Transcript Omega-3 Fatty Acids (DHA/EPA)

AREDS 2 and U
Bruce E. Onofrey, OD, RPh, FAAO, FOGS
Professor, University of Houston UEI
a Novartis company
DISCLOSURES
• I’M AN ADVISOR TO :
• KEMIN PHARMA
• ALCON
• B AND L
• ALLERGAN
Age-Related Eye Disease Study (AREDS):
Rationale and Significance
PART 2
a Novartis company
AREDS 2 The Age Related Eye Disease
Study-Part 2
•JAMA, May 2013
• Lutein (+) Zeaxanthin and Omega 3 fatty acids
for age related macular degeneration: AREDS
2
•The QUESTIONS:
• 1. Does adding lutein (+) zeaxanthin, the
Omega 3 fatty acids DHA (+) EPA or both to
the original AREDS formula decrease the risk
of developing advanced AMD?
QUESTION #2
• Does removal of betacarotene or reduction in the
amount of zinc increase the
risk of developing AMD?
QUESTION #3
•JAMA, JULY 2013
• Does L/Z supplementation affect the rate of
cataract surgery or cataract associated vision
loss?
AREDS: NEI Trial Overview
Feature
Objective
Description
To evaluate the effect of high-dose
vitamin supplementation, age-related
macular degeneration (AMD)
progression and visual acuity.
Design
Double-masked, randomized, placebocontrolled trial
Population
3640 high risk patients (55-80 years)
Duration
6.3 years supplementation and follow up
Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled clinical Trial of High-Dose Supplementation With Vitamins C and E,
Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36.
ARED (Age related eye disease) Study
results
Archives of Ophthalmology-October
2001
• Categories
• 1. NO AMD
2. Mild AMD
• 3. Moderate AMD
• 4. Advanced AMD
Daily Dosage: Placebo VS AREDS formula
Supplements were manufactured to have the following minimum contents:
Supplement
Dosage
Antioxidants
Beta-carotene
15 mg
Vitamin C
500 mg
Vitamin E
400 IU
Essential Trace Elements
Copper
2 mg
Zinc
80 mg
Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E,
Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36.
AREDS Rationale: Beta-Carotene
• Why is it important?
▫ Body unable to synthesize1
▫ Antioxidant capability1
• What dose was studied?
▫ 15 mg/day (AREDS)2
• Where can I get it in my diet?
▫ Carrots, broccoli, spinach, kale3
▫ 15 mg beta-carotene = 1.6 cups of carrots3
▫ 15 mg beta-carotene = 47.1 cups of broccoli3
1.
Paiva SAR, et al. Β-Carotene and Other Carotenoids as Antioxidants. J Am Coll Nutr 1999;18(4):426–33.
2.
Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C
and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36.
USDA National Nutrient Database for Standard Reference, Release 18, Beta-carotene. Available at:
http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w321.pdf. Accessed May 1, 2012.
3.
DON’T FORGET THE
CONTRAINDICATIONS - Beta
Carotene and Cancer
The three beta-carotene intervention trials: the Beta Carotene
and Retinol Efficacy Trial (CARET), Alpha-Tocopherol, BetaCarotene Cancer Prevention Study (ATBC), and Physician's
Health Study (PHS) have all pointed to a lack of effect of
synthetic beta-carotene in decreasing cardiovascular disease or
cancer risk in well-nourished populations. The
contribution of beta-carotene supplementation
to increased risk of lung cancer in smokers has
been raised as a significant concern. Risk
increase = approx 30% (avg of 3 studies)
DON’T SMOKE:
Cigarette smoking and retinal carotenoids: implications for agerelated macular degeneration.
Subjects were matched with respect to age, sex, dietary
patterns and overall pigmentation (i.e., eye, skin and hair
color). The
smoking group had a mean MP of
0.16 (SD = 0.12) compared to a mean MP of
0.34 (SD = 0.15) for nonsmokers (P < 0.0001).
MP density and smoking frequency were
inversely related (r = -0.498 P < 0.001) in a
dose-response relationship.
AREDS Rationale: Vitamin C
• Why is it important?
▫ Body unable to synthesize1
▫ Antioxidant capability1
• What dose was studied?
▫ 500 mg/day (AREDS)2
• Where can I get it in my diet?
▫ Citrus fruits and juices3
▫ 500 mg vitamin C = 4 cups/32 fl oz of orange
juice3
1.
Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5(2):66-74.
2.
Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E,
Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36.
USDA National Nutrient Database for Standard Reference Release 18, Vitamin C. Available at:
http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w401.pdf. Accessed May 1, 2012.
3.
AREDS Rationale: Vitamin E
• Why is it important?
▫ Body unable to synthesize1
▫ Antioxidant capability1
• What dose was studied?
▫ 400 IU/day (AREDS)2
• Where can I get it in my diet?
▫ Nuts, fortified cereals, sweet potatoes3
▫ 400 IU vitamin E = 182.6 sweet potatoes3
1.
2.
3.
Traber MG, Stevens JF. Vitamins C and E: Beneficial Effects From a Mechanist Perspective. Free Radic Biol Med 2011;51(5):1000-13.
Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and
E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36.
USDA National Nutrient Database for Standard Reference Release 18, Vitamin E. Available at:
http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w323.pdf. Accessed May 1, 2012.
AREDS Rationale: Zinc: Early studies suggested
ability to slow progression, but not VA loss in
AMD
• Why is it important?
▫ Essential trace element1
• What dose was studied?
▫ 80 mg zinc/day (AREDS)2
• Where can I get it in my diet?
▫ Red meat, poultry, mixed nuts2
▫ 80 mg zinc = 55.8 oz of red meat3
▫ 80 mg zinc = 50.3 oz of nuts3
1.
2.
3.
Grahn, BH, et al. Zinc and the eye. J Am Coll Nutr 2001;20(2 Suppl):106-18.
Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and
E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36.
USDA National Nutrient Database for Standard Reference Release 18, Zinc. Available at:
http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w309.pdf Accessed May 1, 2012.
AREDS Rationale: Copper
• Why is it important?
▫
▫
▫
▫
Essential trace element1
Both an anti-oxidant and pro-oxidant2
Body unable to synthesize2
High zinc may cause copper deficiency3
• What dose was studied?
▫ 2 mg/day (AREDS)4
• Where can I get it in my diet?
▫ Seafood, Liver, Nuts, Legumes2
▫ 2 mg copper = 1/2 oz of liver5
▫ 2 mg copper = 5 cups of beans5
1.
2.
3.
4.
5.
Determinants of Copper Needs Across the Lifespan. Office of Dietary Supplements, National Institutes of Health. Available at: at: http://ods.od.nih.gov/News/Copper.aspx. Accessed August 31,
2011.
Copper Overview. University of Maryland Medical Center. Available at: http://www.umm.edu/altmed/articles/copper-000296.htm. Accessed August 31, 2011.
NIH Dietary Supplement Fact Sheet: Zinc. National Institutes of Health. Available at: http://ods.od.nih.gov/factsheets/Zinc-HealthProfessional / Accessed 21 July 2011
Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related
Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol 2001;119(10):1417-36.
USDA National Nutrient Database for Standard Reference Release 18, Copper. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/nutrlist/sr18w312.pdf Accessed May 1, 2012
AREDS 1: THE RESULTS
• 21 published reports
• Those likely to benefit from
AREDS formula:
- extensive intermediate-size
drusen
- at least one large drusen
- noncentral geographic atrophy
- advanced AMD
- vision loss in one eye
ARED Study results
Archives of Ophthalmology-October 2001
• 1. Patients over 55 years should have DFE to be
4.
8% decrease
of progression
evaluated
for risk of AMD.
• from
2. If extensive
intermed. 3
Drusen,
Catagory
to 4 at least 1 large
druse, non-central geographic atrophy in 1 or
Reduced
visualAMD
acuity
both eyes or advanced
and noloss by
contraindications-TX
19%
in Catagory 3 and 4
• 3. Vit C 500mg, Vit E 400IU, Beta carotene
15mg + Zinc 80mg and Copper 2mg (Oxides)
IMPORTANT TO NOT TAKE
AREDS TOO FAR
• DID NOT PREVENT AMD
• DID NOT REVERSE AMD
WHY AREDS 2?
• WHY L/Z?
• WHY OMEGA 3’S?
AREDS 1: Observations
• Lutein/zeaxanthin and omega-3 fatty acid: Intake
was independently linked with decreased
likelihood of:1,2
• Neovascular AMD (Lutein/zeaxanthin, Omega-3s)
• Geographic atrophy (Lutein/zeaxanthin, Omega-3s)
• Large or extensive intermediate drusen
• Omega-3 fatty acids were of particular benefit in
groups at higher risk for neovascular AMD and
geographic atrophy3
1.
