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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