Results from the Age-Related Eye Disease Study2 (AREDS2)

2,433 views

Published on

Emily Y. Chew, MD
and the AREDS2 Research Group
National Eye Institute/National Institutes of Health

Published in: Health & Medicine, Business
  • Be the first to comment

Results from the Age-Related Eye Disease Study2 (AREDS2)

  1. 1. Results from the Age-Related Eye Disease Study2 (AREDS2) Emily Y. Chew, MD and the AREDS2 Research Group National Eye Institute/National Institutes of Health
  2. 2. Financial Disclosure None
  3. 3. Objectives • To recognize the population who would benefit from nutritional supplements • To be knowledgeable regarding the nutritional factors studied and the nutritional factors that were found to be beneficial in the treatment of age-related macular degeneration and cataract. • To recognize adverse side-effects of the AREDS/AREDS2 formulation
  4. 4. Causes of Blindness in the US Age related macular degeneration (AMD) 54.4% AMD Cataract Glaucoma Diabetic eye disease Other
  5. 5. U.S. Population  Leading cause of central blindness in the US (54%)  Primarily affects reading, writing, & driving  7 million Americans are at risk of developing AMD  1.75 Million American have advanced AMD  15% white women older than 80 years (NV and GA)  In 2020, AMD will increase by 50% to 2.95 Million
  6. 6. Pathogenesis of AMD  Unknown  Increasing Age-Major Risk Factor
  7. 7. AMD Epidemiology Risk Factors Genetic Smoking Body Mass Index Cardiovascular – Neovascular Nutritional Risk Factors Fundus Features
  8. 8. Nutrition and AMD Factors associated with age-related macular degeneration. An analysis of data from the first National Health and Nutrition Examination Survey (NHANES) survey Am J Epid. 1988;128:700-10 A diet rich in fruits and vegetables with vitamins A and C, was inversely associated with AMD Goldberg J, Flowerdew J, Smith E, Brody JA, Tso MO
  9. 9. The Age-Related Eye Disease Study
  10. 10. Methods  Prospective Natural History Study  Randomized, Multi-Center, Double-Masked, Placebo-Controlled 6-Year Clinical Trial (2001) 4757 Participants with < 2% Loss to F/U  Additional 5-Year Follow-up Study (2005) 3687 Participants with 4% Loss to F/U
  11. 11. Category 1 No or Few Small Drusen (<63 microns) N=1117
  12. 12. AREDS Categories of AMD 2. Early 3. Intermediate 4. Advanced
  13. 13. Baseline 3 Years
  14. 14. Baseline 3 Years
  15. 15. Baseline 7 Years
  16. 16. Age-Related Eye Disease Study (AREDS) Treatment Assignment Randomized Participants N=4757 Placebo N=1,483 Antioxidant N=1,482 Zinc N=904 Antioxidant & Zinc N=888
  17. 17. Antioxidants – Daily Oral Dose  Vitamin C – 500 mg  Vitamin E – 400 IU  Beta-carotene – 15 mg (Equivalent to 25,000 IU Vitamin A)
  18. 18. Zinc Treatment – Daily Oral Dose  Zinc – 80 mg  Copper – 2 mg
  19. 19. Rates to Advanced AMD Estimated Probability AMD Categories 3 and 4 by Treatment Group Placebo Antioxidants Zinc Antioxidants + Zinc 40% 28% 30% 20% 20% 25% Risk Reduction 10% 0% P vs. A+Z – p<0.01 P vs. Z – p<0.01 0 1 2 3 Years 4 5 6 7
  20. 20. Long-Term Rates to Advanced AMD Estimated Probability AMD Categories 3 and 4 by Treatment Group Placebo Antioxidants Zinc Antioxidants + Zinc 40% 44% 30% 34% 20% 27% Risk Reduction P vs. A+Z – p<0.01 P vs. A – p<0.01 10% 0% 0 1 2 3 4 5 6 Years 7 8 9 10
  21. 21. AREDS Formulation Recommended: • patients with intermediate AMD (bilateral large drusen) • patients with advanced AMD in one eye • NOT for current smokers
  22. 22. Who should take the AREDS formulation? Should offsprings of affected individuals with AMD take the AREDS formulation?  No, unless they have bilateral large drusen or advanced AMD in one eye  AREDS formulation does not prevent early AMD from progressing along the mild to the moderate severity of AMD
