EYE & BRAIN HEALTH DISEASE 3x more AMD

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1 AREDS 2 Lessons Learned Stuart Richer, OD, PhD, FAAO Director, Ocular Preventive Medicine Eye Clinic James A Lovell Federal Health Care Center North Chicago North Chicago, IL Associate Professor, Family & Preventive Medicine Rosalind Franklin University of Medicine & Science North Chicago Assistant Clinical Professor, UIC Dept of Ophthalmology and Visual Science Chicago Stuart.Richer1@VA.Gov Refined sugars, grains, vegetable oils and dairy = 70.9% of energy in the U.S. food supply Refined Vegetable Oils Refined Sugars Grains Meats, Fish Dairy Eggs Nuts, Seeds Legumes Fruits Vegetables Refined sugars, grains, vegetable oils and dairy represent Neolithic & Industrial era foods that were not present in traditional ancestral human diets By default, their inclusion displaces minimally processed, wild plant and animal foods. Miscellaneous Gerrior S, Bente I Nutrient Content of the U.S. Food Supply, : A Summary Report. U.S.D.A, Center for Nutrition Policy and Promotion. Home Economics Research Report No. 55 EYE & BRAIN HEALTH DISEASE 3x more AMD Corn Oil Trans Fat Fried Food High Carbs HEALTH 1/3rd less AMD F & V Fish Nuts At 10 years, AREDS formulation still reduces risk of AMD progression January 22, 2013, Macula 2013 Meeting AREDS 1 dietary supplements continued to reduce the risk of advanced age related macular degeneration or neovascular AMD 10 years out, Patients assigned to the AREDS formulation had a significantly lower risk of developing advanced AMD or neovascular AMD than those assigned to the placebo (P <0.001). In addition, moderate vision loss was significantly less prevalent in the AREDS formulation group than in the placebo group (P = 0.002). The Age Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report # 1). Ophthalmology 2012 Nov;119(11): The primary purpose of AREDS2 was to evaluate the efficacy and safety of lutein plus zeaxanthin (L+Z) and/or ω 3 long chain polyunsaturated fatty acid (LCPUFA) supplementation in reducing the risk of developing advanced AMD. The study also assessed the reduction in zinc and the omission of β carotene from the original AREDS formulation. L / Zx: AREDS Report # 22 Arch Ophthalmol Sep;125(9): Demographic, lifestyle, and medical characteristics were ascertained on 4519 AREDS participants aged 60 to 80 years at enrollment. Highest vs lowest quintiles of intake, after adjustment for total energy intake and non-nutrient-based covariates. Dietary lutein/zeaxanthin intake was inversely associated Large or extensive intermediate drusen (OR 0.73; 95% CI, ). Neovascular AMD (OR 0.65; 95% CI ). Geographic atrophy (OR 0.45; 95% CI, ) 1

2 Lutein/Zx + n3 fats build MP that is associated with all 3 AMD Risk factors AREDS II POPULATION & OUTCOME Demographics N=4203 participants at 82 US clinical Mean age, 74 y; 57% female; 97% white; 7% current smokers; 19% with prior cardiovascular disease; and 44% and taking statinclass cholesterol lowering drugs and 50% on aspirin. Ocular & Visual Characteristics 59% with bilateral large drusen, 32% with advanced AMD in 1 eye Mean VA of 20/32 in eyes without advanced AMD. MAIN OUTCOME MEASURE Progression to advanced AMD determined by centralized grading of annual fundus photographs.; POWERED to DETECT a 25% IMPROVEMENT BEYOND THE AREDS 1 SUPPLEMENT (CONTROL). AREDS2 Inclusion Criteria Demographic Differences Bilateral Large Drusen or Late AMD in One Eye Large Drusen GA NV AMD This is a different population than AREDS! AREDS 1 Younger age 69 All AMD stages Typical US Diet Diabetes 7 % 67 % on Centrum Silver AREDS 2 Older age 74 Sicker AREDS 3, 4 Well Nourished 3 4 X the average L + Z intake of average Americans Diabetes 13 % 89 % on centrum Silver Few Hispanics (2 %) Remarkably Well Nourished When compared to 18 cohorts and NHANES, the median dietary L/Z intake in AREDS2 was exceeded in only 2 cohorts. Range mg L+Z per day mcg lutein and zeaxanthin intake * mean for ages Johnson, E. J., et al. (2010) J Am Diet Assoc 110, National Health and Nutrition Examination Survey AREDS2 Research Group. (2013) JAMA, In Press. 4. Zhang, X, et al. (2012) Am J Clin Nutr 95, AREDS 1 and 2 NEI Studies vs. Recommended Daily Allowance RDA (for 98-99% of population) is not a maximum or minimum, but a place to start. RDA vs. AREDS I & II doses IU = International Units Conversion factor different for different nutrients IU = quantity that produces desired affect RDA AREDS A 900/700 mcg 8600 mcg 28,640 IU 3000/2310 IU C 75/90mg 452mg E 15mg 22.5 IU 400IU Zinc 11/8 mg 69.6 mg Cu 2 mg 1.6mg L / Z? 10/2 mg W3? 1000 mg 2

