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Dietary Supplements: Do They
Really Work to Reduce
Cardiovascular Risk?
Ty J. Gluckman, MD, FACC
Providence Heart and Vascular Institute, St.
Vincent Medical Center, Portland, Oregon
Ciccarone Center for the Prevention of
Heart Disease, Johns Hopkins University,
Baltimore, Maryland
Disclosures
None
Leading Causes of Death in the United States
2006 Statistics
1,000,000
Alzheimer
CLRD
Cancer
Other CVD
Stroke
Heart Disease
800,000
600,000
400,000
200,000
0
All Ages
<85 Years
Lloyd-Jones D et al. Heart Disease and Stroke Statistics 2010 Update. Accessed online 12/21/09
85+ Years
Why Do We Have This Problem?
Evolution—The Ultimate Paradox
Cover Illustration, The Economist, Dec 13, 2002
So Really, Why Do We Have This Problem?
Frequency of Cardiovascular Risk Factors in the United States
Physical Inactivity (70%)
Overweight or Obese (66%)
Dyslipidemia (48%)
Hypertension (34%)
Tobacco Use (21%)
Diabetes (10%)
Scope of the Problem—It’s Only Getting Worse
Prevalence of U.S. Heart Disease
30
24.6
Patients (Millions)
25
20
12.4
15
10
5
0
1970
1980
Foot DK et al. JACC 2000;35:1067-81
1990
2000
2010
Year
2020
2030
2040
2050
Prevention is the Solution
Primordial Prevention: Prevention of CHD risk
factors
Primary Prevention: Modification of risk factors
in order to prevent or delay the onset of CHD
Secondary Prevention: Initiation of therapy to
reduce recurrent CHD events and decrease
cardiac mortality in patients with established CHD
CHD=Coronary heart disease
The Solution is Easy, Right?
•
•
•
•
•
•
Be active
Eat a healthy diet
Lower cholesterol
Reduce blood pressure
Stop smoking
Prevent diabetes
Are Supplements the Next Best Thing?
• Congress defined a "dietary supplement" in the Dietary
Supplement Health and Education Act (DSHEA) of 1994.
• A dietary supplement is a product taken by mouth that
contains a "dietary ingredient" intended to supplement the
diet.
• The "dietary ingredients" in these products may include:
vitamins, minerals, herbs or other botanicals, amino acids,
and substances such as enzymes, organ tissues,
glandulars, and metabolites.
• Whatever their form may be, DSHEA places dietary
supplements in a special category under the general
umbrella of "foods," not drugs, and requires that every
supplement be labeled a dietary supplement.
U. S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, January 3, 2001,
www.cfsan.fda.gov/~dms/ds-oview.html, Accessed 2/9/09
Why Consider a Dietary Supplement?
• Dietary supplements are taken for numerous reasons
– Ensuring nutritional adequacy
– Protecting tissue structure and function
– Decreasing the risk of diseases and age-related
changes
– Enhancing physical performance
• Although dietary supplements cannot legally claim to
cure, mitigate or treat disease, many patients believe
they nonetheless convey these benefits
• In 2008, approximately 25 billion dollars were spent on
dietary supplements, amounting to approximately
$82.00 per U.S. resident/year
How Often Are Supplements Taken?
Cross-sectional national survey of 33,005 community residing individuals
(aged 57-84 years) to assess use of supplements
Supplement
%
Supplement
%
Multivitamin
28.0
Magnesium
3.0
Calcium
17.4
Eye Vitamins
2.6
Vitamin C
9.0
Zinc
2.6
Vitamin E
8.4
MSM
2.2
Any Vitamin B*
7.7
Niacin
1.7
Chondroitin-glucosamine
7.4
Saw palmetto
1.7
Potassium
6.8
Flax
1.5
Folic acid
5.2
Garlic
1.4
Omega-3 fatty acids
4.5
Coenyzme Q-10
1.4
Vitamin D
4.5
Ginkgo
1.4
55% of women and 43% of men use at least 1 supplement
*Includes Vitamin B6, Vitamin B12, or any B-complex vitamin
Qato DM et al. JAMA 2008;300:2867-2878
Using Megadoses
What is a megadose?
