progress
includes the formation of
capillary
microaneurysms,
vascular permeability and
capillary closure.

48. Diabetic Retinopathy
 4 Levels of Severity
1. Mild 2. Moderate
3. Severe 4. Very Severe
 The extent of intraretinal
microvascular abnormalities
(IRMA), venous
abnormalities, and retinal
heme.s are the determining
factors.

49.  Microaneurysms
 Intraretinal hemorrhages (dot/blot)
◦ Mild to moderate in less than 4 quadrants
 Hard exudates
◦ Lipoproteins
 Follow-up: 9 months to one year
 Risk of Diabetic Macular Edema is < 5%

52.  Microaneurysms / hemorrhages
◦ Mild to moderate in 4 quadrants
 Hard exudates
 Cotton wool spots
◦ Indicative of retinal ischemia that causes obstruction of
axoplasmic flow. Subsequent swelling (ends of ruptured
axons) of RNFL give their characteristic appearance.
◦ Histology – cytoid bodies

53.  Venous beading in less than two quadrants
◦ Occurs when the dilated venular walls have the presence of
saccular microaneurysms.
 Intra-retinal microvascular abnormalities to mild degree
◦ They are dilated capillaries that seem to function as collateral
channels. Occur secondary to hypoxia.
◦ Key ddx is neovascularization.
 Follow-up: 6 months

60.  4-2-1 Rule: (*at least one of the following)
◦ Microaneurysms / hemorrhaging in all 4 quadrants-
SEVERE (20 / quadrant)
◦ Venous beading in 2 or more quadrants
◦ Moderately severe IRMA in one quadrant

61.  Any two of the following:
◦ Severe intraretinal hemorrhages in 4 quadrants
◦ Venous beading in 2 quadrants
◦ Moderately severe IRMA in 1 quadrant

62.  Follow-up: 3 months or retinal consult
◦ Studies show PRP may be beneficial at this stage
(based on ETDRS)
◦ Most retinal surgeons will hold off on PRP until PDR
develops
◦ 50% develop PDR within 15 months.

67.  Baseline Fundus Photography
◦ Seven Standard Diabetic Photographic Fields
 ONH centered, Macula centered, Temporal to macula,
Superotemporally,
Inferotemporally,
Superonasally and
Inferonasally
(*all exclude ONH
except for #1)

69. ◦ CPT: 92250 (*Bilateral procedure)
 Modifier 52 if performed on only 1 eye
◦ Requires Interpretation and Report
◦ Reimbursement ~ $87.00
◦ Cannot do on the same day as scanning laser, extended
ophthalmoscopy or external photography (slit lamp)
◦ Can be done up to two times per year

70.  Extended ophthalmoscopy
◦ Presence of pathology / Colored drawings (4”x4”)
◦ CPT: 92225 (*Unilateral code: 92225-RT/92225-LT)
◦ Requires interpretation and report
◦ Reimbursement ~ $28
◦ CPT: 92226 = Subsequent follow-up of the same condition
◦ Requires interpretation and report
◦ Reimbursement ~ $26
 Can be done 6x’s / year for diabetic
 retinopathy / glc (*condition dependent)

71.  Why did you do it?
 What did you find? (*Clinical Findings)
 What are you going to do? (*Clinical
Management)
 Change in condition

72.  Amsler Grid
 OCT
 Fluorescein Angiography – assessing vascular
integrity

73. Diabetic Macular Edema
 CPT: 92133 (ONH) / 92134
(Retina)
 Requires Interpretation and
Report
 Reimbursement ~ $51
 Unilateral or Bilateral
 Cannot do same day as
DFE/Fundus Photos (*if
billing)
 4x’s per year unless acute
condition

76.  Is a vascular response to retinal hypoxia
 Many theories about the cause of retinal hypoxia. .
◦ Capillary closure
◦ Alterations in capillary b. membrane
◦ Increase blood viscosity
◦ Altered ability of blood to transport oxygen
◦ Abnormal metabolic pathways in the retinal capillaries
◦ Production of VEGF (Vascular Endothelial Growth
◦ Factors)

77.  VEGF – thought to play a significant role in the
proliferation of neovascularization.
 The neovascularization is initially intraretinal but
breaks through the ILM and lies between it and
the vitreous.
 Fibrous component / ground substance develops
and contracts as the neovascularizaton increases.

78.  Classification once neovascularization occurs or
if a pre-retinal or vitreous hemorrhage is
present.
 Neovascularization can occur. . .
◦ At the iris (NVI)
◦ Elsewhere (NVE)
◦ At the disc (NVD)
 Gonioscopy – should be performed in presence
of neovascularization of the iris.