3 Randomized Participants 4203 AREDS 2 Randomization Primary Randomization Agents Placebo Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA 10 mg/2 mg 350 mg/650 mg 10 mg/2 mg; 350 mg/ 650 mg Control 1012 L/Z* 1044 DHA/EPA 1068 L/Z* + DHA/EPA 1079 Secondary Randomization Agents Formulation # Vitamin C Vitamin E Beta carotene Zinc oxide Cupric oxide No ATS** 19 *Lutein/Zeaxanthin **AREDS type supplements ATS** 659 No ß C 863 ATS** formulation s 3036 Low Zn 689 ATS** 1148 No ß C & Low Zn mg 400 IU 15 mg 80 mg 2 mg mg 400 IU 0 mg 80 mg 2 mg mg 400 IU 0 mg 25 mg 2 mg mg 400 IU 15 mg 25 mg 2 mg AREDS 2 protocol; version 5.2, 23 September 2009, accessed at : 13 protocol.pdf Primary Outcome Analysis (JAMA ABSTRACT + Press Release) Progression to Advanced AMD (AAMD) Lutein/Zeaxanthin DHA/EPA Hazard Ratio Tree Lutein/Zeaxanthin+DHA/EPA Placebo (reference) Favors Treatment Favors Placebo p= Hazard Ratio (98.7%CI) p=0.70 p=0.10 Main Effect Analysis Progression to AAMD by Primary and Secondary Randomization Main Effects L/Z vs. No L/Z DHA/EPA vs. No DHA/EPA Low Zinc vs. High Zinc Beta Carotene Yes vs. No Favors Treatment Favors Control Placebo p=0.05 p=0.1 2 p=0.7 0 p= Hazard Ratio (95%CI) AREDS2 Research Group. (2013) JAMA, In Press. AREDS2 Research Group. (2013) JAMA, In Press. Comparison of Lutein/Zeaxanthin vs. No Lutein/Zeaxanthin Advanced AMD: HR: 0.90 P= % further reduction in the risk of progression to AAMD with Lutein/Zeaxanthin Neovascular AMD: HR: 0.89 P= % further reduction in the risk of progression to neovascular AMD with Lutein/Zeaxanthin No statistically significant reduction of CGA Hidden Online Supplement E Figure 1a: Comparison of the Main Effects of Lutein + Zeaxanthin vs No Lutein + Zeaxanthin on Progression to Advanced AMD, Stratified by Various Groupings of Dietary Intake of Lutein + Zeaxanthin (A, Tertiles; B, Quartile; C, Decile) Quintiles 0.7 mg / 1.1 mg / 1.6 mg / 2.2 mg / 3.9 mg L+Z 3

4 Pp = 0.02 P = 0.01 What JAMA did not say about substituting L + Z The net result of this 34 % reduction, is that several hundred thousand Americans will be able to drive and won t need expensive & invasive intravitreal injections That means 66 % of these advanced cases still convert the most practical advice for OD s according to Dr. Jeff Gerson: PREVENT AMD IN THE FIRST PLACE! PROMOTE VISUAL PERFORMANCE INDIVIDUALIZE CARE EDUCATE PATIENTS Visual Acuity Outcomes Lutein/Zeaxanthin vs. Beta-Carotene Favors AREDS Minus Beta- Favors Visual Acuity Carotene with L/Z AREDS VA Loss 10+ Letters VA Loss 15+ Letters VA Loss 30+ Letters HR=0.84 VA Worse Than 20/100 HR= Hazard Ratio (95%CI) * Eyes with NV-AMD included in all VA loss groups 4

