The Diabetic Retinopathy Clinical Research Network

1. The Diabetic Retinopathy Clinical Research Network Exploratory Analysis of Diabetic Retinopathy Progression through 3 Years in a Randomized Clinical Trial Comparing IntravitrealTriamcinolone with Focal/Grid Photocoagulation Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services

2. Background • Current treatments for reducing the risk of progression of retinopathy: • Glycemic control • PRP – associated with side effects and potential complications • Identification of other treatments is desirable • Rationale for corticosteroids: • Down regulates VEGF and reduces breakdown of blood-retinal barrier • Anti-angiogenic properties • Intravitrealtriamcinolone shown to prevent retinal neovascularization in animal and clinical studies

3. DRCR.net Protocol B: Laser vs. Intravitreal Triamcinolone for DME • 840 eyes (693 subjects) at 88 sites • Laser group: N = 330 • 1 mg IVT group: N = 256 • 4 mg IVT group: N = 254 • Major Eligibility Criteria: • VA 20/40 to 20/320 • CSF >= 250 microns on OCT • Visits (and retreatment assessment) every 4 months through 3 years • Primary Outcome: VA at 2 years

4. Primary Results • Focal/Grid Laser was more effective (VA and CSF) with fewer side effects (IOP and cataract) than 1 mg or 4 mg IVT at 2 years • Longer term 3 year results were consistent with 2 year results • Change in retinopathy level was a planned secondary outcome • An exploratory analysis was pursued to evaluate effect of IVT on a multilevel definition of progression of retinopathy

5. Outcome Definition • Progression of retinopathy up to 3 years (any of the following): • Progressed from NPDR at baseline to PDR during follow-up* • Received PRP between baseline and follow-up • Reported a vitreous hemorrhage between baseline and follow-up • Worsened 2 or more levels on the ETDRS diabetic retinopathy scale* • *Based on Reading Center grading of annual fundus photos

6. Cumulative Probability* of Progression of Retinopathy Months 0 4 8 12 16 20 24 28 32 36 *calculated using the life-table method Note: 14% were censored prior to 2 yr visit and an additional 34% between the 2 and 3 yr visits (of which only 7% had the potential to complete the 3 yr visit due to early closeout of the study) 6

7. Treatment Group Comparisons at 1, 2, and 3 Years *From a proportional hazards model adjusting for baseline VA, history of prior macular photocoagulation, and baseline retinopathy severity

8. Cumulative Probability* of Progression of Retinopathy up to 2 Years *calculated using the life-table method 8

9. Cumulative Probability* of Progression of Retinopathy up to 2 Years *calculated using the life-table method 9

10. Cumulative Probability* of Progression of Retinopathy up to 3 Years *calculated using the life-table method 10

11. Cumulative Probability* of Progression of Retinopathy up to 3 Years *calculated using the life-table method 11

12. Discussion • 4 mg IVT can reduce the risk of progression of retinopathy at 1, 2, and 3 years • Difference cannot be explained by an increase in retinopathy caused by focal/grid laser • Similar risk in laser group and 1 mg group • Similar risk of development of PDR in ETDRS immediate laser group (11.1%) and deferred laser group (10.8%) • Results in Fluocinolone Acetonide Implant Study Group trial support DRCRnet results • Lower rate of retinopathy worsening compared to standard of care group (P<0.002, P=0.012, and P<0.015 at 1, 2, and 3 years, respectively)

13. Conclusions • Use of IVT to reduce risk of progression of retinopathy is not warranted at this time • IVT is associated with cataract and elevated IOP • PDR can be treated relatively safely with PRP • Further investigation of treatments to reduce risk of progression of retinopathy safely is needed