Dietary supplements—case studies in efficacy and safety assessment

SUZANNE HENDRICH, PHD U N I V E R S I T Y P R O F E S S O R , F O O D S C I E N C E & H U M A N N U T R I T I O N , L U R A M . L O V E L L F E L L O W , I O W A B O T A N I C A L S C E N T E R , S H E N D R I C @ I A S T A T E . E D U

Learning outcomes

   Gain perspective on dietary supplement use.

Appreciate general safety concerns and resources regarding dietary supplement use.

Explore effects and contraindications for several of the most commonly used dietary supplements.

Echinacea Ginkgo Garlic Ginseng Fish oil Ginger Soy

Fish oil Glucos amine Echi nacea Flaxseed Ginseng Combi Ginkgo Herbs Chon droitin Garlic Co-Q-10

Botanical use

     Example: elders, > 65 y ~25% of Asians & Hispanics used herbs, ~10% of Whites & Blacks More herb users were women, college educated, Westerners, younger (65-69y) >70% of herb users thought it very to somewhat important to their health Arcury et al. 2007. J Gerontol Soc Sci 62b: S142-9.

Vitamin supplement toxicities

Water soluble vitamins RDA (Per day, adults) toxicity UL, adults Endpoint to set UL niacin Vitamin B6 1.3-1.7 mg Vitamin C Other B complex 14-16 mg 75-90 mg Flushing, nausea and vomiting, liver toxicity, impaired glucose tolerance High intakes (>= 2000 mg/d) with development of sensory neuropathy and dermatological lesions High intakes (>3000 mg/d) may cause diarrhea and other gastrointestinal disturbances 35 mg 100 mg 2000 mg Flushing Sensory neuropathy Osmotic diarrhea and gastrointestinal disturbance No UL available for vitamin B12, Biotin, carotenoids, pantothenic acid, riboflavin and thiamin Folate has been set up RDA and UL Folate 400 μg Excess intake of folate may mask the diagnosis of vitamin B12 deficiency, which can result in unrecognized neurological damage 1000 μg Exacerbation of neuropathy in vitamin B12-deficient individuals Fat-soluble vitamins RDA or AI (adults, per day) Toxicity UL , adults Endpoint for setting up UL Vitamin A Vitamin D Vitamin E 700-900 μg 5-15 μg 15 mg Nausea, vomiting, headache, increased cerebrospinal fluid pressure, vertigo (dizzy), blurred vision, muscular incoordination and bulgind fontanel (infants) Polyuria (excessive secretion of urine), polydipsia (excessive or abnormal thirty), hypercalciuria, calcification of soft tissues, anorexia, nausea, vomiting and reduced renal function Potential hemorrhagic toxicity and diminished blood coagulation in individuals who are deficient in vitamin K and/or anticoagulant therapy 3000 μg 50 μg 1000 mg Liver abnormalities (adult) Teratogenicity (lactating women) Serum calcium concentrations (prevent hypercalcemia) Increased tendency to hemorrhage

Substances with greatest rate of exposure increase in 2010, AAPCC report

  Vitamins were 6 th on the list of top 25 substances with increasing rate of exposure, with an increase of ~2300 cases over the previous year Dietary botanical supplements were 20 with an increase of 900 exposure cases in 2010 compared with 2009 th on the list

Vitamin exposures reported to PCs

70000 60000 50000 40000 30000 20000 10000 0 <6yrs 6 to 19 yrs >19 yrs unintentional total •June 19, 2002: American Medical Association recommends that all adults should take a multi-vitamin •2006—AAPCC reporting format changes—total  single case exposures

Deaths contributed to by vitamins, minerals and botanical supplements, 2001-2010 (AAPCC annual reports) Vitamin Mineral

2001 2002 2003 2004 2005 * 2006 *

0 7 2 5 4 8 3 9 1 13 1 3

2007 2008 2009 2010

0 0 0 3 0 2 0 3 Botanical 12 4 13 10 13 2 0 0 1 4 *2005 Codex Guidelines adopted for vitamin and mineral supplements.

