Antioxidants and Nutrients in the Treatment and Prevention of Age

Antioxidants and Nutrients in the Treatment and Prevention of Age-Related Macular Degeneration Michael B. Gorin, M.D. Ph.D. Department of Ophthalmology University of Pittsburgh UPMC Eye Center Nutrition - Vision and Ocular Health • Folklore: • Carrots are good for your sight • Bilberry jam will improve your night vision • Knowledge from deficiencies • Vitamin A deficiency - nightblindness, poor color vision, dry eyes • Vitamin E deficiency- retinopathy, increased light damage • Abetalipoproteinemia - retinal degeneration (partially reversed by Vitamin E) • Zinc deficiency - retinopathy (rats & monkeys) Eye Diseases that have been treated with vitamins & nutrients • Dry Eyes • TheraTears Nutrition • Retinitis Pigmentosa • Vitamin A, DHA • Vaso-occlusive disease caused by elevated homocysteine • Folate, Vitamin B12 • Glaucoma • Ginko biloba • Age-related macular degeneration • Vitamins C & E, -carotene, zinc, lutein (and others) NUTRITIONAL EYE RESEARCH SUMMARIES - Preventing Blindness Through Nutritional Intervention o MACULAR DEGENERATION STUDIES o GLAUCOMA STUDIES o DIABETIC EYE STUDIES o CATARACT STUDIES o RETINITIS PIGMENTOSA STUDIES http://www.i-care.net Age-related macular degeneration • The eye uses the cornea and lens to focus light on the back surface of the eye (retina). • The central portion of the retina (macula) is essential for reading vision and recognizing faces • Macular degeneration refers to a collection of conditions that cause progressive damage to the macular portion of the retina. • Not all conditions that damage the macula are considered macular degeneration. The Eye What the doctor sees in your eye A Normal Retina The Retina What is Age-Related Macular Degeneration? • Age-related maculopathy (ARM) refers to changes in the retina and adjoining pigment epithelium with or without vision loss. • Age-related macular degeneration (ARMD, also known as AMD or SMD) is included within agerelated maculopathy but includes the requirement that there is vision loss resulting from the changes in the back of the eye. Features of Age-Related Macular Degeneration • DRY ARM or AMD • Drusen - deposits of material under the retina • Pigment disturbances - changes in the pigmented cells under the retina from chronic injury • Pigment epithelial detachments - blisters that form under the retina and pigment epithelium • Geographic atrophy - areas in which the pigment cells become unable to function properly and the retina can no longer see in those locations Age-related Macular Degeneration DRY FORM: Drusen - soft / hard Pigment epithelial detachment Geographic atrophy Features of Age-Related Macular Degeneration • WET AMD • Choroidal neovascular membranes blood vessels that grow from the choriocapillaris and spread under the pigment epithelium and/or retina leading to leakage and bleeding and scarring (Disciform scars). These vessels are not tumors. Age-related Macular Degeneration WET FORM: Choroidal neovascular membrane Disciform scarring Symptoms • Early: • Difficulty adjusting to lights at night • Distortion of central vision - wavy lines • Late: • Blurred central vision • Central dark spot • Symptoms tend to be: • gradual for the DRY form • more sudden and rapid for the WET form Risk Factors • Smoking - 2.5 fold increased risk • Family History - 6 to 12 fold increased risk • Controversial evidence for increased risk: • • • • Light exposure Diet Hypertension Cataract surgery AMD Theories of Pathogenesis • Oxidative Stress • Lipid peroxidation • Accumulation of reactive molecules • Protection by macular carotenoids - lutein & zeaxanthin • Choroidal Circulation • Association of AMD and atherosclerosis, BMI, obesity, hypertension (+/-) • Degeneration of Bruch’s membrane • Histologic data, role of zinc and iron • Inflammation • Genetic evidence of variants in complement factors that heavily influence the risk of having AMD. • Histologic evidence of complement factors in drusen Age-related macular degeneration • Antioxidants • • • • Vitamin E Vitamin C -carotene (vitamin A) Lutein zeaxanthin Anthocyanins (Bilberry, pycnogenol, others) Quercetin Coenzyme Q-10 • Nutrients and Cofactors • Omega-3 and Omega-6 Fatty acids (DHA) • Zinc Copper • Folic Acid Alcohol • Medications • Statins NSAIDS Age-related macular degeneration • Antioxidants • Vitamin E • epidemiologic studies suggested an association • Several prospective studies - VECAT (1193 participants - 4years) no benefit, two other trials - no benefit (low numbers), • Positive benefit in AREDS • Vitamin C • some epidemiologic studies suggested increased AMD risk with low plasma levels, but higher levels were not protective. • -carotene (vitamin A precursor) • Three randomized trials (15-40 mg daily) - no benefit (? Too small) • Positive benefit in AREDS Age-related macular degeneration • Antioxidants • Lutein & zeaxanthin • Epidemiologic studies (Dietary) with association between AMD and amount of macular pigment (EDCCS +. Beaver Dam -), • Anthocyanins (Bilberry, pycnogenol, others) • No studies (some epidemiologic associations with wine intake) • Quercetin • No studies • Coenzyme Q-10 • No studies Age-related macular degeneration • Nutrients and Cofactors • Omega-3 and Omega-6 Fatty acids (DHA) • DHA does reduce inflammation, retina dependent on these