5 L/Z plus AREDS Minus Beta Carotene vs. AREDS with Beta Carotene for Vision Vision loss of 30+ letters compared with baseline: HR: 0.84 P= % reduction in the risk of this degree of vision loss with lutein/zeaxanthin Visual Acuity <20/100: HR: 0.82 P= % reduction in legal blindness with lutein/zeaxanthin Visual acuity (circa 1865), used in AREDS II, is an inappropriate measure of AMD visual function, as foveal vision is preserved until the late stage of the disease. Better to measure cone glare recovery, rod based dark adaptometry, contrast sensitivity, shape discrimination or macula scotomas / retinal sensitivity. MAIN EFFECTS CATARACT REPORT # 4 Lutein/Zeaxanthin for the Treatment of Age Related Cataract AREDS2 Randomized Trial Report No. 4 EXPLORATORY CATARACT (JAMA understates the result) In subjects in the lowest quintile of dietary lutein and zeaxanthin intake, there was a 32% reduction in progression to cataract surgery, a 30% reduction in development of any cataract, and a 36% reduction in development of any severe cataract. 5

6 Safety concerns: Lung Cancer SAFETY Beta Carotene Main Effect on Lung Cancer β Carotene (N = 1348) Lutein/Zeaxanthin Main Effect on Lung Cancer Lutein/Zeaxanthin (N = 2123) No β Carotene (N = 1341) No Lutein/Zeaxanthin (N = 2080) P value 23 cases (2.0%) 11 cases (0.9%) 0.04 Increased risk of lung cancer with β Carotene 91% former smokers (quit > 1 year prior to randomization) *Analysis includes smokers P value 33 cases (1.5%) 31 cases (1.5%) 0.80 No increased risk of lung cancer with Lutein/Zeaxanthin 62% former smokers, equal in both arms AREDS2 Research Group. (2013) JAMA, In Press. CONCLUSIONS AREDS REPORTS #3, #4 AREDS2 JAMA Efficacy CONCLUSION Comparisons of the three active arms to control (primary analyses) did not significantly reduce risk of progression to AAMD. (25% hurdle) and also no main efficacy effect against cataract The addition of lutein/zeaxanthin to the AREDS formulation as analyzed by the main effect showed 10% additional decrease in risk of progression to AAMD (over the AREDS 1 formula) No main efficacy effect with DHA/EPA Percentage of All Individuals (2 yrs & older) Not Meeting 100% of 1989 RDAs in US ( ) 14 Nutrients Most Lacking in U.S. Diet Zinc = 73.3 % Calcium = 65.1 % Magnesium = 61.6 % Vitamin A = 56.2 % Vitamin B6 = 53.6 % Iron = 39.1 % Vitamin C = 37.5 % Folate = 33.2 % Vitamin B1 = 30.2 % Vitamin B2 = 30.0 % Vitamin B3 = 25.9 % Protein = 20.5 % Vitamin B12 = 17.2 % Supplemental Zinc had the strongest effect in AREDS 1. The 80mg dose is high but Zinc Oxide is poorly absorbed. 6