• A supplement consumed at a dose many times greater than
the RDA to prevent or treat disease
Which supplements are most commonly megadosed?
• Vitamin C is by far the most commonly megadosed
supplement with purported benefits that include the
prevention/treatment of the common cold, cancer, and polio
• This approach is known as “orthomolecular medicine”
What is the rationale for megadosing?
• Achievement of cellular levels similar to other primates
which not only consume, but also synthesize Vitamin C
• Because many disease processes result from oxidative
injury, increased antioxidant doses should provide benefit
RDA=Recommended dietary allowance
Vitamins C and E and Beta-Carotene
Vitamin C (L-ascorbate)
• Required for a range of essential metabolic reactions
• Recommended dietary allowance (90 mg/day for men, 75
mg/day for women)
Vitamin E (collective name of 8 tocopherols)
• Alpha-tocopherol is the most important lipid-soluble
antioxidant by protecting against lipid peroxidation
• Recommended dietary allowance (15 mg/day* for adults)
Beta-Carotene (Terpenoid)
• Beta-Carotene is a lipophilic precursor of Vitamin A
• Recommended dietary allowance (3000 IU/day of Vitamin A)
*Equivalent to 22.5 IU/day
Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000), www.nap.edu, Accessed 2/9/09
Oxidation Occurs Early in Atherogenesis
Role of Antioxidants
Modified from Crawford MH, DiMarco JP, editors: Cardiology, London, 2001, Mosby.
Mosby items and derived items copyright © 2004, 2000 by Mosby, Inc.
Pre-2007 Data on Antioxidants in Prevention
Largest Observational Studies
Study
Vitamin E
Vitamin C
Nurses Health Study
34% in CHD
20% in CHD
22% in CHD
Health Professionals Follow-Up Study
40% in CHD
25% in CHD
29% in CHD
34% in CVD
--
NHANES 1
--
Beta-Carotene
Largest Randomized Studies
Study
Vitamin E
Vitamin C
Beta-Carotene
ATBC
4% in CVD
--
11% in CVD
CHAOS
40% in CVD
--
--
GISSI
2% in CVD
--
--
HOPE
4% in CVD
--
--
CARET
--
--
16% in CVD
Physican’s Health Study
--
--
10% in CVD
Heart Protection Study
0% in CVD
0% in CVD
0% in CVD
Primary Prevention Project
6% in CVD
--
--
Women’s Health Study
7% in CVD
--
--
CHD=Coronary heart disease, CVD=Cardiovascular disease
o
Vitamins C and E in 1 Prevention
Physicans’ Health Study II (PHS II)
Number of cardiovascular
events**/1000 personyears
14,641 men (>50 years) randomized (2 x 2 x 2 x 2) to Vitamin C (500
mg/day), Vitamin E (400 IU every other day), a multivitamin, and beta
carotene (50 mg every other day)* for a mean of 8 years
HR=0.99
P=0.91
12
10.8
10.9
HR=1.01
P=0.86
10.8
10.9
8
4
0
Vitamin C Placebo
Vitamin E Placebo
Antioxidants provide no benefit to men without CV disease
*Beta-carotene intervention was stopped by the data and safety monitoring board prior to study completion
**Includes nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death
Sesso HD et al. JAMA 2008;300:2123-33
o
Vitamins C, E, & Beta-Carotene in 2 Prevention
Women’s Antioxidant Cardiovascular Study (WACS)
Number of major
cardiovascular events*
8,171 women with known CV disease or with >3 CV risk factors randomized
(2 x 2 x 2) to Vitamin C (500 mg/day), Vitamin E (600 IU every other day),
and beta carotene (50 mg every other day) for a mean of 9.4 years
800
750
HR=1.02
P=0.71
731
HR=0.94
P=0.23
742
719
HR=1.02
P=0.71
731
708
719
700
0
Vitamin C Placebo
