Standard Photo 2A

HMAs

Standard Photo 6B
Venous Beading

Standard Photo 8A
IRMA

Standard Photo 7
NVE

Standard Photo 10A

NVD

19

High Risk PDR

DCCT Evaluating
Type 1 Diabetes:
Intensive Blood Glucose Control vs. Standard Blood Glucose Control

Blood Glucose Control

Intervention Studies: Glycemic Control

DCCT* (Type 1 diabetes)
10

DCCT showed beneficial effects of intensive glycemic control

Reduced risk of onset of DR Reduced risk of p progression g of DR

9.1
P< 0.001 Conventional therapy Intensive therapy

Drawbacks to intensive control

Hypoglycemia Weight gain Early worsening of DR

Mean 8 HbA 1c (%)

6

7.2

0 N = 1,441 patients
*After 6.5 years Adapted from DCCT Research Group. N Engl J Med. 1993;329:977-986.

DCCT: Intensive Glucose Control in Type 1 diabetes mellitus

Compared to conventional insulin therapy, intensive insulin therapy reduced the risk of development and progression of: Risk Reduction* Retinopathy Nephropathy Neuropathy
*Compared with conventional treatment Urinary albumin excretion 300 mg/24 h Adapted from DCCT Research Group. N Engl J Med. 1993;329:977-986.

HbA1c and Microvascular Complications: DCCT

15 13 11 Relative 9 Risk 7 5 3 1 7 8 9 10 HbA1c, % 11 12 Neuropathy Nephropathy Retinopathy

63% 54% 60%

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

120

20

Early Worsening of DR
DCCT found long long-term benefit of tight control outweighs early worsening 65% reduction in long term progression of DR, DR despite early worsening

Early Worsening of DR
Risks for early worsening

Higher HbA1C Reduction of HbA1C by 1% or more Baseline retinopathy more severe Duration of diabetes longer

Management
Monitor before initiation of treatment, and every 3 mo intervals Delay tight glycemic control to complete PRP in high risk DR (especially if HbA1C is high)

Type 1 DM
In the DCCT, for each 10% decrease in A1C (e.g., 9.0% decreased to 8.1% or 8.0% decreased to 7.2%) there is a 39% decreased risk of DR over the range of A1c levels.
The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 1995; 44:96844:968-983. The Writing Team for the Diabetes Control and Complications Trial/Epidemi9logfy of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002;287:2563 2002;287:2563-2569.

UKPDS Evaluating
Type 2 Diabetes: Intensive Blood Glucose Control vs vs. Standard Blood Glucose Control similar results to DCCT

UKPDS: Study Overview

UKPDS
37 39% had retinopathy at baseline *
WESDR showed 21% - mean A1c was 10.37%)

A 20 20-year, multicenter, prospective, randomized, interventional trial Recruited 5102 newly diagnosed type 2 diabetes patients Mean duration from randomization: 11 years Randomized to intensive glucose control vs. conventional control

Intensive control showed

34% reduction in p progression g of retinopathy** p y 29% reduction in need for laser treatment 16% reduction in legal blindness

21

UKPDS: Intensive Glucose Control in Type 2 Diabetes Mellitus

Glycemic control deteriorated with time regardless of initial therapy Intensive glycemic control reduced HbA1c by 0.9% over 10 years, with resulting decrease in clinical complications

Risk reduction*

Type 2 DM
In the UKPDS, the overall microvascular complications rate was 25% lower in subjects on intensive treatment vs. conventional treatment. For every 1% decrease in A1C level (e.g., 10% reduced to 9 % or 9% reduced to 8%), 8%) there was a 35% reduction in the risk of microvascular complications.
American Diabetes Association. Implications of the Diabetes Control and Complications Trial. Diabetes Care 2002;25 (supplement 1); S25S25-S26. UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 38). BMH 1998; 317:703317:703-713.

