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Diabetic Macular Edema 2010

Diabetic Macular Edema 2010. Pravin U. Dugel, MD Managing Partner, Retinal Consultants of Arizona, Phoenix, AZ Clinical Associate Professor, Doheny Eye Institute, Los Angeles, CA Founding Partner, Spectra Eye Institute, Phoenix, AZ. World Diabetes Trends.

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Diabetic Macular Edema 2010

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  1. Diabetic Macular Edema 2010 Pravin U. Dugel, MD Managing Partner, Retinal Consultants of Arizona, Phoenix, AZ Clinical Associate Professor, Doheny Eye Institute, Los Angeles, CA Founding Partner, Spectra Eye Institute, Phoenix, AZ

  2. World Diabetes Trends Diabetes Atlas, 3rd ed, International Diabetes Federation, 2006.

  3. 1990 1995 2001 No Data <4% 4%-6% 6%-8% 8%-10% >10% Diabetes Trends Among US Adults (Includes Gestational Diabetes) BRFSS, 1990,1995, and 2001 By the year 2025 an estimated 30 million Americans will be living with diabetes CDC Web site. www.cdc.gov; Mokdad et al. Diabetes Care. 2000;23:1278-1283; J Am Med Assoc. 2001;286:10; ADA.

  4. Percentage of Diabetic Macular Edema Increases as NPDR Progresses N=1585 % Patients With Macular Edema n=47 Increased Risk of Diabetic Macular Edema n=114 n=228 NPDR: nonproliferative diabetic retinopathy. Figure reproduced from Henricsson M et al. Acta Ophthalmol Scand. 1999;77:218–223.

  5. ETDRS Laser Photocoagulation:Prevented Moderate Visual Loss 60 50 40 30 20 10 0 In CSME and Less Severe DR1 % of Patients with Moderate Visual Loss *3-step loss on ETDRS chart Focal + FU Scatter (N=299) Deferral (N=611) 33% * • P<0.01 • P<0.001 13% 3 4 2 1 Years after randomization 50% reduction in moderate visual loss 1ETDRS. Arch Ophthalmol 1995;113:1144-1145.

  6. Treatment Options: Laser Photocoagulation • Focal or Grid Photocoagulation • Focal PC: light, small-sized burns to leaking microaneurysms • Grid PC: a grid of burns to areas of edema from capillary leakage or nonperfusion Focal 1AAO. 2003. Preferred Practice Pattern®: Diabetic retinopathy 2003; 2ETDRS Research Group. Ophthalmology 1991;98(5 suppl):766-785.

  7. After Grid Laser Treatment 3 Months 3 Months

  8. Specific growth factors1 IGF-1 inhibition VEGF inhibition PEDF expression Intracellular signaling1 PKC inhibition MAPK pathway inhibition Extracellular matrix and integrin factors1 Integrin inhibition Matrix metalloproteases inhibition Steroid compounds Inflammation2 Reactive oxygen species2 Nonenzymatic glycation inhibition2 Nitric oxide synthase2 Pharmacologic Targets to Inhibit Diabetic Retinopathy 1Speicher MA et al. Expert Opin Emerg Drugs 2003;8:239-250; 2Frank RN. NEJM 2004;350:48-58.

  9. Diabetic Macular EdemaContributing Anatomical Changes Chronic inflammation Capillary nonperfusion Leukostasis x x x Pericyte loss Taurine transport of RPE x Diabetic Macular Edema Hypoxia x Antioxidant capacity of RPE Thickened basement membrane Tight junctions Vision loss x Corticosteroid

  10. Intraocular Steroids in Development

  11. The Diabetic Retinopathy Clinical Research Network • A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide to Focal/Grid Photocoagulation for Diabetic Macular Edema • 2 and 3 Year Results • Sponsored by the National Eye Institute, • National Institutes of Health, U.S. Department of Health and Human Services

  12. Primary Outcome:Mean Change in Visual Acuity at 2 Years * Adjusted for baseline VA and prior focal/grid laser

  13. Mean Visual Acuity Over 3 Years in All Eyes 20/32 20/40 Visual Acuity 20/50 Score 20/63 20/80 20 36 8 24 28 0 16 12 32 4 Months 14

  14. Protocol B: Subgroup Analysis Baseline Data 2 Year Data Table 5. Change in Visual Acuity at 2-Year Primary Outcome among Subgroups

  15. FAME Phase III Study24 Month Results

  16. Iluvien Drug Delivery Insert • Non-bioerodable cylindrical tube 3.5 mm long, 0.37 mm in diameter • Injected through a self sealing wound via 25-gauge proprietary inserter • Two doses compared 0.2µg (Low Dose) and 0.5µg (High Dose) of FAc per day Iluvien is under review by the FDA, it is not approved in the United States.