7 ZN Safety Conclusion Secondary randomization suggests no differences in the progression to AAMD for elimination of β Carotene or lowering Zinc dose. No differences in adverse side effects (gastrointestinal disorders or others) between low and high groups. Insufficient data to make a recommendation for zinc. AREDS II Conclusions The main effect of lutein/zeaxanthin demonstrated additional 10% reduction of AAMD ~20% reduction in the risk of progression to AAMD of L/Z beyond the effects of AREDS supplement in persons with the lowest dietary intake of L/Z ~20% reduction in the risk of progression to AAMD, particularly neovascular AMD, of L/Z in head to head comparison with β Carotene Emily Chew Conclusion ARVO Meeting 5 May 2013 Improve the safety of the AREDS supplements by removing β Carotene to decrease the risk of lung cancer in smokers and former smokers who compose >50% of persons with AMD Considering the totality of evidence, Lutein/Zeaxanthin may be an appropriate carotenoid substitution for β Carotene in the AREDS formulation Emily Y. Chew, MD AREDS II Study Lead "Adding a 10% relative risk reduction to a formula that already has a robust effect (AREDS 1) has significant public health implications and supports addition of L/Z to the AREDS formula." AREDS2 Formulation Vitamin C (500 mg) Vitamin E (400 IU) Beta Carotene (15mg) Lutein (10 mg)/zeaxanthin (2 mg) Zinc (80 mg zinc oxide) Copper (2 mg cupric oxide) Omega 3 fatty acids (DHA/EPA) 650 MG EPA / 350 DHA MG ARM IN AREDS II WAS NEUTRAL 7

8 Omega 3 Background.. The original AREDS 1 study, Blue Mountain study and woman s health study all found the largest effect in early incident AMD, the type of patient an optometrist is likely to examine. Dietary w3 Fatty Acid and Fish Intake and Incident AMD in Women The Women s Health Study Christen GS et al Arch Ophthalmol. 2011; 129 (7):921-9 OBJECTIVE: To examine whether intake of w-3 fatty acids and fish affects incidence of AMD in women Design N= 38,022 female health professionals (>54.6 SD 7 years) free of AMD completed a FFI (Food Frequency Questionnaire) MAIN OUTCOME MEASURE: incident AMD responsible for a reduction in best corrected VA to 20/30 or worse based on self-report confirmed by medical chart review. Results 235 / 38,022 confirmed AMD cases - average of 10 years follow-up. The highest tertile DHA intake had a multivariate adjusted RR of AMD of 0.62 (95% CI ) The highest tertile EPA intake had a multivariate adjusted RR of AMD of 0.66 (95% CI ) Consistent with the findings for DHA and EPA, women who consumed 1 or more servings of fish per week, compared with those who consumed less than 1 serving per month, had a relative risk of AMD of 0.58 (95% confidence interval, ). Omega-3 s and the Eye (clinically significant dose in AREDS II) DHA is the most ubiquitous polyunsaturated FA (PUFA) in the mammalian retina Dietary ω 3 FA s leads to Retinal DHA DHA required for optimal retinal function ω 3 fish oil seems to protect against lightinduced retina damage despite susceptibility to lipid peroxidation. dietary vitamin E (food, supplements) BENEFITS AMD, DRY EYE & COGNITION N3 fats: AREDS Report # 20. The relationship of dietary lipid intake and age related macular degeneration in a case control study Arch Ophthalmol May;125(5): n Dietary total omega 3 long chain polyunsaturated fatty acid (LCPUFA) intake u inversely associated with neovascular (NV) AMD (OR 0.61; 95% CI ) u (DHA) docosahexaenoic acid a LCPUFA (OR, 0.54; 95% CI, ) u comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. n Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR 0.61; 95% CI, and OR 0.65; 95% CI, , respectively). n Dietary arachidonic acid was directly associated with NV AMD prevalence (OR 1.54; 95% CI, ). 8