85.  The Diabetic Retinopathy Study (DRS) identified
risk factors for proliferative diabetic retinopathy
(PDR).
 Purpose of the study was to determine:
◦ Does photocoagulation prevent severe vision loss in eyes
with PDR.
◦ Laser photocoagulation was found to reduce the risk of
severe vision loss by more than 50% in eyes with high risk
PDR.

86.  Low risk
◦ NVD less than 1/4 to 1/3 the disc
◦ NVE (*without presence of traction)
 Obtain a retinal consult within 1 week

90.  High Risk
◦ NVD greater than 1/4 to 1/3 the disc
◦ NVD less than 1/4 to 1/3 the disc with associated
vitreous/pre-retinal hemorrhage
◦ NVE with associated vitreous/pre-retinal hemorrhage
 Obtain a retinal consult within 24-48 hours

91.  Pan-retinal photocoagulation (PRP)
◦ DRS proved benefit of immediate PRP
 Argon laser applied throughout the mid-
peripheral and peripheral retina.
 Reduces the retina’s need for oxygen >
decreases hypoxia > decreases vasoproliferative
mediators > regression of new vessel growth

92.  PRP reduced the rate of severe vision loss by 50% for
eyes with high risks characteristics.
 PRP typically divided into 2 to 3 sessions(w/orbital block)
 1200 – 1600 moderately intense burns placed ½ burn
width apart, using a 500 micron diameter spot size and
exposure time = 0.1 sec.s
 Do not go any closer than 2dd from the center of the
macula (sup/inf/temp) and 1/2dd nasal to the disc.

93.  The Diabetic Retinopathy Vitrectomy Study
(DRVS) addressed the question of the timing of
vitrectomy surgery for the management of PDR.
(1976-1980: when they typically waited 1 year
before doing a vitrectomy in one with a vitreous
hemorrhage)
◦ Early intervention lead to better outcomes with Type I
DM patients w/vitreous hemorrhage (5mo.s)
 Enhances oxygen to retina by 10 fold
 Use of intra-operative VEGF

101.  Decreased night vision and dark adaptation
 Decreased visual field / peripheral vision
 Atrophic creep- Becomes problematic when the
laser is applied too close to the macula or nerve
 Choroidal detachment
 Makes RNFL testing / analysis difficult.

104.  Classified into focal and diffuse types.
◦ Focal macular edema is caused by foci of vascular
abnormalities, primarily microaneurysms
◦ Diffuse macular edema is caused by dilated retinal
capillaries in the retina.
 Two types of laser treatment for diabetic
macular edema are focal and grid.
◦ Focal laser treatment for focal macular edema
◦ Grid laser treatment for diffuse diabetic macular
edema

105.  Retinal thickening at or within 500 microns (1/3
DD) of center of macula
 Hard exudates at or within 500 microns of the
center of the macula with adjacent retinal
thickening
 Retinal thickening greater than 1 DD in size which
is within 1 DD from the center of the macula

106.  Large multicenter study sponsored by NEI, which
recruited over 3,700 patients
 Asked 3 questions:
◦ Is photocoagulation effective in the treatment of diabetic
macular edema (DME)
◦ Is aspirin effective in changing the course of diabetic
retinopathy?
◦ When should PRP be initiated so as to be the most
effective?

107. ◦ Is photocoagulation effective in the treatment of diabetic
macular edema (DME)
 YES
◦ Is aspirin effective in changing the course of diabetic
retinopathy?
 NO
◦ When should PRP be initiated so as to be the most
effective?
 Early laser reduced the risk of the need for vitrectomy and
the risk of progression to high-risk retinopathy. For those
with “high risk” characteristics.

111.  Can occur at any level of retinopathy.
 ETDRS Study: demonstrated benefit of focal
and or grid laser in maintaining vision.
 Untreated, 25-30% of patients with CSME
exhibit a doubling of the visual angle within 3
years.
 Treated, the risk drops by 50%.
 Would you refer a patient for focal laser to treat
CSME if they were seeing 20/20?

112.  An option for eyes with media opacities or eyes
refractory to photocoagulation.
 Vitrectomy facilitates greater blood flow through retinal
vessels.
 Useful in eyes with DME if there is evidence of
vitreomacular traction.
 Concern: complications of the procedure

113.  One study demonstrated 61-73% resolution of
edema
 Supplementing with removal of the internal
limiting membrane may improve outcomes.
 Recent analysis demonstrates that this
procedure may only be beneficial for pt’s who
exhibits signs of macular traction.

