Global Diabetes Prevalence Is Projected to Increase 242% Between 2000 and 2030

Global data2000: 151 million patients2010: 221 million patients2030: 366 million patients

Amos AF, et al. Diabet Med. 1997;14:S7-S85.Wild S, et al. Diabetes Care. 2004;27:1047-1053.

2000: 14.2 M2010: 17.5 M

+23%

2000: 9.4 M2010: 14.2 M

+50%

2000: 84.5 M2010: 132.3 M

+57%

2000: 15.6 M2010: 22.5 M

+44%

2000: 26.5 M2010: 32.8 M

+24%

2000: 1.04 M2010: 1.33 M

+28%

Potential Metabolic Pathways Leading to Diabetic Microvascular Complications

Polyolpathway

Diabetic nephropathy

Diabetic retinopathy

Diabetic neuropathy

Diabetes

Ulcers/amputations

Hyperglycemia

Superoxideoverproduction

PKC βactivation

Vision loss

Renal disease

Diabetes-induced microvascular damage

GlycationDiacylglycerol

©2005 International Medical Press

A-II VEGF

Not shown in this diagram due to space limitations: activation of additional inflammatory and growth factors.

Purpose, Benefits, and Limitations of Common Retinal Diagnostic Procedures

Test name Purpose Benefits Limitations

Dilated stereo fundoscopy with slit-lamp biomicroscopy

Assess posterior pole, midperipheral, and peripheral retina

Detects CSME, PDR

Superior to fundus photography for detecting retinal thickening

Opacity may limit exam

Indirect ophthalmos-copy

Assess peripheral retina

Alternative to slit-lamp biomicroscopy

Opacity may limit exam

Stereoscopic 30° color fundus photography

Document retinal status

Permits objective comparison over time

More sensitive and reproducible than clinical exam

Requires trained photographer and trained reader

Opacity may degrade image quality

American Academy of Ophthalmology. Preferred Practice Pattern: Diabetic Retinopathy. San Francisco, California: American Academy of Ophthalmology; 2003.

Purpose, Benefits, and Limitations of Advanced Retinal Diagnostic Procedures

Test name Purpose Benefits Limitations

Fluorescein angiography

Assess retinal perfusion

Provides guidance for treating CSME

Diagnose unexplained decreased visual acuity

Diagnose clinically obscure retinal neovascularization

Not needed to diagnose CSME or PDR

Not routinely indicated

Not indicated for screening

Opacity may degrade image quality

Ultrasound Assess retinal thickness

Allows retinal assessment even if opacity is present

Lower image resolution than OCT

Optical coherence tomography (OCT)

Diagnose and quantify DME

Diagnose macular holes or cysts, vitreomacular traction

Provides high-resolution, cross-sectional images of the vitreoretinal interface, retina, and subretinal space

Opacity may degrade image quality

American Academy of Ophthalmology. Preferred Practice Pattern: Diabetic Retinopathy. San Francisco, California: American Academy of Ophthalmology; 2003.

• Allows for retinal imaging in presence of media opacity

• Aids in diagnosis of retinal detachment

• Assesses need and urgency for vitreoretinal surgery

Ultrasonography

Image courtesy of Thomas Ciulla, MD

Retinal detachment + Hemorrhage

• IVFA is good for:– Highlighting

microaneurysms– Showing ischemia– Showing break-

down of the blood retinal barrier

– Diagnosing proliferative diabetic retinopathy

Utility of Intravenous Fluorescein Angiography (IVFA)

Photographic fundus image

Fluorescein angiogram

OCT and DME

• Sponge-like fluid accumulation in the outer retina

(60% to 96% of eyes) corresponds to focal/diffuse ME

OCT and DME

• Cystoid macular edema (CME) (50%)

OCT and DME

• Mechanical—hyaloidal traction and/or ERM (16%)

OCT and DME

• Serous macular detachment with or without traction (15%)

Signs and Symptoms of Diabetic Retinopathy

Preclinical NPDR PDR DME

Symptoms None None, or blurred vision and glare

None, or reduced vision and floaters

None, or blurred vision

Clinical signs

Normal-appearing retina

Retinal venous dilation

Microaneurysms

Cotton-wool spots

Intraretinal hemorrhages

IRMAs

Venous beading

Retinal venous dilation

Venous beading

IRMAs

Neovascularization

Swelling of retina

Increased capillary leakage

Fluid accumulation in retinal layers

IRMA = intraretinal microvascular abnormalityGardner TW, Aiello LP. Pathogenesis of diabetic retinopathy. In: Flynn HW, Smiddy WE, eds. Diabetes and Ocular Disease: Past, Present, and Future Therapies. AAO Monograph Number 14. San Francisco: The Foundation of the

American Academy of Ophthalmology; 2000:1-17.

