2 Dietary Supplements : The Science You Need to Know Duffy MacKay, ND Vice President, of Scientific and Regulatory Affairs Council for Responsible Nutrition
3 Disclaimer:Employed by a Dietary Supplement Trade AssociationFounded in 1973Trade association representing dietary supplement manufacturers and ingredient suppliersCRN companies produce a large portion of the dietary supplements marketed in the United States and globally
4 The Science You Need to Know Supplement 101Basics of Regulatory FrameworkState of the ScienceFilling Nutrition GapsSpecialty SupplementsRecent Controversies in NutritionIowa Women’s Health StudyCalcium and Cardiovascular HealthSafety ConsiderationsConclusion
6 FOODS OR DRUGS? Conventional Rx Drugs Foods Drugs Dietary Supplements Supplements are Foods: Congress has considered the legal classification of dietary supplements on at least 3 separate occasions in past 70 years, and every time has concluded that they belong in the food category
7 Regulation is a Four-Legged Stool 11. The ingredients are safe.3. The product is manufactured in a manner that assures quality.Ingredient SafetyManufacturing Standards2. The ingredients are effective - the product does what the marketer says it will do.4. The product is being monitored in the marketplace.Labeling/ClaimsPost-Market Surveillance
8 Label Claims Nutrient Content claims Structure/Function claims Nutrient Deficiency claimsHealth ClaimsQualified Health ClaimsAll of these can now be used in the labeling of both dietary supplements and conventional foods.
9 Claims & Nutrition Labeling LegislationDescriptionApplicationHealth Claim1990 NLEADescribes the relationship between a food or substance and a disease or health-related condition, Significant Scientific Agreement standardFood & SupplementsStructure/Function Claim1994 DSHEADescribe an effect on the structure or function of the bodyFoods & SupplementsHealth Claim/Nutrient Content Claim1997 FDAMAPermits health claims based on authoritative statements of scientific bodies (NIH, CDC, USDA, etc…)Qualified Health Claim1999 Pearson v. ShalalaQualifying language for claim depending on strength of evidenceFDA review and approval?YesNo
10 FDA Approved Health Claims Dietary substanceDisease riskYear approvedCalcium, Vitamin DOsteoporosis1993, 2008Dietary LipidsCancer1993Dietary Saturated Fat and CholesterolCHDDietary Non-cariogenic Carbohydrate SweetenersDental caries1996Folic AcidNeural Tube DefectsFruits and VegetablesFruits, Vegetables and Grain Products that contain fiberSodiumHypertensionSoluble Fiber from Certain Foods1997Soy Protein1999Stanols/Sterols2000Whole grain foodsCHD, Cancer2003
11 Claims EnforcementFDA: authority over label claims that are false or misleading or not substantiated, and unapproved drug claims.FDA Guidance: ation/GuidanceDocuments/DietarySupplements/ucm htmFTC: authority over advertising claims that are false, misleading or not substantiated.FTC Guidance:
12 FDA Enforcement Myth = Unregulated “Your products are represented as dietary supplements . . .; however, the products do not meet the definition of a dietary supplement in section 201(ff) of the Federal Food, Drug and Cosmetic Act Your products are intended to affect the structure or function of the body by, among other things, building muscle, increasing strength, and affecting the levels of estrogens and androgens in the body Accordingly, [these products] are drugs . . Furthermore, your products are "prescription drugs" as defined at section 503(b)(I)(A) of the Act (21 U.S.C. § 353(b)(1)(A)), in that because of their toxicity or other potentiality for harmful effect, or the method of their use, or the collateral measures necessary to their use, they are not safe for use except under the supervision of a practitioner ” FDA warning letter to Americell Labs, July 27, 2009
13 FDA Enforcement“…Only products that are intended for ingestion may be lawfully marketed as dietary supplements. Topical products and products intended to enter into the body directly through the skin or mucosal tissues, such as transdermal or sublingual products, are not dietary supplements. For these products, both disease and structure/function claims may cause them to be new drugs” – Stated in multiple warning letters from FDA
17 Basic Premise of the Dietary Guidelines is that nutrient needs should be met primarily through eating food.Fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise might be consumed in less than recommended amounts.
