Dietary Supplements, Selenium and Dietary Supplements, Selenium and

Chronic Disease PreventionChronic Disease Prevention

Saverio Stranges, MD, PhDSaverio Stranges, MD, PhD

Clinical Sciences Research InstituteClinical Sciences Research Institute

University of Warwick Medical School, UKUniversity of Warwick Medical School, UK

OutlineOutline

Context on Dietary SupplementsContext on Dietary Supplements

Physiological Role of SeleniumPhysiological Role of Selenium

Selenium and Human HealthSelenium and Human Health

PerspectivesPerspectives

Dietary SupplementDietary Supplement

“ “A dietary supplement is a preparation intended to A dietary supplement is a preparation intended to

supply nutrients (such as vitamins, minerals, or supply nutrients (such as vitamins, minerals, or

amino acids) that are amino acids) that are missingmissing or or notnot consumed in consumed in

sufficient quantitysufficient quantity in a person's diet” in a person's diet”

Context: Context: Dietary Supplement Use in US Dietary Supplement Use in US

1994: 1994: “Dietary Supplement Health and Education Act”“Dietary Supplement Health and Education Act”

1997-onwards: 1997-onwards: Dramatic increase in supplement sales Dramatic increase in supplement sales $18.8 billion in 2003 $18.8 billion in 2003

1999/2000: 1999/2000: 52% of US adults take some52% of US adults take sometype of dietary supplements (NHANES)type of dietary supplements (NHANES)

1990:1990: “Nutrition Labeling and Education Act” “Nutrition Labeling and Education Act”

Dietary Supplement Use in US Adults (≥ 20 ys)Dietary Supplement Use in US Adults (≥ 20 ys)

56.7

46.9

38.0

31.7

13.511.7

1.0 1.10

10

20

30

40

50

60

Pre

vale

nce

use

rs (

%)

Women Men

NHANES 1999-2000. Am J Epidemiol. 2004; 160:339-49NHANES 1999-2000. Am J Epidemiol. 2004; 160:339-49

Any dietary Any dietary supplementsupplement

Multivitamin/Multivitamin/multimineralmultimineral

SeleniumSeleniumVitamin EVitamin E

Trends in Daily Use of Vitamin/Mineral Trends in Daily Use of Vitamin/Mineral Supplements - US Adults (≥ 18 ys)Supplements - US Adults (≥ 18 ys)

26.8

19.2

26.8

20.2

38.7

28.7

0

5

10

15

20

25

30

35

40

Pre

vale

nce

use

rs (

%)

1987 1992 2000

Women Men

National Health Interview Survey. J Am Diet Assoc. 2004; 104:942-950National Health Interview Survey. J Am Diet Assoc. 2004; 104:942-950

Context: Context: Dietary Supplement Use in Europe Dietary Supplement Use in Europe

2002: 2002: Directive 2002/46/EC - Directive 2002/46/EC - Food Supplements DirectiveFood Supplements Directive

2004: 2004: Decreto Legislativo 169/2004Decreto Legislativo 169/2004 (Italy)(Italy)

150 millions150 millions euros/year in dietary supplements (Italy) euros/year in dietary supplements (Italy)

20-30%20-30% dietary supplement users (among adults) in Europe dietary supplement users (among adults) in Europe

Dietary Supplements in the MarketDietary Supplements in the Market

CategoryCategory ExampleExampleSingle Vitamin Vitamin A, C, E

Multiple Vitamins B complex, CentrumTM

Single Minerals calcium, zinc, selenium

Multiple Minerals iron and zinc, calcium and magnesium

Vitamins + Minerals (VM) centrumTM with minerals

VM + other products One-a-DayTM with Gingko

Amino Acids lysine, methionine, tryptophan

Fish Oils omega-3 fatty acids

Glandulars pancreas, liver, organ extracts

Fiber fiberwafersTM, florabiberTM

Botanicals, herbs Echinacea, ginseng, St. John’s Wort

Antacids as calcium suppl. Tums Antacid/Calcium SupplementTM

Why Do People Take Dietary Why Do People Take Dietary Supplements?Supplements?

Balance a poor diet/promote optimal health, fitnessBalance a poor diet/promote optimal health, fitness

Prevent/manage minor ailments or chronic diseasePrevent/manage minor ailments or chronic disease

Distrust of conventional medicineDistrust of conventional medicine

Media pressureMedia pressure

Co-responsibility of health professionals… Co-responsibility of health professionals…

Social Perception of Dietary Supplement UseSocial Perception of Dietary Supplement Use

85

34

73

19

49

33

24

0

10

20

30

40

50

60

70

80

90

Ye

s (

%)

Regular users Nonusers

Blendon JB et al. Arch Intern Med. 2001; 161:805-810Blendon JB et al. Arch Intern Med. 2001; 161:805-810

Supplements are Supplements are good for health?good for health?

Access is very Access is very importantimportant

Supplements are Supplements are adequately testedadequately tested

Stop using Stop using if ineffectiveif ineffective

Use of “Antioxidants” among Physicians…Use of “Antioxidants” among Physicians…

44.0

39.0

32.0

19.0

0

5

10

15

20

25

30

35

40

45

Pre

vale

nce

use

rs (

%)

Am J Cardiol. 1997; 79:1558-60Am J Cardiol. 1997; 79:1558-60

AnyAny Vitamin EVitamin E ββ Carotene CaroteneVitamin CVitamin C

Doctor, why should I take

this pill?