Microvascular disease Retinopathy progression Microalbuminuria Myocardial infarction

*Compared with conventional therapy At 12 years

25% 21% 33% 16%

ACCORD

ACCORD STUDY
10,251

Action to Control Cardiovascular Risk in Diabetes NHLBI Study ~ 10 000 patients with type 2 diabetes followed for 3.5 - 5 years. Baseline characteristics mean age, age 62 to 66 years; Patients either had heart disease or two risk factors for heart disease. Does HbA1c level of <6.0% reduce the rate of cardiovascular events > targets of HbA1c of 7.0% to 7.9%
duration of diabetes, 8 to 10 years; median glycated hemoglobin level, 7.2 to 8.1%.

patients (mean age 62) with a median A1c of 8.1% were assigned to receive intensive therapy (aiming for A1c goal less than 6%) or standard therapy (with goal A1c of 7 7-7.9%). Multi Multi-center clinical study conducted in 77 centers across U.S. and Canada. Patients had known cardiovascular disease (35% ( had prior CV events) or albuminuria, LVH, or 2 additional risk factors (HBP, hyperlipidemia, smoker, or obesity). Study included 38% women and 64% were Caucasian. Average BMI was 32. Primary outcome composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes. Intensive therapy group was discontinued after 3.5 years of followfollow -up due to higher mortality.

ADVANCE STUDY
11,240

patients with Type 2 diabetes randomized to standard(A1c goal defined based on local standards) or intensive control (target goal less than 6.5%). Study was conducted at 215 centers in 20 countries( from Asia, Australia, Europe and North America). Patients enrolled were over 55 y.o. and a history of major macrovascular disease or microvascular disease and one other risk factor for vascular disease. Patients in standard group were seen at month 3,4,and 6 then every 6 months thereafter whereas patients in the intensive group were seen at months 1,2,3,4 and 6 then every 3 months. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal MI, nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy)

ADVANCE

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Baseline characteristics of the participants in both studies were typical for adults with type 2 diabetes: Approximately one third of patients in each study had a history of macrovascular disease, so both trials assessed the effect of intensive glycemic control in patients with without preexisting macrovascular disease

22

ADVANCE

Enrollment, Randomization, and Follow-up of Study Participants

The primary outcome in the ADVANCE trial was a composite end point of macrovascular and microvascular events The role of glucose lowering in the prevention of cardiovascular events is the principal unanswered question; it is already well known that intensive glycemic control reduces microvascular complications. In the ADVANCE study, nonglycemic cardiovascular risk factors were not optimally controlled.

The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

Glucose Control at Baseline and during Follow-up, According to Glucose-Control Strategy

Cumulative Incidences of Events, According to Glucose-Control Strategy

The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

Study Overview

Final thoughts

As compared with standard glucose control in patients with type 2 diabetes, intensive glucose control in the ADVANCE trial reduced the risk of nephropathy but not the risk of macrovascular events There was no significant difference between the two groups in overall mortality These findings, along with those of the ACCORD trial, raise complex questions about the role of intensive glucose control in type 2 diabetes

Current evidence would be that tight glycemic control (aiming for near normal A1c) in patients with Type 2 diabetes and established coronary artery disease will not improve macrovascular disease(and might increase CVEs) CVEs). Need to individualize glycemic goals depending on patient co co-morbid conditions. Aggressive treatment of lipid levels and blood pressure control as well as use of aspirin has been shown to decrease cardiovascular events in patients with diabetes.

23

Major Diabetes Complications Can Be Prevented With Optimal Care

Estimated cases p per year in US
100,000
Nonpreventable

Case Studies - Patient CL

4747-year old female Type 1 DM x 26 years LEE - 6 months ago (undilated) Dilated retinal examination 2 years ago POHx mild retinopathy No ocular or visual complaints

80,000 60 000 60,000 40,000 20,000 0 Blindness

Preventable

Kidney failure

Amputation

http://www.cdc.gov/diabetes/pubs/estimates.htm

Case Studies - Patient CL

VA

Case CL OD
Mild/mod NPDR PDR<HRC No evidence of DME

= 20/20 OD, 20/30 OS Sensorimotor examination intact SLE early cataract OD No evidence of NVI

CL OS
Mild/mod NPDR PDR with HRC PRH
Case CL post treatment

24

Diabetes Mellitus
Clinical Pathologic Process in DR

Retinal Signs of Hypoxia

Cotton wool spots Venous caliber abnormalities IRMA Featureless retina

Significant impairment of retinal blood flow

autoregulation Capillary nonperfusion leads to loss of function of pericytes of retinal capillaries Pericytes support endothelial vessel wall function and integrity Outpouching of capillary walls form microaneurysms, which occur in clusters typically around areas of capillary nonperfusion Angiogenic factors may play a role in early diabetic retinal changes

Diabetic Retinopathy
Features Altered retinal blood flow Increased vascular permeability Closure of retinal capillaries and arterioles Cotton-wool spots IRMA 70% of NVE occurs in same area as IRMA Proliferation of new vessels Fibrous proliferation with VH and RD Absence