18 American Nutrient Inadequacy Because consumption of vegetables, fruits, whole grains, milk and milk products, and seafood is lower than recommended, intake by Americans of some nutrients is low enough to be of public health concern.These are potassium, dietary fiber, calcium, and vitamin DIn addition intake of iron, folate, and vitamin B12 is of concern for specific population groups.
19 PotassiumPotassium is an essential mineral needed to regulate water balance, levels of acidity, blood pressure, and neuromuscular function and the transmission of electrical impulses in the heart.Dietary potassium can lower blood pressure by blunting the adverse effects of sodium on blood pressure and reduced risk of developing kidney stones and decreased bone loss.The Adequate Intake (AI) for potassium for adults is 4,700 mg per day.AIs are amounts of a nutrient that are adequate for almost everyone in the population; therefore, intake below an AI may be adequate for some people.
20 PotassiumFew Americans, including all age-gender groups, consume potassium in amounts equal to or greater than the AI.In view of the health benefits of adequate potassium intake and its relatively low current intake by the general population, increased intake of potassium is warranted.Individuals with kidney disease and those who take certain medications, such as ACE inhibitors, should consult with their health care provider for specific guidance on potassium intake.
21 Dietary Fiber The AI for fiber is 14 g per 1,000 calories 25 g per day for women38 g per day for menMost Americans greatly under-consume dietary fiber, and usual intake averages only g per day.
22 Calcium Adequate calcium is important for optimal bone health. Calcium serves vital roles in nerve transmission, constriction and dilation of blood vessels, and muscle contraction.Age groups of particular concern due to low calcium intake -children ages 9 y/o +, adolescent girls, adult women, adults ages 51 y/o +All ages are encouraged to meet their Recommended Dietary Allowance (RDA) for calcium.800 to 1,500 mg daily depending on age and dietary calcium intake
23 Vitamin DVitamin D’s most important role is maintaining blood levels of calcium, which it accomplishes by increasing absorption of calcium from food and reducing urinary calcium loss.Vitamin D also supports breast, colon, immune and prostate health and contributes to the maintenance of a healthy mood.The RDAs for vitamin D, which assume minimal sun exposure, are 600 IU (15 mcg) per day for children and most adults and 800 IU (20 mcg) for adults older than 70 years.
24 “Several large-scale studies have found that vitamin D deficiency is widespread —one in 10 U.S. children are estimated to be deficient — and that 60 percent of children may have suboptimal levels of vitamin D. “
25 Nutrients of Concern for Specific Groups Women capable of becoming pregnantIron – mgFolic Acid – 400 mcgWomen who are pregnant or breastfeedingFolic Acid – 600 mcgOmega-3 fatty acidsEPA + DHA (250 – 500 mg)Iron – 27 mgIndividuals ages 50 years and olderVitamin B122.4 mcg
26 Beyond the Dietary Guidelines Optimizing HealthBeyond the Dietary Guidelinesdietary supplements one aspect of a total wellness package
27 Omega-3 Fatty Acids REFERENCE DAILY DOSAGE of EPA & DHA STUDIES The ADA and Dieticians of Canada500 mg/day EPA + DHA 2 servings of fatty fish/week (1/4 can of sardines/week)ISSFAL500 mg/day EPA + DHAUK's Scientific Advisory Committee on Nutrition450 mg/day EPA + DHAAustralia and New Zealand National Health and Medical Research Council610 mg/day EPA + DHA 430 mg/day DPAWorld Health Organizationmg/day EPA + DHA 1-2 servings of fish per week (1/4 can of sardines/week)American Heart Associationmg/dayBritish Nutrition Foundation Task Forcemg/dayUK Department of Health200 mg/dayInstitutes of Medicine Dietary Reference Intakesmg/day (based on 10% of AI for ALA in 2002)STUDIES1. Brownawell AM, Harris WS, Hibbelin JR500 mg/d of EPA + DHA2. Gebauer, Pstoa, Harris, Kris-Etherton3. Harris WS, Kris-Etherton PMmg/d of EPA + DHA4. Pepping. Am J Health-System Pharmacy2 - 4g fish oil caps/day5. Simopoulous AP, Leaf A, Salem N JrMinimum of 500mg of EPA + DHA/day6. Kris-Etherton PM, Grieger JA, Etherton TDHighly recommend establishing EPA + DHA DRI's above present 100mg
29 The American Thyroid Association recommends that women receive 150 mcg iodine supplements daily during pregnancy and lactation and that all prenatal vitamin/mineral preparations contain 150 mcg of iodine.
30 Phytonutrients from plant-based foods Substantial research has demonstrated the heart health benefits of eating a dietary pattern high in fruits and vegetables.Nutritionally, fruits and vegetables are lower calorie sources of key nutrients, such as potassium, dietary fiber, folic acid, and vitamins A, C and E.They also contain literally thousands of naturally-occurring compounds referred to as phytochemicals or phytonutrients, which have health benefits beyond basic nutrition.
31 America’s Phytonutrient Report Quantify American intake of 14 select phytonutrientsPhytonutrients are not considered “essential” to human health, there are no Dietary Reference Intakes (DRIs), as there are for macro and micronutrients.Using NHANES and USDA datasets, the report identified the median intakes of phytonutrients by the subpopulation of adults who meet recommended daily intakes of fruits and vegetables (“meeters”).The median intake was referred to as the “prudent intake” (PI), because that is the intake level among adults eating a “prudent diet” that contains recommended amounts of fruits and vegetables.
32 On average, 8 out of 10 Americans (76%) have a “phytonutrient gap” – that is, they fall short in consuming key phytonutrients from plant-based foods that could benefit their health.
33 Heart health Female health Cognitive Health Gut Health Allergy Support Overview of all categories is beyond the scope of a one hour presentationResources are availableHeart healthFemale healthCognitive HealthGut HealthAllergy SupportImmune Support
36 Calcium and Heart Disease No suggestions of serious adverse effects from this supplemental calcium intake had been reported until a series of reports from Bolland, Reid, and colleaguesBolland et al., raise the issue of a possible increase in risk for adverse cardiovascular events in men and women associated with the use of calcium or calcium plus vitamin D supplementsThe initial reports were from two clinical trials in which women and men had been randomly assigned to receive a calcium supplement or placebo and were followed for 2y (men) or 5y (women) .
37 Calcium Controversies The primary outcome measure was the change in bone mineral density in each of these studies; however, adverse cardiovascular events were pre-specified secondary outcomes.Trends were reported toward increased cardiovascular events in the groups receiving calcium supplementation in both studies.
38 Calcium ControversyThe Institute of Medicine Food and Nutrition Board’s report on calcium and vitamin D assessed the early Bolland, Reid, and colleagues’ RCTs and first meta-analysisThe IOM concluded that the studies included are small, the event frequency is low, and most outcomes have confidence intervals that overlapIn the meta-analysis cardiovascular events were not a primary outcome, the events may not have been well adjudicated, and renal function was not considered as a covariateFacts are stubborn, but statistics are more pliableIf you torture the data long, and hard enough...it will confessThe IOM stands by the current RDAs for CalciumRDAs are target levels to be achieved from total calcium intake (diet + supplementation)
39 Iowa Women’s Health Study Observational Study of about 4,000 Women from IowaPrimary endpoint was distribution of body fat and disease incidenceQuestionnaire asked about education smoking, alcohol use, leisure time activity, diet and supplement useSurveys conducted in 1986, 1997, and 2004.In 2011 an article reported on dietary supplement use and mortalitySupplement users were healthier, so the data was adjusted to remove this variableAfter data adjustmentsSmall (2.4%) increased increase in risk of mortality in women who used a multivitaminSmall (3.8%) decreased risk in women who took calcium
40 None detected an increase in mortality Iowa Women’s Health Study Concludes “No reason to supplement unless strong medically based cause, such as symptomatic nutrient deficiency disease”Researchers at the Harvard School of Public Health identified major flaws in the authors conclusionsStudy did not exclude women who already had disease (cancer heart disease, etc)No analysis of duration of supplement useResults based on questionnaires – no biomarkers of status or interventionNo discussion of other similar studies in authors notes, accompanying editorial, or media coverageMultiethnic Cohort Study, (n = 180,000)Women’s Health Initiative, (n=160,000)Pocobelli, Peters, et al (n=77,000)Watkins, Erickson et al., (n= 1,000,000)None detected an increase in mortality
