1. Update on Prevention, Diagnosis & Treatment of Diabetic Macular Edema (DME) Part 3 A. Paul Chous, MA, OD, FAAO Specializing in Diabetes Eye Care & Education Tacoma, WA Adjunct Instructor, Nova Southeastern University College of Optometry Principal Investigator for the Diabetes Visual Function Supplement Study (DiVFuSS)

2. Importance of Early Treatment Mean change in BCVA from baseline (pooled) With crossover from laser to 1 year of 0.5 mg ranibizumab therapy at third year, original sham (laser) treatment group’s visual gains were lower than those seen in first year of ranibizumab-treated groups (2.8 vs 10.6 and 11.1 letters)With crossover from laser to 1 year of 0.5 mg ranibizumab therapy at third year, original sham (laser) treatment group’s visual gains were lower than those seen in first year of ranibizumab-treated groups (2.8 vs 10.6 and 11.1 letters) Delayed treatment reduced magnitude of VA benefits of anti-VEGF therapyDelayed treatment reduced magnitude of VA benefits of anti-VEGF therapy RISE and RIDE Research Group. Ophthalmology. 2013;120:2013-2022. Lucentis Laser

3. ETDRS letters Week *P < 0.0001 vs. laser VIVID10.72q810.52q4 1.2Laser ETDRS; Compared to baseline; FAS; LOCF; VISTA – Laser: n=154; 2q4: n=154; 2q8: n=151 VIVID - Laser: n=132; 2q4: n=136; 2q8; n=135 *P < 0.0001 vs. laser VISTA12.52q410.72q8 0.2Laser Aflibercept: Mean Improvement in Best-Corrected Visual Acuity v. Laser Korobelnik JF, et al. Ophthalmology. 2014 Jul 8.Ophthalmology.

4. Is It Safe???? Meta-analysis of 2500 Meta-analysis of 2500 patients shows no significantly increased risk of CVA, MI, vascular death or mortality with Lucentis for DME (but 95% CIs = 0.37 to 4.73) patients shows no significantly increased risk of CVA, MI, vascular death or mortality with Lucentis for DME (but 95% CIs = 0.37 to 4.73) There is a dose-dependent increased risk of mortality (p = 0.04) that dissipates when Lucentis is used pro en reta to p = 0.133 There is a dose-dependent increased risk of mortality (p = 0.04) that dissipates when Lucentis is used pro en reta to p = 0.133 Retina. 2014 Apr;34(4):629-35

5. What anti-VEGF is Best for DME? Avastin, Lucentis & Eylea are now being studied head-to-head – results due in 2016 (DRCR.net Protocol T) Avastin, Lucentis & Eylea are now being studied head-to-head – results due in 2016 (DRCR.net Protocol T) Outcomes appear comparable by 15 RCTs and 8 observational studies, but evidence for superiority is insufficient Outcomes appear comparable by 15 RCTs and 8 observational studies, but evidence for superiority is insufficient Cost-effectiveness is best with Avastin Cost-effectiveness is best with Avastin Adverse events with Avastin are under- reported Adverse events with Avastin are under- reported Int J Technol Assess Health Care. 2013 Oct;29(4):392-401

6. Protocol T – 1 year data Aflibercept results in ‘significantly better’ VA versus ranibizumab or bevacizumab APTC Events: Eylea = 2%, Avastin = 4%, Lucentis = 5% Caution: 1-year data, not published Regeneron Press Release, 10/17/14 APTC = Antiplatelet Trialists Collaboration Diabetic Retinopathy Clinical Research Network

7. Steroids in DME There is a significant inflammatory component to DME There is a significant inflammatory component to DME Steroids result in improved vision in the short term but Steroids result in improved vision in the short term but Invariably result in cataract formationInvariably result in cataract formation Often result in increased intraocular pressure/glaucomaOften result in increased intraocular pressure/glaucoma Diabetic Retinopathy Clinical Research Network, Elman MJ et al. Ophthalmology. 2010;117(6):1064-1077.e35. Improved visual acuity (more letters on eye chart) from intravitreal steroid injections wanes over time

8. Intravitreal Steroid Implants Slow release Dexamethasone (Ozurdex TM ) – Lasts up to 6 mos Fluocinolone (Iluvien TM ) – Lasts up to 3 years Some recent investigations such as the DRCR.net Protocol I have supported the use of combination therapy in the treatment of DME, including anti-VEGFs, laser & steroids with greater improvements in visual acuity noted* * Ophthalmology. 2010;117:1064-1077. Grain of rice compared to Ozurdex™ implant

9. Does Good Blood Glucose Control Even Matter Once We Start Using anti-VEGF Agents for DR/DME? YES!!