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Results from the Age-Related Eye Disease Study2 (AREDS2)
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
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
5.
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
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
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
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)
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
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
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
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
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
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
Editor's Notes
The above median values of the 4 nutrients results in a 35% reduction of AMD….Incdient cases of about 560 cases over an 8 year period
Moved AMD categories left a bit to center over graph
Moved AMD categories left a bit
Two nutrients were found to be inversely associated with the risk of either prevalent or incident AMD. They include the Xanthophylls (a member of the carotenoid family), lutein/zeaxanthin and omega-3 fatty acids. Found in these groups of food….
Is this better, compared with the previous one?
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Remove the numbers for this slide here.
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The rationale for the cataract analyses is that only lutein/zeaxanthin have any biologic plausibility of influencing the course of lens opacities. Only l/z were evaluated.
WE found NO beneficial effect of L/Z for the outcome of cataract surgery, or the progression to any or more severe cataracts as documented by reflex lens photographs obtained on all participants .
The primary analyses consisted of the each of the treatment groups (L/Z, DHA/EPA) or combination to be compared with the placebo or control group. ebo. We consider placebo to be really the control and not placebo group all participants are also receiving some form of the AREDS formulation.
The power of the 2 X 2 factorial design lies in the ability to evaluate the groups randomly assigned to a treatment and they are compared with the groups in which that treatment was not given. In this case, all participants randomized to L/Z are compared with those who are randomized to No L/Z. These are called the Main effects.
We evaluated the main effects for all the nutrients studied, including L/Z, omega-e, low zinc vs. high zinc, and beta-carotene vs. no beta-carotene.They all cross one and are not statistically significant except for the analysis of L/z vs. no L/Z.
We then evaluated the effect of L/Z vs. No L/Z stratified by the dietary intake. In those participants whose dietary intake of L/Z was the lowest, in the lowest quintile, we see a beneficial effect. Say something about DHA/EPA similar analyses were done by NOT significant and NO trends with DHA/EPA. If time permits and the audience understands the issue, one would say there was no interaction of L/Z with DHA/EPA.
When this group was evaluated for the progression to AAMD and the two forms, again the HR for CGA crossed one and both the development of AAMD or Neovascular AMD had HRs that were to the left of one, signifying beneficial effect.
In this comparison of lutein to beta-carotene, there was 11% reduction of progression to AAMD with HR of 0,89.
The HR for NV AMD was 0.78, indicating a 22% reduction in progression to NV AMD.
However, when we evaluate again the direct effect of lutein/z vs. beta-carotene, we found for VA loss of 30 or more letters or vision of legal blindness, there were suggestion of beneficial effects.
Prefer this to the figure?
Conclusions need to be more clinical oriented for the audience…..