  23. 23. Who should take the AREDS formulation? Should the AREDS formulation be taken for general eye health?  No, unless they have bilateral large drusen or advanced AMD in one eye  AREDS formulation does not prevent cataract progression or early AMD progression
  24. 24. Who should take the AREDS formulation? Is it okay to take the AREDS formulation and a multivitamin?  Yes, AREDS participants were given Centrum as part of the study to standardize their vitamin intake  Centrum also provided other vitamins such as vitamin D and the B complex.
  25. 25. AREDS Formulation Adverse Effects: • Beta-carotene increased the risk of lung cancer and it associated mortality • High levels of zinc resulted in increased hospitalizations for genitourinary causes (mostly hypertrophy of the prostate)
  26. 26. AREDS Formulation Recommended: • patients with intermediate AMD (bilateral large drusen) • patients with advanced AMD in one eye • NOT for current smokers
  27. 27. The Age-Related Eye Disease Study Lutein/Zeaxanthin Spinach, Kale and Collard Greens Omega-3 Long-chain Polyunsaturated Fatty Acids (LCPUFAs) (DHA/EPA)
  28. 28. Study Design Randomized, Multi-Center (82 clinics) Academic and Community Centers
  29. 29. Study Design Inclusion Criteria • Bilateral Large Drusen or Late AMD in One Eye Large Drusen GA NV AMD
  30. 30. Study Design Primary Objective: • Test effects of adding • Lutein/Zeaxanthin • Omega-3 Long-Chain Polyunsaturated Fatty Acids (DHA & EPA) • Combination to the AREDS Formulation on AMD outcomes
  31. 31. Study Design Dietary Supplements • Carotenoids (Xanthophylls) Lutein/Zeaxanthin (L/Z) – 10mg/2mg • Omega-3 Long Chain Polyunsaturated Fatty Acids Docosahexaenoic Acid (DHA) – 350mg Eicosapentaenoic Acid (EPA) – 650mg
  32. 32. Primary Randomization Randomized Participants Control* Lutein/Zeaxanthin * No placebo group because AREDS treatment is considered standard of care DHA/EPA AREDS-I Type Supplements L/Z + DHA/EPA
  33. 33. AREDS Formulation • Vitamin C (500 mg) • Vitamin E (400 IU) • Beta Carotene (15 mg) • Zinc (80 mg zinc oxide) • Copper (2 mg cupric oxide)
  34. 34. 2nd Randomization AREDS Formulations Vitamin C Vitamin E β-carotene Zinc Oxide Cupric Oxide 500 mg 400 IU 15 mg 80 mg 2 mg 2* 500 mg 400 IU 0 mg 80 mg 2 mg 500 mg 400 IU 15 mg 25 mg 2 mg 4* 500 mg 400 IU 0 mg 25 mg 2 mg 1 3 *Smokers randomized to treatments without beta-carotene.
  35. 35. AREDS2-2nd Randomization Modification of AREDS formulation Randomized Participants AREDS Formulation AREDS minus Beta -Carotene AREDS + Low Zinc AREDS minus Beta-Carotene + Low Zinc
  36. 36. Study Design Randomized Participants n=4203 Control 1012 Lutein and Zeaxanthin 1044 No AREDS 19 AREDS 659 AREDS minus ß-Carotene 863 DHA and EPA 1068 AREDS 3036 AREDS + Low Zinc 689 Lutein/Zeaxanthin + DHA/EPA 1079 AREDS 1148 AREDS minus ß-Carotene + Low Zinc 825
  37. 37. Study Design Randomized Participants n=4203 Lutein and Zeaxanthin 1044 Control 1012 DHA and EPA 1068 Lutein/Zeaxanthin + DHA/EPA 1079 Primary Randomization No AREDS 19 AREDS 659 AREDS minus ß-Carotene 863 AREDS 3036 AREDS + Low Zinc 689 AREDS 1148 AREDS minus ß-Carotene + Low Zinc 825
  38. 38. Study Design Randomized Participants n=4203 Control Lutein and Zeaxanthin 1044 DHA and EPA 1068 Lutein/Zeaxanthin + DHA/EPA 1079 Secondary Randomization 1012 NonNo AREDS Randomized 19 AREDS 659 AREDS 3036 AREDS minus ß-Carotene 863 AREDS + Low Zinc 689 NonAREDS Randomized 1148 AREDS minus ß-Carotene + Low Zinc 825