2.
3.
Age-Related Eye Disease Study Research Group. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a
case-control study: AREDS Report No. 22. Arch Ophthal 2007;125(9):1225-32.
Age-Related Eye Disease Study Research Group. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS
Report No. 20. Arch Ophthalmol 2007;125(5):671-9
Sangiovanni JP, et al. 6{omega}-3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central
geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study. Am J Clin Nutr 2009;90(6):1601-7.
Significance of Lutein and Zeaxanthin
• Several carotenoids are present in human
serum, but only lutein and zeaxanthin are
present in macula and provide a yellow
color known as macular pigment1
• This macular pigment protects the macula
from the damaging photo-oxidative effects
of blue light1
• Body cannot synthesize2
• 5:1 ratio of lutein to zeaxanthin in the diet3
• Powerful Antioxidant4
Yellow macular pigment
composed of
lutein and zeaxanthin
– Reduces free radical damage in the eye
1.
2.
3.
4.
Lutein and Zeaxanthin. Alternative Medicine Review 2005;10(2):128-35.
Nutritional Supplements for Eye Health. Bausch & Laumb Website. Available at: http://www.preservision.co.uk/. Accessed 3 October 2011
Thurnham DI. Macular Zeaxanthins and Lutein—A Review of Dietary Sources and Bioavailability and Some Relationships with Macular Pigment Optical
Density and Age-Related Macular Disease. Nutr Res Rev 2007;20:163–79.
Subczynski WK, et al. Location of Macular Xanthophylls in the Most Vulnerable Regions of Photoreceptor Outer-Segment Membranes. Arch Biochem
Biophys 2010;504:61–6.
Lutein Antioxidant Supplementation Trial (L.A.S.T.)
and Macular Pigment Optical Density (MPOD)
– Mean age: 75
– Mean number of smoking pack
years: 7
• Treatment arms:
– 10 mg
lutein
– 10 mg FloraGLO® lutein +
antioxidants
– Placebo
FloraGLO®
• Significant improvements from
baseline in visual function1
– Greatest benefit in patients
with lowest baseline MPOD2
1.
2.
Macular pigment optical density
• 90 patients with AMD (4 females,
86 males):
0.6
36%
improvement
*
0.5
0.4
43%
improvement
*
*
*
*
*
0.3
0.2
0.1
0 Right eye Left eye
Lutein
Baseline
Right eye Left eye Right eye Left eye
Lutein +
antioxidants
Placebo
Final visit
Richer S, et al. Double-Masked, Placebo-Controlled, Randomized Trial of Lutein and Antioxidant Supplementation in the Intervention of Atrophic AgeRelated Macular Degeneration: the Veterans LAST Study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75(4):216-30.
Richer S, et al. LAST II: Differential Temporal Responses of Macular Pigment Optical Density in Patients with Atrophic Age-Related Macular
Degeneration to Dietary Supplementation with Xanthophylls. Optometry 2007;78(5):213-9.
*FloraGlo is a registered trademark of Kemin Industries, Inc.
*P<0.05
Long-term FloraGLO® Lutein and Zeaxanthin
Supplementation Improves MPOD in patients with AMD
LUTEGA STUDY
• 172 subjects (50+, AMD)
• Double-masked, randomized:
MPOD CHANGES
QD Daily supplementation
Placebo
Absolute Change in ODU*degree²
–10 mg FloraGLO® Lutein /
1 mg Zeaxanthin /
255 mg Omega-3 QD
–10 mg FloraGLO® Lutein /
1 mg Zeaxanthin /
255 mg Omega-3 BID
– Placebo
• 4 evaluations over 12 months
Supplementation in Months
Jentsch S, et al. The Lutega-Study: Lutein And Omega- 3- Fatty Acids And Their Relevance For Macular Pigment In Patients with Age-related Macular
Degeneration (AMD). Invest Ophthalmol Vis Sci 2011;52:E-Abstract 3632.
*FloraGLO is a registered trademark of Kemin Industries, inc.
Increased MPOD is linked to Positive Effects
on Visual Performance
•
•
•
•
Glare tolerance1
Glare recovery1
Contrast sensitivity2
Amsler defect and
VA improvement3
• Chromatic aberration2
• Photophobia4
1.