9 OMEGA 3 PUFAs Intake & AMD Protection (Preponderance of evidence says YES!) Results of Observational Studies AMD Risk People consuming high fat in diet showed an > AMD risk AMD Protection People with high fish intake showed a < risk of AMD Study #1: Mares-Perlman et al, Arch Ophthalmol Beaver Dam Eye Study 80% increased risk of AMD Study #2: Smith et al, Arch Ophthalmol Blue Mountain Eye Study 171% increased risk of AMD 54% reduced risk of AMD Study #3: Heuberger et al, Arch Ophthalmol NHANES Survey 40% increased risk of AMD 60% reduced risk of AMD Study #4: Seddon et al, Arch Ophthalmol EDCCS Study 44% increased risk of AMD 40% reduced risk of AMD Study #5: Cho et al, Am J Clin Nutr, % increased risk of AMD 35% reduced risk of AMD Study #6: Seddon et al, Arch Ophthalmol % increased risk of AMD 64% reduced risk of AMD Study #7: SanGiovanni et al, ARVO AREDS Study 51% reduced risk of AMD 49 Global Pharmaceuticals Category Study #8: Chua et al, Arch Ophthalmol % reduced risk of early AMD; 75% reduced risk of late AMD AREDS 2 DESIGN CONCERNS Placebo dietary n3 intake was simply too high, and confounding the main effects analysis? The omega III index was likely too low to mitigate disease in patients with such advanced disease? As with macula pigment optical density, the RBC HS Index was not determined in AREDS2. Not co administered with folate or genetically characterized with respect to folic acid conversion that effects 1/3 rd of the US population. DHA may be more important or an unnatural DHA/EPA ratio may be what matters based on AMD stage? TG based (not EE) Fish Oil should have been used? Comparison of Serum Levels of Lutein + Zeaxanthin and DHA + EPA in the Age Related Eye Disease Study 2 (AREDS2) Participants and the National Health and Nutrition Examination Survey (NHANES) Participants THE HS OMEGA 3 INDEX The HS Omega 3 Index a measure of the Omega 3 fatty acid level in the blood. The desired level is above 8%. 1. If your Index is over 8%, continue with current intake of omega 3 fatty acids. 2. If your Index is between 4% and 8%, increase intake of omega 3 fatty acids by 500 mg/day 3. If your Index is below 4%, increase intake of omega 3 fatty acids by 1000 mg/day If your HS Omega 3 Index is below the desirable 8% target, you should increase your EPA+DHA intake by 500 to1000 mg per day. This can be accomplished in two ways: eating more oily fish such as salmon or albacore tuna or taking fish oil supplements. The N3 dose was not high enough to effect the RBC HS Omega III Index If you weigh lbs (the majority of patients) you need EPA of mg and DHA of mg to achieve > 8 %. This dose will bring your omega index over 9% Clinical Experience Michael Lange, OD, CNS Ocular Nutrition Society Member 9

10 William Harris, PhD Internationally recognized expert in omega 3 and heart disease. Recipient of 5 NIH grants for studies on the effects of omega 3 fatty acids (EPA and DHA) on human health. Over 100 publications relating to omega 3 fatty acids in medical literature and was co author of the AHA's scientific statement, "Fish Consumption, Fish Oil, Omega 3 Fatty Acids and Cardiovascular Disease" published in 2002 in Circulation Serves as the Director of the Cardiovascular Health Research Center at Sanford Research/USD in Sioux Falls, SD and is a Research Professor of Medicine at the Sanford School of Medicine at the University of South Dakota AMD is associated w CVDz Albert (NEJM 2002) reported a 90% reduction in risk for death from sudden cardiovascular death in patients that had a blood level of omega 3 of 6.8% versus patients with a level less than 4% (the American average). Dr. Harris is the Chief Scientific Advisor to OmegaQuant Analytics. NAT 2 (OPPOSITE RESULT OF AREDS II) IN SUBGROUP WITH HIGH LEVELS OF SERUM DHA French study shows impact of omega 3 on preventing AMD progression Nutritional AMD Treatment 2 (NAT2) study Souied EH et al, Ophthalmology Feb 7 Randomized, placebo controlled, double blind, parallel, comparative study. N= 263, age years. Neovascular AMD in 1 eye & 0.4 VA or better in Study Eye 2 groups 840mg DHA + 270mg EPA daily Placebo (olive oil) The primary outcome measure: Time to occurrence of choroidal neovascularization (CNV) in the Study eye. Secondary outcome measures : incidence of CNV developing in patients, changes in visual acuity, occurrence and progression of drusen, and changes in EPA plus DHA level in red blood cell membrane (RBCM). RESULTS Primary 3yrs no difference in incidence of neovascularization However, 25% of the patients in the DHA group were found to have steadily high levels of DHA in the blood. [In] these patients, the risk of developing CNV was reduced by almost 70% over 3 years. The NAT 2 study subgroup showed a + DHA Result despite Olive Oil being a TERRIBLE Choice for Placebo Better Placebos than Olive Oil 1. Non saponifiable oil 2. Mono unsaturated canola oil 3. Pumice oil Hydroxytyrosol HTS is a mitochondrial targeting antioxidant nutrient and dietary administration of HTS may be an effective measure in reducing and or preventing cigarette smoke induced or age related retinal pigment epithelial degeneration, such as age associated macular degeneration J Neurochem Dec; 103(6):

