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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
Dietary Supplements: Do They Really Work to Reduce Cardiovascular Risk?
None
DisclosuresDisclosures
0
200,000
400,000
600,000
800,000
1,000,000Alzheimer
CLRD
Cancer
Other CVD
Stroke
Heart Disease
Lloyd-Jones D et al. Heart Disease and Stroke Statistics 2010 Update. Accessed online 12/21/09
Leading Causes of Death in the United StatesLeading Causes of Death in the United States
2006 Statistics
All Ages <85 Years 85+ Years
Cover Illustration, The Economist, Dec 13, 2002
Evolution—The Ultimate Paradox
Why Do We Have This Problem?Why Do We Have This Problem?
So Really, Why Do We Have This Problem?So Really, Why Do We Have This Problem?
Physical Inactivity (70%)
Frequency of Cardiovascular Risk Factors in the United States
Overweight or Obese (66%)Dyslipidemia (48%)Hypertension (34%)
Tobacco Use (21%)Diabetes (10%)
0
5
10
15
20
25
30
1970 1980 1990 2000 2010 2020 2030 2040 2050
Foot DK et al. JACC 2000;35:1067-81
12.4
24.6
Prevalence of U.S. Heart DiseaseP
atie
nts
(Mill
ions
)
Year
Scope of the Problem—It’s Only Getting WorseScope of the Problem—It’s Only Getting Worse
Prevention is the SolutionPrevention 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?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?Are Supplements the Next Best Thing?
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
• 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.
Why Consider a Dietary Supplement?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?How Often Are Supplements Taken?
Multivitamin 28.0
Calcium 17.4
Vitamin C 9.0
Vitamin E 8.4
Any Vitamin B* 7.7
Chondroitin-glucosamine 7.4
Potassium 6.8
Folic acid 5.2
Omega-3 fatty acids 4.5
Vitamin D 4.5
Qato DM et al. JAMA 2008;300:2867-2878
Cross-sectional national survey of 33,005 community residing individuals (aged 57-84 years) to assess use of supplements
Magnesium 3.0
Eye Vitamins 2.6
Zinc 2.6
MSM 2.2
Niacin 1.7
Saw palmetto 1.7
Flax 1.5
Garlic 1.4
Coenyzme Q-10 1.4
Ginkgo 1.4
Supplement % Supplement %
*Includes Vitamin B6, Vitamin B12, or any B-complex vitamin
55% of women and 43% of men use at least 1 supplement
Using MegadosesUsing Megadoses
• 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
What is a megadose?
• A supplement consumed at a dose many times greater than the RDA to prevent or treat disease
RDA=Recommended dietary allowance
Which supplements are most commonly megadosed?
Vitamins C and E and Beta-CaroteneVitamins 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)
Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000), www.nap.edu, Accessed 2/9/09
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
Modified from Crawford MH, DiMarco JP, editors: Cardiology, London, 2001, Mosby.Mosby items and derived items copyright © 2004, 2000 by Mosby, Inc.
Role of Antioxidants
Oxidation Occurs Early in AtherogenesisOxidation Occurs Early in Atherogenesis
Pre-2007 Data on Antioxidants in PreventionPre-2007 Data on Antioxidants in Prevention
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
NHANES 1 -- 34% in CVD --
Study Vitamin E Vitamin C Beta-Carotene
Largest Observational Studies
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 -- --
Largest Randomized StudiesStudy Vitamin E Vitamin C Beta-Carotene
CHD=Coronary heart disease, CVD=Cardiovascular disease
Vitamins C and E in 1Vitamins C and E in 1oo Prevention Prevention
Physicans’ Health Study II (PHS II)
Sesso HD et al. JAMA 2008;300:2123-33
*Beta-carotene intervention was stopped by the data and safety monitoring board prior to study completion
Vitamin C
10.812
8
4
0
HR=0.99P=0.91
Num
ber
of c
ardi
ovas
cula
r ev
ents
**/1
000
pers
on-
year
s
10.9
Placebo Vitamin E Placebo
10.8
HR=1.01P=0.86
10.9
**Includes nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death
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
