Dietary Supplements : The Science You Need to Know

2. Dietary Supplements : The Science You Need to Know Duffy MacKay, NDVice President, of Scientific and Regulatory AffairsCouncil 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 FDA review and approval? Yes No Yes Yes

10. FDA Approved Health Claims

11. Claims Enforcement • FDA: authority over label claims that are false or misleading or not substantiated, and unapproved drug claims. • FDA Guidance: http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm103340.htm • FTC: authority over advertising claims that are false, misleading or not substantiated. • FTC Guidance: http://www.ftc.gov/bcp/edu/pubs/business/adv/bus09.pdf

12. Myth = Unregulated FDA Enforcement “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

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.

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 10 -15 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 – 10 -18 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. Optimizing Health Beyond the Dietary Guidelines dietary supplements one aspect of a total wellness package

27. Omega-3 Fatty Acids

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. 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 2010 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. 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, 2011 (n = 180,000) • Women’s Health Initiative, 2009 (n=160,000) • Pocobelli, Peters, et al. 2009 (n=77,000) • Watkins, Erickson et al., 2000 (n= 1,000,000) • None detected an increase in mortality

41. Improper Comparison 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

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, 2008.

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. 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.

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