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Emily Y. Chew, MD and the AREDS2 Research Group National Eye Institute/National Institutes of Health
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Results from the Age-Related Eye Disease Study2 (AREDS2)
Emily Y. Chew, MDand the AREDS2 Research Group
National Eye Institute/National Institutes of Health
Financial Disclosure
None
• 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
• Lutein/Zeaxanthin
• Omega-3 Long-Chain Polyunsaturated Fatty Acids (DHA & EPA)
• Combination
Objectives
Causes of Blindness in the US
Age related maculardegeneration (AMD)
Cataract
Glaucoma
Other
Diabetic eye disease
54.4%
AMD
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
Pathogenesis of AMD
Unknown Increasing Age-Major Risk Factor Oxidative Stress Implicated Retina particularly susceptible Inflammation may play an important role
Risk Factors AMD Epidemiology
Genetic
Smoking
Body Mass Index
Fundus Features
Cardiovascular – Neovascular
Nutritional Risk Factors
Factors associated with age-related macular degeneration. An analysis of data from the first National Health and Nutrition
Examination Survey (NHANES) survey
A diet rich in fruits and vegetables with vitamins A and C, was
inversely associated with AMD
Nutrition and AMD
Goldberg J, Flowerdew J, Smith E, Brody JA, Tso MO
Am J Epid. 1988;128:700-10
The Age-RelatedEye Disease Study
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
Category 1 No or Few Small Drusen (<63 microns)
N=1117
AREDS Categories of AMD
Early
Intermediate
Advanced
2.
4.
3.
Baseline 3 Years
Baseline 3 Years
Baseline 7 Years
Age-Related Eye Disease Study(AREDS) Treatment Assignment
RandomizedParticipants
N=4757
Antioxidant &Zinc
N=888N=1,483Placebo
N=1,482Antioxidant Zinc
N=904
Antioxidants – Daily Oral Dose
Vitamin C – 500 mg
Vitamin E – 400 IU
Beta-carotene – 15 mg (Equivalent to 25,000 IU Vitamin A)
Zinc Treatment – Daily Oral Dose
Zinc – 80 mg
Copper – 2 mg
AMD Categories 3 and 4 by Treatment Group
30%
20%
10%
0%
40%
0Years
1 2 3 4 5 6 7
PlaceboAntioxidantsZinc
Antioxidants + Zinc
P vs. A+Z – p<0.01 P vs. Z – p<0.01
20%
28%
EstimatedProbability
Rates to Advanced AMD
25% Risk Reduction
Long-Term Rates to Advanced AMD
44%
34%
P vs. A+Z – p<0.01 P vs. A – p<0.01
PlaceboAntioxidantsZinc
Antioxidants + Zinc
AMD Categories 3 and 4 by Treatment Group
30%
20%
10%
0%
40%
0 Years1 2 3 4 5 6 7
EstimatedProbability
8 9 10
27% Risk Reduction
AREDS Formulation Recommended:
• patients with intermediate AMD (bilateral large drusen)
• patients with advanced AMD in one eye
• NOT for current smokers
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
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
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.
Who should take the AREDS formulation?
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)
AREDS Formulation Recommended:
• patients with intermediate AMD (bilateral large drusen)
• patients with advanced AMD in one eye
• NOT for current smokers
Omega-3 Long-chain Polyunsaturated Fatty Acids
(LCPUFAs) (DHA/EPA)
Spinach, Kale and Collard Greens
Lutein/Zeaxanthin
The Age-Related Eye Disease Study
Randomized, Multi-Center (82 clinics)
Academic and Community Centers
Study Design
Inclusion Criteria• Bilateral Large Drusen or Late AMD in One Eye
Large Drusen GA NV AMD
Study Design
Primary Objective:
• Test effects of adding
• Lutein/Zeaxanthin
• Omega-3 Long-Chain Polyunsaturated Fatty Acids (DHA & EPA)
• Combination
Study Design
to the AREDS Formulation
on AMD outcomes
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
Study Design
RandomizedParticipants
Lutein/Zeaxanthin DHA/EPA
L/Z + DHA/EPA
Control*
AREDS-I Type
Supplements
Primary Randomization
* No placebo group because AREDS treatment is considered standard of care
AREDS Formulation• Vitamin C (500 mg)
• Vitamin E (400 IU)
• Beta Carotene (15 mg)
• Zinc (80 mg zinc oxide)
• Copper (2 mg cupric oxide)
2nd RandomizationAREDS Formulations
Vitamin C Vitamin E Zinc Oxide
500 mg
-carotene Cupric Oxide
1
500 mg
500 mg
500 mg
2*
3
4*
400 IU
400 IU
400 IU
400 IU
15 mg
0 mg
15 mg
0 mg
80 mg
80 mg
25 mg
25 mg
2 mg
2 mg
2 mg
2 mg
*Smokers randomized to treatments without beta-carotene.
