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 Association
Founded in 1973
Trade association representing dietary supplement manufacturers and ingredient suppliers
CRN companies produce a large portion of the dietary supplements marketed in the United States and globally

4. The Science You Need to Know
Supplement 101
Basics of Regulatory Framework
State of the Science
Filling Nutrition Gaps
Specialty Supplements
Recent Controversies in Nutrition
Iowa Women’s Health Study
Calcium and Cardiovascular Health
Safety Considerations
Conclusion

5. Dietary Supplement 101

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 Safety
Manufacturing Standards
2. The ingredients are effective - the product does what the marketer says it will do.
4. The product is being monitored in the marketplace.
Labeling/Claims
Post-Market Surveillance

8. Label Claims Nutrient Content claims Structure/Function claims
Nutrient Deficiency claims
Health Claims
Qualified Health Claims
All of these can now be used in the labeling of both dietary supplements and conventional foods.

9. Claims & Nutrition Labeling
Legislation
Description
Application
Health Claim
1990 NLEA
Describes the relationship between a food or substance and a disease or health-related condition, Significant Scientific Agreement standard
Food & Supplements
Structure/
Function Claim
1994 DSHEA
Describe an effect on the structure or function of the body
Foods & Supplements
Health Claim/
Nutrient Content Claim
1997 FDAMA
Permits health claims based on authoritative statements of scientific bodies (NIH, CDC, USDA, etc…)
Qualified Health Claim
1999 Pearson v. Shalala
Qualifying language for claim depending on strength of evidence
FDA review and approval?
Yes No

10. FDA Approved Health Claims
Dietary substance
Disease risk
Year approved
Calcium, Vitamin D
Osteoporosis
1993, 2008
Dietary Lipids
Cancer
1993
Dietary Saturated Fat and Cholesterol
CHD
Dietary Non-cariogenic Carbohydrate Sweeteners
Dental caries
1996
Folic Acid
Neural Tube Defects
Fruits and Vegetables
Fruits, Vegetables and Grain Products that contain fiber
Sodium
Hypertension
Soluble Fiber from Certain Foods
1997
Soy Protein
1999
Stanols/Sterols
2000
Whole grain foods
CHD, Cancer
2003

11. Claims Enforcement
FDA: authority over label claims that are false or misleading or not substantiated, and unapproved drug claims.
FDA Guidance: ation/GuidanceDocuments/DietarySupplements/ucm htm
FTC: 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

14. FTC Enforcement

15. FDA-regulated products
Pre-market approval
Pre-market notification
GMPs
Labeling require-ments
Facility registration
Post-market surveillance
Advertising
(FTC or FDA*)
Foods 
Dietary supplements
Drugs *
Biologics
Medical devices

16. Filling Nutrition Gaps

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 D
In addition intake of iron, folate, and vitamin B12 is of concern for specific population groups.

19. Potassium
Potassium 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. Potassium
Few 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 women
38 g per day for men
Most 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 D
Vitamin 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 pregnant
Iron – mg
Folic Acid – 400 mcg
Women who are pregnant or breastfeeding
Folic Acid – 600 mcg
Omega-3 fatty acids
EPA + DHA (250 – 500 mg)
Iron – 27 mg
Individuals ages 50 years and older
Vitamin B12
2.4 mcg

26. Beyond the Dietary Guidelines
Optimizing Health
Beyond the Dietary Guidelines
dietary 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 Canada
500 mg/day EPA + DHA 2 servings of fatty fish/week (1/4 can of sardines/week)
ISSFAL
500 mg/day EPA + DHA
UK's Scientific Advisory Committee on Nutrition
450 mg/day EPA + DHA
Australia and New Zealand National Health and Medical Research Council
610 mg/day EPA + DHA 430 mg/day DPA
World Health Organization
mg/day EPA + DHA 1-2 servings of fish per week (1/4 can of sardines/week)
American Heart Association
mg/day
British Nutrition Foundation Task Force
mg/day
UK Department of Health
200 mg/day
Institutes of Medicine Dietary Reference Intakes
mg/day (based on 10% of AI for ALA in 2002)
STUDIES
1. Brownawell AM, Harris WS, Hibbelin JR
500 mg/d of EPA + DHA
2. Gebauer, Pstoa, Harris, Kris-Etherton
3. Harris WS, Kris-Etherton PM
mg/d of EPA + DHA
4. Pepping. Am J Health-System Pharmacy
2 - 4g fish oil caps/day
5. Simopoulous AP, Leaf A, Salem N Jr
Minimum of 500mg of EPA + DHA/day
6. Kris-Etherton PM, Grieger JA, Etherton TD
Highly recommend establishing EPA + DHA DRI's above present 100mg