Severe NPDR

Nonproliferative Diabetic Retinopathy

Severe NPDR, courtesy of Diabetic Retinopathy Study Research Group

Neovascularization

Hemorrhage

©2005 International Medical Press

Proliferative Diabetic Retinopathy

• Cystoid macular edema

• Focal macular edema– Usually seen as

circinate exudates– Microaneurysms at

the center

• Diffuse macular edema

Diabetic Macular Edema: 3 Clinical Varieties

Image courtesy of JS Duker, MD

• Tx–intravitreal triamcinolone

Diabetic Macular Edema

Inferior Superior

INL

IS/OS

ONL

OPL

RPE/OS

ELM

IPL

GCL

RNFL

500μm

2x

Retinal Layers on Ultrahigh Resolution OCT

Early Treatment of Diabetic Retinopathy Study (ETDRS) Scale

Level Severity Definition

10 No retinopathy

Diabetic retinopathy absent

20 Very mild NPDR

Microaneurysms only

35 Mild NPDR Microaneurysms with hard exudates, cotton-wool spots, and/or mild retinal hemorrhages

43 Moderate NPDR

Microaneurysms plus mild IRMA or moderate retinal hemorrhages

47 Moderate NPDR

More extensive IRMA, severe retinal hemorrhages OR

Venous beading in 1 quadrant

53 Severe NPDR Severe retinal hemorrhages in 4 quadrants OR

Venous beading in at least 2 quadrants OR

Moderately severe IRMA in at least 1 quadrant

NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; IRMA = intraretinal microvascular abnormalities

DCCT. Arch Ophthalmol. 1995;113:36-51.

International Clinical Diabetic Macular Edema Disease Severity Scale

Proposed Disease Severity Level

Findings Observable Upon Dilated Ophthalmoscopy

DME apparently absent No apparent retinal thickening or hard exudates in posterior pole

DME apparently present Some apparent retinal thickening or hard exudates in posterior pole

If DME is present, it can be categorized as follows:

Mild DME Some retinal thickening or hard exudates in posterior pole but distant from the center of the macula

Moderate DME Retinal thickening or hard exudates approaching the center of the macula but not involving the center

Severe DME Retinal thickening or hard exudates involving the center of the macula

DME = diabetic macular edema Wilkinson CP, et al. Ophthalmology. 2003;110:1677-1682.American Academy of Ophthalmology. Preferred practice pattern: diabetic retinopathy.

San Francisco, Calif: American Academy of Ophthalmology; 2003.

International Clinical Diabetic Retinopathy Disease Severity Scale

Proposed Disease Severity Level

Findings Observable Upon Dilated Ophthalmoscopy

No apparent retinopathy No abnormalities

Mild NPDR Microaneurysms only

Moderate NPDR More than just microaneurysms but less than severe NPDR

Severe NPDR

(4:2:1 Rule)

Any of the following:• More than 20 intraretinal hemorrhages in each of 4

quadrants• Definite venous beading in 2 or more quadrants• Prominent IRMA in 1 or more quadrants and no signs of

PDR

PDR One or both of the following:• Neovascularization• Vitreous/preretinal hemorrhage

NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; IRMA = intraretinal microvascular abnormalities

Wilkinson CP, et al. Ophthalmology. 2003;110:1677-1682; American Academy of Ophthalmology. Preferred practice pattern: diabetic retinopathy. San Francisco, Calif: American Academy of Ophthalmology; 2003.

DCCT: Lower A1C Slows Development and Progression of Retinopathy

Primary Cohort: No Baseline Retinopathy

Secondary Cohort: Some Retinopathy at Baseline

Primary conventional: n = 378Primary intensive: n = 348

Secondary conventional: n = 352Secondary intensive: n = 363

DCCT. N Engl J Med. 1993;329:977-986.

Percentage of Patients Experiencing Sustained 3-Step Decrease

60 Cumulative Incidence

Study Year

Pe

rce

nt

P < .001 CON

INT

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9

60 Cumulative Incidence

Study Year

Pe

rce

nt

P < .001 CON

INT

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9

UKPDS*: Lower A1C Correlates With Reduced Risk of Development and Progression of

Retinopathy in Type 2 Diabetes

Development:

P<.001

Progression:

P<.001

Stratton IM, et al. Diabetologia. 2001;44:156-163.Matthews DR, et al. Arch Ophthalmol. 2004;44:1631-1640.