CL - Notes
of HM/as No ocular or visual complaints Last exam eye exam 2 years ago High risk PDR Three diagnoses Clinical pearls
Few HMas is not always reassuring Superior temporal quadrant

Oxidative Stress StressInduced Vasculopathy in Diabetes

Glucose
Activation of polyol pathway Glucose autoxidation PKC-dependent activation

Protein glycation

Mitochondrial hyperproduction of superoxide radicals

AGE formation

ROS
Structural and functional modifications of proteins Vascular dysfunction, cardiovascular risk Microangiopathy (retinopathy, nephropathy, neuropathy)
Bonnefont-Rousselot. Treat Endocrinol. 2004;3:41-52

25

Pathophysiology of DR
Relative hypoxia Biochemical changes/glucose mediated microvascular changes (PKC, advanced glycation end products, products VEGF VEGF, et al.) ) Compromised neuroretinal function Inflammation diabetic retinitis Glucose excess/insulin deficiency

DR Pathophysiologic Processes
Alterations in retinal blood flow Loss of pericytes of retinal capillaries Outpouchings of capillary walls to form microaneurysms Closure of retinal capillaries and arterioles with shunting Breakdown of blood/retinal barrier with edema Proliferation of new vessels and fibrous tissue Contracture of vitreous and fibrous proliferation

Hyperglycemia and the Retina

Oxidative Stress & Diabetes

Causes Hyperglycemia Hyperleptinemia tissue lipids AGEs protein kinase C antioxidant defenses free radical formation Chronic inflammation Effects 1. Cellular Insulin Resistance 2. Pancreatic Beta Cell Dysfunction 3. Accelerated arterioarteriol & sclerosis arteriolarsclerosis 4. Neuropathy 5. Retinopathy

Increase the amount of free radicals produced in the body. Free radicals may cause increased levels of oxidative stress. Oxidative and perioxidative stress leads to the accumulation of AGEs AGEs contribute to microangiopathy in diabetes including DR. Complications in these vessels may contribute to diabetic retinopathy and other microvascular abnormalities Antioxidants contained in Ocuvite DF may help reduce oxidative stress*

HK Vincent and AG Taylor, Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans, International Journal of Obesity, 30 p400-18, 2006

International Clinical DME Severity Scale

Proposed Disease Severity Level Observable Findings No retinal thickening or HE in posterior pole

DME absent
Disease Severity Level

If DME is present classified as:

Observable Findings Some retinal thickening or HE in posterior pole but away from the center of the macula Retinal thickening or HE approaching the center of the macula but not involving the center Retinal thickening or HE involving the center of the macula

Mild DME Moderate DME Severe DME

26

International Classification of DR Disease Severity Scale

Proposed Disease Severity Level

Standard Photographs & Image Resources

Observable Findings

No apparent DR Mild NPDR Moderate NPDR Severe NPDR

No abnormalities HMAs only More than mild but less than severe Any of the following:
20 Definite Prominent

http://eyephoto.ophth.wisc.edu/ http://eyephoto ophth wisc edu/ ResearchAreas/Diabetes/DiabStds.htm

or more intraretinal hemorrhages in 4 quadrants venous beading in 2 or more quadrants IRMA in 1 or more quadrants and no NV

Proliferative DR

1 or more of the following:

Definite Preretinal

neovascularization or vitreous hemorrhage

Diagnosis of Diabetic Retinopathy

Consider International classifications Remember 4 4-2-1 rule (sentinel lesions of DR)

Type 1 Vs. Type 2

Type considered when initiating timing of PRP PRP is indicated at time of highhigh-risk PDR ETDRS showed PRP may be indicated before highhigh-risk PDR
Type 2 only Early PRP decreases risk of SVL or need for vitrectomy by 50% after 5 years

HM/as HM/ Venous beading IRMA

DRCR Network Overview Diabetic Retinopathy Clinical Research Network

DRCR.net: Dedicated to multicenter clinical research ofdiabetic retinopathy, macular edema & associated disorders

Funding:
National Eye Institute Institute-sponsored cooperative agreement initiated September 2002

O Objective:
The development of a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions.