41 Improper Comparison Other Flaws “User”MV12,769“Non-User”control25,47517,428 Calcium users10,905 Vit C users5,403 Vit E usersetcOther FlawsA “user” of a particular supplement was compared against everyone else in the study (not a true non-user of vitamins)e.g. mortality of multivitamin users (n= 12,769) was compared against mortality of everyone else in the study (n = 25,000, which included 17,428 calcium-alone users)Relative risks were very small making all of these limitations to the study significant in tempering conclusions that can be made form the data
42 Randomized controlled trials impose constraints ill-suited to testing of nutrients DrugsNutrientsExampleControl GroupDrug-free stateNutrient-free state unethical and impossibleWHI conclusion “Ca+ and Vit D not effective for maintaining bone health”median intake of Ca+ in pPlacebo group:1,100 mg Ca$625 million NIH studyBaseline nutrient status influences effectNo baseline statusNutrient-sufficiency state may mask effect(unintended ingestion)PHS II. C, E, beta-carotene, & MV not effective for prevention of CV dz, total ca, prostate ca.60 -73% % risk reduction for those enrolled in the study vs not in the studyEffect sizeLarge(if no effect in 6-12 months no investment)Modest, aggregate over time and aggregate across multiple systemsSubclinical iodine deficiency may result in mental deficiencies in offspringScope of effectTarget a single systemNutrients impact all cells and tissuesOmega-3 fatty acids are found in every cell in the human bodyOmega-3 effect the structure, function, and cell signaling for all cells
43 Safety Considerations Drug Nutrient Interactions
44 Dietary Supplement use is Mainstream More than 150 million Americans use dietary supplements each year as part of an overall approach to wellnessCRN survey data80% of Americans take at least one pharmacologically active agent on a regular basis.Kaufman DW, Kelly JP, Rosenberg L, et al. JAMA 2002.
45 Potential Interactions between conventional drug therapies and herbal and nutritional therapies exists and presents both a challenge and an opportunityChallenge = unanticipated adverse reactionsOpportunity = discovery of new synergies that enhance the depth and breadth of mainstream medicine
46 Practical Consideration A small number of prescription medications and dietary supplements account for the majority of possible interactions.Actual potential for harm is low.Sood A, et al. Potential for Interactions Between Dietary Supplements and Prescription Medications. Am J Med,
47 Survey of 1,795 Mayo clinic patients Approximately 700 used both Rx and DSonly 185 medical records showed DS use (26%)236 pts demonstrated potential for 369 interactions107 interactions with potential clinical significancenone resulted in serious harm during 10 month study periodSood A, et al. Am J Med, 2008.
48 Survey of 1,795 Mayo clinic patients Approximately 700 used both Rx and DSonly 185 medical records showed DS use (26%)236 pts demonstrated potential for 369 interactions107 interactions with potential clinical significancenone resulted in serious harm during 10 month study periodSood A, et al. Am J Med, 2008.
49 4 most common Rx accounted for 94% of possible interactions 8 most commonly used DS accounted for approx 86% of possible interactionsGarlic, Valerian, Kava, Ginkgo, St. John’s Wort, Glucosamine, Ginger, Ginseng4 most common Rx accounted for 94% of possible interactionsAnti-thrombotic, Sedatives, Anti- depressants, Anti-diabeticsNo data on actual interactionsSood A, et al. Am J Med 2008.Pareto principle 80% of the effects come from 20% of the causes (also known as the rule, the law of the vital few, and the principle of factor states that, for many events, roughly 80% of the effects come from 20% of the causes. areto principle (also known as the rule
50 Safety Considerations Three pieces of advice can address most dietary supplement safety considerationsFollow all label instructionsTalk to your doctor, pharmacist, or other qualified health- care practitioner about drugs and supplements you are takingEvaluate supplement use in context with known allergens
51 Conclusions:Dietary supplements are regulatedDietary supplements can help fill nutrition gapsSpecialty supplements are a popular option for proactive health maintenanceResources are available to support responsible marketing of dietary supplementsControversies in nutrition are inappropriately sensationalized before proper scientific conclusions