<6.2 6.2-7.4 ≥7.5 <6.2 6.2-7.4 ≥7.5

Baseline A1C, %

0.1

1

8

Rel

ativ

e R

isk

• n = 1,919

• Development: new retinopathy >6 years for patients without retinopathy at baseline

• Progression: 2 or more steps on the final ETDRS scale >6 years for patients with retinopathy at baseline

*United Kingdom Prospective Diabetes Study

UKPDS: Lower BP Reduces Relative Risk of Development and Progression of Retinopathy

Over 7.5 Years in Type 2 Diabetes

Matthews DR, et al. Arch Ophthalmol. 2004;44:1631-1640.

• n = 1,148

• Tight blood pressure control: <150/85 mm Hg

• Less tight blood pressure control: <180/105 mm Hg

• Results shown for both cohorts (with and without baseline retinopathy) randomized to tight blood pressure control

Sign or outcome Relative risk

P value

≥5 microaneurysms 0.66 <.001

Hard exudates 0.53 <.001

≥1 cotton-wool spot 0.53 <.001

≥2-step ETDRS loss 0.66 .001

Laser photocoagulation

0.63 .03

Blindness in 1 eye (VA worse than 20/200)

0.76 .46

High-risk PDR

(3 or 4 high-risk features)

No Usually No

Yes Usually Usually

Indications for Laser Photocoagulation Therapy in Diabetic Retinopathy

Adapted from: American Academy of Ophthalmology. Preferred practice pattern: diabetic retinopathy. San Francisco, Calif: American Academy of Ophthalmology; 2003.

Mild to moderate NPDR

No No No

Yes No Usually

Severe or very severe PDR

No Sometimes, especially type 2 No

Yes Sometimes, especially type 2 Usually

Non–high-risk PDR

(1 or 2 high-risk features)

No Sometimes, especially type 2 No

Yes Sometimes, especially type 2 Usually

Severity of retinopathy

CSME present?

Scatter laser photocoagulation

Focal laser photocoagulation

Indications for Vitrectomy and Potential Complications

American Academy of Ophthalmology. Preferred practice pattern: diabetic retinopathy. San Francisco, Calif: American Academy of Ophthalmology; 2003.

Flynn HW, Smiddy WE, eds. Diabetes and Ocular Disease: Past, Present, and Future Therapies. AAO Monograph No 14. San Francisco: The Foundation of the American Academy of Ophthalmology; 2000.

Diabetic Retinopathy Vitrectomy Study report number 2. Arch Ophthalmol. 1985;103:1644-1652.

Indications

• Nonclearing vitreous hemorrhage• Severe fibrovascular proliferation

before traction detachment involves the macula

• Traction macular detachment• Combined traction-

rhegmatogenous retinal detachment

• Vitreous hemorrhage precluding scatter photocoagulation

Potential Complications

• Retinal detachment• Recurring vitreous

hemorrhage• Rubeosis iridis• Severe visual loss• Eye pain• Ocular infection

Intravitreal Triamcinolone Improves VA and Reduces DME

Chieh JJ, et al. Retina. 2005;25:828-834.

Clinical Resolution of Edema

Mea

n C

han

ge

in V

A (

Lo

gM

AR

)

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

0.18

0.2

1 3 6

0

10

20

30

40

50

60

70

Re

so

lve

d

Imp

rov

ed

No

ch

an

ge

Se

ve

reD

ME

1 month 6 months

Improvement in VA Relative to Baseline

Per

cen

t o

f E

yes

Month

Pegaptanib Decreases Retinal Thickness at Center Point of Central Subfield in CSME

-80

-70

-60

-50

-40

-30

-20

-10

0

10

Sham (n = 42)

0.3 mg (n = 44)

1 mg (n = 44)

3 mg (n = 42)

Cunningham ET Jr, et al. Ophthalmology. 2005;112:1747-1757.

Pegaptanib Dose

Note: Authors state that study was not powered to detect dose-dependent treatment effects.

Ch

ang

e in

Cen

tral

Ret

inal

T

hic

knes

s, μ

m

P = .02

Pegaptanib Improves VA Outcomes in DME

Cunningham ET Jr, et al. Ophthalmology. 2005;112:1747-1757.

Note: Authors state that study was not powered to detect dose-dependent treatment effects.

Increase in VA

(letters)

Pegaptanib Dose

Sham

(n = 41)

0.3 mg

(n = 44)

1 mg

(n = 43)

3 mg

(n = 42)

≥ 10 10% 34%

P = .003

30% 14%

≥ 15 7% 18%

P = .12

14% 7%

Patients attaining ≥ 2-line increase after 36 weeks of treatment

Pegaptanib Adverse Events

Event Sham Pegaptanib

Eye pain 17 31

Vitreous floaters 7 22

Conjunctival hemorrhage 10

Vitreous opacities 5 9

Vitreous disorder NOS 7

Visual disturbance NOS 2 7

Sterile endophthalmitis 1

Ocular adverse events that occurred significantly more often in study eyes1

Cunningham ET Jr, et al. Ophthalmology. 2005;112:1747-1757.