28. Iodine

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 phytonutrients
Phytonutrients 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 presentation
Resources are available
Heart health
Female health
Cognitive Health
Gut Health
Allergy Support
Immune Support

35. Controversies in Nutrition

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 colleagues
Bolland 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 supplements
The 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 Controversy
The 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-analysis
The IOM concluded that the studies included are small, the event frequency is low, and most outcomes have confidence intervals that overlap
In 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 covariate
Facts are stubborn, but statistics are more pliable
If you torture the data long, and hard enough...it will confess
The IOM stands by the current RDAs for Calcium
RDAs 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 Iowa
Primary endpoint was distribution of body fat and disease incidence
Questionnaire asked about education smoking, alcohol use, leisure time activity, diet and supplement use
Surveys conducted in 1986, 1997, and 2004.
In 2011 an article reported on dietary supplement use and mortality
Supplement users were healthier, so the data was adjusted to remove this variable
After data adjustments
Small (2.4%) increased increase in risk of mortality in women who used a multivitamin
Small (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 conclusions
Study did not exclude women who already had disease (cancer heart disease, etc)
No analysis of duration of supplement use
Results based on questionnaires – no biomarkers of status or intervention
No discussion of other similar studies in authors notes, accompanying editorial, or media coverage
Multiethnic 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” MV
12,769
“Non-User”
control
25,475
17,428 Calcium users
10,905 Vit C users
5,403 Vit E users
etc
Other Flaws
A “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
Drugs
Nutrients
Example
Control Group
Drug-free state
Nutrient-free state unethical and impossible
WHI conclusion “Ca+ and Vit D not effective for maintaining bone health”
median intake of Ca+ in p
Placebo group:1,100 mg Ca
$625 million NIH study
Baseline nutrient status influences effect
No baseline status
Nutrient-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 study
Effect size
Large
(if no effect in 6-12 months no investment)
Modest, aggregate over time and aggregate across multiple systems
Subclinical iodine deficiency may result in mental deficiencies in offspring
Scope of effect
Target a single system
Nutrients impact all cells and tissues
Omega-3 fatty acids are found in every cell in the human body
Omega-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 wellness
CRN survey data
80% 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 opportunity
Challenge = unanticipated adverse reactions
Opportunity = 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 DS
only 185 medical records showed DS use (26%)
236 pts demonstrated potential for 369 interactions
107 interactions with potential clinical significance
none resulted in serious harm during 10 month study period
Sood A, et al. Am J Med, 2008.

48. Survey of 1,795 Mayo clinic patients
Approximately 700 used both Rx and DS
only 185 medical records showed DS use (26%)
236 pts demonstrated potential for 369 interactions
107 interactions with potential clinical significance
none resulted in serious harm during 10 month study period
Sood 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 interactions
Garlic, Valerian, Kava, Ginkgo, St. John’s Wort, Glucosamine, Ginger, Ginseng
4 most common Rx accounted for 94% of possible interactions
Anti-thrombotic, Sedatives, Anti- depressants, Anti-diabetics
No data on actual interactions
Sood A, et al. Am J Med 2008.
Pareto principle 80% of the effects come from 20% of the causes (also known as the rule,[1] 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.[2][3] areto principle (also known as the rule

50. Safety Considerations
Three pieces of advice can address most dietary supplement safety considerations
Follow all label instructions
Talk to your doctor, pharmacist, or other qualified health- care practitioner about drugs and supplements you are taking
Evaluate supplement use in context with known allergens

51. Conclusions:
Dietary supplements are regulated
Dietary supplements can help fill nutrition gaps
Specialty supplements are a popular option for proactive health maintenance
Resources are available to support responsible marketing of dietary supplements
Controversies in nutrition are inappropriately sensationalized before proper scientific conclusions