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Dietary Supplements, Selenium and Chronic Disease Prevention. Saverio Stranges, MD, PhD Clinical Sciences Research Institute University of Warwick Medical School, UK. Outline. Context on Dietary Supplements Physiological Role of Selenium Selenium and Human Health Perspectives. - PowerPoint PPT Presentation
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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