Antioxidants provide no benefit to men without CV
disease
Vitamins C, E, & Beta-Carotene in 2Vitamins C, E, & Beta-Carotene in 2oo PreventionPrevention
Cook NR et al. Arch Intern Med 2007;167:1610-8
Women’s Antioxidant Cardiovascular Study (WACS)
Vitamin C
731
800
750
700
0
HR=1.02P=0.71
Num
ber
of m
ajor
ca
rdio
vasc
ular
eve
nts*
719
Placebo Vitamin E Placebo
708
HR=0.94P=0.23
742
Beta-Carotene
Placebo
731
HR=1.02P=0.71
719
*Includes myocardial infarction, stroke, coronary reveascularization, or cardiovascular disease death
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
Antioxidants provide no benefit to women with CV disease
Vitamin BVitamin B66, B, B1212, and Folic Acid, 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)
Welch G et al. NEJM 1998;338:1042-50
Vitamin BVitamin B66, B, B1212, and Folic Acid & Homocysteine, and Folic Acid & Homocysteine
Cofactors of Homocysteine
Metabolism
• Vitamin B6
• Vitamin B12
• Folic acid
Pre-2006 Data on Vitamin BPre-2006 Data on Vitamin B66, B, B1212 and Folic Acid and Folic Acid
Randomized Trials of Lowering Homocysteine Levels
Wald DS et al. BMJ 2006;333:1114-7
Vitamin BVitamin B66, B, B1212, and Folic acid in 1, and Folic acid in 1oo/2/2oo PreventionPrevention
Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS)
227
300
200
100
0
HR=1.03P=0.65
Num
ber
of c
ardi
ovas
cula
r ev
ents
*/10
000
pers
on-
year
s
220
Placebo
Albert CM et al. JAMA 2008;299:2027-36
B-vitamins/Folic acid
12.1
14
12
10
0
P=0.001
Med
ian
hom
ocys
tein
e le
vel (
mic
rom
oles
/L)
9.8
Placebo
12.5
P=0.99
11.8
B-vitamins/Folic acid
*Includes myocardial infarction, stroke, coronary reveascularization, or cardiovascular disease mortality
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
B-vitamins and folic acid provide no benefit in 1oo/2/2oo
PreventionPrevention
HOPE 2 Investigators. NEJM 2006;354:1567-1577
Heart Outcomes Prevention Evaluation (HOPE)-2 Study
DM=Diabetes mellitus
Vitamin BVitamin B66, B, B1212, and Folic acid in 2, and Folic acid in 2oo PreventionPrevention
B-vitamins/Folic acid
12.2
14
12
10
0Mea
n ho
moc
yste
ine
leve
l (m
icro
mol
es/L
)
9.7
Placebo
12.2
12.9
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
B-vitamins and folic acid provide no benefit in 22oo
PreventionPrevention
Bonna KH et al. NEJM 2006;354:1578-1588
• 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
Treatment Arms
*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
Vitamin BVitamin B66, B, B1212, and Folic acid in 2, and Folic acid in 2oo PreventionPrevention
*
Baseline 13.1 12.9 13.3 13.2
Study End 9.5 9.8 13.3 13.6
Homocysteine Level
Vit B6/12 Folic acid
Vit B12 Folic acid
Vit B6 Placebo
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
B-vitamins and folic acid provide no benefit in 22oo
PreventionPrevention
Vitamin DVitamin 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 DeficiencyCardiovascular Effects of Vitamin D Deficiency
Vitamin D Deficiency
PTH
Insulin Resistance
-Cell DysfunctionInflammation RAAS
Diabetes Mellitus Metabolic Syndrome
Hypertension HypertrophyAtherosclerosis
Adapted from Lee JH et al. JACC 2008;52:1949-56
Wang TJ et al. Circulation 2008;117:503-11
Vitamin D Levels and Cardiovascular EventsVitamin D Levels and Cardiovascular Events
Framingham Offspring Study
*Includes myocardial infarction, unstable and stable angina, stroke, TIA, peripheral claudication, or heart failure
1,739 individuals without known cardiovascular disease in whom 25-dihydroxyvitamin D levels were measured and cardiovascular
events were assessed over 5.4 years
Lower Vitamin D levels are associated with increased CV
risk
Haz
ard
Rat
io o
f CV
Eve
nts*
25-OH D Levels
Vitamin D Supplementation and MortalityVitamin D Supplementation and Mortality
Autier P et al. Arch Intern Med 2007;167:1730-7
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
