1. Global Diabetes Prevalence Is Projected to Increase 242% Between 2000 and 2030 Global data 2000: 151 million patients 2010: 221 million patients 2030: 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 M 2010: 17.5 M +23% 2000: 9.4 M 2010: 14.2 M +50% 2000: 84.5 M 2010: 132.3 M +57% 2000: 15.6 M 2010: 22.5 M +44% 2000: 26.5 M 2010: 32.8 M +24% 2000: 1.04 M 2010: 1.33 M +28% Fig 1

2. Potential Metabolic Pathways Leading to Diabetic Microvascular Complications Polyol pathway Diabetic nephropathy Diabetic retinopathy Diabetic neuropathy Diabetes Ulcers/amputations Hyperglycemia Superoxide overproduction PKC β activation Vision loss Renal disease Diabetes-induced microvascular damage Glycation Diacylglycerol ©2005 International Medical Press A- II VEGF Not shown in this diagram due to space limitations: activation of additional inflammatory and growth factors. Fig 2

3. Purpose, Benefits, and Limitations of Common Retinal Diagnostic Procedures Test namePurposeBenefitsLimitations 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. Fig 3

4. Purpose, Benefits, and Limitations of Advanced Retinal Diagnostic Procedures Test namePurposeBenefitsLimitations 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 UltrasoundAssess 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. Fig 4

5. 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 Fig 5

6. 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 Fig 6

7. OCT and DME Sponge-like fluid accumulation in the outer retina (60% to 96% of eyes) corresponds to focal/diffuse ME Fig 7

8. OCT and DME Cystoid macular edema (CME) (50%) Fig 8

9. OCT and DME Mechanical—hyaloidal traction and/or ERM (16%) Fig 9

10. OCT and DME Serous macular detachment with or without traction (15%) Fig 10

11. Signs and Symptoms of Diabetic Retinopathy PreclinicalNPDRPDRDME SymptomsNoneNone, 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 abnormality Gardner 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. Fig 11

12. Severe NPDR Nonproliferative Diabetic Retinopathy Severe NPDR, courtesy of Diabetic Retinopathy Study Research Group Fig 12

13. Neovascularization Hemorrhage ©2005 International Medical Press Proliferative Diabetic Retinopathy Fig 13

14. 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 Fig 14

15. Tx– intravitreal triamcinolone Diabetic Macular Edema Fig 15

16. InferiorSuperior INL IS/OS ONL OPL RPE/OS ELM IPL GCL RNFL 500μm 2x Retinal Layers on Ultrahigh Resolution OCT Fig 16

17. Early Treatment of Diabetic Retinopathy Study (ETDRS) Scale LevelSeverityDefinition 10No retinopathy Diabetic retinopathy absent 20Very mild NPDR Microaneurysms only 35Mild NPDRMicroaneurysms with hard exudates, cotton-wool spots, and/or mild retinal hemorrhages 43Moderate NPDR Microaneurysms plus mild IRMA or moderate retinal hemorrhages 47Moderate NPDR More extensive IRMA, severe retinal hemorrhages OR Venous beading in 1 quadrant 53Severe NPDRSevere 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. Fig 17

18. International Clinical Diabetic Macular Edema Disease Severity Scale Proposed Disease Severity Level Findings Observable Upon Dilated Ophthalmoscopy DME apparently absentNo apparent retinal thickening or hard exudates in posterior pole DME apparently presentSome apparent retinal thickening or hard exudates in posterior pole If DME is present, it can be categorized as follows: Mild DMESome retinal thickening or hard exudates in posterior pole but distant from the center of the macula Moderate DMERetinal thickening or hard exudates approaching the center of the macula but not involving the center Severe DMERetinal 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. Fig 18

19. International Clinical Diabetic Retinopathy Disease Severity Scale Proposed Disease Severity Level Findings Observable Upon Dilated Ophthalmoscopy No apparent retinopathyNo abnormalities Mild NPDRMicroaneurysms only Moderate NPDRMore 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 PDROne 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. Fig 19

20. DCCT: Lower A1C Slows Development and Progression of Retinopathy Primary Cohort: No Baseline Retinopathy Secondary Cohort: Some Retinopathy at Baseline Primary conventional: n = 378 Primary intensive: n = 348 Secondary conventional: n = 352 Secondary intensive: n = 363 DCCT. N Engl J Med. 1993;329:977-986. Percentage of Patients Experiencing Sustained 3-Step Decrease 60 Cumulative Incidence StudyYear Percent P <.001CON INT 50 40 30 20 10 0 0123456789 60 Cumulative Incidence StudyYear Percent P <.001CON INT 50 40 30 20 10 0 0123456789 Fig 20