Vitamin E Placebo
BetaPlacebo
Carotene
Antioxidants provide no benefit to women with CV disease
*Includes myocardial infarction, stroke, coronary reveascularization, or cardiovascular disease death
Cook NR et al. Arch Intern Med 2007;167:1610-8
Vitamin B6, B12, and Folic Acid
Vitamin B6 (Pyridoxine)
• Precursor of pyridoxal phosphate (PLP), a cofactor in a
number of enzymes involved in amino acid metabolism
• Recommended dietary allowance (1.3-1.7 mg/day)
Vitamin B12 (Cyanocobalamin)
• Involved in cellular metabolism, especially DNA synthesis,
fatty acid synthesis, and energy production
• Recommended dietary allowance (2-3 mcg/day)
Folic acid (Vitamin B9 or Folacin)
• Essential to nucleotide synthesis (especially during rapid
cell division and growth)
• Recommended dietary allowance (400 mcg/day)
Vitamin B6, B12, and Folic Acid & Homocysteine
Cofactors of
Homocysteine
Metabolism
• Vitamin B6
• Vitamin B12
• Folic acid
Welch G et al. NEJM 1998;338:1042-50
Pre-2006 Data on Vitamin B6, B12 and Folic Acid
Randomized Trials of Lowering Homocysteine Levels
Wald DS et al. BMJ 2006;333:1114-7
o
o
Vitamin B6, B12, and Folic acid in 1 /2 Prevention
Women’s Antioxidant and Folic Acid Cardiovascular Study
(WAFACS)
P=0.001
P=0.99
14
12.5
12.1
11.8
12
9.8
10
0
B-vitamins/
Folic acid
Placebo
Number of cardiovascular
events*/10000 personyears
Median homocysteine
level (micromoles/L)
5,442 women with known cardiovascular disease or >3 cardiovascular risk
factors randomized to folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin
B12 (1 mg) or placebo for 7.3 years
HR=1.03
P=0.65
300
227
220
200
100
0
B-vitamins/ Placebo
Folic acid
B-vitamins and folic acid provide no benefit in 1o/2o Prevention
*Includes myocardial infarction, stroke, coronary reveascularization, or cardiovascular disease mortality
Albert CM et al. JAMA 2008;299:2027-36
o
Vitamin B6, B12, and Folic acid in 2 Prevention
Heart Outcomes Prevention Evaluation (HOPE)-2 Study
Mean homocysteine level
(micromoles/L)
5,522 patients with vascular disease or DM randomized to folic acid (2.5
mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) or placebo for 5 years
14
12.9
12.2
12.2
12
9.7
10
0
B-vitamins/
Folic acid
Placebo
B-vitamins and folic acid provide no benefit in 2o Prevention
DM=Diabetes mellitus
HOPE 2 Investigators. NEJM 2006;354:1567-1577
o
Vitamin B6, B12, and Folic acid in 2 Prevention
3,749 patients with a recent myocardial infarction randomized in a 2 x 2
factorial design to B-vitamins + folic acid or placebo for 40 months
Treatment Arms
*
• Vitamin B6 (40 mg), Vitamin B12 (0.4
mg), and Folic acid (0.8 mg)†
• Vitamin B12 (0.4 mg) and Folic acid (0.8
mg)‡
• Vitamin B6 (40 mg)^
• Placebo
Homocysteine
Level
Vit B6/12
Folic acid
Vit B12
Folic acid
Vit B6
Placebo
Baseline
13.1
12.9
13.3
13.2
Study End
9.5
9.8
13.3
13.6
B-vitamins and folic acid provide no benefit in 2o Prevention
*Includes recurrent myocardial infarction, stroke, and sudden death attributed to coronary artery disease
†HR=1.22,
P=0.05 compared to placebo, ‡HR=1.08, P=0.31 compared to placebo, ^HR=1.14, P=0.09 compared to placebo
Bonna KH et al. NEJM 2006;354:1578-1588
Vitamin D
• Group of fat-soluble prohormones with 2 major forms:
– Vitamin D2 (ergocalciferol)—From plant and fungal sources
– Vitamin D3 (cholecalciferol)—From animal sources and made in