114.  Clinically significant macular edema
 Pre-retinal / vitreous hemorrhage
 Retinal Detachment

115.  Is a potent enhancer of vascular permeability and
a key inducer of angiogenesis (growth of new
blood vessels).
 Angiogenic triggers include hypoxia and retinal
ischemia
 VEGF Isoform 165 is a critical isoform for both
developmental and pathologic retinal
angiogenesis

116.  VEGF is expressed by retinal endothelial cells
and retinal pigment epithelial cells.
 Anti-VEGF agents are very effective in
managing DME and PDR
◦ Prevents breakdown of blood retinal barrier, decreases
vascular permeability and retinal neovascularization

117.  Binds to and blocks the effects of VEGF165
 First drug approved by the FDA for tx of
neovascular ARMD (0.3mg dose).
 Studied in a phase II trial for DME – followed for 36
weeks.
 Overall improvement vs the “sham” injection
group. (*reduction of 69microns vs 4 microns)

118.  Binds and inhibits all forms of VEGF.
 Is also approved by the FDA for tx of ARMD
(0.5mg) and macular edema following retinal vein
occlusion.
 READ-1 Study (Ranibizumab for Edema of the mAcula in
Diabetes)
◦ Looked at bioactivity and safety of intravitreal
ranibizumab on 10 pts with DME for 1 year
◦ Mean retinal thickness decreased from ~500 microns to
~ 250 microns.
◦ No patients lost vision or had any systemic or ocular
adverse events.

119.  The READ-2 Study was a clinical study evaluating
ranibizumab vs focal laser photo. vs combination
therapy.
◦ The greatest gain in VA was seen in the ranibizumab only group –
8 letter improvement at month 6.
◦ The greatest reduction in retinal thickening (57%) was also seen
in the same group.(*11% - laser / 42% combo)
◦ By year 2, there was no statistically significant difference in mean
VA among the 3 treatment groups.
◦ No associated ocular or systemic adverse events occurred during
the study.

120.  RIDE & RISE studies
◦ 2 Phase III (36-mo.) multi-center studies to evaluate efficacy
& safety in patients with DME
◦ RIDE study – includes 58 investigators in the U.S. and 7 in
Latin America
◦ RISE study - includes 63 investigators in the US and 2 in
Argentina
◦ Overall, after 24 months 3 line improvement in treatment
group vs placebo group. More likely to achieve 20/40 vision
& less progression.

121.  In 2012, the FDA has approved Lucentis for the
treatment of diabetic macular edema.
◦ 0.3*-0.5mg dosed monthly for DME
◦ Common adverse effects: subconjunctival hemorrhage,
eye pain, increased IOP and floaters

122.  Is a mouse-derived monoclonal antibody to all
isoforms of VEGF.
 Is FDA approved for systemic treatment of
metastatic colon cancer but not for ophthalmic
indications.
 “off label” use in conditions such as ARMD,
diabetic retinopathy and DME.

123.  Short term studies have shown that intravitreal
bevacizumab is associated with rapid regression
of disc, retinal, and iris neo- secondary to PDR,
we well as resolution of macular edema.
 Patients typically need an injection roughly every
12 weeks up to the six month follow up (for DME).

124.  Back in 2011 - Dept of Veterans Affairs stopped
using Bevacizumab for ophthalmic purposes due
to incidents that have occurred at 3 different
facilities in Florida (12), Tennessee (4) and Los
Angeles (5).

125.  Diabetic Retinopathy Clinical Research Network
sponsored study – Phase 2 evaluation of Anti-
VEGF Therapy for Diabetic Macular Edema
 2-year study demonstrated that Avastin is more
effective than focal laser in pt’s with diabetic
macular edema.
◦ Injections at baseline, 6 and 12 weeks
◦ Until macular thickness was stable over 3 visits & within
20 microns of the pt’s thinnest recorded measurement.

126.  This study also found no difference between
1.25mg and 2.5mg of bevacizumab and similar
outcomes were found in other studies
◦ Pan-American Collaborative Retina Study Group
(PACORES)
◦ Study by Lam et al

127.  Is a fully human VEGF receptor fusion protein
designed to be a potent blocker of all forms of
VEGF-A.
 It binds to VEGF-A with greater affinity than native
receptors and penetrates all layers of the retina.

128.  A phase 2 randomized clinical trial (DA VINCI
study) was completed with 219 pt.s with 5 different
arms (4 different doses of VEGF Trap and 1 group
receiving focal laser)
 Statistically significant improvement in VA in all
aflibercept treated groups (2.0mg treated group
showed most gains)
◦ Key fact: a considerable number of re-injections were
necessary.