Data are percentage of total patient group. Zeroes omitted. NOS = not otherwise specified.1Punctate keratitis, cataracts, and eye discharge occurred at approximately equal rates in both sham and pegaptanib groups. No clinically relevant differences were observed between treatment groups for cardiac, hemorrhagic, thromboembolic, or gastrointestinal disorders.

Epalrestat Shows Trend Toward Reduced Retinal Vascular Leakage

Steele JW, Faulds D, Goa KL. Drugs Aging. 1993;3:532-555.

Treatment regimen (disease stage)

Treatment duration, months

Number of eyes

FA improved or unchanged, %

FA worse, %

100 mg TID epalrestat (NPDR)

36 34 97 3

Untreated control (NPDR)

137 72 28

100 mg TID epalrestat (PP)

36 45 58 42

Untreated control (PP)

25 20 80

FA = fluorescein angiography; PP = preproliferative (severe) NPDR

Epalrestat Adverse Events

Steele JW, Faulds D, Goa KL. Drugs Aging. 1993;3:532-555.

Liver enzyme elevations

Alanine aminotransferase 1.0%

Aspartate aminotransferase 1.0%

Glutamyl transpeptidase 1.0%

Diarrhea 0.2%

Erythema 0.2%

Skin bullae 0.2%

Serum creatinine elevation 0.2%

Midostaurin (PKC412) Reduces Foveal Thickness in DME

Campochiaro PA, et al. Invest Ophthalmol Vis Sci. 2004;45:922-931.

Ch

ang

e in

Fo

veal

Th

ickn

ess

(mic

ron

s)

Placebo (n = 34)

PKC412 50 mg/d (n = 32)

PKC412 100 mg/d (n = 38)

PKC412 150 mg/d (n = 37)

25

0

-75

-25

-50

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Month

Treatment period from Month 0-3

100: P = .015150: P = .039

50: P = .016

100 mg/day Midostaurin Improves Mean VA by About 1 Line at 3 Months

Campochiaro PA, et al. Invest Ophthalmol Vis Sci. 2004;45:922-931.

Placebo (n = 34)

PKC412 50 mg/d (n = 32)

PKC412 100 mg/d (n = 38)

PKC412 150 mg/d (n = 37)

Month

Ch

ang

e in

VA

(n

um

ber

of

lett

ers) 100: P = .007

150: P = .019

50: P = .029

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Treatment period from Month 0-3

6

0

-5

Midostaurin (PKC412) Adverse Events

Campochiaro PA, et al. Invest Ophthalmol Vis Sci. 2004;45:922-931.

Data are percentage of total patient group. Zeroes omitted.NOS = not otherwise specified; PBO = placebo

Organ system

Event PBO 50 mg/d 100 mg/d 150 mg/d

Gastro-intestinal

Nausea 3% 6% 21% 38%

Diarrhea NOS 3% 3% 16% 19%

Vomiting 3% 3% 19%

HepaticIncreased ALT 6% 8% 14%

Increased AST 3% 8% 8%

Events occurring in >5% of patients in any treatment group

Ruboxistaurin Reduces Risk of Moderate or Worse Visual Loss in Diabetic Retinopathy With or Without DME

PKC-DRS Study Group. Diabetes. 2005;54:2188-2197.

Placebo (n = 100 eyes)8 mg (n = 99 eyes)16 mg (n = 104 eyes)32 mg (n = 108 eyes)

50

40

Pro

bab

ilit

y o

f M

VL

, %

Months

Log Rank P values:Overall: .06932 mg vs Placebo: .038

0 6 12 18 24 30 36 42

30

20

10

0

MVL = moderate visual loss (≥15 letters)

Ruboxistaurin Adverse Events

PKC-DRS Study Group. Diabetes. 2005;54:2188-2197.

Data are percentage of total patient group.CAD = coronary artery disease; NOS = not otherwise specified; 1° AV block = first-degree atrioventricular block

Organ system Event PBO 4/8 mg/d 16 mg/d 32 mg/d

GastrointestinalDiarrhea NOS 16.9 13.6 24.4 14.9

Flatulence 1.7 1.3 4.2 0.4

CardiovascularCAD NOS 6.8 3.5 13.0 4.7

1° AV Block 0 1.3 1.3 3.4

Pulmonary Asthma NOS 0.8 1.8 1.7 4.7

RenalDysuria 1.3 0.9 1.7 4.3

Proteinuria 0.8 1.3 3.8 0.9

Dermatological Hyperkeratosis 5.5 6.6 2.5 2.1

Events occurring in >3% of patients in any treatment group and with statistically significant difference between groups