27

DRCR Network Sites

DRCR.net Clinical Studies

A. Laser for diabetic macular edema B. IV triamcinolone vs. laser C. OCT diurnal variation D. Vitrectomy Study d E. Peribulbar triamcinolone study F. PRP PRP-DME study G. Subclinical DME study

DRCR DRCR.net t >199 sites overall >123 community >672 total PIs >1900 study personnel 45 States

www.DRCR.net

DRCR.net Clinical Studies

H. Bevacizumab (Avastin) phase 2 study I. Laser Laser-ranibizumab ranibizumab-triamcinolone for DME J. LaserLaser-ranibizumab ranibizumab-triamcinolone for DME + PRP K. LaserLaser-response study L. Evaluation of VA Measurements in Eyes with Diabetic Macular Edema

DRCR.net Clinical Studies

O. Comparison of Time Domain OCT and Spectral Domain OCT Retinal Thickness Measurement in Diabetic Macular Edema P. Pilot Study in Individuals with Center Center-Involved Diabetic Macular Edema Undergoing Cataract Surgery Q. Observational Study in Individuals with Diabetic Retinopathy without CenterCenter-Involved Diabetic Macular Edema Undergoing Cataract Surgery

Ongoing DR Studies General Classes

PKC Inhibitors - ruboxistaurin Anti Anti-VEGF Avastin Avastin, , Lucentis Lucentis, , Macugen Steroids triamcinolone triamcinolone, , dexamethasone dexamethasone, , fluocinolone, fluocinolone , implants Interventional Techniques laser, PPV Neuroprotection Neuroprotection/Inflammation /Inflammation doxycycline, doxycycline , bromfenac Vitreolysis - microplasmin

IVSI
Steroids are appealing and efficacious for treating Multifactorial effect of steroids
leukocyte l k t endothelial d th li l cell ll adhesion dh i tight junction protein remodeling inflammatory mediators makes steroids a very appealing part of DME treatment

28

Intravitreal Triamcinolone: Mechanism of Action

Reduces blood blood-retinal barrier breakdown Reduces inflammation Downregulates VEGF production Inhibits MMP 2 & 9

(which are responsible for tissue remodeling of type IV collagen)

Intraocular Formulation Comparison with Kenalog - 40

Ingredient Triamcinolone Acetonide Benzyl Alcohol Polysorbate 80 Sodium Chloride Sodium Phosphate Sodium Hydroxide/ Hydrochloric Acid Allergan Form 2 and 8% To Isotonicity 0.34% to pH 7.3 Kenalog - 40 4% 0.99% 0.04% To Isotonicity to pH 5.0 -7.5

Formulation and Packaging

Preservative & endotoxin free Isotonic and pH Balanced SingleSingle -unit Dosing Allergan

Intravitreal Triamcinolone: Complications

Increased IOP:
3030-50% eyes require glaucoma gtts <1% refractory (requiring surgery)

Sterile, , prefilled p (0.05ml), ( ), singlesingle-dose, readyready-to to-use syringe with attached 2727gauge needle.

Endophthalmitis:
Noninfectious: ~ 2 % Infectious: ~0.5 %

ShelfShelf-stable and requires no shaking to re re-suspend. Homogeneous, white suspension, easily delivered.

Cataract:
~2% (6 mo)mo)-Probably underestimated Likely higher w/time & repeat injections

Ongoing DR Studies General Classes

PKC Inhibitors - ruboxistaurin Anti Anti-VEGF Avastin Avastin, , Lucentis Lucentis, , Macugen Steroids triamcinolone triamcinolone, , dexamethasone dexamethasone, , fluocinolone, fluocinolone , implants Interventional Techniques laser, PPV Neuroprotection Neuroprotection/Inflammation /Inflammation doxycycline, doxycycline , bromfenac Vitreolysis - microplasmin

Objective Determine whether IVT injections at doses of 1mg or 4mg produce greater benefit, with an acceptable safety profile, than macular laser p photocoagulation. g Major Eligibility Criteria BCVA 24 letters (20/320 or better) and 73 letter score (worse than 20/32) CenterCenter-involved DME on clinical exam and OCT Enrollment (7/04(7/04-5/06) Total enrolled: 693 subjects/840 eyes at 88 sites

Protocol B: Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for DME

29

Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for DME

VA

benefit in 4 mg IVT group at 4 months consistent with published case series visual acuity differences by 1 year VA benefit b fi and df fewer side id effects ff (IOP & cataract) in laser group at 3 years results mirrored visual acuity results

Importance of Focal/Grid Photocoagulation

No

Greater G OCT

Laser

or IVT likely improves VA over 3 years compared with expected untreated course
Arch Ophthalmol 2009; 127:245-251.