129.  In 2011aflibercept was recommended by FDA for
tx of wet ARMD. (*completed successful phase III
trials)
 Based on results of a couple of phase 3 trials –
VIEW 1 and VIEW 2

130.  Has shown promise in preliminary studies for the
treatment of DME.
 Larger studies are ongoing and we should be
getting results shortly.
 Improved delivery will be necessary in order to
avoid repeated intravitreal injections and the
cumulative risk of endophthalmitis.

131.  Triamcinolone acetonide suppresses
inflammation, reduces extravasation of fluid from
leaking blood vessels, inhibits fibrovascular
proliferation, and down regulates production of
VEGF.
 Desired route is intravitreal.
 Peak action is at 1 week (*3-6 mo.s)
 Complications: elevated IOP’s (50%), cataract
formation, and endophthalmitis (injection-related).

132.  A phase 3 randomized clinical trial evaluating the
safety and efficacy of preservative-free IVT vs
focal/grid laser
◦ At 4 months the IVT-treated group showed greater gains
in VA but by month 8 the gain narrows and at month 12
the VA gain of the laser treated exceeds the IVT-treated
groups (1mg / 4mg), which persisted to 24 months.
◦ OCT findings regarding retinal thickness were similar.
◦ IOP rise (33%) and cataract development seen in IVT
groups (51%/23% vs 13%)

133.  Implants are being developed to circumvent the
need for repeated injections.
◦ Ozurdex (Allergan)
◦ Retisert (Bausch & Lomb)
◦ Iluvien (Alimera Sciences)
◦ Ivation (Surmodics)

134.  Is a biodegradable dexamethasone pellet
(0.7mg)that is delivered to the posterior segment
in-office using an applicator (22 gauge).
 1st
FDA approved drug treatment for macular
edema following RVO (biodegradable)
 20-30% of pt’s experienced 3 line improvement in
BVA that occurred in the first 2-3 months

135.  Patented drug delivery system – sterile, single use
applicator preloaded with implant
 Designed to last 37 days (dissolves completely)
 ~25% developed increased IOP’s (>10mmhg)
 ~5% developed cataracts

137.  Consists of a tiny drug reservoir designed to
deliver sustained levels of the fluocinolone
acetonide, for approximately two-and-a-half years
(30 months). FDA approved for chronic
noninfectious uveitis therapy.
 0.59mg implant implanted in posterior segment

138.  Complications related to the development of
glaucoma and cataracts makes it use limited.
◦ At 3 yr.s 71% developed increase of IOP (>10mmhg)
◦ Nearly all patients developed cataracts
◦ 85% experienced improvement or stabilization in VA
(23% gained 3 lines or more)

140.  Is a narrow, 3.5mm long / 0.37mm in diameter,
cylindrical fluocinolone acetonide implant (190ug).
 Implanted non-surgically in-office with a 25 gauge
injector (*stays in vitreous base)
 Initial release rate of either 0.23 or 0.45 mcg per
day (lowest available) lasting up to 36 months.

141.  36 month FAME study completed in October
◦ Fluocinolone Acetonide in Diabetic Macular Edema
◦ ~29% demonstrated improvement in BCVA of 15 letters
from baseline at 3 years.
 Has not been approved by FDA.
◦ Asking for more data
 Has been resubmitted with results of patients being
treated in the UK and Germany.

143.  Metallic coil coated with triamcinolone
 Inserted with 25 gauge needle
 Can release the drug up to 2 years.
 Phase I study
◦ At 2 yr visit mean reduction in central retinal thickness
was 126 um
◦ VA improved then declined and then improved again
(found to be due to cataract development)
 No sustained elevations in IOP were noted in the
study group (*avg change was < 2mmHg)

144.  Phase II trials have been suspended
 Intended to evaluate the safety and efficacy
 NEI had released a study suggesting laser tx over
intravitreal injections of TA

147.  Micropulse Photocoagulation over standard laser
for DME
◦ Subthreshold diode laser
◦ Produces less damage/scarring

148.  Biodegradable microspheres and nanoparticles
 Looking at encapsulating of either Macugen or
Avastin into these particles for extended delivery.
 These would be biodegradable and intended to be
injected into the vitreous with a small gauge
needle.

149.  Encapsulated Cell Technology
◦ Involves genetically engineering (plasmid transfection)
certain cells, which encodes the therapeutic factor
which in then incorporated into the cell’s genome.
Cells produce desired therapeutic effect.
◦ The cells within the membrane are implanted and
begin to produce the desired therapeutic factor, which
diffuses throughout the retina.

150.  Questions??
 rmaeda@westernu.edu