It won’t hurt and might

help, so why not take it?

BUT…BUT…

The Beta-Carotene and Retinol Efficacy Trial Beta Carotene + Retinol (Vitamin A)

Lung Cancer IncidenceLung Cancer Incidence MortalityMortality

CARETrial. N Engl J Med. 1996; 334:1150-5CARETrial. N Engl J Med. 1996; 334:1150-5

Miller ER et al. Ann Intern Med 2005;142:37-46Miller ER et al. Ann Intern Med 2005;142:37-46

Vitamin E Supplementation and Mortality

Mortality in Randomized Trials of Mortality in Randomized Trials of Antioxidant SupplementsAntioxidant Supplements

0.7

0.8

0.9

1

1.1

1.2

1.3

Overall BetaCarotene

Vitamin A Vitamin C Vitamin E Selenium

RR

(9

5%

CI) **

*P < .05

****

**

Bielakovic G. JAMA. 2007; 297:842-857Bielakovic G. JAMA. 2007; 297:842-857

……Selene, Moon Goddess…Selene, Moon Goddess…

Physiological Role of SeleniumPhysiological Role of Selenium

Selenium is an essential trace mineralSelenium is an essential trace mineral

Selenium is incorporated as seleno-cysteine (Sec)Selenium is incorporated as seleno-cysteine (Sec)

At least 25 seleno-proteins in humansAt least 25 seleno-proteins in humans

Complex genetic mechanism encoded by the UGA codonComplex genetic mechanism encoded by the UGA codon

Selenium MetabolismSelenium Metabolism

Papp LV. Antioxid. Redox Signal. 2007; 9:775-806Papp LV. Antioxid. Redox Signal. 2007; 9:775-806

Physiological Functions of SeleniumPhysiological Functions of Selenium

Redox Homeostasis Redox Homeostasis

(e.g., glutathione peroxidases, thioredoxin reductases )(e.g., glutathione peroxidases, thioredoxin reductases )

Thyroid Hormone MetabolismThyroid Hormone Metabolism

(iodothyronine 5’-deiodinase)(iodothyronine 5’-deiodinase)

Reproduction/Testosterone BiosynthesisReproduction/Testosterone Biosynthesis

Membrane IntegrityMembrane Integrity

Immune Function/Prostacyclin ProductionImmune Function/Prostacyclin Production

Bioavailability of SeleniumBioavailability of Selenium

Geographical variations in soil selenium contentGeographical variations in soil selenium content

Plant foods are the major dietary sourcesPlant foods are the major dietary sources

Meats, seafood, and bread are common sourcesMeats, seafood, and bread are common sources

55 µg/day: recommended intake (RDA) to optimize GPx activity55 µg/day: recommended intake (RDA) to optimize GPx activity

70-90 µg/L: plasma Se levels to optimize GPx activity70-90 µg/L: plasma Se levels to optimize GPx activity

400 µg/day: tolerable upper intake level (UL)400 µg/day: tolerable upper intake level (UL)

Increasing use of Se-enriched foods and fertilizers Increasing use of Se-enriched foods and fertilizers

Food µg % Daily Value

Brazil nuts, 1 ounce 544 780

Daily Value (DV) for Selenium Daily Value (DV) for Selenium 7070 100100

Tuna, light, canned in oil, drained, 3 ounces 63 95

Beef, cooked, 3½ ounces 35 50

Cod, cooked, 3 ounces 32 45

Turkey, light meat, roasted, 3½ ounces 32 45

Chicken Breast, meat only, roasted, 3½ ounces 20 30

Noodles, enriched, boiled, 1/2 cup 17 25

Macaroni, elbow, enriched, boiled, 1/2 cup 15 20

Egg, whole, 1 medium 14 20

Cottage cheese, low fat 2%, 1/2 cup 12 15

Rice, white, enriched, long grain, cooked, 1/2 cup 12 15

Rice, brown, long-grained, cooked, 1/2 cup 10 15

Bread, enriched, whole wheat, 1 slice 10 15

Dietary Sources of SeleniumDietary Sources of Selenium

High

Good

http://dietary-supplements.info.nih.gov/factsheets/selenium.asp

……Strategies to Increase Selenium Intake…Strategies to Increase Selenium Intake…

Rayman MP. Lancet 2000; 356:233-241Rayman MP. Lancet 2000; 356:233-241

Optimal GPx activity

Dietary Selenium Intake Worldwide (90’s)Dietary Selenium Intake Worldwide (90’s)

Selenium Status in ItalySelenium Status in Italy

Sesana G et al. Sci Total Environ. 1992 ;120:97-102.Sesana G et al. Sci Total Environ. 1992 ;120:97-102.

118.8 μg/L

0

40

80

120

160

200

240

Se-P GPx Se-Met

μμg

sel

eniu

m/L

pla

sma

g s

elen

ium

/L p

lasm

a

US Ave

rage

US Ave

rage

100

µg

100

µg

Se/day

Se/day RDA

RDA

55 µ

g Se/

day

55 µ

g Se/

day

China

China

10

µg S

e/day

10

µg S

e/day

Plasma Selenium and SelenoproteinsPlasma Selenium and Selenoproteins

Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79

High-

Dose

(UL)

High-

Dose

(UL)

400

µg

400

µg

Se/da

y

Se/da

y

Selenium and Human Health Selenium and Human Health Where Did it Begin…? Where Did it Begin…?