the skin when 7-dehydrocholesterol interacts with UV light
• Regardless of the source of Vitamin D3, it undergoes 2
reactions
– Hydroxylation in the liver by 25-hydroxylase, which converts it to
25-hydroxycholecalciferol 25(OH)D3
– Hydroxylation in the kidneys by 1a-hydroxylase, which coverts it to
two compounds, including the main biologically active hormone,
1,25-dihydroxycholecalciferol 1,25(OH)2D3 (also known as
calcitriol)
• Calcitriol mediates its biological effects by binding to the
Vitamin D receptor in the nuclei of target cells, acting as a
transcription factor to modulate gene expression
• Recommended dietary allowance (1000 IU/day)
Cardiovascular Effects of Vitamin D Deficiency
Vitamin D Deficiency
PTH
Insulin Resistance
b-Cell Dysfunction
Inflammation
Diabetes Mellitus
Metabolic Syndrome
Atherosclerosis
Adapted from Lee JH et al. JACC 2008;52:1949-56
RAAS
Hypertension
Hypertrophy
Vitamin D Levels and Cardiovascular Events
Framingham Offspring Study
Hazard Ratio of CV Events*
1,739 individuals without known cardiovascular disease in whom 25dihydroxyvitamin D levels were measured and cardiovascular
events were assessed over 5.4 years
25-OH D Levels
Lower Vitamin D levels are associated with increased CV risk
*Includes myocardial infarction, unstable and stable angina, stroke, TIA, peripheral claudication, or heart failure
Wang TJ et al. Circulation 2008;117:503-11
Vitamin D Supplementation and Mortality
Meta-analysis of 57,311 patients randomized to Vitamin D supplementation
for a mean of 5.7 years
Vitamin D supplementation reduces all-cause mortality
Autier P et al. Arch Intern Med 2007;167:1730-7
Flax (Linseed)
• Contains high levels of
lignans (phytoestrogens)
and omega-3 fatty acids
• Is used both in whole
seed form and as an
extracted oil
• Is one of the oldest fiber
products and can be used
as a laxative
• Purported cardiovascular
benefits include:
– Improvement in lipid
parameters
– Stabilization of glycemic
control
Flax, Lipid Levels, and Glycemic Control
62 patients with LDL-C of 130200 mg/dL randomized to
flaxseed containing products (40
g/day) or wheat bran products
for 10 weeks
0
P=0.07
P=0.02
P=0.03
179 menopausal women
randomized to flaxseed
(40 g/day) or wheat germ
(40 g/day) for 12 months
P=0.011
12
P=0.047
8
%
%
10
Flaxseed
Wheat germ
20
4
30
0
LDL-C
Lp(a)
HOMA-IR
Apo A1
Levels
Apo B
Levels
Flaxseed has mixed effects on lipid and glycemic parameters
HOMA-IR=Homoeostatic model assessment of insulin resistance
Bloedon LT et al. J Am Coll Nutr 2008;27:65-74
Dodin S et al. Nutrition 2008;24:23-30
Herbal Supplements—Garlic and Ginkgo Biloba
Garlic (Allium sativum)
• Purported cardiovascular benefits include:
– Modification of lipid parameters
– Vasdilation through catabolism of garlic-derived
polysufides to hydrogen sulfide in red blood
cells
Ginkgo biloba (yín xìng or EGb 761)
• Contains flavanoid glycosides and
terpenoids
• Purported cardiovascular benefits include:
– Improvement in microvascular blood flow
– Antioxidant effect through reduction of free
radical damage
– Blockade of platelet-activating factor
Garlic and Lipid Levels
192 patients with LDL-C levels of 130-190 mg/dL randomized to raw garlic,
powdered garlic, or aged garlic extract (at doses equivalent to an
average-sized garlic clove 6 days/week) or placebo for 6 months