Flax (Linseed)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 ControlFlax, Lipid Levels, and Glycemic Control
12
8
4
0
P=0.011
%Apo A1 Levels
0
10
20
30
P=0.07
%
LDL-C
Flaxseed has mixed effects on lipid and glycemic
parameters
P=0.02
62 patients with LDL-C of 130-200 mg/dL randomized to
flaxseed containing products (40 g/day) or wheat bran products
for 10 weeks
179 menopausal women randomized to flaxseed
(40 g/day) or wheat germ (40 g/day) for 12 months
Lp(a) HOMA-IR
P=0.03
HOMA-IR=Homoeostatic model assessment of insulin resistance
Bloedon LT et al. J Am Coll Nutr 2008;27:65-74Dodin S et al. Nutrition 2008;24:23-30
P=0.047
Wheat germFlaxseed
Apo B Levels
Herbal Supplements—Garlic and Ginkgo BilobaHerbal 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
Gardner CD et al. Arch Intern Med 2007;167:346-53
Garlic and Lipid LevelsGarlic 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
90
60
30
0
P=0.28
P
ain
Fre
e W
alki
ng
Tim
e (S
econ
ds)
PlaceboGinkgo Biloba
90
60
30
0
P=0.12
M
axim
al T
read
mill
W
alki
ng T
ime
(Sec
onds
)
PlaceboGinkgo Biloba
Ginkgo Biloba and ClaudicationGinkgo Biloba and Claudication
62 patients with peripheral artery disease randomized to Ginkgo biloba (300 mg/day) or placebo for 4 months
Ginkgo biloba has no significant effect on claudication
Gardner CD et al. J Cardiopulm Rehabil Prev 2008;28:258-65
Coenzyme Q10Coenzyme 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
AcetylCoA
HMG-CoA
Mevalonate Farnesylpyrophosphate
Squalene Cholesterol
Squalenesynthase
Dolichol
Farnesyl-transferase
Farnesylatedproteins
E,E,E-Geranylgeranylpyrophosphate
Geranylgeranylatedproteins
Ubiquinones
HMG-CoA Reductase
Inhibition of the Cholesterol Biosynthetic Pathway
Statin-Induced Depletion of UbiquinonesStatin-Induced Depletion of Ubiquinones
• 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)
Kashani A et al. Circulation 2006;114:2788-97
74,102 subjects in 35 randomized clinical trials with statins
Skeletal myocyte
Statin Myopathy and Ubiquinone DepletionStatin Myopathy and Ubiquinone Depletion
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
Coenzyme Q10 and Statin MyopathyCoenzyme Q10 and Statin Myopathy
6.0
9
6
3
0
P=0.63
Mya
lgia
Sco
re
PlaceboCo Q10
0
15
30
45
P<0.001
%
Muscle Pain
Coenzyme Q10 has mixed effects on myopathic symptoms
Pain Interference
P<0.02
Caso G et al. Am J Cardiol 2007;10:1409-12Young JM et al. Am J Cardiol 2007;100:1400-3
2.3
18 patients with statin myopathy randomized to coenzyme Q10
(100 mg) or placebo for 30 days
44 patients with statin myalgia randomized to coenzyme Q10
(200 mg) or placebo for 12 weeks
Summary of CV Effects of SupplementsSummary of CV Effects of Supplements
Multivitamin --
Calcium --
Vitamin C
Vitamin E
Any Vitamin B*
Chondroitin-glucosamine --
Potassium --
Folic acid
Omega-3 fatty acids --
Vitamin D
Magnesium --
Eye Vitamins --
Zinc --
MSM --
Niacin --
Saw palmetto --
Flax
Garlic
Coenyzme Q-10
Ginkgo
Supplement Effect Supplement Effect
*Includes Vitamin B6, Vitamin B12, or any B-complex vitamin
Most of the commonly used supplements provide no CV
benefit
CV=Cardiovascular
Too Much of a Not So Good Thing?Too Much of a Not So Good Thing?
Multivitamin --
Calcium --
Vitamin C >2000 mg/day
GI upset and diarrhea
Vitamin E >1000 mg/day
Muscle weakness and
bleeding
Vitamin B6 >300-500 mg/day
Neurotoxicity
Chondroitin-glucosamine
--
Potassium --
Folic acid >5000 mcg/day
Masks pernicious
anemia
Omega-3 fatty acids
--
Vitamin D >50,000 IU/day
Hypercalcemia
Magnesium --
Eye Vitamins --
Zinc --
MSM --
Niacin --
Saw palmetto
--
Flax Raw flaxseed
Increased cyanide levels
Garlic Not known None known
Coenyzme Q-10
>800-1000 mg/day
GI upset and diarrhea
Ginkgo Unboiled seeds
Seizures
Supplement Toxic Dose Effect Supplement Toxic Dose Effect
Supplement megadoses produce a number of adverse effects
Question and Answer SessionQuestion and Answer Session