21. 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 Baseline A1C, % 0.1 1 8 Relative Risk 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 Fig 21

22. 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 outcomeRelative risk P value ≥5 microaneurysms0.66<.001 Hard exudates0.53<.001 ≥1 cotton-wool spot0.53<.001 ≥2-step ETDRS loss0.66.001 Laser photocoagulation 0.63.03 Blindness in 1 eye (VA worse than 20/200) 0.76.46 Fig 22

23. High-risk PDR (3 or 4 high-risk features) NoUsuallyNo YesUsually 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 YesNoUsually Severe or very severe PDR NoSometimes, especially type 2No YesSometimes, especially type 2Usually Non–high-risk PDR (1 or 2 high-risk features) NoSometimes, especially type 2No YesSometimes, especially type 2Usually Severity of retinopathy CSME present? Scatter laser photocoagulation Focal laser photocoagulation Fig 23

24. 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 Fig 24

25. Intravitreal Triamcinolone Improves VA and Reduces DME Chieh JJ, et al. Retina. 2005;25:828-834. Clinical Resolution of Edema Mean Change in VA (LogMAR) Improvement in VA Relative to Baseline Percent of Eyes Month Fig 25

26. Pegaptanib Decreases Retinal Thickness at Center Point of Central Subfield in CSME 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. Change in Central Retinal Thickness, μm P =.02 Fig 26

27. 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) ≥ 1010%34% P =.003 30%14% ≥ 157%18% P =.12 14%7% Patients attaining ≥ 2-line increase after 36 weeks of treatment Fig 27

28. Pegaptanib Adverse Events EventShamPegaptanib Eye pain1731 Vitreous floaters722 Conjunctival hemorrhage10 Vitreous opacities59 Vitreous disorder NOS7 Visual disturbance NOS27 Sterile endophthalmitis1 Ocular adverse events that occurred significantly more often in study eyes 1 Cunningham ET Jr, et al. Ophthalmology. 2005;112:1747-1757. Data are percentage of total patient group. Zeroes omitted. NOS = not otherwise specified. 1 Punctate 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. Fig 28

29. 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) 3634973 Untreated control (NPDR) 1377228 100 mg TID epalrestat (PP) 36455842 Untreated control (PP) 252080 FA = fluorescein angiography; PP = preproliferative (severe) NPDR Fig 29

30. Epalrestat Adverse Events Steele JW, Faulds D, Goa KL. Drugs Aging. 1993;3:532-555. Liver enzyme elevations Alanine aminotransferase1.0% Aspartate aminotransferase1.0% Glutamyl transpeptidase1.0% Diarrhea0.2% Erythema0.2% Skin bullae0.2% Serum creatinine elevation0.2% Fig 30

31. Midostaurin (PKC412) Reduces Foveal Thickness in DME Campochiaro PA, et al. Invest Ophthalmol Vis Sci. 2004;45:922-931. Change in Foveal Thickness (microns) 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 15 Month Treatment period from Month 0-3 100: P =.015 150: P =.039 50: P =.016 Fig 31

32. 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 Change in VA (number of letters) 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 Fig 32

33. 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 EventPBO50 mg/d100 mg/d150 mg/d Gastro- intestinal Nausea3%6%21%38% Diarrhea NOS3% 16%19% Vomiting3% 19% Hepatic Increased ALT6%8%14% Increased AST3%8% Events occurring in >5% of patients in any treatment group Fig 33

34. 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 Probability of MVL, % Months Log Rank P values: Overall:.069 32 mg vs Placebo:.038 06 1218 24 30 36 42 30 20 10 0 MVL = moderate visual loss (≥15 letters) Fig 34

35. 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 systemEventPBO4/8 mg/d16 mg/d32 mg/d Gastrointestinal Diarrhea NOS16.913.624.414.9 Flatulence1.71.34.20.4 Cardiovascular CAD NOS6.83.513.04.7 1° AV Block01.3 3.4 PulmonaryAsthma NOS0.81.81.74.7 Renal Dysuria1.30.91.74.3 Proteinuria0.81.33.80.9 DermatologicalHyperkeratosis5.56.62.52.1 Events occurring in >3% of patients in any treatment group and with statistically significant difference between groups Fig 35