Garlic has no significant effects on lipid levels
Gardner CD et al. Arch Intern Med 2007;167:346-53
Ginkgo Biloba and Claudication
62 patients with peripheral artery disease randomized to Ginkgo biloba (300
mg/day) or placebo for 4 months
D Pain Free Walking
Time (Seconds)
D Maximal Treadmill
Walking Time (Seconds)
P=0.12
90
60
30
0
Ginkgo
Biloba
Placebo
90
60
30
P=0.28
0
Ginkgo
Biloba
Placebo
Ginkgo biloba has no significant effect on claudication
Gardner CD et al. J Cardiopulm Rehabil Prev 2008;28:258-65
Coenzyme Q10
• Also known as ubiquinone, coenzyme Q, or CoQ10
• It is a component of the electron transport train in
mitochondria and participates in the generation of cellular
energy
• Because it’s able to transfer electrons, it is considered an
antioxidant and may help in preventing statin myopathy
Statin-Induced Depletion of Ubiquinones
Inhibition of the Cholesterol Biosynthetic Pathway
Squalene
synthase
HMG-CoA
Reductase
Acetyl
CoA
HMGCoA
Mevalonate
Farnesyl
pyrophosphate
Dolichol
Squalene
Cholesterol
Farnesyltransferase
Farnesylated
proteins
E,E,EGeranylgeranyl
pyrophosphate
Geranylgeranylated
proteins
Ubiquinones
Statin Myopathy and Ubiquinone Depletion
74,102 subjects in 35 randomized clinical trials with statins
• 15.4% incidence of myalgias
(18.7% incidence in control arm)
• 0.9% incidence of myositis (0.4%
incidence in control arm)
• 0.2% incidence of rhabdomyolysis
(0.1% incidence in control arm)
Skeletal myocyte
Is there a link between statin use and skeletal myopathy
• Skeletal muscle has a high concentration of mitochondria
• Statin therapy is associated with a depletion in skeletal muscle
and serum levels of coenzyme Q
Kashani A et al. Circulation 2006;114:2788-97
Coenzyme Q10 and Statin Myopathy
18 patients with statin myopathy
randomized to coenzyme Q10
(100 mg) or placebo for 30 days
P<0.001
P<0.02
%
15
30
45
Muscle
Pain D
D Pain
Interference
P=0.63
9
Myalgia Score D
0
44 patients with statin myalgia
randomized to coenzyme Q10
(200 mg) or placebo for 12 weeks
6
6.0
3
2.3
0
Co Q10
Placebo
Coenzyme Q10 has mixed effects on myopathic symptoms
Caso G et al. Am J Cardiol 2007;10:1409-12
Young JM et al. Am J Cardiol 2007;100:1400-3
Summary of CV Effects of Supplements
Supplement
Effect
Supplement
Effect
Multivitamin
--
Magnesium
--
Calcium
--
Eye Vitamins
--
Vitamin C
Zinc
--
Vitamin E
MSM
--
Any Vitamin B*
Niacin
---
Chondroitin-glucosamine
--
Saw palmetto
Potassium
--
Flax
Folic acid
Omega-3 fatty acids
Garlic
--
Vitamin D
Coenyzme Q-10
Ginkgo
Most of the commonly used supplements provide no CV benefit
*Includes Vitamin B6, Vitamin B12, or any B-complex vitamin
CV=Cardiovascular
Too Much of a Not So Good Thing?
Supplement
Toxic Dose
Multivitamin
--
Calcium
--
Vitamin C
Vitamin E
Vitamin B6
GI upset and
diarrhea
>1000
mg/day
Muscle
weakness and
bleeding
>300-500
mg/day
Neurotoxicity
--
Potassium
--
Folic acid
>5000
mcg/day
Supplement
Vitamin D
>2000
mg/day
Chondroitinglucosamine
Omega-3
fatty acids
Effect
--
Effect
>50,000
IU/day
Hypercalcemia
Magnesium
--
Eye Vitamins
--
Zinc
--
MSM
--
Niacin
--
Saw
palmetto
--
Flax
Masks
pernicious
anemia
Toxic Dose
Raw
flaxseed
Increased
cyanide levels
Garlic
Not known
None known
Coenyzme
Q-10
>800-1000
mg/day
GI upset and
diarrhea
Unboiled
seeds
Seizures
Ginkgo
Supplement megadoses produce a number of adverse effects
Question and Answer Session