1. Harvey Richman, OD, FAAO, FCOVD The Science Behind Ocular Health and Nutrition

2. Age-Related Eye Disease Study (AREDS): Rationale and Significance

3. AREDS: NEI Trial Overview A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001.119(10): 1417-36. FeatureDescription Objective To evaluate the effect of high-dose vitamin supplementation on age-related macular degeneration (AMD) progression and visual acuity. Design Double-masked, randomized, placebo- controlled trial Population 3640 high risk patients (55-80 years) Duration 6.3 years supplementation and follow up

4. AREDS Rationale for Studying AMD  A leading cause of vision impairment and blindness in the United States 1.  Common in age 60 or older 2.  Macula damage (for sharp, detailed central vision) 2.  Presentation 2  No Pain / Blurred Vision / Drusen  Advanced Disease 3  Drusen 125+ μ m / Neovascular AMD / Geographic atrophy 1. The Age-Related Eye Disease Study (AREDS): Design Implications: AREDS Report No.1 Arch Ophthalmol 1999 December ; 20(6): 573–600. 2. Age-related Eye Diseases and Conditions. NEI Slide Presentation. Available at: http://www.nei.nih.gov/nehep/programs/visionandaging/materials/VandAToolkit_Mod2_Powerpoint_508.pdf-10-15-2010. Accessed July 20, 2011 3. Potential Public Health Impact of Age-Related Eye Disease Study: AREDS Report No. 11 Arch Ophthalmol 2003 November ; 121(11): 1621–1624..

5. AREDS Rationale: AMD Risk Factors Advanced age Race Family history Female Current or former smoker Poor diet Obesity www.neh.nih.gov/health/maculardegen/ARMD

6. Daily Dosage in AREDS SupplementDosage Beta-carotene15 mg Vitamin C500 mg Zinc80 mg Copper2 mg Vitamin E400 IU Supplements were manufactured to have the following minimum contents: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001.119(10): 1417-36.

7. AREDS Rationale: Beta-Carotene Why is it important? ▫ Body unable to synthesize 1 ▫ Antioxidant capability 1 How much do I need each day? ▫ 15 mg/day (AREDS) 2 Where can I get it in my diet? ▫ Carrots, broccoli, spinach, kale 3 1.Paiva SAR, Russell RM, Dutta SK. β-carotene and other carotenoids as antioxidants. Journal of the American College of Nutrition. 1999;18(5):426–433. 2.A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10): 1417-36. 3. USDA National Nutrient Database for Standard Reference http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/SR23/nutrlist/sr23a320.pdf Accessed 21 July 2011

8. Why is it important? ▫ Body unable to synthesize 1 ▫ Antioxidant capability 1 How much do I need each day? ▫ 500 mg/day (AREDS) 2 Where can I get it in my diet? ▫ Citrus fruits and juices 3 Why is it important? ▫ Body unable to synthesize 1 ▫ Antioxidant capability 1 How much do I need each day? ▫ 500 mg/day (AREDS) 2 Where can I get it in my diet? ▫ Citrus fruits and juices 3 AREDS Rationale: Vitamin C 1. G. Sotoudeh G, Vitamin C function and status in chronic disease. Nutrition in clinical care. 2002; 5(2): 66-74. 2.A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10): 1417-36. 3.USDA National Nutrient Database for Standard Reference http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/SR23/nutrlist/sr23w401.pdf Accessed 21 July 2011

9. AREDS Rationale: Vitamin E Why is it important? ▫ Body unable to synthesize 1 ▫ Antioxidant capability 1 How much do I need each day? ▫ 400 IU/day (AREDS) 2 Where can I get it in my diet? ▫ Nuts, fortified cereals, sweet potatoes 3 1.Traber et al. Vitamins C and E: Beneficial effects from a mechanist perspective. Free Radic Biol Med. 2011 May 25. [Epub ahead of print] 2.A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10): 1417-36. 3.USDA National Nutrient Database for Standard Referencehttp://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/SR23/nutrlist/sr23w323.pdf Accessed 21 July 2011

10. AREDS Rationale: Zinc Why is it important? ▫ Essential trace element 1 How much do I need each day? ▫ 80 mg zinc/day (AREDS) 2 Where can I get it in my diet? ▫ Red meat, poultry, mixed nuts 2 1.Grahn, BH, Paterson PG, et al. Zinc and the eye. Journal of the American College of Nutrition 2001; 20(2 Suppl: 106-18. 2.A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10): 1417-36.

11. AREDS Rationale: Copper Why is it important? ▫ Essential trace element 1 ▫ Both an anti-oxidant and pro-oxidant 2 ▫ Body unable to synthesize 2 ▫ High zinc may cause copper deficiency 3 How much do I need each day? ▫ 2 mg/day (AREDS) 4 Where can I get it in my diet? ▫ Seafood, Liver, Nuts, Legumes 2 1.Determinants of copper needs across the lifespan. Office of Dietary Supplements. National Institues of Health. Accessed at: http://ods.od.nih.gov/News/Copper.aspx. Accessed August 31, 2011. 2.Copper Overview. University of Maryland Medical Center. Accessed at: http://www.umm.edu/altmed/articles/copper-000296.htm. Accessed August 31, 2011. 3.NIH Dietary Supplement Fact Sheet: Zinc. Available at: http://ods.od.nih.gov/factsheets/Zinc-HealthProfessional / Accessed 21 July 2011 4.A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age- related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119(10): 1417-36.