Results re-affirm importance of laser in management of DME It was as widely idel believed belie ed that the ETDRS showed laser reduces vision loss, but did not improve VA . . . however . . . majority of eyes in ETDRS were better than 20/40 (no room for substantial improvement)

Conclusion
Focal/grid is more effective than IVT with fewer side effects Laser or IVT likely improve VA over 2 years compared with expected untreated course Focal/grid currently most effective treatment for patients with DME Focal/grid currently benchmark for clinical trials for DME

Intravitreal Steroids and DME

Unanswered Questions Magnitude of effect Duration of effect Magnitude of effect compared with laser Effectiveness in more extensive DME Effectiveness after prior focal/grid photocoagulation Extent of long long-term side effects

Corticosteroid Implants

B&L Fluocinolone Acetonide Implant: Retisert

Sutured implant (Retisert) Injected implant (Posurdex)

Fluocinolone 0.5 mg 2-3 year duration

Clinical trials underway

From Regillo, Brown, Flynn, eds. Vitreoretinal Disease: The Essentials. Thieme 1999

Dexamethasone 3-4 month duration

30

Posurdex Delivery

Posurdex
Biodegradable dexamethasone implant, a sustained medication release device Drug is incorporated into the polymer matrix Polymer erodes while the drug is released

VEGF

VEGF in the Normal Eye

VEGF and VEGF receptors expressed in normal eye Receptors present in neural elements of inner retina High VEGF expression in retinal pigment endothelium Researchers hypothesize VEGF may be important for choriocapillaris survival and/or fenestrae maintenance

A naturally occurring protein Stimulates angiogenesis Proinflammatory Induces permeability Macugen and Lucentis are the only FDA approved anti anti-VEGF AMD drugs at this point Others being studied Current route of administration is injection IV administration likely to be next

Role of normal VEGF expression in the eye is unknown

Kim et al. IOVS. 1999; Witmer et al. Prog Ret & Eye Res. 2002; Adamis & Shima. In press.

VEGF in the Diseased Eye

VEGF is implicated in: Choroidal neovascularization (CNV)/ AMD Diabetic retinopathy Retinal vein occlusion Retinopathy of prematurity Corneal neovascularization Iris neovascularization

AntiAnti -VEGF Drugs

Macugen (pegaptanib sodium): aptamer that inhibits VEGFVEGF-A165 Lucentis (ranibizumab ranibizumab): ): humanized, affinity maturated antibody fragment (Fab (Fab) ) that binds to VEGF VEGF-A121 Avastin (bevacizumab bevacizumab): ): humanized anti antiVEGF monoclonal antibody that is FDA approved firstfirst-line treatment for metastatic colorectal cancer in combination with chemotherapy (off(off-label use in the eye)

31

VEGF Role in Eye Disease

VEGF in Human Ocular Fluids

VEGF (ng/ml)

Extensive supporting evidence

Biochemical Cellular Animal Human

30 25
=aqueous fluid

20 15 10 5 0
No Proliferative Diseases

=vitreous fluid

=mean

1983-present: Senger, Dvorak, Leung, Ferrara, Adamis, Folkman, Aiello, Bursell, Campochiaro, DAmico, DAmore, Gragoudas, Keshet, King, Miller, Plouet, Risau, Robinson, Shima, Shweiki, Smith, Tolentino, Yeo et al.

Diabetes, without PDR

Diabetes, quiescent PDR

Diabetes, active PDR

Aiello et al. N. Engl. J. Med. 1994;331:1480-7.

Targeting VEGF Pathway

Anti-VEGF (bevacizumab, Avastin) (ranibizumab, Lucentis)

Aptamer (pegaptanib, Macugen)

Anti-VEGF Approaches Antiin the Diabetic Eye

VEGF

VEGF Trap

VEGF receptor
Also long acting subconjunctival and topical agents

All appear to have limited adverse effects All appear to have a limited duration of action All have shown some improvement in visual acuity All appear to effectively regress neovascularization All have shown some reduced retinal thickening All have had variable macular edema response

Macugen (Pegaptanib) for DR

(n=900 patients)

Macugen for DME

Visual Acuity at 36 weeks
0.3 mg 1.0 mg 3.0 mg Sham
80 70 60

Anti-VEGF aptamer; intraocular injectable AntiImproved visual acuity Decreased retinal thickening 50% less likely to require laser Regressed neovascularization Favorable safety profile