2.
3.
4.
Stringham JM, et al. Macular Pigment and Visual Performance in Glare: Benefits for Photostress Recovery, Disability Glare, and Visual Discomfort. Invest
Ophthalmol Vis Sci 2011;52(10):7406-15.
Loughman J, et al. The Relationship Between Macular Pigment and Visual Performance. Vision Res 2010;50(13):1249-56.
Richer S, et al. Double-Masked, Placebo-Controlled, Randomized Trial of Lutein and Antioxidant Supplementation in the Intervention of Atrophic Age-Related
Macular Degeneration: the Veterans LAST Study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75(4):216-30.
Wenzel AJ, et al. Macular Pigment Optical Density and Photophobia Light Threshold. Vision Res 2006;46:4615-22.
ICP11003SK
Omega-3 Fatty Acids (DHA/EPA)
• Important for proper visual
development and retinal function1
• Docosahexaenoic acid (DHA) is
found in the highest concentration in
the retina1
• Eicosapentaenoic acid (EPA) is
used in DHA biosynthesis1
1.
Essential Fatty Acids. American Optometric Association. Available at: http://www.aoa.org/x11853.xml. Accessed October 3, 2011
Omega-3 Fatty Acids (DHA/EPA)
• Benefits of DHA/EPA
– Intake is associated with a decreased risk of
progression from bilateral drusen to
geographic atrophy1
• Low levels of DHA and EPA
associated with chronic eye
conditions such as:2
–
–
–
–
1.
2.
Diabetic retinopathy
Age-related macular degeneration (AMD)
Retinopathy of prematurity
Dry eye disease
SanGiovanni JP, et al. The Relationship of Dietary -3 Long-Chain Polyunsaturated Fatty Acid Intake Inversely Associated With 12-Year Progression
to Advanced Age-Related Macular Degeneration: AREDS Report No. 23. Arch Ophthalmol 2008;127(1):110-2.
Essential Fatty Acids. American Optometric Association. Available at: http://www.aoa.org/x11853.xml. Accessed October 3, 2011
AREDS2*
Feature
Objective
Description
Assess effect of a alternative
combination of vitamins and minerals
on the progression of AMD and vision
loss
Design
NEI 5 year, multi-center, randomized,
double-masked, placebo-controlled trial
Population
4000 patients at higher risk of
developing AMD (Men and women;
50-85 years*)1,2
*Age limit 5 years younger than AREDS
1.
2.
Age-Related Eye Disease Study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011.
AREDS2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011.
PROTOCOL
•NO NORMALS
•1-3 MONTH RUN IN WITH AREDS (+)
PLACEBOS
•IF PATIENT COMPLIES WITH DRUG USE
AND SHOWS UP-RANDOMIZED TO TX
•ANNUAL EXAM (+) FUNDUS PHOTOS
•ANNUAL BLOOD TESTS FOR ANTIOXIDANT BLOOD LEVELS
AREDS2: To Evaluate…
Ingredients being studied in AREDS2:
•
FloraGLO® lutein (10mg)
•
OPTISHARP® zeaxanthin (2mg)
•
Omega-3 fatty acids (350 mg DHA, 650 mg EPA)
•
With and without β-carotene (15 mg vs 0 mg)
•
High vs low zinc levels (80mg vs 25mg)
Patients in the AREDS2 study are assigned to different
combinations of ingredients
Age-Related Eye Disease Study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011.
*FloraGlo is a registered trademark of Kemin Industries, Inc.
* Optisharp is a registered trademark of DSM IP Assets B.V.
AREDS 2 WAS COMPLICATED
• 16 RANDOMIZED GROUPS
• NO NORMALS
• 2 LEVELS OF RANDOMIZATION
• SPECIAL RULES FOR SMOKERS
• CENTRUM SILVER FOR THOSE ON A MV
SUPPLEMENT
• STATISTICS LIMITED BY COHORT SIZE AND
DURATION OF STUDY
AREDS2 Study Design
Randomized Participants
~4000
Placebo
L/Z
DHA/EPA
• No smoker can be
in an arm with
beta-carotene
L/Z+DHA/EPA
ATS* Options
No
ATS*
ATS*
AREDS2 Vitamin /
Mineral Evaluation
No ß-C
Low Zn
• Background
multivitamin
supplementation
is allowed, but is
standardized
Original
ATS*
No ß-C & Low Zn
Age-Related Eye Disease study 2 Protocol. Available at: www.emmes.com/study/areds2 . Accessed July 14, 2011.
