Effect of long-term selenium supplementation on mortality

Results from a multiple-dose, randomised controlled trial

Margaret P. Rayman, Kristian Hillert Winther, Roberto Pastor-Barriuso, Frederick Cold, Marianne Thvilum, Saverio Stranges, Eliseo Guallar, Søren Cold

Research output: Contribution to journalArticle

Abstract

Background: Selenium, an essential trace element, is incorporated into selenoproteins with a wide range of health effects. Selenoproteins may reach repletion at a plasma selenium concentration of ∼ 125 μg/L, at which point the concentration of selenoprotein P reaches a plateau; whether sustained concentrations higher than this are beneficial, or indeed detrimental, is unknown. Objective: In a population of relatively low selenium status, we aimed to determine the effect on mortality of long-term selenium supplementation at different dose levels. Design: The Denmark PRECISE study was a single-centre, randomised, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. Participants were 491 male and female volunteers aged 60-74 years, recruited at Odense University Hospital, Denmark. The trial was initially designed as a 6-month pilot study, but supplemental funding allowed for extension of the study and mortality assessment. Participants were randomly assigned to treatment with 100, 200, or 300 μg selenium/d as selenium-enriched-yeast or placebo-yeast for 5 years from randomization in 1998-1999 and were followed up for mortality for a further 10 years (through March 31, 2015). Results: During 6871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis, the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 μg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 μg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar. Conclusions: A 300 μg/d dose of selenium taken for 5 years in a country with moderately-low selenium status increased all-cause mortality 10 years later. While our study was not initially designed to evaluate mortality and the sample size was limited, our findings indicate that total selenium intake over 300 μg/d and high-dose selenium supplements should be avoided.

Original languageEnglish (US)
JournalFree Radical Biology and Medicine
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Selenium
Randomized Controlled Trials
Mortality
Selenoproteins
Placebos
Denmark
Yeast
trichostatin A
Selenoprotein P
Yeasts
Withholding Treatment
Intention to Treat Analysis
Trace Elements
Random Allocation
Sample Size
Volunteers
Hazards
Health
Clinical Trials
Confidence Intervals

Keywords

  • Cancer mortality
  • Cardiovascular mortality
  • Denmark PRECISE
  • Mortality
  • Plasma selenium concentration
  • Randomised controlled trial
  • Selenium
  • Selenium dose
  • Selenium intake
  • Selenium toxicity

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Effect of long-term selenium supplementation on mortality : Results from a multiple-dose, randomised controlled trial. / Rayman, Margaret P.; Winther, Kristian Hillert; Pastor-Barriuso, Roberto; Cold, Frederick; Thvilum, Marianne; Stranges, Saverio; Guallar, Eliseo; Cold, Søren.

In: Free Radical Biology and Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Rayman, Margaret P. ; Winther, Kristian Hillert ; Pastor-Barriuso, Roberto ; Cold, Frederick ; Thvilum, Marianne ; Stranges, Saverio ; Guallar, Eliseo ; Cold, Søren. / Effect of long-term selenium supplementation on mortality : Results from a multiple-dose, randomised controlled trial. In: Free Radical Biology and Medicine. 2018.
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abstract = "Background: Selenium, an essential trace element, is incorporated into selenoproteins with a wide range of health effects. Selenoproteins may reach repletion at a plasma selenium concentration of ∼ 125 μg/L, at which point the concentration of selenoprotein P reaches a plateau; whether sustained concentrations higher than this are beneficial, or indeed detrimental, is unknown. Objective: In a population of relatively low selenium status, we aimed to determine the effect on mortality of long-term selenium supplementation at different dose levels. Design: The Denmark PRECISE study was a single-centre, randomised, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. Participants were 491 male and female volunteers aged 60-74 years, recruited at Odense University Hospital, Denmark. The trial was initially designed as a 6-month pilot study, but supplemental funding allowed for extension of the study and mortality assessment. Participants were randomly assigned to treatment with 100, 200, or 300 μg selenium/d as selenium-enriched-yeast or placebo-yeast for 5 years from randomization in 1998-1999 and were followed up for mortality for a further 10 years (through March 31, 2015). Results: During 6871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis, the hazard ratio (95{\%} confidence interval) for all-cause mortality comparing 300 μg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 μg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar. Conclusions: A 300 μg/d dose of selenium taken for 5 years in a country with moderately-low selenium status increased all-cause mortality 10 years later. While our study was not initially designed to evaluate mortality and the sample size was limited, our findings indicate that total selenium intake over 300 μg/d and high-dose selenium supplements should be avoided.",
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AU - Winther, Kristian Hillert

AU - Pastor-Barriuso, Roberto

AU - Cold, Frederick

AU - Thvilum, Marianne

AU - Stranges, Saverio

AU - Guallar, Eliseo

AU - Cold, Søren

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N2 - Background: Selenium, an essential trace element, is incorporated into selenoproteins with a wide range of health effects. Selenoproteins may reach repletion at a plasma selenium concentration of ∼ 125 μg/L, at which point the concentration of selenoprotein P reaches a plateau; whether sustained concentrations higher than this are beneficial, or indeed detrimental, is unknown. Objective: In a population of relatively low selenium status, we aimed to determine the effect on mortality of long-term selenium supplementation at different dose levels. Design: The Denmark PRECISE study was a single-centre, randomised, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. Participants were 491 male and female volunteers aged 60-74 years, recruited at Odense University Hospital, Denmark. The trial was initially designed as a 6-month pilot study, but supplemental funding allowed for extension of the study and mortality assessment. Participants were randomly assigned to treatment with 100, 200, or 300 μg selenium/d as selenium-enriched-yeast or placebo-yeast for 5 years from randomization in 1998-1999 and were followed up for mortality for a further 10 years (through March 31, 2015). Results: During 6871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis, the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 μg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 μg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar. Conclusions: A 300 μg/d dose of selenium taken for 5 years in a country with moderately-low selenium status increased all-cause mortality 10 years later. While our study was not initially designed to evaluate mortality and the sample size was limited, our findings indicate that total selenium intake over 300 μg/d and high-dose selenium supplements should be avoided.

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KW - Selenium dose

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KW - Selenium toxicity

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