* * *

Mean Change (letters) 0.3mg +4.7 1.0mg +4.7 3.0mg +1.1 Sham -0.4 *

% of Patien nts

50 40 30 20 10 0

35 36 24 22 >0 Lines Gained

26 19 13 14 >1 Line Gained

15 13 >2 Lines Gained

>3 Lines Gained

* P < 0.05 vs sham

Macugen DRS Group. Ophthalmology 2005

32

DR AntiAnti-VEGF Trial Status

AntiAnti -VEGF Approaches in the Diabetic Eye: Initial Impressions

Pegaptanib (Macugen) Ranibizumab (Lucentis) Bevicizumab (Avastin)

Proliferative o e at e Diabetic abet c Retinopathy et opat y may ay be

Markedly responsive Very sensitive

Diabetic Macular Edema response may be

Different, although some effect present More variable, less complete, slower onset

VEGF Role in Diabetic Eye Disease

Important, but Is VEGF the whole story?

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, TGFTGF-, VEGF, endothelin Angiogenesis Endothelial permeability

Potential Role of PKCPKC- in Diabetic Retinopathy

Hyperglycemia
PKC- Activation Retinal Vascular Injury and Dysfunction C Capillary Nonperfusion f VEGF Production PKC- Activation Macular Edema Neovascularization Proliferative Retinopathy Impaired Visual Function

Ongoing DR Studies General Classes

PKC Inhibitors - ruboxistaurin AntiAnti -VEGF Avastin Avastin, , Lucentis Lucentis, , Macugen Steroids triamcinolone triamcinolone, , dexamethasone dexamethasone, , fluocinolone, fluocinolone , implants Interventional Techniques laser, PPV Neuroprotection Neuroprotection/Inflammation /Inflammation doxycycline, doxycycline , bromfenac Vitreolysis - microplasmin

Vascular Leakage

PKC- Activation

33

PKC Activity Correlates with Severity of Diabetic Retinopathy

160

Study Question

PKC Activity in Monocytes (pmol/min/mg g protein)

140 120 100 80 60 40 20 0

*p<0.03 *
21 22

*
27

24

Can the once a day oral administration of a PKC PKC- Inhibitor reduce moderate visual loss that is sustained 6 months or longer (SMVL)?

No DM

No DR

NPDR

PDR

Increasing Retinopathy Severity

PKC Beta Inhibitor Trials Ruboxistaurin

Event Rate

Development of Moderate Vision Loss

Placebo 32 mg

(Protein Kinase C - inhibitor) Well-tolerated WellReduced risk of sustained vision loss Reduced R d d need d for f initial i iti l focal f l laser l Slowed macular edema progression Increased chance of visual improvement

Oral Ruboxistaurin

50% 40% 30% 20% 10% 0% 0 1 P = 0.019

Years

Diabetes 2005; 54:2188-97. Ophthalmology 2006; 113:2221-2230.

Protein Kinase C Inhibition

PKCPKC- in Diabetic Retinopathy

Hyperglycemia
PKC- Activation Retinal Vascular Injury and Dysfunction Capillary Nonperfusion Vascular Leakage PKC- PKC Activation PKC- Activation VEGF/VPF Production Macular Edema PKC- Activation Neovascularization Proliferative Retinopathy

PKC inhibition May reduce vascular permeability May benefit retinal microvasculature* Ruboxistaurin (LY333531) Selective inhibitor of PKC Potential treatment for diabetic retinopathy and DME

*Ishii et al, Science 1996;272:728 1996;272:728-731, Danis et al, IOVS 1998;39:171 1998;39:171-179, Aiello et al, IOVS 1999;40:S192

34

RBX
The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial.
Diabetes. 2005 Jul;54(7):2188Jul;54(7):2188-97.

PKC Beta Inhibitor Trials Ruboxistaurin

Event Rate

Development of Moderate Vision Loss

Placebo 32 mg

50% 40% 30% 20% 10% 0% 0 1 P = 0.019

Years

Pars Plana Vitrectomy

Do We Really Know What Makes Us Healthy?

Refractory CSME
Best results if vitreomacular traction (VMT) or taut posterior hyaloid is present Variable visual benefit

OCT often useful pre pre-operatively Surgical technique:

Posterior hyaloid separation Epiretinal membrane (or ILM) peeling Intravitreal triamcinolone (sometimes)

Small, noncomparative series

September 16, 2007

The Future
Prevention Migrate

toward earlier therapies targeting to diseasedisease-specific cellular response Move beyond latelate-stage complication complicationoriented therapy Patient specific therapies

35