Keshan

Keshan Disease Research Group. Chin Med J. 1979; 92:471-476Keshan Disease Research Group. Chin Med J. 1979; 92:471-476

Keshan Disease, Endemic CardiomyopathyKeshan Disease, Endemic Cardiomyopathy

Diseases Related to SeleniumDiseases Related to Selenium

Selenium DeficiencySelenium Deficiency

• Keshan disease (endemic cardiomyopathy)Keshan disease (endemic cardiomyopathy)

• Viral Infections (HIV) and immune diseaseViral Infections (HIV) and immune disease

• Reproduction-related disorders (miscarriage, male infertility)Reproduction-related disorders (miscarriage, male infertility)

Selenium Status/Supplements and Chronic DiseaseSelenium Status/Supplements and Chronic Disease

• Cancer, all-cause mortalityCancer, all-cause mortality

• Cardiovascular diseaseCardiovascular disease

• Metabolic disease: type 2 diabetes, serum lipidsMetabolic disease: type 2 diabetes, serum lipids

Cancer Incidence- Cancer Incidence- MortalityMortality

Geographic Studies: Selenium Levels in Forage Crops*

10% higher cancer mortality for major cancer sites in low-Se areas

*L C Clark et al., 1991

The Nutritional Prevention of The Nutritional Prevention of Cancer (NPC) TrialCancer (NPC) Trial

Clark LC et al. JAMA 1996; 276: 1957-1963Clark LC et al. JAMA 1996; 276: 1957-1963

Arizona Cancer CenterArizona Cancer Center

Selenium Supplementation and Selenium Supplementation and Chronic Disease PreventionChronic Disease Prevention

NPC Study PopulationNPC Study Population

• Multi-center, double-blind, randomized, placebo-controlledMulti-center, double-blind, randomized, placebo-controlled

• 1,312 residents from Eastern United States1,312 residents from Eastern United States

• Previous history of non-melanoma skin cancerPrevious history of non-melanoma skin cancer

• Mean age, 63 years; range, 18-80 years; ¾ malesMean age, 63 years; range, 18-80 years; ¾ males

• 200 μg selenium per day (as selenium yeast)200 μg selenium per day (as selenium yeast) or placeboor placebo

• Blinded phase of the trial: 1983-1996Blinded phase of the trial: 1983-1996

• Compliance: 79.3%Compliance: 79.3%

NPC EndpointsNPC Endpoints

Primary EndpointPrimary Endpoint

• Recurrent skin basal (BCC) and squamous cell (SCC) carcinomasRecurrent skin basal (BCC) and squamous cell (SCC) carcinomas

Secondary EndpointsSecondary Endpoints

• All-cause mortality All-cause mortality

• Total cancer mortalityTotal cancer mortality

• Total and site-specific cancer incidence (lung/prostate/colorectal)Total and site-specific cancer incidence (lung/prostate/colorectal)

• Cardiovascular disease (CVD) incidence and mortalityCardiovascular disease (CVD) incidence and mortality

• Type 2 diabetesType 2 diabetes

Selenium

Placebo

05

01

00

150

200

250

Pla

sm

a s

ele

niu

m (n

g/m

L)

0 12 24 36 48 60 72 84 96 108 120 132 144Months from randomization

Plasma Selenium Concentrations during NPCPlasma Selenium Concentrations during NPC

Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639

NPC Findings: Cancer Incidence NPC Findings: Cancer Incidence (1983-1996, 7.4 years follow-up)(1983-1996, 7.4 years follow-up)

Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639Duffield-Lillico AJ et al. Duffield-Lillico AJ et al. J Natl Cancer Inst. 2003; 95:1477-81J Natl Cancer Inst. 2003; 95:1477-81

CancerCancerCasesCases Adjusted hazard ratios*Adjusted hazard ratios*

SeSe PlaceboPlacebo HRHR 95% CI95% CI PP

Total Cancer IncidenceTotal Cancer Incidence 105105 137137 0.750.75 0.58-0.970.58-0.97 0.030.03

ProstateProstate 2222 4242 0.480.48 0.28-0.800.28-0.80 0.0050.005

ColorectalColorectal 99 1919 0.460.46 0.21-1.020.21-1.02 0.0570.057

Total Cancer MortalityTotal Cancer Mortality 4040 6666 0.590.59 0.39-0.870.39-0.87 0.0080.008

Non-melanoma skinNon-melanoma skin 1.171.17 1.02-1.341.02-1.34 0.030.03

*adjusted for age, gender, and smoking status at randomization*adjusted for age, gender, and smoking status at randomization

NPC Findings: Cancer-Specific NPC Findings: Cancer-Specific (1983-1996, 7.4 years follow-up)(1983-1996, 7.4 years follow-up)

NPC - Total Cancer Incidence NPC - Total Cancer Incidence (1983-1996, 7.4 years follow-up)(1983-1996, 7.4 years follow-up)

Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639

Cases

CasesCases Adjusted hazard ratiosAdjusted hazard ratios

SeSe PlaceboPlacebo HRHR 95% CI95% CI PP P, intP, int

GenderGender

  FemaleFemale 2323 2020 1.201.20 0.66–2.200.66–2.20 0.550.55 0.140.14  MaleMale 8282 117117 0.670.67 0.50–0.890.50–0.89 0.0050.005

Smoking statusSmoking status

  NeverNever 2525 2626 0.810.81 0.47–1.410.47–1.41 0.460.46 0.760.76  FormerFormer 4242 6161 0.660.66 0.44–0.970.44–0.97 0.040.04

  CurrentCurrent 3838 5050 0.860.86 0.56–1.310.56–1.31 0.470.47

By baseline SeBy baseline Se

≤ ≤ 105.2 (ng/ml)105.2 (ng/ml) 2727 5454 0.510.51 0.32–0.810.32–0.81 0.0050.005 0.0070.007105.3–121.6105.3–121.6 3434 4646 0.700.70 0.44–1.090.44–1.09 0.110.11

>121.6 (ng/ml)>121.6 (ng/ml) 4444 3737 1.201.20 0.77–1.860.77–1.86 0.430.43

NPC - Total Cancer Incidence NPC - Total Cancer Incidence (1983-1996, 7.4 years follow-up)(1983-1996, 7.4 years follow-up)

Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639Duffield-Lillico AJ et al. Cancer Epidemiol Biomarkers Prev. 2002; 11:630-639

Cases

Adjusted* HRAdjusted* HR 95% CI95% CI PP P trendP trend

Selenium GroupSelenium Group

By baseline SeBy baseline Se 0.010.01

≤ ≤ 105.2 (ng/ml)105.2 (ng/ml) 1.001.00

105.3–121.6105.3–121.6 1.291.29 0.78–2.150.78–2.15 0.320.32

>121.6 (ng/ml)>121.6 (ng/ml) 1.881.88 1.15–3.051.15–3.05 0.010.01

Placebo GroupPlacebo Group

By baseline SeBy baseline Se 0.200.20

≤ ≤ 105.2 (ng/ml)105.2 (ng/ml) 1.001.00

105.3–121.6105.3–121.6 0.880.88 0.59–1.310.59–1.31 0.520.52

>121.6 (ng/ml)>121.6 (ng/ml) 0.760.76 0.50–1.160.50–1.16 0.200.20*adjusted for age, gender, and smoking status at randomization*adjusted for age, gender, and smoking status at randomization

Int.Int. PlaceboPlacebo RRRR 95% CI95% CI PP P, intP, int

Cancer IncidenceCancer Incidence

OverallOverall 267267 295295 0.900.90 0.76-1.060.76-1.06 0.190.19

GenderGender 0.020.02

  FemaleFemale 179179 171171 1.041.04 0.85-1.290.85-1.29 0.530.53

  MaleMale 8888 124124 0.690.69 0.53-0.910.53-0.91 0.0080.008

Total MortalityTotal Mortality

OverallOverall 7676 9898 0.770.77 0.57-1.000.57-1.00 0.090.09

GenderGender 0.110.11

  FemaleFemale 3636 3535 1.031.03 0.64-1.630.64-1.63 0.920.92

  MaleMale 4040 6363 0.630.63 0.42-0.930.42-0.93 0.020.02

SUMIVAX Trial, FranceSUMIVAX Trial, France 7.5 years follow-up, n=13,0177.5 years follow-up, n=13,017

Hercberg S et al. Arch Intern Med. 2004;164:2335-2342Hercberg S et al. Arch Intern Med. 2004;164:2335-2342

100 μg Selenium +120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc

Selenium Status and Cancer MortalitySelenium Status and Cancer Mortality NHANES III, 13,887 US adultsNHANES III, 13,887 US adults

Bleys J et al. Arch Inter Med. 2008; 168:404-410Bleys J et al. Arch Inter Med. 2008; 168:404-410

Selenium Status and All-Cause MortalitySelenium Status and All-Cause Mortality NHANES III, USNHANES III, US

Bleys J et al. Arch Inter Med. 2008; 168:404-410Bleys J et al. Arch Inter Med. 2008; 168:404-410

CVD CVD Incidence/MortalityIncidence/Mortality

Selenium Status and CVDSelenium Status and CVD Eastern FinlandEastern Finland

2.9

2.2 2.1

0

1

2

3

4

OR

CHD death CVD death MI

Low serum selenium (<45μg/l)

Serum selenium (≥45μg/l)

* *

*

*P < 0.001

Salonen JT et al. Lancet. 1982; 2:175-9Salonen JT et al. Lancet. 1982; 2:175-9

Selenium Status and CVD MortalitySelenium Status and CVD Mortality NHANES III, 13,887 US adultsNHANES III, 13,887 US adults

Bleys J et al. Arch Inter Med. 2008; 168:404-410Bleys J et al. Arch Inter Med. 2008; 168:404-410

Int.Int. PlaceboPlacebo RRRR 95% CI95% CI PP P, intP, int

CHD IncidenceCHD Incidence

OverallOverall 134134 137137 0.970.97 0.77-1.200.77-1.20 0.800.80

GenderGender 0.440.44

  FemaleFemale 2727 2323 1.171.17 0.67-2.050.67-2.05 0.570.57

  MaleMale 107107 114114 0.820.82 0.71-1.200.71-1.20 0.540.54

Antioxidant Supplementation and CHD IncidenceAntioxidant Supplementation and CHD Incidence SUMIVAX Trial, France, 7.5 years follow-upSUMIVAX Trial, France, 7.5 years follow-up