12. 1.. Age-Related Eye Disease Study Research Group. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22 Arch Ophthal 2007. 125(9), 1225-1232. 2.SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007 May;125(5):671-9 3. Sangiovanni JP, Agrón E, Meleth AD, et al. 6. {omega}-3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study. Am J Clin Nutr. 2009 Dec;90(6):1601-7. Epub 2009 Oct 7. AREDS: Observations AMD: a nutrition responsive disorder. 1-3 Placebo: 29% progression risk from baseline at 5 years. 1 Antioxidants and zinc: 25% risk-reduction from baseline of visual acuity loss. 1 Lutein/zeaxanthin and omega-3 fatty acid: Intake was independently linked with decreased likelihood of: 1,2,3 Neovascular AMD (Lutein/zeaxanthin, Omega-3s) Geographic atrophy (Lutein/zeaxanthin, Omega-3s) Large extensive intermediate drusen (Lutein/zeaxanthin)

13. Macular Pigment

14. Significance of Lutein and Zeaxanthin Only dietary carotenoids are found in the macula 1 Body cannot synthesize 2 5:1 ratio of lutein to zeaxanthin in the diet 3 Powerful Antioxidant 4 Reduces free radical damage in the eye 1.Lutein and Zeaxanthin Alternative Medicine Review 2005; 10(2): 128-135. 2. Nutritional Supplements for Eye Health. Bausch & Laumb Website; Available at: http://www.preservision.co.uk/. Accessed 3 October 2011 3. Thurnham DI. Macular zeaxanthins and lutein—A review of dietary sources and bioavailability and some relationships with macular pigment optical density and age-related macular disease. Nutr Res Rev. 2007;20:163–179. 4. Subczynski WK, et al. Location of macular xanthophylls in the most vulnerable regions of photoreceptor outer-segment membranes. Archives of Biochemistry and Biophysics 504 (2010) 61–66. Yellow macular pigment composed of lutein and zeaxanthin

15. Converted from Lutein How much? Meso Zeaxanthin

16. Lutein Antioxidant Supplementation Trial (L.A.S.T.) and Macular Pigment Optical Density (MPOD) 90 males with AMD: 10 mg FloraGLO ® lutein 10 mg FloraGLO ® lutein + antioxidants Placebo Improvements in visual function Richer et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age- related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004 Apr;75(4):216-230. *FloraGlo is a registered trademark of Kemin Industries, Inc. * * * LuteinLutein + antioxidants Placebo 0 0.6 Right eye 0.5 0.4 0.3 0.2 0.1 Macular pigment optical density BaselineFinal visit *P<0.05 36% improvement 43% improvement Left eye

17. Long-term FloraGLO ® Lutein and Zeaxanthin Supplementation Improves MPOD in AMD LUTEGA S TUDY 172 subjects (50+, AMD) Double-masked, randomized: 10 mg FloraGLO ® Lutein / 1 mg Zeaxanthin / 255 mg Omega-3 QD 10 mg FloraGLO ® Lutein / 1 mg Zeaxanthin / 255 mg Omega-3 BID Placebo 4 evaluations over 12 months Supplementation in Months Absolute Change in ODU*degree² QD Daily supplementation Placebo MPOD C HANGES Jentsch S, et al. The Lutega- Study: Lutein And Omega- 3- Fatty Acids And Their Relevance For Macular Pigment In Patients With Age-related Macular Degeneration (AMD). Poster presented at: 2011 Association Research in Ophthalmology Meeting. May 1-5, 2011. Ft. Lauderdale, FL. P3623/A624. *FloraGLO is a registered trademark of Kemin Industries, inc.

18. Increased MPOD May Have an Effect on Visual Performance Improvement of visual performance associated with increase MPOD include: Glare tolerance 1 Glare recovery 1 Contrast sensitivity 2 Amsler defect and VA improvement 3 Chromatic aberration 2 Photophobia 4 1.Stringham JM, Garcia PV, Smith PA, et al. Macular Pigment and Visual Performance in Glare: Benefits for Photostress Recovery, Disability Glare, and Visual Discomfort. Invest Ophthalmol Vis Sci. 2011 Feb 4.. 2. Loughman J, Akkali MC, Beatty S, et al. The relationship between macular pigment and visual performance.. Vision Res. 2010 Jun 18;50(13):1249-56. Epub 2010 Apr 13.. 3. Richer et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004 Apr;75(4):216-230. 4. Wenzel et al., 2006 A.J. Wenzel, K. Fuld, J.M. Stringham and J. Curran-Celentano, Macular pigment optical density and photophobia light threshold. Vision Research, 46 28 (2006), pp. 4615– 4622. ICP11003SK

