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