This document provides information about diabetes and diabetic retinopathy for medical students. It outlines learning objectives related to understanding diabetes demographics, diagnosis, complications, and treatments. Key points include that diabetes affects over 29 million Americans and has significant medical costs. Diabetic retinopathy is a leading cause of blindness and its progression can be slowed by controlling blood sugar and blood pressure. The document also defines the stages of diabetic retinopathy and diabetic macular edema.

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