11 Lakshminarayana R, Lutein and zeaxanthin in leafy greens and their bioavailability: olive oil influences the absorption of dietary lutein and its accumulation in adult rats J Agric Food Chem Jul 25;55(15): Zhongbo Liu et al Hydroxytyrosol (HTS) protects retinal pigment epithelial cells from acroleininduced oxidative stress and mitochondrial dysfunction J Neurochem Dec; 103(6): Chong EW, Fat consumption and its association with age related macular degeneration, Arch Ophthalmol May;127(5): The NAT 2 Placebo is so good, you can buy the active ingredients as a nutritional supplement It is very possible not enough patients in the U.S. AREDS II study achieved higher blood levels of DHA omega 3 fish oil to produce a measurable difference as found in the French NAT 2 Study. AREDS II did not measure the HS Omega 3 Index. THE FOLIC ACID DHA NEXUS (THE FRENCH DIET IS RICHER IN FOOD FOLATE VITAMIN B9) Folic Acid DHA Nexus Folic acid enhances the plasma concentrations of DHA and EPA. High blood levels of DHA can be achieved by Food Folate, Folic Acid supplementation in approx 2/3 rd of patients or 5 MTHF supplementation in approximately 1/3 rd of US patients with a genetic mutation AKA Folic Acid misbehavers. These 2 nutrients should be examined together. Umhau JC et al, The relationship between folate and docosahexaenoic acid in men, Eur J Clin Nutr Mar;60(3): Retrospectively determine if the blood concentrations of folate and DHA are correlated in humans. N= 15 normal and n=22 aggressive men, mean age 38y RBC folate was significantly correlated with plasma DHA, r=0.57, P=0.005 in the aggressive group. Age, smoking and alcohol consumption did not alter the results. No other essential fatty acids were significantly associated with RBC folate in either group. DHA and Folate are both important to CVDz & aggression. 11

12 TG based n3 All significant epidemiologic and prospective experimentation to date including the AREDS II study is based upon ethyl ester fish oil Prescription GSK Lovasa is ethyl ester form Absorption of ethyl ester depends on individual physiology and not entirely on the molecule.... i.e. bile salts and fat in diet. Nonetheless, 20 to 30% increased bioavailability potential (some patients w GI issues). WHY I ADVISE ALL MY AMD PATIENTS TO TAKE FISH OIL. 1) Additional Systemic Benefit 2) CVDz is associated with AMD 3) n3 is an essential cellular nutrient HDL triglycerides Blood pressure Heart Beat rate arrhythmias (studies show as effective as a pacemaker) sudden death heart attack Violent Behavior; Mood Cognitive function MI, CVA, CA & AMD 3 published DHA studies on better memory & reaction time. The Eye & Brain both require DHA (i.e Fish) & Lutein /Zx (i.e spinach/yellow peppers) LUTEIN /Zx Brain DHA 50% of neuron plasma mb is EFA, and half of that is DHA LUTEIN / Zx Retinal DHA 93% of Omega-3 in retina is DHA N3 Summary Omega 3 fatty acids are essential for every organ/tissue in your body including your eyes. Diets low in omega 3 increase risk for the development of dry eyes and many diseases besides AMD. Consuming a diet (supplements included) rich in omega 3 will likely require higher doses to achieve a healthy omega III index to quell inflammation and replete tissue status in advanced disease. Testing with the Holman Omega 3 Test allows a patient to determine whether or not their supplemental and dietary strategy has them in a healthy omega 3 zone. AREDS 2 LESSONS LEARNED Carotenoids The AREDS 2 population is that of a well nourished, well educated, non smoking, largely non Hispanic (2 %) highly at risk AMD cohort. Those patients don t look anything like the average patient an optometrist examines. Despite, this mis sampling of the US population, advanced AMD AREDS II patients having the lowest tertile intake of lutein/zeaxanthin, when supplemented, had a statistically significant Main Effect reduction in development of advanced AMD (tertile hazard ratio 0.83 (CI 95% ; P<0.05). 12