fatty acids • No prospective studies • Zinc • Cofactor for enzyme antioxidants • Beaver Dam Eye Study - some supportive evidence • Supported by AREDS • Copper • Cofactor for superoxide dismutase • No studies Age-related macular degeneration • Nutrients and Cofactors • Folic Acid (1 mg/day) • Some reports of hyperhomocysteinemia and AMD association • No prospective studies • Selenium • Suggested by one small study, no replication • Alcohol • NHANES-1: association study suggesting that red wines may lower risk (possibly through antioxidants), not replicated. Age-related macular degeneration • Medications • Statins • Suggested by some studies but not others • No prospective studies • NSAIDS • No strong epidemiologic evidence • Recent report that patients with Rheumatoid Arthritis have less AMD - attributed to anti-inflammatory medications. • No prospective studies Age-related Eye Disease Study (AREDS) Supplementation Vitamin C Vitamin E -carotene Zinc Copper Total Daily Dose 50 mg 400 IU 15 mg 80 mg 2 mg Lutein, Zeaxanthin, Bilberry, DHA - not tested Age-related Eye Disease Study (AREDS) • 3,640 patients (55-80 yrs) • Four treatment arms • High-dose antioxidants + zinc for nonsmoking patients - showed benefit • Outcomes - progression to advanced AMD and moderate visual acuity loss (> 15 letters) • Approximately a 20% reduction in rate of progression. AREDS interpretation • Study failed to find a benefit for those with mild ARM - could be do to the fact that these individuals were at lower risk for progression • Unclear if therapy would be effective for a younger population with earlier and/or milder disease • Not recommended for the general population - not clear who should take it. Vitamin E and smokers • Increased risk of lung cancer shown in at least 2 large studies • There is a formulation that leaves out the Vitamin E and substitutes Lutein Arora, S., M. Musadiq, et al. (2004). Eye 18(5): 470-3 "Eye nutrient products for age-related macular degeneration: what do they contain?” RESULTS: We identified 22 eye nutrient products. Analysis of their constituents showed that, although over 75% contained all the constituents used in AREDS, only two matched the dosage profiles recommended in the study. CONCLUSION: The authors draw no conclusion on the efficacy of nutritional supplements in the prevention of AMD. In order to advise their patients, ophthalmologists should be familiar with these products. The compiled list in this paper should provide a useful reference for them. Is nutrient therapy cost-effective? Trevithick, J., D. Massel, et al. (2004). "Model study of AREDS antioxidant supplementation of AMD compared to Visudyne: a dominant strategy?” Ophthalmic Epidemiol 11(5): 337-46. Is nutrient therapy cost-effective? • OBJECTIVES: In Ontario, Canada, in a cohort of all people initially aged 50-54 years, modeling whether the AgeRelated Eye Disease Study (AREDS) antioxidant supplementation for stage 3 and 4 AMD would decrease the costs of photodynamic treatment with Visudyne. • PERSPECTIVE: Third party payer, the Ontario Health Insurance Plan. METHODS: Using reported risk reductions, prevalence data by age and sex from the Beaver Dam studies, and yearly costs: AREDS 182.50 Canadian dollars, potential savings were calculated as the difference or incremental cost between the estimated medical costs for the untreated cohort of 17,000 Canadian dollars for Visudyne treatment of individuals with neovascularization and the same cohort if stage 3 and 4 AMD patients were treated with antioxidants, decreasing progression to neovascularization. Different scenarios were explored for sensitivity analysis of direct cost savings. Is nutrient therapy cost-effective? • RESULTS: For the Ontario cohort of approximately 788,000 aged 51-55 years in 2001, for photodynamic therapy of the untreated cohort, modeled costs were 1.7 billion Canadian dollars. AREDS treatment costs would be 513 million Canadian dollars. AREDS would reduce photodynamic therapy costs, a net saving of 431 million Canadian dollars, a saving of 547 Canadian dollars per person in the total cohort, or 6,753 Canadian dollars per stage 3 and 4 patient treated. To explore the sensitivity of this model to AMD incidence rather than prevalence data, Framingham incidence data were incorporated in the model: net savings of 70.3 million Canadian dollars were modeled using Framingham incidence data. Is nutrient therapy cost-effective? • CONCLUSION: Under reasonable assumptions, if the case progresses to wet AMD • (1) AREDS with Visudyne is less expensive than Visudyne alone in every five-year time period for the cohort that is age 50-54 right now until they become 75-79; thus, the lifetime cost is lower; • (2) AREDS with Visudyne yields more QALYs than Visudyne alone in every five-year interval; • (3) under all but the most extreme assumptions, the conclusions reached are robust. Even when AREDS costs a little more, it yields more QALYs at a reasonable cost per QALY. • Thus, AREDS antioxidant supplementation appears to be a dominant strategy for macular degeneration. Applied to the whole Canadian population, the potential medical cost savings for Visudyne treatment of neovascular AMD are 5.6 billion Canadian dollars in direct costs. These values would be tenfold higher for the USA, because of the currency and population size differences.