Hercberg S et al. Arch Intern Med. 2004;164:2335-2342Hercberg S et al. Arch Intern Med. 2004;164:2335-2342

100 μg Selenium +120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc

Stranges S et al. Am J Epidemiol 2006; 163:694-699Stranges S et al. Am J Epidemiol 2006; 163:694-699

Selenium Supplementation and Selenium Supplementation and CVD Incidence/MortalityCVD Incidence/Mortality

NPC Trial (1983-1996)NPC Trial (1983-1996)

*adjusted for age, gender, and smoking status at randomization*adjusted for age, gender, and smoking status at randomization

CVDCVDCasesCases Adjusted hazard ratios*Adjusted hazard ratios*

SeSe PlaceboPlacebo HRHR 95% CI95% CI PP

All CVDAll CVD 103103 9696 1.031.03 0.78-1.370.78-1.37 0.810.81

All CHDAll CHD 6363 5959 1.041.04 0.73-1.490.73-1.49 0.810.81

ALL CVAALL CVA 4040 3737 1.021.02 0.65-1.590.65-1.59 0.940.94

CVD MortalityCVD Mortality 4040 3131 1.221.22 0.76-1.950.76-1.95 0.410.41

All-cause MortalityAll-cause Mortality 110110 111111 0.950.95 0.73-1.240.73-1.24 0.710.71

Participants Participants without prevalent CVDwithout prevalent CVD at randomization (n = 1,004) at randomization (n = 1,004)

Mean follow-up: 7.6 yearsMean follow-up: 7.6 years

Stranges S et al. Am J Epidemiol 2006; 163:694-699Stranges S et al. Am J Epidemiol 2006; 163:694-699

*adjusted for age, gender, and smoking status at randomization*adjusted for age, gender, and smoking status at randomization

CVDCVDCasesCases Adjusted hazard ratios*Adjusted hazard ratios*

SeSe PlaceboPlacebo HRHR 95% CI95% CI PP

All CVDAll CVD 5656 6565 0.790.79 0.55-1.140.55-1.14 0.210.21

All CHDAll CHD 4242 4848 0.800.80 0.53-1.220.53-1.22 0.290.29

ALL CVAALL CVA 1414 1717 0.760.76 0.37-1.550.37-1.55 0.450.45

CVD MortalityCVD Mortality 3030 2828 1.061.06 0.63-1.780.63-1.78 0.810.81

All-cause MortalityAll-cause Mortality 4545 5858 0.760.76 0.51-1.120.51-1.12 0.160.16

Participants Participants with prevalent CVDwith prevalent CVD at randomization (n = 246) at randomization (n = 246)

Mean follow-up: 5.5 yearsMean follow-up: 5.5 years

Selenium Supplementation and Selenium Supplementation and Recurrent CVDRecurrent CVD NPC Trial (1983-1996)NPC Trial (1983-1996)

Mateo GF et al. Am J Clin Nutr 2006; 84:762-773Mateo GF et al. Am J Clin Nutr 2006; 84:762-773

Meta-analysis of Trials on Selenium and CHDMeta-analysis of Trials on Selenium and CHD

Type 2 Diabetes/Lipids Type 2 Diabetes/Lipids

Ceriello A, Motz E. ATVB 2004; 24: 816-823Ceriello A, Motz E. ATVB 2004; 24: 816-823

The Common Soil Hypothesis RevisitedThe Common Soil Hypothesis Revisited

Selenium Supplementation Selenium Supplementation and Incidence of Type 2 Diabetes and Incidence of Type 2 Diabetes

NPC Trial (1983-1996)NPC Trial (1983-1996)

• To examine the efficacy of selenium supplementation in To examine the efficacy of selenium supplementation in

the primary prevention of type 2 diabetesthe primary prevention of type 2 diabetes

• 1,202 participants free of type 2 DM at randomization1,202 participants free of type 2 DM at randomization

• Self-reported diagnosis/medical records for type 2 DM Self-reported diagnosis/medical records for type 2 DM

ascertainment (for both incident and prevalent cases)ascertainment (for both incident and prevalent cases)

• 200 μg of selenium/day (n=600) or placebo (n=602)200 μg of selenium/day (n=600) or placebo (n=602)

No difference between treatment groups was statistically significant (P ≤ 0.05)No difference between treatment groups was statistically significant (P ≤ 0.05)

Characteristics of Participants at RandomizationCharacteristics of Participants at Randomization

CharacteristicsCharacteristics SeleniumSelenium PlaceboPlaceboParticipants randomized (no.)Participants randomized (no.) 600600 602602Age, yearsAge, years 63.4 (10.2)63.4 (10.2) 63.0 (9.9)63.0 (9.9)Education, yearsEducation, years 12.9 (3.4)12.9 (3.4) 12.9 (3.3)12.9 (3.3)Gender, males (%)Gender, males (%) 7474 7575Body mass index, kg/mBody mass index, kg/m22 25.6 (3.9)25.6 (3.9) 25.5 (4.1)25.5 (4.1)Smoking status (%)Smoking status (%)