AREDS 2 Study Overview. Available at: http://clinicaltrials.gov/ct2/show/NCT00345176?term=AREDS2&rank=1. Accessed July 21, 2011.
*AREDS type supplements.
32 | ICP12167SK Ocular Nutrition | May 2012 | Business Use Only
NEI AREDS2 Dosage Options1
Lutein
(FloraGLO®)
Zeaxanthin
(OPTISHARP®)
•10 mg/day
•2 mg/day
• 5:1 ratio of lutein to zeaxanthin commonly found in
American diet2
1.
2.
Age-Related Eye Disease Study 2 Protocol. Available at: www.emmes.com/study/areds2 . Accessed July 14, 2011.
Thurnham DI. Macular Zeaxanthins and Lutein—A Review of Dietary Sources and Bioavailability and Some Relationships with Macular Pigment Optical
Density and Age-Related Macular Disease. Nutr Res Rev 2007;20:163–79.
FloraGLO is a registered trademark of Kemin Industries, Inc.
Optisharp is a registered trademark of DSM IP Assets B.V.
AREDS2: To Evaluate…
Endpoints:
Progression to advanced
AMD
•• Progression
to advanced
AMD
Progression to moderate
vision loss
•• Progression
to moderate
vision loss
Progression of lens
•• Progression
of opacity
lens opacity
••
••
Effective cognitive
Cognitive function
function
Effective
Cardiovascular morbidity/mortality
morbidity/mortality
Cardiovascular
Age-Related Eye Disease Study 2 Protocol. Available at: www.emmes.com/study/areds2. Accessed July 14, 2011.
LIES, DAMN LIES AND
STATISTICS
•SPINNING THE AREDS 2 DATA
Re-interpretation of results at ARVO 2013 by
lead investigator, Emily Chew et al
• Adding omega 3’s to AREDS: No benefit
• Adding L/Z to AREDS and evaluating the
effect on the total cohort (study population)
• 1. L/Z reduced advanced AMD by 10%
• 2. Neovasc. AMD 11%
• 3. Neovasc AMD 26% in low L/Z diets
• 4. Cataract progression 30% in low L/Z diets
• 5. Beta carotene doubles risk of lung cancer
in all participants, 0.9% VS 2% W-BC
Lutein + zeaxanthin intake (mg/day)
Consumption of Lutein/Zeaxanthin in the US is
LOW
•
10
8
6
AREDS2 Intake
4
Women
2
0
19-30
Men
31-50
Age
51-70
Figure courtesy of Kemin Health, Inc.
71+
The average American only gets between 1 mg to 2.3mg per day of combined
lutein and zeaxanthin in their diet which is below the AREDS2 intake of 10mg
CDC. National Health and Nutrition Examination Survey Data 2001-2002. Available at: http://www.cdc.gov/nchs/about/major/nhanes/nhanes01-02.htm. Accessed July 14, 2011.
37 | ICP11001SK Ocular Nutrition | October 2011 | Business Use Only
The Bottom Line on
ARMD/AREDS 1
•
•
•
•
•
DON’T BE Northern European
DON’T GET OLDER
DON’T SMOKE
DON’T GIVE SMOKERS ANTIOX
CONTROL VASCULAR DISEASE RISK
FACTORS
• SUPPLEMENTS DON’T REPLACE A BAD
LIFESTYLE
ADDITIONAL
RECOMMENDATIONS FROM
AREDS 2
• NEVER use beta-carotene in
ANYBODY
• INCREASE L/Z foods in patients diet-if
not, then supplement
• OMEGA 3’s have value, but NOT for
AMD
MY RESEARCH INTEREST
• WHY DO STUDIES HAVE TO LAST
SSSSSOOOOOOOO LONNNGG?
• WAY TOOOO EXPENSIVE
• STRUCTURE VS FUNCTION
• ADAPTIVE OPTICS (Dr. Porter)
• Supplement X 6 months-evaluate VA, 10-2VF,
OCT and retinal cone density and
morphology-supplement vs no supplement
• CAN AO’s predict vision loss
• Can we take a photo-objective test and
measure stability VS progression
QUESTIONS?