19. Omega-3 Fatty Acids (DHA/EPA) Important for proper visual development and retinal function. Docosahexaenoic acid (DHA) is found in the highest concentration in the retina. Eicosapentaenoic acid (EPA) is used in DHA biosynthesis. Low levels of DHA and EPA have also been associated with chronic eye conditions such as diabetic retinopathy, age-related macular degeneration (AMD), and retinopathy of prematurity. Figure accessed at: http://lancastria.net/blog/omega-3-and-obesity.html Accessed July 18, 2011. American Optometric Association. Essential Fatty Acids; Available at: http://www.aoa.org/x11853.xml. Accessed 3 October 2011

20. Age-Related Eye Disease Study (AREDS2): Key Issues

21. AREDS2* Age-Related Eye Disease study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011. AREDS2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011. FeatureDescription ObjectiveAssess effect of a alternative combination of vitamins and minerals on the progression of AMD and vision loss DesignNEI 5 year, multi-center, randomized, double-masked, placebo-controlled trial Population4000 patients at higher risk of developing AMD (Men and women; 50 – 85 years)

22. AREDS2: To Evaluate… Ingredients being studied in AREDS2: FloraGLO ® lutein (10mg) OPTISHARP ® zeaxanthin (2mg) Omega-3 fatty acids (350 mg DHA, 650 mg EPA) No β -carotene Decreased zinc levels (80mg vs. 25mg) Patients in the AREDS2 study are assigned to different combinations of ingredients Age-Related Eye Disease study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011. AREDS 2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011. *FloraGlo is a registered trademark of Kemin Industries, Inc. * Optisharp is a registered trademark of DSM IP Assets B.V.

23. AREDS2: To Evaluate… Progression to advanced AMD Progression to moderate vision loss Progression of lens opacity Effective cognitive function Cardiovascular morbidity/mortality Age-Related Eye Disease study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011. AREDS 2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011.

24. AREDS2 Disposition No ATS* AREDS2 Vitamin / Mineral Evaluation ATS*No ß-C & Low ZnNo ß-CLow Zn Randomized Participants ~4200 Original ATS* *AREDS type supplements. Age-Related Eye Disease study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011. AREDS 2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011. Placebo DHA/EPA L/ZL/Z+DHA/EPA ATS* Options No smoker can be in an arm with beta-carotene The AREDS2 ATS meets DSHEA requirements The original AREDS ATS met USP requirements

25. Dietary Supplementation Recommendations: Daily Intake of Key Ingredients

26. NEI AREDS2 Dosage Options Lutein (FloraGLO ® ) Zeaxanthin (OPTISHARP ® ) Age-Related Eye Disease study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011. AREDS2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011. FloraGLO is a registered trademark of Kemin Industries, Inc. Optisharp is a registered trademark of DSM IP Assets B.V. 10 mg/day 2 mg/day

27. Dietary Sources of Lutein/Zeaxanthin The U.S. Department of Agriculture National Nutrient Database for Standard Reference, Release 23. http://www.nal.usda.gov/fnic/foodcomp/search/ Accessed October 3 rd, 2011.http://www.nal.usda.gov/fnic/foodcomp/search/ KaleSpinach Romaine lettuce Photos Courtesy of www.shutterstock.com

28. A single dose of spirulina (an cyanbacteria) can increase mean serum zeaxanthin concentration Spirulina

29. CDC. National Health and Nutrition Examination Survey Data 2001-2002. Available at: http://www.cdc.gov/nchs/about/major/nhanes/nhanes01-02.htm. Accessed July 14, 2011. Consumption of Lutein/Zeaxanthin in the US Figure courtesy of Kemin Health, Inc. The average American only gets between 1 to 2.3mg per day of combined lutein and zeaxanthin in their diet which is below the suggested intake of 10mg 29 | ICP11001SK Ocular Nutrition | October 2011 | Business Use Only

30. Rank #1 Rank #2 Base: Recommend Singe Supplement or Both Ocular Vitamins and Single Supplement Q1555: When recommending supplements with specific ingredients, which of the following do you recommend most often? Please rank the three you recommend most often by putting a 1 next to your most recommended, a 2 next to your second most recommended, and a 3 next to your third most recommended. Alcon Data on File Single Supplements Recommended Most Often by Eye Care Specialists 30 | ICP11001SK Ocular Nutrition | October 2011 | Business Use Only

31. Ocular Vitamin Consumer Profile People who take ocular vitamin take an average of 364 tablets/capsules a year Thus people who take ocular vitamins take one tablet/capsule per day What opportunity exists to optimize ocular health and increase patient compliance? Homescan Product Library March 2011. Nielsen HH Panel Data.

32. Conclusions AREDS identified AMD as a nutrition responsive disorder, particularly in relationship to high levels of lutein/zeaxanthin and omega-3. AREDS2 is accessing additional dietary ingredients including lutein, zeaxanthin and omega-3s. Most Americans do not ingest 10 mg lutein and 2 mg of zeaxanthin (the dose evaluated in AREDS2) on a daily basis. Physicians recommend lutein and omega-3s, as the most commonly recommended single supplements. Data shows that patients who take ocular vitamins, take on average one tablet/capsule per day.

33. Discussion / Questions