Never Never 34.034.0 30.030.0 FormerFormer 39.039.0 40.040.0 CurrentCurrent 27.027.0 30.030.0Pack-years of smokingPack-years of smoking 56.8 (40.3)56.8 (40.3) 56.6 (39.0)56.6 (39.0)Plasma selenium, ng/mlPlasma selenium, ng/ml

Mean Mean 114.4 (22.6)114.4 (22.6) 114.0 (21.5)114.0 (21.5) 3333rdrd 105.6105.6 104.8104.8 5050thth 113.6113.6 113.2113.2 6666thth 122.4122.4 121.2121.2

Selenium

Placebo

Log-rank test p value = 0.050

0.0

00

.05

0.1

00

.15

Incid

ence

0 5 10 15Years of follow-up

Cumulative Incidence of Type 2 DiabetesCumulative Incidence of Type 2 Diabetes

Stranges S et. al. Ann Intern Med 2007; 147:217-223

Incidence of Type 2 DM by Baseline CharacteristicsIncidence of Type 2 DM by Baseline Characteristics

*mutually adjusted for other baseline covariates*mutually adjusted for other baseline covariates

CasesCases IncidenceIncidence Adjusted hazard ratios*Adjusted hazard ratios*

SeSe PlaceboPlacebo SeSe PlaceboPlacebo HRHR 95% CI95% CI PP P, P, intint

OverallOverall 5858 3939 12.612.6 8.48.4 1.551.55 1.03-2.331.03-2.33 0.030.03

Age (yrs.)Age (yrs.) 0.880.88

6565 2525 1818 9.89.8 6.76.7 1.531.53 0.83-2.820.83-2.82 0.170.17

> 65> 65 3333 2121 15.915.9 10.810.8 1.601.60 0.92-2.760.92-2.76 0.090.09

GenderGender 0.540.54

FemaleFemale 99 88 6.86.8 6.36.3 1.381.38 0.52-3.640.52-3.64 0.510.51

MaleMale 4949 3131 14.814.8 9.29.2 1.621.62 1.04-2.551.04-2.55 0.030.03

CasesCases IncidenceIncidence Adjusted hazard ratios*Adjusted hazard ratios*

SeSe PlaceboPlacebo SeSe PlaceboPlacebo HRHR 95% CI95% CI PP P, P, intint

SmokingSmoking 0.530.53

NeverNever 1515 1212 9.19.1 8.28.2 1.161.16 0.54-2.490.54-2.49 0.700.70

FormerFormer 3030 1818 17.217.2 10.010.0 1.671.67 0.93-3.000.93-3.00 0.090.09

CurrentCurrent 1313 99 10.410.4 6.66.6 1.701.70 0.71-4.000.71-4.00 0.240.24

BMIBMI 0.230.23

< 25< 25 1818 99 7.87.8 3.63.6 2.112.11 0.95-4.720.95-4.72 0.080.08

≥ ≥ 2525 4040 3030 17.517.5 14.714.7 1.251.25 0.78-2.000.78-2.00 0.360.36

*mutually adjusted for other baseline covariates*mutually adjusted for other baseline covariates

Incidence of Type 2 DM by Baseline CharacteristicsIncidence of Type 2 DM by Baseline Characteristics

Incidence of Type 2 DM by Baseline Plasma SeleniumIncidence of Type 2 DM by Baseline Plasma Selenium

*adjusted for age, BMI, gender, and smoking status at randomization*adjusted for age, BMI, gender, and smoking status at randomization

CasesCases IncidenceIncidence Adjusted hazard ratios*Adjusted hazard ratios*

SeSe PlaceboPlacebo SeSe PlaceboPlacebo HRHR 95% CI95% CI PP P, P, intint

By medianBy median 0.0280.028

113.4 113.4 2626 2525 11.111.1 10.710.7 1.041.04 0.60-1.800.60-1.80 0.890.89

> 113.4> 113.4 3232 1414 14.114.1 6.16.1 2.502.50 1.32-4.771.32-4.77 0.0050.005

By tertilesBy tertiles 0.0380.038

105.2105.2 1818 1818 11.611.6 11.311.3 1.131.13 0.58-2.180.58-2.18 0.720.72

105.3-1105.3-121.621.6 1414 1010 8.88.8 6.56.5 1.361.36 0.60-3.090.60-3.09 0.630.63

> 121.6> 121.6 2626 1111 17.517.5 7.37.3 2.702.70 1.30-5.611.30-5.61 0.0080.008

Summary of ResultsSummary of Results

• No benefit from selenium supplementation on type 2 DMNo benefit from selenium supplementation on type 2 DM

• Potential adverse effects of long-term se supplementationPotential adverse effects of long-term se supplementation

• Higher risk of type 2 DM at higher selenium concentrationsHigher risk of type 2 DM at higher selenium concentrations

client.dssimon.com/viewvideo/acp28.wmv

LimitationsLimitations

• Diabetes incidence was not a primary end-point of the trialDiabetes incidence was not a primary end-point of the trial

• Small number of diabetes cases Small number of diabetes cases

• Self-reported diagnosisSelf-reported diagnosis

• Lack of biomarkers of glucose metabolismLack of biomarkers of glucose metabolism

• Lack of additional potential confounders Lack of additional potential confounders

• Selected nature of participants (elderly, eastern US)Selected nature of participants (elderly, eastern US)