AREDS2-2nd RandomizationModification of AREDS formulation
AREDS Formulation
AREDS minus Beta -
Carotene
AREDS+ Low Zinc
AREDS minus Beta-Carotene
+ Low Zinc
RandomizedParticipants
RandomizedParticipants
n=4203
Study Design
Lutein/Zeaxan-thin + DHA/EPA
1079
DHA and EPA1068
Control
1012
Lutein and Zeaxanthin
1044
No AREDS19
AREDS 1148
AREDS minus ß-Carotene + Low
Zinc 825
AREDS + Low Zinc
689
AREDS minus ß-Carotene
863
AREDS
659
AREDS3036
RandomizedParticipants
n=4203
Study Design
Lutein/Zeaxan-thin + DHA/EPA
1079
DHA and EPA1068
Control
1012
Lutein and Zeaxanthin
1044
No AREDS 19
AREDS 1148
AREDS minus ß-Carotene + Low
Zinc 825
AREDS + Low Zinc
689
AREDS minus ß-Carotene
863
AREDS
659
AREDS 3036
Primary Randomization
RandomizedParticipants
n=4203
Study Design
Lutein/Zeaxan-thin + DHA/EPA
1079
DHA and EPA1068
Control
1012
Lutein and Zeaxanthin
1044
No AREDS 19
AREDS 1148
AREDS minus ß-Carotene + Low
Zinc 825
AREDS + Low Zinc
689
AREDS minus ß-Carotene
863
AREDS
659
AREDS
3036
Secondary Randomization
Non-Randomized
Non-Randomized
Primary / Secondary OutcomesEvaluate 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
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
Cataract Surgery/Lens Opacity Progression
0.85 0.95 1 1.05 1.15
Hazard Ratio (95%CI)
Cataract Surgery
Any Cataract
Severe Cataract
Favors L/Z
Favors No L/Z
jamanetwork.com
Available at www.jama.co
m
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
RandomizedParticipants
4203
Lutein/Zea-xanthin(1044)
DHA/EPA(1068)
Lutein/Zeaxanthin DHA/EPA
(1079)
Placebo (Control)
(1012)
Primary Randomization
Three Primary Analyses
30%
20%
10%
0%
40%
0Years
1 2 3 4 5
Placebo - AREDS
DHA/EPAL/Z & DHA/EPA
29%
EstimatedProbability
L/Z
30%
31%31%
Probability of Progression to AAMD
AAMD: advanced AMD
RandomizedParticipants
4203
Lutein/Zeaxanthin
DHA/EPA
Lutein/Zeaxanthin DHA/EPA
Placebo (Control)
Primary Randomization
Analyses of Main Effects ofLutein/Zeaxanthin vs. No Lutein/Zeaxanthin
Progression to Advanced AMD by Primary and Secondary Randomization Main Effects
0.8 0.9 1 1.1 1.2
Hazard Ratio (95%CI)
L/Z vs. No L/Z
DHA/EPA vs. No DHA/EPA
Low Zinc vs. High Zinc
Beta-Carotene Yes vs. No
FavorsTreatment
FavorsControl
HR=0.90
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
Progression to Advanced AMD by Quintiles of Dietary Intake of Lutein/Zeaxanthin
Intake QuintileL/Z Dietary
0.5 0.6 0.7 0.8 0.9 1 1.1 1.3 1.5
Hazard Ratio (95%CI)
1
2
3
4
5
Favors L/Z Favors No L/Z
Highest
Lowest HR=0.74
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
AREDS Formulation with Beta-CaroteneN = 1117 eyes
vs.
Lutein/Zeaxanthin plusAREDS Formulation minus Beta-Carotene
N = 1114 eyes
Compare AREDS formulation with lutein/zeaxanthin substituted for beta-
carotene vs. AREDS formulation
30%
20%
10%
0%
40%
0Years
1 2 3 4 5
AREDS with βC
30%
EstimatedProbability
AREDS without βC with L/Z34%
Probability of Progression to AAMD
P=0.02
Progression to Advanced AMDExploratory Analyses of Lutein/Zeaxanthin
0.6 0.7 0.8 0.9 1 1.2 1.4
Hazard Ratio (95%CI)
Advanced AMD
Neovascular AMD
Central Geographic Atrophy
Favors AREDS minus beta-carotene with L/Z
Favors AREDS
HR=0.82
HR=0.78
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
Visual Acuity OutcomesLutein/Zeaxanthin vs. Beta-Carotene
0.6 0.7 0.8 0.9 1 1.2 1.4
Hazard Ratio (95%CI)
Visual Acuity
VA Loss 10+ Letters
VA Loss 15+ Letters
VA Loss 30+ Letters
VA Worse Than 20/100
Favors AREDS Minus Beta-Carotene with L/Z
Favors AREDS
* Eyes with NV-AMD included in all VA loss groups
HR=0.84
HR=0.82
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
Safety Outcome: Lung Cancer
Beta-carotene Main Effectβ-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-Carotene91% former smokers (quit > 1 year prior to randomization)
Analysis excludes smokers
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 cancer62% were former smokers, equal in both arms
Analysis includes smokers
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. beta-carotene
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
Conclusions• Improve the safety of the AREDS
supplements by removing beta-carotene 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
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)
Recommendations:
• Maintain healthy diet replete with fish, green leafy vegetables
• Stop smoking
• Consider AREDS supplements with lutein/zeaxanthin instead of beta-carotene for those with bilateral large drusen & advanced AMD in one eye
Further Analyses in AREDS2
• Fundus autofluorescence
• Optical Coherence Tomography (OCT)
• Optos fundus images
• Macular Pigment Measurements
• Genetic associations
• Cognitive function testing
• Cardiovascular disease
200720/250
200920/500
Halo of increased autofluorescence predicts GA?
Further Analyses in AREDS2
• Fundus autofluorescence
• Optical Coherence Tomography (OCT)
• Optos fundus images
• Macular Pigment Measurements
• Genetic associations
• Cognitive function testing
• Cardiovascular disease
OPTOS system
OPTOS system
Further Analyses in AREDS2
• Fundus autofluorescence
• Optical Coherence Tomography (OCT)
• Optos fundus images
• Macular Pigment Measurements
• Genetic associations
• Cognitive function testing
• Cardiovascular disease
• 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
Genetic Testing
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)
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