*FDA ban on Ephedra upheld by US Appeals Court.

Multi vitamin w/Fe

200 1

14 Other B 12 Multi vitamin adult 6 B6 10 C Niacin A D total 3 3 0 2 59

Vitamins: major adverse events

2002 2003 2004 2005 2006 2007 2008 2009

15 12 5 4 2 10 3 1 64 10 16 9 5 3 5 2 2 63 14 15 3 9 3 3 2 0 53 11 18 8 10 2 12 1 0 73 0 0 2 0 2 2 0 0 7 3 3 2 0 2 4 0 1 17 1 1 0 0 0 2 0 0 8 1 1 1 1 1 7 0 2 17 In July of 2005, Codex Alimentarius Commission adopted the

Guidelines for Vitamin and Mineral Food Supplements.

(from FDA website)

2010

3 0 1 5 1 0 0 2 17

Vitamin supplements--summary

   Exposure reports seem to be on a continual increase, 25% from 2001-2010 Overall US population increased 8.8% from 2001 2010 Deaths and major adverse events (requiring hospitalization) are minimal, perhaps benefitted by Codex Guidelines.

Minerals

Calcium Magnesium Fluoride Iron

RDA or AI

Mineral supplement toxicities

Toxicity UL, adults Endpoints for developing UL adults, amt/d

1000-1200 mg Kidney stones, milk-alkali-syndrome, the interaction with absorption of iron, magnesium, zinc et al 2500 mg 265-350 mg Nausea, diarrhea, impaired renal function sensitive to magnesium toxicity 350 mg Milk-alkali-syndrome: hypercalcemia and renal insufficiency Diarrhea from non-food sources (pharmacological purposes) 3-4 mg 6-18 mg Enamel fluorosis and skeletal fluorosis Liver damage 10 mg/d 45mg Skeletal fluorosis (>9 years old, 10 mg/d for 10y) Gastrointestinal distress Potassium Sodium Zinc 4.7 g Hyperkalemia (high serum potassium), gastrointestinal discomfort 1.2-2.3 g High blood pressure in sensitive individuals 6.8-7.4 mg Decreasing copper absorption NA NA 40 mg Chromium Selenium 20-35 µg 45-55 µg People with renal and liver disease sensitive to overdose of chromium Hair and nail brittleness and loss, skin rash, garlic breath odor, fatigue, irritability, nervous system abnormalities NA 400 µg/d Urinary potassium excretion regulated very well in healthy people Impact of sodium on blood pressure Excess zinc alters copper metabolism Low toxicity based on very poor absorption Selenosis: hair and nail brittleness and loss

Mineral exposures (2001-2010)

35000 30000 25000 20000 15000 10000 5000 0 * <6 yrs 6 to 19 yrs >19 yrs unintentional total *Calcium accounted mainly for increased exposure cases from 2003 on.

Note Change in reporting format from 2006 on to show single exposures only.

Major adverse events—mineral supplements— AAPCC reports

Ca F Fe Mg K Na Zn other total 2001 8 0 18 4 19 1 4 2 63 2002 11 0 19 10 20 1 4 0 69 2003 12 0 17 2 23 2 0 0 62 2004 9 0 15 5 22 5 2 1 69 2005 12 0 27 4 16 6 1 0 70 2006 1 0 7 1 1 1 0 0 14 2007 2 0 8 3 1 4 1 0 25 2008 1 0 3 2 4 4 0 0 19 2009 2 0 8 1 1 1 0 1 18 2010 0 0 8 0 1 1 2 0 14

Deaths contributed to by mineral supplements—AAPCC reports

Ca F Fe Mg K Na Zn total 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 0 0 1 0 1 0 0 0 0 0 1 0 0 5 0 1 7 0 4 0 1 0 0 5 0 2 0 3 2 0 8 0 1 1 7 0 0 9 0 3 2 4 2 0 13 0 0 0 0 2 1 3 0 0 0 0 0 0 0 0 0 0 0 3 0 3 0 1 0 0 1 0 2 0 1 0 0 2 0 3

Mineral supplements--summary

   Exposure reports seem to have leveled off since 2003.  Not clear why but trend differs from vitamins for which exposures seem to have been increasing.

Increased reports related to calcium did not result in increases in serious adverse events.

Codex guidelines may have helped reduce serious adverse events from 2006 on, especially from Fe and K, the major contributors before.

30000 25000 20000 15000 10000 5000 0

Dietary supplements: exposures reported to Poison Control Centers

<6 yrs 6 to 19 yrs >19 yrs unintentional total Note greater proportion of adult: child exposures compared with vitamins or minerals: but recent trends are that for all three classes (vitamins, minerals, dietary supplements),

exposures of young children predominate!

Dietary supplements: major adverse events reported to PCs—2001-2010

Ma huang Multi- + Ma huang 2001 10 87 2002 20 88 2003 23 71 2004 26 51 2005 7 14 2006 3 6 2007 1 3 2008 2 0 2009 0 0 2010 0 1 Gingko biloba Echinacea Ginseng Kava kava St. John's wort Yohimbe unknown total 5 4 4 1 1 0 0 0 0 0 6 5 0 2 5 5 1 3 2 2 0 2 0 2 1 1 1 2 1 0 1 1 0 0 0 1 0 0 0 2 0 0 3 5 9 3 3 2 2 0 25 32 16 10 0 0 0 0 7 172 195 173 176 111 35 34 38 24

FDA published “A Dietary Supplement Labeling Guide” in 2005.

0 0 1 0 0 1 0 0 0 0 11 33

Deaths contributed to by dietary supplements reported to PCs

Ma huang Multi- + Ma huang 2002 3 3 2003 1 2 2004 3 2 2005 5 2 2006* 1 0 2007 0 0 2008 0 0 2009 0 0 2010 0 0 Gingko biloba Echinacea Ginseng Kava kava St. John's wort Yohimbe unknown total 0 0 0 1 0 0 2 12 0 0 0 0 0 0 1 4 0 0 0 0 0 2 0 13 0 0 0 0 0 0 0 10 0 0 0 1 1 0 0 13 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

*FDA ban on Ephedra upheld by US Appeals Court.

FDA published “A Dietary Supplement Labeling Guide” in 2005.

In 2010, the other 2 deaths were from 1 “other” and 1 homeopathic supplement.

0 0 0 0 0 0 2 4

Trends for botanical supplements

    An abrupt change of increased apparent safety after 2005 is noted—related to FDA guidance re: supplement labeling?

Exposures reported for children continue to increase—why?

Stable exposure trend for adults recently.

Is efficacy data (science!) having an impact?

Comparing vitamins, minerals and dietary supplements: PC exposure reports 2001-2010

70000 60000 50000 40000 30000 20000 10000 0 * vitamins minerals botanicals *calcium supplement use accounts for the increase

Major adverse effects of vitamins, minerals and botanical supplements: PC reports 2001-2010

250 200 150 100 50 0 vitamins minerals botanicals Vitamin exposures occur in much greater numbers but with similar numbers of adverse effects compared with minerals.

Why the steeper drop in adverse events from botanicals? We might credit attention to labeling and to scientific findings, but unknowns in botanicals are much more an issue than with vitamins and minerals.

What do you conclude?

   How toxic are dietary supplements?

Is the current regulatory framework safe enough? Why or why not?

What additional information or monitoring needs to be done?

Case studies—dietary supplements

  Vitamin C Top selling botanicals   Garlic Survey of efficacy and contraindications of commonly used botanicals

Principles of evidence for herbal efficacy

     Consistency—similar results across studies and populations; most studies agree.

Strength of association—the effect is as powerful as a standard known to be effective.

Dose response—an increased dose causes an increased response.

Biological plausibility—cellular, animal and human studies show similar effects; mechanisms are known.

Temporality—symptomatic improvement is clearly seen after the herb is administered.

 “Gold standard”: well-controlled, sufficiently large human intervention trials.

Vitamin C supplements—effects?

    National Library of Medicine (NLM) provides information on evaluation of supplements,.e.g. the following for vitamin C http://www.nlm.nih.gov/medlineplus/druginfo/natural /patient-vitaminc.html

The following criteria are used A: Strong scientific evidence for this use; B: Good scientific evidence for this use; C: Unclear scientific evidence for this use; D: Fair scientific evidence against this use; F: Strong scientific evidence against this use.

Vitamin C NLM claim ratings

Treating the common cold. There is a lot of controversy about the effectiveness of vitamin C for treating the common cold. However, the majority of evidence shows that taking high doses of vitamin C might shorten the course of the cold by 1 to 1.5 days in some patients. But it is not effective for preventing the common cold.

C

Decreasing lung infections caused by heavy exercise. Using vitamin C in amounts of 600 mg to 1 gram per day before heavy physical exercise, such as a marathon, might prevent upper respiratory infections that sometimes follow heavy exercise.

C

Reducing the risk of certain cancers of the mouth and breast. This only works when fresh fruits and vegetables high in vitamin C are eaten, not with vitamin C supplements.

C Common cold prevention (general)

More than 30 clinical trials including more than 10,000 participants have examined the effects of taking daily vitamin C on cold prevention. Overall, no significant reduction in the risk of developing colds has been observed. In people who developed colds while taking vitamin C, no difference in severity of symptoms has been seen overall, although a very small significant reduction in the duration of colds has been reported (approximately 10% in adults and 15% in children).

D

Vitamin C and extreme environments

  Metaanalysis of 6 trials of 642 total marathon runners, skiers, soldiers in the sub-arctic showed a reduced relative risk (RR = 0.5) of the common cold when supplemented with > 0.2 g vitamin C per day compared with placebo.

Douglas RM, Hemilä H, Chalker E, Treacy B. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000980. Vitamin C for preventing and treating the common cold.

Vitamin C supplementation

 Numerous studies have been done with this vitamin as a supplement  Very little evidence that vitamin C supplements are beneficial  Consuming foods rich in vitamin C will prevent scurvy and improve iron absorption (main proven benefits)  GI disturbances are the main contraindication from high doses—what is not absorbed passes through

Garlic

 General description:  Allium sativum, fresh or dried bulb, garlic oil  Study data:  140 patients with advanced atherosclerotic plaques showed ~2% reduction of these lesions after taking 900 mg garlic powder daily for 4 years, in comparison to 140 controls given a placebo, who showed an increase in severity of plaques of ~15% (Koscielny et al. 1999, Atheros 144:237-49).  192 subjects with moderate high cholesterol showed no cholesterol lowering by raw, dried or aged garlic (equal to one average garlic clove/day, 6 days/week) compared with placebo over 6 mos (Gardner et al. 2007, Arch Intern Med 167: 346-53).

http://www.garlic.mistral.co.uk/  Garlic may prevent some factors in heart disease but not all.

 Contraindications:  Avoid concomitant use of garlic supplements with anticoagulant drugs or NSAIDs  Halitosis, body odor

Botanical efficacy chart

Herb Name Echinacea Garlic Ginkgo Ginger Leaf/ seed root Ginseng Root Saw palmetto fruit Peppermint Chamomile St John’s wort Plant part: Root Bulb Flower Flower Flower Benefit: Anti-infection, not proven Atherosclerosis Improved cognition/psych. function in dementia* Anti-nausea in pregnancy Cancer preventive Prostate health, not proven Irritable bowel syndrome Modest anxiolytic Depression*

*meta-analyses supportive

Cautions: MS, HIV GI distress, NSAIDs diabetes, NSAIDs GI distress Hypoglycemia iron deficiency Gallstones None Diabetes

FDA resources

 Alerts  http://www.fda.gov/Food/DietarySupplements/Al erts/default.htm

    Adverse event reporting http://www.fda.gov/Food/DietarySupplements/Al erts/ucm111110.htm

Tips for dietary supplement users http://www.fda.gov/Food/DietarySupplements/C onsumerInformation/ucm110567.htm