StrengthsStrengths

• Only trial with a long-term selenium supplementationOnly trial with a long-term selenium supplementation

• High compliance with the intervention (80.3% s, 78.4% p)High compliance with the intervention (80.3% s, 78.4% p)

Se-Quintile 1 Se-Quintile 1 (<111.62 ng/ml)(<111.62 ng/ml)

Se-Quintile 5 Se-Quintile 5 (137.66 ng/ml)(137.66 ng/ml)

Cases/non-casesCases/non-cases 285/1,708285/1,708 311/1,266311/1,266

Fully-adjusted ORFully-adjusted OR 1.00 (reference)1.00 (reference) 1.57 (1.16–2.13)1.57 (1.16–2.13)

Selenium Status and Selenium Status and Prevalent DiabetesPrevalent Diabetes NHANES III, 8,876 US adultsNHANES III, 8,876 US adults

Bleys J et al. Diabetes Care. 2007; 30:829-834Bleys J et al. Diabetes Care. 2007; 30:829-834

Antioxidant Supplementation and Antioxidant Supplementation and Glucose LevelsGlucose Levels SUMIVAX Trial, France, 7.5 years follow-up, n=3,146SUMIVAX Trial, France, 7.5 years follow-up, n=3,146

Czernichow S et al. Am J Clin Nutr. 2006; 84:395-399Czernichow S et al. Am J Clin Nutr. 2006; 84:395-399

100 μg Selenium +120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc

Baseline Plasma concentrationBaseline Plasma concentration β β ± SE± SE PP

        ß-carotene, 0.5 µmol/Lß-carotene, 0.5 µmol/L ––0.032 ± 0.0080.032 ± 0.008 <0.0001<0.0001

        Vitamin C, 4.9 µg/mLVitamin C, 4.9 µg/mL ––0.015 ± 0.0070.015 ± 0.007 0.04550.0455

        Vitamin E, 7.7 µmol/LVitamin E, 7.7 µmol/L 0.005 ± 0.0070.005 ± 0.007 0.51640.5164

        Selenium, 0.2 µmol/LSelenium, 0.2 µmol/L 0.030 ± 0.0080.030 ± 0.008 <0.0001<0.0001

        Zinc, 1.8 µmol/LZinc, 1.8 µmol/L ––0.002 ± 0.0080.002 ± 0.008 0.81080.8108

Antioxidant Supplementation and Antioxidant Supplementation and LipidsLipids SUMIVAX Trial, France, 7.5 years follow-up, n=12,741SUMIVAX Trial, France, 7.5 years follow-up, n=12,741

Hercberg S et al. Lipids. 2005; Hercberg S et al. Lipids. 2005; 40:335-4240:335-42

100 μg Selenium +120 mg Vitamin C, 30 mg Vitamin E, 6 mg of β-carotene, 20 mg of zinc

LipidsLipids Suppl vs. PlaceboSuppl vs. Placebo PP

Mean CholesterolMean Cholesterol No differenceNo difference

HypercholesterolemiaHypercholesterolemia Higher in Suppl (women)Higher in Suppl (women) <0.05<0.05

Mean triglycerides Higher in Suppl (both sexes)Higher in Suppl (both sexes) <0.05<0.05

HypertriglyceridemiaHypertriglyceridemia Higher in Suppl (men)Higher in Suppl (men) <0.05<0.05

Selenium Status and Selenium Status and LipidsLipids NHANES III, 5,452 US adultsNHANES III, 5,452 US adults

Bleys J, Navas-Acien A, Stranges S et al. Am J Clin Nutr. 2008; 88:416-23 Bleys J, Navas-Acien A, Stranges S et al. Am J Clin Nutr. 2008; 88:416-23

Total CholesterolApolipoprotein A1LDL-cholesterolTriglyceridesApolipoprotein BHDL-cholesterol

4.8

5

5.2

5.4

5.6

5.8

mm

ol/L

UK US

Q1 <77.4

Q4 ≥95.6

Q1 <113.7

Q4 ≥134.7

Selenium Quartiles Selenium Quartiles (µg/L)(µg/L)

Stranges S et al. (under review)

Total Cholesterol by Se Quartiles: UK NDNS 2000/01; US NHANES III

Selenium Status and CVD Risk FactorsSelenium Status and CVD Risk Factors Olivetti Heart StudyOlivetti Heart Study

Jossa F et al. Atherosclerosis. 1991; 87:129-34 Jossa F et al. Atherosclerosis. 1991; 87:129-34

Biological PlausibilityBiological Plausibility

Rayman MP. Lancet 2000; 356:233-241Rayman MP. Lancet 2000; 356:233-241

Selenium Status in the NPC Trial vs. EuropeSelenium Status in the NPC Trial vs. Europe

0

40

80

120

160

200

Se-P GPx Se-Met

µg

sel

eniu

m/L

pla

sma

µg

sel

eniu

m/L

pla

sma

US Ave

rage

US Ave

rage

100

µg

100

µg

Se/day

Se/day US R

DA

US RDA

5

5 µg

5

5 µg

Se/day

Se/day

China

China

10

µg S

e/day

10

µg S

e/day

Plasma Selenium and SelenoproteinsPlasma Selenium and Selenoproteins

Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79Modified from Burk RF. Nutr Clin Care. 2002; 5:75-79