  17. Near zero-order kinetics Submicrogram daily dose delivery Posterior point of release Iluvien Technology ® • Active compound: Fluocinolone acetonide (FAc) • Total dose: 0.19 mg • Approximate daily release: 0.2 µg/d and 0.5 µg/d • Method of delivery: Intravitreal Injection • Approximate duration of action: At least 2 years Kane FE, et al. Expert Opin Drug Deliv. 2008;5:1039-1046.Iluvien. Draft package insert.

  18. Primary Efficacy Analysis: Percent of Patients With ≥ 15-Letter Improvement Over Baseline 40 Sham (n = 185) P = .002 for both doses 0.2 µg/d FAc (n = 376) 35 0.5 µg/d FAc (n = 395) 28.7% 30 28.6% 25 Patients (%) 20 16.2% 15 10 5 0 0 3 6 9 12 15 18 21 24 Time (Months) The 0.2 µg/d dose of FAc has been submitted for regulatory approval. Alimera Sciences. Data on File.

  19. % of Patients with ≥ 15-Letter Improvement in BCVA Over Baseline Through 30 Months n = 123 40 39.8% Sham (n = 185) 0.2 µg/d FAc (n = 376) 35 30 P = .002 25 Patients (%) 20 17.5% n = 63 15 10 5 0 Baseline 3 6 9 12 15 18 21 24 27 30 Time (Months) Ciulla T, et al. Data presented at Association for Research in Vision and Ophthalmology. Ft Lauderdale, FL. May, 2010.

  20. Cataract-Related Events IOP-Related Events * Phakic subjects only. Alimera Sciences. Data on File.

  21. Mean BCVA Letter Change in Iluvien (0.2 µg/d FAc) Patients Mean Change From Baseline in BCVA Letter Score Months Alimera Sciences. Data on File.

  22. VEGF in Human Ocular Fluids Aiello et al. NEJM 1994;331:1480-7.

  23. READ-2 Month 12: Mean Change in Visual Acuity from Baseline Nguyen QD, Shah SM, Heier JS, Do D, Lim J, Boyer D, Abraham P, Dugel P, Campochiaro P, for the READ-2 Research Group. Ranibuzumab for Edema of the Macula in Diabetes (READ-2) Preliminary one year updates.

  24. DA VINCI: VEGF trap versus laserMean Change in Visual Acuity 2q4* 11.4 2prn+ 10.3 2q8^ 8.5 0.5q4† 8.6 ETDRS letters Laser 2.5 *P < 0.0001 ^P = 0.0085 +P = 0.0004 †P = 0.0054 vs. laser (ANCOVA) No statistical differences among VTE arms. Week LOCF analysis; n=44 (laser, 0.5q4, 2q4); n=42 (2q8); n=45 (2prn)

  25. DRCR Protocol I Primary outcome: Change in visual acuity from baseline to 1 year (intent to treat analysis). Eyes Randomized: N = 854 (691 Participants) Sham + Prompt Laser (N = 293) Ranibizumab + Prompt Laser (N = 187) Ranibizumab + Deferred Laser (N = 188) Triamcinolone + Prompt Laser (N = 186) The Diabetic Retinopathy Clinical Research Network. Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology. Jun;117(6):1064-1077.

  26. DRCR Protocol I Visual acuity The Diabetic Retinopathy Clinical Research Network. Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology. Jun;117(6):1064-1077.

  27. BOLT Prospective, randomized, masked, single-center, 2-year, 2-arm clinical trial. Randomized to: Laser group (N = 38). Bevacizumab group (N = 42). Primary outcome: Comparison of mean ETDRS BCVA at 12 months between Laser and Bevacizumab arms. Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce C, Leslie RD, Hykin PG. A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT Study): 12-Month Data Report 2. Ophthalmology. 2010 Jun;117(6):1078-1086.e2.

  28. BOLT * * * * * = p < 0.05

  29. BOLT

  30. Conclusion Diabetic macular edema is a multi-factorial disease Laser remains the standard of care in most cases, although combination treatment holds promise The socio-economic impact of practicing evidence-based medicine must be considered

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