13 AREDS 2 LESSONS LEARNED n3 FATS Placebo dietary n3 intake was simply too high, and confounded the AREDS 2 main effects analysis? More likely, the omega III index was likely too low to mitigate disease in patients with such advanced disease? As with macula pigment optical density, the RBC HS Index was not determined in AREDS2 as it was in NAT 2. EPA/ DHA was not co administered with synergistic folate and subjects were not genetically characterized with respect to folic acid conversion that effects 1/3 rd of the US population further reports? DHA may be more important or an unnatural DHA/EPA ratio may be what matters as the disease advances to effect retinal structure and not just function? TG based Fish Oil or higher dose EE could have been used with possibly a better outcome? NAT 2 Lessons learned.. Patients with advanced wet macular degeneration who wish to try taking DHA omega 3 fish oil would be wise to increase their consumption of green leafy vegetables at the same time, or take a folate food supplement. Future AREDS II Reports? Genotype sub group analysis coming soon. Food Folate intake matters AREDS 1 vs. AREDS 2 Head to Head analysis as patients in AREDS II were older and sicker with more diabetes. The AREDS1 subjects were comprised of individuals who had all stages of AMD. AREDS2 subjects were at a more advanced stage of the disease and were on average 5 years older (average age 74) than the participants in AREDS1 (average age 69). Risk of progression to advanced AMD for those taking a true placebo in AREDS 1 was 28% for AREDS Cat 3 and 4 which is better than rates of progression seen with some AREDS intervention in AREDS2. Glycemic index matters as higher DM rate (13% in AREDS 2 vs. 7% in AREDS 1) Dr Paul Chous. Why did geographic patients not benefit? Medication sub analysis Chronic ASA smoking Sugar, HFCS + Stress & Hormonal changes Vitamin E isomers tocotrienols B vitamins Vitamin D Drug Muggers Carotenoids L/M + Zx + AstaZ N3 fats Vitamin C / bioflava noids Sulfur i.e. GSH / Lipoic Acid ZN ++ / MG++ / Selenium Fried Food in vegetable oil CU ++ FE ++ CA ++ Lessons Learned.. Practicing Optometrist We know that the advanced leaky wet form of macular degeneration occurs more frequently in smokers, aspirin users and high carbohydrate intake, and we know that tobacco, aspirin and simple sugars all deplete the body of vitamin C. Evidence Based Medicine addresses the average patient. We examine 1 patient at a time. AREDS II shows us that its tough to treat a disease once it becomes advanced so we better start examining and talking to the children of AMD patients about their diet and supplementation. Genetically, these patients have a 45 % risk of developing AMD if 1 parent has AMD. The authors suggest that a greater reduction in AMD progression may have been demonstrated if the subjects diets had been more representative to that of the general US population. In the US, the dietary intake of lutein and zeaxanthin is typically less than 1 mg per day. This amount is well below the 10 mg lutein and 2 mg zeaxanthin that the study has proven to be effective. 13

14 The value of MP measurement & carotenoid supplementation Any patient with high risk AREDS signs Any patient with a strong AMD risk factor age (over 50) smoker obese poor diet Any patient with a family history of AMD Any patient with diabetes Any patient with photophobia i.e. smokers Any patient with a non refractive reading / driving issue Anyone in the transportation industry (3%) Athletes i.e. Skiers (glare); Baseball (fine acuity) Factoid: L/Z make you Smart! Xanthophyls (lutein & zeaxanthin) are good for brain health and cognition MPOD related to indices that evaluate processing speed,accuracy and completion 1 More L/Z in brain = better cognitive function 2 More AMD and worse VA = worse cognitive function 3 More green veges associated w less cognitive decline w age 4 1. Renzi LM et al. FASEB J 22 (abstract 877.5), Miller LS et al. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 17:575-90, Arch Ophth (4):537-43, Kang, et al. Ann Neurol 57: , 2005 Modifying environmental factors is currently the only approach to reduce the genetic risk of AMD (and promise better vision too). THANK YOU A Society Focused on Ocular Nutrition Education 14