NPC - Dos

e

NPC - Dos

e

200

µg

200

µg

Se/da

y

Se/da

y

Humans

• Narrow therapeutic window of seleniumNarrow therapeutic window of selenium

• Inter-individual variability in selenium metabolismInter-individual variability in selenium metabolism

• Pro-oxidative/apoptotic effects (methylselenol, ROS), which Pro-oxidative/apoptotic effects (methylselenol, ROS), which

largely account for the Se-induced anti-cancer effectslargely account for the Se-induced anti-cancer effects

• Hypothyroidism/body weight gain in high-selenium dietsHypothyroidism/body weight gain in high-selenium diets

• Adverse effects on growth hormone metabolism (low Adverse effects on growth hormone metabolism (low IGF-1)IGF-1)

• Upregulation of genes (FoXO) involved in insulin metabolismUpregulation of genes (FoXO) involved in insulin metabolism

Animal Models

• Over-expression of glutathione peroxidase activityOver-expression of glutathione peroxidase activity

• Enzyme over-expression may cause insulin resistanceEnzyme over-expression may cause insulin resistance

• Release of glucagon with hyperglycemia at high dosesRelease of glucagon with hyperglycemia at high doses

• Insulin-mimetic activities at low dosesInsulin-mimetic activities at low doses

• Selenium may accumulate in the pancreatic tissueSelenium may accumulate in the pancreatic tissue

PerspectivesPerspectives

• Balance of benefits and harms of selenium supplementationBalance of benefits and harms of selenium supplementation

• Consider dietary intake/selenium status of different populationsConsider dietary intake/selenium status of different populations

• Subtle toxicity for chronic high exposure Subtle toxicity for chronic high exposure

• Need to establish the optimal selenium intake to minimize risksNeed to establish the optimal selenium intake to minimize risks

• Need for mechanistic studies/randomized trialsNeed for mechanistic studies/randomized trials

• High-quality prospective studies across different countriesHigh-quality prospective studies across different countries

• Concern on the widespread use of selenium supplementsConcern on the widespread use of selenium supplements

Benefits and Harms of Benefits and Harms of Selenium SupplementationSelenium Supplementation

DiseaseDisease BenefitsBenefits HarmsHarmsOverall MortalityOverall Mortality UnprovedUnproved

Cancer IncidenceCancer Incidence

TotalTotal PossiblePossible

ProstateProstate PossiblePossible

ColorectalColorectal PossiblePossible

Non-melanoma SkinNon-melanoma Skin PossiblePossible

Cardio-metabolic Cardio-metabolic

CVDCVD UnprovedUnproved

Type 2 DiabetesType 2 Diabetes PossiblePossible

HyperlipidemiaHyperlipidemia PossiblePossible

Type 2 Diabetes

Prostate Cancer

Selenium ??++

--

0

0.2

0.4

0.6

0.8

1

1.2

OR

ProstateCancer

Low grade High grade

Non-diabetics

Diabetics

……Diabetes and Prostate Cancer Risk…Diabetes and Prostate Cancer Risk…

Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2006; 15:1977-83 Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2006; 15:1977-83

*P < 0.001

****

**- 47%- 47%- 28%- 28%

……Diabetes and Prostate Cancer Risk…Diabetes and Prostate Cancer Risk…

Hsing AW et al. Am J Clin Nutr 2007;86:843S-857SHsing AW et al. Am J Clin Nutr 2007;86:843S-857S

SelSeleniumenium and Vitaminand Vitamin EE CCancer Preventionancer Prevention TTrialrial (SELECT) (SELECT)

Cost: $175,000,000

Vitamin EVitamin E(400 (400 μμg/day)g/day)

SeleniumSelenium(200 (200 μμg/day)g/day)

++ -- TT

++

--

8,1008,100 8,1008,100 16,20016,200

16,20016,2008,1008,100 8,1008,100

TT 16,20016,200 16,20016,200 32,40032,400

http://www.cancer.gov/newscenter/pressreleases/SELECTresults2008

Review of Prostate Cancer Prevention Study Shows No Benefit for Use of Selenium and Vitamin E Supplements

Initial, independent review of study data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), funded by the National Cancer Institute (NCI) and other institutes that comprise the National Institutes of Health shows that selenium and vitamin E supplements, taken either alone or together, did not prevent prostate cancer.

The data also showed two concerning trends: a small but not statistically significant increase in the number of prostate cancer cases among the over 35,000 men age 50 and older in the trial taking only vitamin E and a small, but not statistically significant increase in the number of cases of adult onset diabetes in men taking only selenium.

Because this is an early analysis of the data from the study, neither of these findings proves an increased risk from the supplements and both may be due to chance.

Keshan

The Nutritional Prevention of The Nutritional Prevention of Cancer (NPC) TrialCancer (NPC) Trial

AcknowledgmentsAcknowledgments

James R MarshallJames R Marshall

Mary E Reid Mary E Reid

Raj NatarajanRaj Natarajan

Gerald F CombsGerald F Combs

Larry C ClarkLarry C Clark††

Richard P DonahueRichard P Donahue

Joan M DornJoan M Dorn

Jo L FreudenheimJo L Freudenheim

Maurizio TrevisanMaurizio Trevisan

Ana Navas-AcienAna Navas-Acien

Joachim BleysJoachim Bleys

Eliseo GuallarEliseo Guallar