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

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. Financial Disclosure
None

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. Causes of Blindness in the US
Age related macular
degeneration (AMD)
54.4%
AMD
Cataract
Glaucoma
Diabetic eye disease
Other

6. 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

7. Pathogenesis of AMD
 Unknown
 Increasing Age-Major Risk Factor

8. AMD Epidemiology
Risk Factors
Genetic
Smoking
Body Mass Index
Cardiovascular – Neovascular
Nutritional Risk Factors
Fundus Features

9. 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

10. The Age-Related
Eye Disease Study

11. 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

12. Category 1
No or Few Small Drusen (<63 microns)
N=1117

13. AREDS Categories of AMD
2.
Early
3.
Intermediate
4.
Advanced

14. Baseline
3 Years

15. Baseline
3 Years

16. Baseline
7 Years

17. 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

18. Antioxidants – Daily Oral Dose
 Vitamin C – 500 mg
 Vitamin E – 400 IU
 Beta-carotene – 15 mg
(Equivalent to 25,000 IU Vitamin A)

19. Zinc Treatment – Daily Oral Dose
 Zinc – 80 mg
 Copper – 2 mg

20. 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

21. 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

22. AREDS Formulation Recommended:
• patients with intermediate AMD
(bilateral large drusen)
• patients with advanced AMD in one eye
• NOT for current smokers

23. 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

24. 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

25. 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.

26. 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)

27. AREDS Formulation Recommended:
• patients with intermediate AMD
(bilateral large drusen)
• patients with advanced AMD in one eye
• NOT for current smokers

28. The Age-Related Eye Disease Study
Lutein/Zeaxanthin
Spinach, Kale and Collard Greens
Omega-3 Long-chain Polyunsaturated Fatty Acids
(LCPUFAs) (DHA/EPA)

29. Study Design
Randomized, Multi-Center (82 clinics)
Academic and Community Centers

30. Study Design
Inclusion Criteria
• Bilateral Large Drusen or Late AMD in One Eye
Large Drusen
GA
NV AMD

31. 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

32. 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

33. 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

34. AREDS Formulation
• Vitamin C (500 mg)
• Vitamin E (400 IU)
• Beta Carotene (15 mg)
• Zinc (80 mg zinc oxide)
• Copper (2 mg cupric oxide)

35. 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.

36. AREDS2-2nd Randomization
Modification of AREDS formulation
Randomized
Participants
AREDS
Formulation
AREDS
minus Beta
-Carotene
AREDS
+ Low
Zinc
AREDS minus
Beta-Carotene
+ Low Zinc

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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)

43. 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

44. Primary Randomization
Randomized
Participants
4203
Placebo
(Control)
(1012)
Lutein/Zeaxanthin
(1044)
DHA/EPA
(1068)
Lutein/Zeaxanthin
DHA/EPA
(1079)
Three Primary Analyses

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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)

54. 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

55. 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

56. 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

57. 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

58. 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

59. 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

60. 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

61. 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

62. 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)

63. 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

64. Further Analyses in AREDS2
• Fundus autofluorescence
• Optical Coherence Tomography (OCT)
• Optos fundus images
• Macular Pigment Measurements
• Genetic associations
• Cognitive function testing
• Cardiovascular disease

65. 2007
20/250
2009
20/500
Halo of increased autofluorescence predicts GA?

66. Further Analyses in AREDS2
• Fundus autofluorescence
• Optical Coherence Tomography (OCT)
• Optos fundus images
• Macular Pigment Measurements
• Genetic associations
• Cognitive function testing
• Cardiovascular disease

67. OPTOS system

68. OPTOS system

69. Further Analyses in AREDS2
• Fundus autofluorescence
• Optical Coherence Tomography (OCT)
• Optos fundus images
• Macular Pigment Measurements
• Genetic associations
• Cognitive function testing
• Cardiovascular disease

70. 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

71. 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)

72. 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