  39. 39. Primary / Secondary Outcomes Evaluate the effects of adding lutein/zeaxanthin and/or DHA/EPA to the AREDS formulation on: • Progression to advanced AMD (AAMD) • Progression to moderate vision loss • Progression to AAMD stratified by dietary intake • Time to cataract surgery • Progression of lens opacities
  40. 40. The Age-Related Eye Disease Study 2 Research Group Lutein/Zeaxanthin for the Treatment of Age-Related Cataract: AREDS2 Randomized Trial Report No. 4 Published online May 5, 2013 Available at www.jamaophth.com jamanetwork.com
  41. 41. Cataract Surgery/Lens Opacity Progression Favors L/Z Favors No L/Z Cataract Surgery Any Cataract Severe Cataract 0.85 0.95 1 1.05 1.15 Hazard Ratio (95%CI)
  42. 42. The Age-Related Eye Disease Study 2 (AREDS2) Research Group Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial Published online May 5, 2013 Available at www.jama.com jamanetwork.com
  43. 43. Primary Randomization Randomized Participants 4203 Placebo (Control) (1012) Lutein/Zeaxanthin (1044) DHA/EPA (1068) Lutein/Zeaxanthin DHA/EPA (1079) Three Primary Analyses
  44. 44. Estimated Probability Probability of Progression to AAMD 40% Placebo - AREDS L/Z DHA/EPA L/Z & DHA/EPA 30% 31% 30% 20% 31% 29% 10% 0% 0 AAMD: advanced AMD 1 2 Years 3 4 5
  45. 45. Primary Randomization Randomized Participants 4203 Placebo (Control) Lutein/ Zeaxanthin DHA/EPA Lutein/Zeaxanthin DHA/EPA Analyses of Main Effects of Lutein/Zeaxanthin vs. No Lutein/Zeaxanthin
  46. 46. Progression to Advanced AMD by Primary and Secondary Randomization Main Effects Favors Favors Treatment Control L/Z vs. No L/Z HR=0.90 DHA/EPA vs. No DHA/EPA Low Zinc vs. High Zinc Beta-Carotene Yes vs. No 0.8 0.9 1 1.1 Hazard Ratio (95%CI) 1.2
  47. 47. Comparison of Lutein/Zeaxanthin vs. no Lutein/Zeaxanthin Advanced AMD: HR: 0.90 P=0.04 10% additional reduction in the risk of progression to AAMD with lutein/zeaxanthin Other HRs were not statistically significant
  48. 48. Progression to Advanced AMD by Quintiles of Dietary Intake of Lutein/Zeaxanthin L/Z Dietary Intake Quintile Lowest 1 2 Favors L/Z Favors No L/Z HR=0.74 3 4 Highest 5 0.5 0.6 0.7 0.8 0.9 1 1.1 Hazard Ratio (95%CI) 1.3 1.5
  49. 49. Lutein/Zeaxanthin vs. no Lutein/Zeaxanthin Lowest Quintile of Dietary Lutein/Zeaxanthin •Lowest Quintile – 26% Reduction in Risk of Progressing to AAMD (p<0.01) •Higher Quintiles – Not Statistically Significant
  50. 50. Compare AREDS formulation with lutein/zeaxanthin substituted for betacarotene vs. AREDS formulation Lutein/Zeaxanthin plus AREDS Formulation minus Beta-Carotene N = 1114 eyes vs. AREDS Formulation with Beta-Carotene N = 1117 eyes
  51. 51. Estimated Probability Probability of Progression to AAMD 40% AREDS with βC AREDS without βC with L/Z 34% 30% 30% 20% 10% P=0.02 0% 0 1 2 Years 3 4 5
  52. 52. Progression to Advanced AMD Exploratory Analyses of Lutein/Zeaxanthin Favors AREDS minus beta-carotene with L/Z Advanced AMD Favors AREDS HR=0.82 Neovascular AMD HR=0.78 Central Geographic Atrophy 0.6 0.7 0.8 0.9 1 1.2 1.4 Hazard Ratio (95%CI)
  53. 53. L/Z plus AREDS Minus Beta-Carotene vs. AREDS (with Beta-Carotene) Advanced AMD: HR: 0.82 P=0.02 18% reduction in the risk of progression to AAMD with lutein/zeaxanthin Neovascular AMD: HR: 0.78 P=0.01 22% reduction in the risk of progression to neovascular AMD with lutein/zeaxanthin Not statistically significant for CGA
  54. 54. Visual Acuity Outcomes Lutein/Zeaxanthin vs. Beta-Carotene Visual Acuity Favors AREDS Minus Beta-Carotene with L/Z Favors AREDS VA Loss 10+ Letters VA Loss 15+ Letters VA Loss 30+ Letters HR=0.84 VA Worse Than 20/100 HR=0.82 0.6 0.7 0.8 0.9 1 1.2 1.4 Hazard Ratio (95%CI) * Eyes with NV-AMD included in all VA loss groups
  55. 55. 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=0.06 16% reduction in the risk of vision loss of 30+ letters Visual Acuity <20/100: HR: 0.82 P=0.03 18% reduction in the risk of vision of <20/100
  56. 56. Safety Outcome: Lung Cancer Beta-carotene Main Effect β-Carotene (N = 1348) No β-Carotene (N = 1341) 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 excludes smokers
  57. 57. Safety Outcome: Lung Cancer Lutein/Zeaxanthin Main Effect Lutein/Zeaxanthin (N = 2123) No Lutein/Zeaxanthin (N = 2080) P-value 33 Cases (1.5%) 31 Cases (1.5%) 0.80 No increased risk of lung cancer 62% were former smokers, equal in both arms Analysis includes smokers
  58. 58. Conclusions • Although no statistically significant results from primary analyses, the main effect of lutein/zeaxanthin demonstrated 10% reduction of AAMD • ~ 20% reduction in the risk of progression to AAMD of L/Z beyond the effects of AREDS supplement for 1) the lowest dietary intake of L/Z, 2) for neovascular AMD, 3) especially in the head-to-head comparison L/Z vs. betacarotene
  59. 59. Conclusions • No effect with DHA/EPA (omega-3 fatty acids) main effect or primary analyses— still consider a diet replete with fish • Secondary randomization suggests no differences in the progression to AAMD for elimination of beta-carotene or lowering zinc dose
  60. 60. Conclusions • Improve the safety of the AREDS supplements by removing betacarotene to decrease the risk of lung cancer in smokers and former smokers who compose 2/3 of persons with AMD. • Considering the totality of evidence, lutein/zeaxanthin may be an appropriate carotenoid substitution for beta-carotene in the AREDS formulation
  61. 61. AREDS2 Formulation • Vitamin C (500 mg) • Vitamin E (400 IU) • Beta Carotene (15 mg) • Lutein (10 mg)/Zeaxanthin (2 mg) • Zinc (80 mg zinc oxide) • Copper (2 mg cupric oxide) • Omega-3 fatty acids (DHA/EPA)
  62. 62. Recommendations: • Maintain healthy diet replete with fish, green leafy vegetables • Stop smoking • Consider AREDS supplements with lutein/zeaxanthin instead of betacarotene for those with bilateral large drusen & advanced AMD in one eye
  63. 63. Further Analyses in AREDS2 • Fundus autofluorescence • Optical Coherence Tomography (OCT) • Optos fundus images • Macular Pigment Measurements • Genetic associations • Cognitive function testing • Cardiovascular disease
  64. 64. 2007 20/250 2009 20/500 Halo of increased autofluorescence predicts GA?
  65. 65. Further Analyses in AREDS2 • Fundus autofluorescence • Optical Coherence Tomography (OCT) • Optos fundus images • Macular Pigment Measurements • Genetic associations • Cognitive function testing • Cardiovascular disease
  66. 66. OPTOS system
  67. 67. OPTOS system
  68. 68. Further Analyses in AREDS2 • Fundus autofluorescence • Optical Coherence Tomography (OCT) • Optos fundus images • Macular Pigment Measurements • Genetic associations • Cognitive function testing • Cardiovascular disease
  69. 69. Genetic Testing • Identify disease mechanisms • Permit early detection and prevention • Guide research into targeted therapies • May help to predict individual’s response to therapy (pharmacogenetics) -personalized medicine
  70. 70. Recognition Thank you to the following: • Office of Dietary Supplements (ODS) • National Center for Complementary and Alternative Medicine (NCCAM) • National Heart Lung and Blood Inst.(NHLBI) • National Institute of Aging (NIA)) • National Institute of Neurological Disorders and Stroke (NINDS)
  71. 71. Recognition Thank you to the following: • NEI AREDS2 Clinical Site-PI Wai Wong, MD, PhD, AREDS2 research team • AREDS2 Investigators and their Research teams • AREDS2 Participants

×