Dietary Supplements : The Science You Need to Know

Duffy MacKay, NDVice President, of Scientific and Regulatory Affairs

Council for Responsible Nutrition

Disclaimer: Employed by a Dietary Supplement Trade AssociationFounded 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

The Science You Need to KnowSupplement 101

Basics of Regulatory FrameworkState of the Science

Filling Nutrition Gaps Specialty Supplements

Recent Controversies in NutritionIowa Women’s Health StudyCalcium and Cardiovascular Health

Safety ConsiderationsConclusion

DIETARY SUPPLEMENT 101

FOODS OR DRUGS?Conventional

Rx DrugsFoods Drugs

Dietary SupplementsSupplements 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

Council for Responsible Nutrition

11. The ingredients are safe.

2. The ingredients are effective - the product does what the marketer says it will do.

3. The product is manufactured in a manner that assures quality.

4. The product is being monitored in the marketplace.

Regulation is a Four-Legged Stool

Ingredient Safety

Manufacturing Standards

Labeling/Claims Post-Market Surveillance

Label Claims

Nutrient Content claimsStructure/Function claimsNutrient Deficiency claims Health Claims

Qualified Health Claims

All of these can now be used in the labeling of both dietary supplements and conventional foods.

Council for Responsible Nutrition November 14, 2011

Claims & Nutrition Labeling

Claim 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…)

Food & Supplements

Qualified Health Claim

1999 Pearson v. Shalala

Qualifying language for claim depending on strength of evidence

Food & Supplements

FDA review and

approval?

Yes

No

Yes

Yes

FDA Approved Health ClaimsDietary substance Disease risk Year approved

Calcium, Vitamin D Osteoporosis 1993, 2008

Dietary Lipids Cancer 1993

Dietary Saturated Fat and Cholesterol

CHD 1993

Dietary Non-cariogenic Carbohydrate Sweeteners

Dental caries 1996

Folic Acid Neural Tube Defects

1996

Fruits and Vegetables Cancer 1993

Fruits, Vegetables and Grain Products that contain fiber

CHD 1993

Sodium Hypertension 1993

Soluble Fiber from Certain Foods CHD 1997

Soy Protein CHD 1999

Stanols/Sterols CHD 2000

Whole grain foods CHD, Cancer 2003

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

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

Myth = Unregulated

Council for Responsible Nutrition

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

FTC Enforcement

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 *

Filling Nutrition Gaps

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.

American Nutrient InadequacyBecause 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.

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.

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.

Dietary FiberThe 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.

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

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.

“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. “

Nutrients of Concern for Specific Groups Women capable of

becoming pregnantIron – 10 -18 mgFolic Acid – 400 mcg

Women who are pregnant or breastfeedingFolic Acid – 600 mcgOmega-3 fatty acids

EPA + DHA (250 – 500 mg)

Iron – 27 mg

Individuals ages 50 years and olderVitamin B122.4 mcg

dietary supplements one aspect of a total wellness package

OPTIMIZING HEALTH BEYOND THE DIETARY

GUIDELINES

Omega-3 Fatty AcidsREFERENCE DAILY DOSAGE of EPA & DHA

The ADA and Dieticians of Canada 500 mg/day EPA + DHA2 servings of fatty fish/week (1/4 can of sardines/week)

ISSFAL 500 mg/day EPA + DHAUK's Scientific Advisory Committee on Nutrition 450 mg/day EPA + DHAAustralia and New Zealand National Health and Medical Research Council

610 mg/day EPA + DHA430 mg/day DPA

World Health Organization200 - 700 mg/day EPA + DHA1-2 servings of fish per week (1/4 can of sardines/week)

American Heart Association 500 - 1000 mg/day

British Nutrition Foundation Task Force 1000 - 1500 mg/day

UK Department of Health 200 mg/dayInstitutes of Medicine Dietary Reference Intakes 110 - 160 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 500 mg/d of EPA + DHA

3. Harris WS, Kris-Etherton PM 400 - 500 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 TDHighly recommend establishing EPA + DHA DRI's above present 100mg

Iodine

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.

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.

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.

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.

Overview of all categories is beyond the scope of a one hour presentation

Heart health

Female health

Cognitive Health

Gut HealthAllergy

SupportImmune

Support

Resources are available

Controversies in Nutrition

Calcium and Heart DiseaseNo 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) .

Calcium ControversiesThe 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.

Calcium ControversyThe 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 covariateFacts are stubborn, but

statistics are more pliableIf 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)

Iowa Women’s Health StudyObservational 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 adjustmentsSmall (2.4%) increased

increase in risk of mortality in women who used a multivitamin

Small (3.8%) decreased risk in women who took calcium

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 use

Results based on questionnaires – no biomarkers of status or intervention

No discussion of other similar studies in authors notes, accompanying editorial, or media coverageMultiethnic 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

Improper ComparisonOther 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

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

Randomized controlled trials impose constraints ill-suited to testing of nutrients

Drug Nutrient Interactions

Safety Considerations

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.

Dietary Supplement use is Mainstream

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

Practical ConsiderationA 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.

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 interactions107 interactions with potential clinical significancenone resulted in serious harm during 10 month study

period

Sood A, et al. Am J Med, 2008.

• 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 interactions107 interactions with potential clinical significancenone resulted in serious harm during 10 month study period

Sood A, et al. Am J Med, 2008.

8 most commonly used DS accounted for approx 86% of possible interactionsGarlic, Valerian, Kava, Ginkgo,

St. John’s Wort, Glucosamine, Ginger, Ginseng

4 most common Rx accounted for 94% of possible interactionsAnti-thrombotic, Sedatives,

Anti-depressants, Anti-diabetics

No data on actual interactions

Sood A, et al. Am J Med 2008.

Safety ConsiderationsThree pieces of advice can address most dietary supplement safety considerations1. Follow all label instructions2. Talk to your doctor, pharmacist, or other

qualified health-care practitioner about drugs and supplements you are taking

3. Evaluate supplement use in context with known allergens

• 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

Conclusions: