Vitamin UpdateVitamin Update

Frank J. Domino, M.D.Frank J. Domino, M.D.

Associate ProfessorAssociate Professor

Family Medicine Clerkship DirectorFamily Medicine Clerkship Director

Dept. of Family Medicine & Community Dept. of Family Medicine & Community Health Health

Un. Of Massachusetts Medical SchoolUn. Of Massachusetts Medical School

DisclosureDisclosure

Editor in Chief: Editor in Chief:

5 Minute Clinical Consult5 Minute Clinical Consult

Author and Editor for Author and Editor for Up To DateUp To Date

Pri Med Curriculum CommitteePri Med Curriculum Committee

Author/Editor: Author/Editor:

www.Epocrates.comwww.Epocrates.com, Rxpalm, Inc., , Rxpalm, Inc.,

www.Familydoctor.orgwww.Familydoctor.org

ObjectivesObjectives

Review most current data on the role of Review most current data on the role of vitamins for the prevention of illnessvitamins for the prevention of illness

Describe and interpret some of the recent Describe and interpret some of the recent literature base on a variety of agents literature base on a variety of agents commonly used and why they have commonly used and why they have become so popularbecome so popular

Review and summarize what does provide Review and summarize what does provide disease prevention and benefit.disease prevention and benefit.

What we spend….What we spend….

2007 CDC: 34 Billion on Alternative Care2007 CDC: 34 Billion on Alternative Care– 15 Billion on Vitamins & Supplements15 Billion on Vitamins & Supplements– 12 Billion on acupuncturists, chiropractors, 12 Billion on acupuncturists, chiropractors,

massage therapistsmassage therapists– 3 Billion on Homeopathy3 Billion on Homeopathy

Motivating Reasons: Motivating Reasons: Pain and FearPain and Fear

VitaminsVitamins

-Mediterranean diets: fruits and vegetables, -Mediterranean diets: fruits and vegetables, Olive Oil and some nuts correlate with lower Olive Oil and some nuts correlate with lower

rates of heart disease and cancerrates of heart disease and cancer

-Packing all of that good stuff into a daily -Packing all of that good stuff into a daily supplement should result in a similar benefit?supplement should result in a similar benefit?

-What -What worksworks and what and what doesn’tdoesn’t

Antioxidant substances include Beta-carotene

Lutein Lycopene Selenium Vitamin A Vitamin C Vitamin E

Anti OxidantsAnti Oxidants

Vitamin C (500 mg)Vitamin C (500 mg)Vitamin E (600 IU QOD)Vitamin E (600 IU QOD)Beta Carotene (50mg QOD)Beta Carotene (50mg QOD)In combinations (2x2x2)In combinations (2x2x2)8000+ Women x 9.4 years8000+ Women x 9.4 years

No benefit Cancer MortalityNo benefit Cancer MortalityNo Benefit in Overall MortalityNo Benefit in Overall Mortality

J Natl Can Inst 2009; 101: 14-23J Natl Can Inst 2009; 101: 14-23

Vitamin C and E Prostate CancerVitamin C and E Prostate Cancer

Physician’s Health Study II, 14,000+ MenPhysician’s Health Study II, 14,000+ Men

RCT 2x2 Factorial Study: RCT 2x2 Factorial Study:

Vit. E 400 IU + Vit. C 500 mg/day x 8 YrsVit. E 400 IU + Vit. C 500 mg/day x 8 Yrs

No Decrease in Prostate Cancer or Total CancerNo Decrease in Prostate Cancer or Total Cancer

JAMA 2009; 301(1): 52-62JAMA 2009; 301(1): 52-62

Selenium and Vitamin ESelenium and Vitamin E

35,000+ Men US, Canada, Puerto Rico35,000+ Men US, Canada, Puerto Rico2x2 Factorial Study2x2 Factorial StudySelenium 200 ug/d, Vit. E IU/d x 5.4 YrSelenium 200 ug/d, Vit. E IU/d x 5.4 Yr

No Significant No Significant DecreaseDecrease in any cancer in any cancerSlight Non-Sig. INCREASE in Slight Non-Sig. INCREASE in

– Prostate Cancer in Vitamin EProstate Cancer in Vitamin E– Type 2 DM in Selenium + Vit. E Type 2 DM in Selenium + Vit. E

JAMA 2009; 301(1): 39-51JAMA 2009; 301(1): 39-51

Anti-oxidants: CDSRAnti-oxidants: CDSR

Vitamin A, C, E, Selenium, beta-carotene, SeleniumVitamin A, C, E, Selenium, beta-carotene, SeleniumCDSR: 230,000 Patients from 68 studiesCDSR: 230,000 Patients from 68 studies

No significant reduction in No significant reduction in overall mortalityoverall mortality

Restricted to 47 Restricted to 47 high qualityhigh quality RCT, -> RCT, -> INCREASE in mortality (RR 1.05, 95% CI 1.02-1.08)INCREASE in mortality (RR 1.05, 95% CI 1.02-1.08)

Cochrane DBSR: 2008; 16(2)Cochrane DBSR: 2008; 16(2)

Folic Acid, B6 & B12 on Cancer Folic Acid, B6 & B12 on Cancer Risk in WomenRisk in Women

5400 female health professionals5400 female health professionals>/= 42 Yr with: Known CAD or 3 or more CHD >/= 42 Yr with: Known CAD or 3 or more CHD Risk Factors x 7.3 yearsRisk Factors x 7.3 yearsFolic Acid 2.5 mg Vit. B6 50 mg+Vit B12 1 mg/dayFolic Acid 2.5 mg Vit. B6 50 mg+Vit B12 1 mg/day

No effect on breast cancer or Total Cancer RiskNo effect on breast cancer or Total Cancer Risk

JAMA 2008; 300(17): 2012-2021 JAMA 2008; 300(17): 2012-2021

Multi Vitamins: WHIMulti Vitamins: WHI

161,000+ Women (68K RCT, 93K Cohort) x 8 Years161,000+ Women (68K RCT, 93K Cohort) x 8 YearsMVI Use and Cancer, CHD, MortalityMVI Use and Cancer, CHD, Mortality

No Association between MVI and Decrease in:No Association between MVI and Decrease in:- Any cancer risk - Any cancer risk

(Breast, C/Rectal, Endometrial, Lung, Ovarian), (Breast, C/Rectal, Endometrial, Lung, Ovarian), – CVD, MI, Stroke, DVT or CVD, MI, Stroke, DVT or

– Mortality Mortality

Arch Intern Med.Arch Intern Med. 2009;169(3):294-304 2009;169(3):294-304

Famous Famous CorrelationsCorrelations that were not that were not Cause & EffectCause & Effect

Blood Letting and HealthBlood Letting and Health

Antibiotics for Otitis Media Antibiotics for Otitis Media

Binding Free Radicals and CancerBinding Free Radicals and Cancer

Vitamin C and improved immunityVitamin C and improved immunity

Low Fat foods and Wt. LossLow Fat foods and Wt. Loss

College Education and Job SecurityCollege Education and Job Security

““No Down Payment” Mortgage & Home No Down Payment” Mortgage & Home OwnershipOwnership

CHD & Folic AcidCHD & Folic Acid

↑↑ homocysteine associated with homocysteine associated with ↑↑ risk of risk of cardiovascular disease. cardiovascular disease.

Supplementation with folic acid, vitamin B6, Supplementation with folic acid, vitamin B6, and vitamin B12 can lower homocysteine and vitamin B12 can lower homocysteine

levelslevels

THEREFORE: THEREFORE: ↓↓ Homocysteine should lower Homocysteine should lower CHD risk, right?CHD risk, right?

Folic Acid and CHDFolic Acid and CHD

SR of 12 RCTSR of 12 RCT of folic acid vs placebo in >16,000 of folic acid vs placebo in >16,000 patients w/CHDpatients w/CHD

NO: decrease in CVD, CHD, CVA & All-Cause NO: decrease in CVD, CHD, CVA & All-Cause MortalityMortality

JAMA: 2006; 296(22): 2720JAMA: 2006; 296(22): 2720Meta-analysis of 5 RCTMeta-analysis of 5 RCT for 2 for 2ndnd Prevention of CVD in Prevention of CVD in 10,000+ patients10,000+ patientsNo Significant Outcome improvementNo Significant Outcome improvementBUT slight, non-significant trend to increased CHD BUT slight, non-significant trend to increased CHD risk in Folic Acid grouprisk in Folic Acid group

Lancet: 2005; 366(9518):1679Lancet: 2005; 366(9518):1679

Ginko biloba for Prevention of Ginko biloba for Prevention of DementiaDementia

RCT: >/= 75; RCT: >/= 75;

2500 Nl + 482 Mild Cog. Impairment 2500 Nl + 482 Mild Cog. Impairment

Ginko 120 mg bid vs. placebo x 8 yearsGinko 120 mg bid vs. placebo x 8 years

No Sig risk reduction in Ginko groupNo Sig risk reduction in Ginko group

No effect on progression to Dementia in MCI No effect on progression to Dementia in MCI groupgroup

JAMA 2008; 300(19): 2253JAMA 2008; 300(19): 2253

USPSTFUSPSTF

1.1. AGAINSTAGAINST: Beta Carotene: Beta Carotene

2.2. InsufficientInsufficient to recommend for/against: to recommend for/against:

--Vitamin A, C, E--Vitamin A, C, E

--Multivitamins w/folic acid or anti oxidant--Multivitamins w/folic acid or anti oxidant

for prevention of CHD or Cancerfor prevention of CHD or Cancer

Ann. Int Med 2003; 139(1):56Ann. Int Med 2003; 139(1):56

So, what Vitamins WORKSo, what Vitamins WORK??

Vitamin DVitamin D

Little new DIRECT outcome dataLittle new DIRECT outcome data1. Vit D. Deficiency 1. Vit D. Deficiency ↑ Risk:↑ Risk:

– Cardiovascular DiseaseCardiovascular Disease– Death from MI/CHD Death from MI/CHD Arch Intern Med 2008; 168(11): 1174Arch Intern Med 2008; 168(11): 1174

- First Cardiac Event First Cardiac Event Circulation 2008; 117(4): 503Circulation 2008; 117(4): 503

2. Vitamin D Supp 2. Vitamin D Supp ↓ Risk of ↓ Risk of Falls in Seniors Falls in Seniors (700-1000/d)(700-1000/d)Bischoff-Ferrari; Bischoff-Ferrari; : : BMJ. 2009 Oct 1;339:b3692BMJ. 2009 Oct 1;339:b3692

AND AND ↓Rates of Nonvertebral ↓Rates of Nonvertebral FracturesFractures; (Hip) RR = 0.82; (Hip) RR = 0.82Arch Inter Med 2009; 169(6): 551Arch Inter Med 2009; 169(6): 551

3. 3. HTNHTN: Short term data (8-12 weeks): Short term data (8-12 weeks)Average ↓: Average ↓: Systolic >5 mmHg (NNT=3), Systolic >5 mmHg (NNT=3),

Diastolic >5 mmHg (NNT=7)Diastolic >5 mmHg (NNT=7)J Clin Endo Met 2001; 86(4): 1633J Clin Endo Met 2001; 86(4): 1633

Early Data on Vitamin D Early Data on Vitamin D SupplementationSupplementation

↓↓URI w/2000 IU/d URI w/2000 IU/d Epid Infect 2009; (10):1396-404Epid Infect 2009; (10):1396-404 ↑ ↑ Athletic Performance Athletic Performance Med Sci Sports 2008; 41(5): 1102Med Sci Sports 2008; 41(5): 1102

↓↓Risk of Breast and Colon Ca Risk of Breast and Colon Ca Am J Public Health. 2006 Am J Public Health. 2006 Feb;96(2):252-61Feb;96(2):252-61

Prenatal Replacement Prenatal Replacement ↓ Pediatric Asthma ↓ Pediatric AsthmaSlow (& ? Prevent) OsteoarthritisSlow (& ? Prevent) OsteoarthritisPrevent Multiple Sclerosis (Neuro 2004; 62: 60)Prevent Multiple Sclerosis (Neuro 2004; 62: 60)

Recommend:Recommend:Breastfed 400 IU at 2 monthsBreastfed 400 IU at 2 months

Children 1000 IU/DayChildren 1000 IU/DayAdults 2000 IU/DayAdults 2000 IU/Day

More on Vitamin D, Obesity and More on Vitamin D, Obesity and DiabetesDiabetes

Calcium+D during weight-loss enhances weight loss & Calcium+D during weight-loss enhances weight loss & lipoprotein profile in T2DMlipoprotein profile in T2DM– Am J Clin Nutr. 2007 Jan;85(1):54-9.Am J Clin Nutr. 2007 Jan;85(1):54-9.

But Calcium alone did But Calcium alone did notnot improve outcomes improve outcomes– Ann Intern Med. 2009 Jun 16;150(12):821-9, W145-6Ann Intern Med. 2009 Jun 16;150(12):821-9, W145-6

Vitamin D reduces insulin resistance in S. Asian women Vitamin D reduces insulin resistance in S. Asian women of New Zealand with Vitamin D Deficiencyof New Zealand with Vitamin D Deficiency– Br J Nutr. 2010 Feb;103(4):549-55. Br J Nutr. 2010 Feb;103(4):549-55.

Treating VDD in T2DM improves insulin secretionTreating VDD in T2DM improves insulin secretion– Int J Clin Pract. 2003 May;57(4):258-61. Int J Clin Pract. 2003 May;57(4):258-61.

VDD associated w/ SubQ & Visceral adiposityVDD associated w/ SubQ & Visceral adiposity– Diabetes. 2010 Jan;59(1):242-8Diabetes. 2010 Jan;59(1):242-8

Vit D Def = ↑Vit D Def = ↑ Risk of Death Risk of Death

Melamed: Cohort 13,000 NHANESMelamed: Cohort 13,000 NHANES

Lowest quartile Lowest quartile ↑ Risk of All Cause M↑ Risk of All Cause Mortalityortality RR=1.26 (95% CI 1.08 - 1.46)RR=1.26 (95% CI 1.08 - 1.46)

Arch Intern Med. 2008;168:1629-1637Arch Intern Med. 2008;168:1629-1637. .

Cohort Study of 3,200+ consecutive adults scheduled Cohort Study of 3,200+ consecutive adults scheduled for Coronary Angiography at 1 SW Germany for Coronary Angiography at 1 SW Germany

Hospital x ~ 8 YearsHospital x ~ 8 Years

22.6% died; Most with CHD22.6% died; Most with CHD

2 lowest 25 Vit D levels -> HR 2.08 (CHD HR =2.22)2 lowest 25 Vit D levels -> HR 2.08 (CHD HR =2.22)

Dobnig 2008; Arch Int Med 168(12): 1340Dobnig 2008; Arch Int Med 168(12): 1340

What Prevents All Cause Mortality?What Prevents All Cause Mortality?

SeatbeltsSeatbelts

Clean WaterClean Water

VaccinesVaccines

Prevention of All Cause Prevention of All Cause MortalityMortality

Meta Analysis:18 studies Meta Analysis:18 studies of 57,000+ Adultsof 57,000+ AdultsExamined Risk of Death Examined Risk of Death Any Cause in Any Cause in RCTRCT Vitamin D Vitamin D SupplementationSupplementationAverage dose > Average dose > 500 IU/D500 IU/D

Decrease in All Cause Decrease in All Cause Mortality (RR = 0.93)Mortality (RR = 0.93)Autier: Arch Int Med Autier: Arch Int Med 2007;167(16): 17302007;167(16): 1730

980 Pages…

Institute of Medicine

Vitamin DVitamin D

Vitamin D’s job is to regulate Vitamin D’s job is to regulate serum Caserum Ca

Annual High Dose Vitamin D & FracturesAnnual High Dose Vitamin D & Fractures

RCT of 500,000 IU D3 x 3-5 YearsRCT of 500,000 IU D3 x 3-5 Years

↑ ↑ Risk of Falls (83/100 Per Yrs vs 72/100 PY)Risk of Falls (83/100 Per Yrs vs 72/100 PY)

↑ ↑ Risk of Fx (4.9/100 PY vs 3.9/100 PY)Risk of Fx (4.9/100 PY vs 3.9/100 PY)

JAMA 2010; 303(18): 1815-22; Editorial 1861JAMA 2010; 303(18): 1815-22; Editorial 1861

Fish OilFish OilDHA: docosahexaenonic AcidDHA: docosahexaenonic AcidEPA eicosapentaenoic AcidEPA eicosapentaenoic Acid

Cardiac:Cardiac: Meta-Analysis of CHD Pts: Meta-Analysis of CHD Pts: Reduces Cardiac Death but no effect on Reduces Cardiac Death but no effect on

arrhythmia or All Cause Mortalityarrhythmia or All Cause MortalityBMJ 2009: 338: a2931BMJ 2009: 338: a2931

InfectionInfection: : 180 Thai children (9-12) 200 mg EPA + 1 gm. 180 Thai children (9-12) 200 mg EPA + 1 gm. DHA 5 d/wk vs placeboDHA 5 d/wk vs placebo

few & shorter “infections” vs placebofew & shorter “infections” vs placebo

J Pedia 2008; 154(3): 391-395J Pedia 2008; 154(3): 391-395

Vitamin CVitamin C

Vitamin C DOES prevents Scurvy Vitamin C DOES prevents Scurvy – Disease of impaired collagen synthesis Disease of impaired collagen synthesis – Symptoms: ecchymoses, bleeding, petechiae, Symptoms: ecchymoses, bleeding, petechiae,

hyperkeratosis, Sjogren's syndrome, arthralgias, hyperkeratosis, Sjogren's syndrome, arthralgias, impaired wound healingimpaired wound healing

BUTBUTVitamin C to lower LDL—NotVitamin C to lower LDL—Not– Circulation 1999 Feb 2;99(4):591-5Circulation 1999 Feb 2;99(4):591-5

Prevent or Tx URI—NotPrevent or Tx URI—Not– Cochrane Database Syst Rev. 2007 Jul 18;(3)Cochrane Database Syst Rev. 2007 Jul 18;(3)

Can cause False + guaiac stoolsCan cause False + guaiac stoolsMay increase risk of calcium oxalate stonesMay increase risk of calcium oxalate stones

Vitamin C is finally good for Vitamin C is finally good for more than Scurvy…more than Scurvy…

Cohort trial of ~47,000 MenCohort trial of ~47,000 Men

Surveyed Vitamin C & new onset GoutSurveyed Vitamin C & new onset Gout

20 Years Follow up20 Years Follow up

Compared to < 250 mg/dCompared to < 250 mg/d

500-999 mg/d 500-999 mg/d RR= 0.83RR= 0.83

1000-1499 mg/d 1000-1499 mg/d RR= 0.66RR= 0.66

>/= 1500 mg/d >/= 1500 mg/d RR = 0.55 RR = 0.55

Arch Intern Med 2009 169(5): 502 p<0.001Arch Intern Med 2009 169(5): 502 p<0.001

45

Elderberry Extract for InfluenzaElderberry Extract for Influenza

3 3 SmallSmall Randomized Controlled trials Randomized Controlled trialsElderberry Extract Lozenges (175 mg) vs Elderberry Extract Lozenges (175 mg) vs placebo QID for 2 daysplacebo QID for 2 days20% reduction in fever & flu symptoms20% reduction in fever & flu symptomsNo Adverse EventsNo Adverse Events– J Pharmacol Pharmacokin; 2009: 5:23J Pharmacol Pharmacokin; 2009: 5:23

Duration of illness shorter by 29 h (25% Duration of illness shorter by 29 h (25% reduction vs placebo)reduction vs placebo)COMPARED TO: Tamiflu (oseltamivir) COMPARED TO: Tamiflu (oseltamivir) Duration of illness shorter by 16.8 hours vs Duration of illness shorter by 16.8 hours vs placeboplaceboElderberry not proven to PREVENT InfluenzaElderberry not proven to PREVENT Influenza

Pelargonium sidoides extract for Pelargonium sidoides extract for Acute BronchitisAcute Bronchitis

Cochrane Systematic review in 6 trials of Cochrane Systematic review in 6 trials of adults and childrenadults and children

Complete resolution at day 7Complete resolution at day 7– Liquid: 39% vs 5%, NNT = 3Liquid: 39% vs 5%, NNT = 3– Tablet: 7% vs 1%, NNT = 15Tablet: 7% vs 1%, NNT = 15– CDSR 2008; 16(3)CDSR 2008; 16(3)– NOT recommended in pregnant or NOT recommended in pregnant or

breastfeeding women or children < 6 yearsbreastfeeding women or children < 6 years

ZincZinc

15 trials, 1300 Participants 15 trials, 1300 Participants

Zinc lozenges (or syrup), started within 24 hours of Zinc lozenges (or syrup), started within 24 hours of symptoms, reduced the severity and duration of cold symptoms, reduced the severity and duration of cold symptoms. symptoms.

Risk of symptoms at day 7 was 50% less than without Risk of symptoms at day 7 was 50% less than without ZincZinc

Prevention: taking zinc supplements for 5 months Prevention: taking zinc supplements for 5 months reduces:reduces:– Cold IncidenceCold Incidence– School AbsenteeismSchool Absenteeism– Antibiotic Rx for ChildrenAntibiotic Rx for Children

CDSR 2011; Meenu, Issue 2CDSR 2011; Meenu, Issue 2

Yogurt Drink to prevent Abx Yogurt Drink to prevent Abx Associated DiarrheaAssociated Diarrhea

135 In Patients on High Risk IV Abx135 In Patients on High Risk IV Abx

Lactobacillus casei, L bulgaricus, and Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus Streptococcus thermophilus

Twice a day during a course of antibiotics and Twice a day during a course of antibiotics and for one week after the course finishedfor one week after the course finished

Diarrhea: 12% Int. vs 34% PlaceboDiarrhea: 12% Int. vs 34% Placebo

? C. difficile? C. difficile

NNT = 5NNT = 5

BMJ. 2007 Jul 14;335(7610):80BMJ. 2007 Jul 14;335(7610):80

SummarySummaryWhat Does NOT Work:What Does NOT Work:Anti Oxidants & Multi VitaminsAnti Oxidants & Multi VitaminsFolic Acid supplementation on CHD riskFolic Acid supplementation on CHD riskGinko Biloba and prevent DementiaGinko Biloba and prevent DementiaVitamin C risk of infection or treat URI Vitamin C risk of infection or treat URI What Does WORKWhat Does WORK::Vitamin C DOES LOWER risk of gout in menVitamin C DOES LOWER risk of gout in menVitamin D DOES LOWER all cause mortality, and will Vitamin D DOES LOWER all cause mortality, and will decrease risk of falls in seniors, decrease of CHD and decrease risk of falls in seniors, decrease of CHD and Cancer, and may prevent osteoporosisCancer, and may prevent osteoporosisOmega 3 Fatty Acids DOES lower risk of CHD DeathOmega 3 Fatty Acids DOES lower risk of CHD DeathConsider Elderberry Extract for Influenza symptomsConsider Elderberry Extract for Influenza symptomsConsider Pelargonium sidoides syrup for BronchitisConsider Pelargonium sidoides syrup for BronchitisZinc treats & Prevents URI’sZinc treats & Prevents URI’sYogurt Drink may help prevent Abx DiarrheaYogurt Drink may help prevent Abx Diarrhea

Get Vitamins the Old Fashioned WayGet Vitamins the Old Fashioned Way

Frank.domino@umassmemorial.org