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