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. Author manuscript; available in PMC: 2014 Sep 27.
Published in final edited form as: Cochrane Database Syst Rev. 2012 Feb 15;2012(2):CD009671. doi: 10.1002/14651858.CD009671

Selenium supplementation for the primary prevention of cardiovascular disease

Karen Rees 1, Louise Hartley 1, Camilla Day 2, Aileen Clarke 1, Saverio Stranges 1
PMCID: PMC4176632  EMSID: EMS58721  PMID: 25267917

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The primary objective is to determine the effectiveness of selenium only supplementation for the primary prevention of CVD. We will also determine potential adverse effects of selenium only supplementation on major CVD risk factors, such as blood pressure, blood lipids and type 2 diabetes. Results will be stratified by baseline selenium status and country where possible, as well as by selenium dosage.

BACKGROUND

Description of the condition

Cardiovascular disease (CVD) is still the number one cause of death and disability worldwide (WHO 2011). The burden of disease will increase with an aging population and increasing levels of obesity and sedentary lifestyles. Prevention of CVD by targeting modifiable factors remains a key public health priority. Diet plays a major role in the aetiology of many chronic diseases including CVD, thereby contributing to a significant geographical variability in morbidity and mortality rates across different countries and populations worldwide (WHO 2003).

Selenium is a trace element essential to humans and is currently the focus of major scientific debate and investigation (Rayman 2009;Stranges 2010a). A recent Cochrane systematic review (Dennert 2011) examining the effect of selenium in the prevention of cancer found that from observational studies people with higher selenium levels or intake had a lower frequency of certain cancers (such as bladder or prostate cancer) but results from trials of selenium supplementation were inconsistent. For CVD, a number of observational studies have examined the association between selenium status and risk of coronary heart disease (CHD) and other CVD endpoints across different populations (Bleys 2008; Bleys 2009;Flores-Mateo 2006; Salonen 1982; Virtamo 1985; Wei 2004). Although some of the early studies suggest possible inverse associations, especially in populations with relatively low dietary selenium intakes (Flores-Mateo 2006; Salonen 1982; Virtamo 1985;Wei 2004), more recent observational evidence is suggestive of a possible U-shaped association between selenium status and CVD risk, at least in selenium-replete populations such as that of the United States (US) (Bleys 2008; Bleys 2009).

Results from randomised controlled trials of selenium supplementation do not however provide conclusive evidence to support a role for selenium in CVD disease prevention (Brown 2001;Flores-Mateo 2006; Hercberg 2004; Korpela 1989; Kuklinski 1994; Stranges 2006; You 2001). In a post-hoc analysis from the Nutritional Prevention of Cancer (NPC) trial in the US (Stranges 2006), selenium supplementation alone (200 μg/day as high-selenium yeast) was not significantly associated with any of the CVD endpoints after 7.6 years of follow-up. Other randomised controlled trials that have examined the effect of selenium in combination with other vitamins or minerals on CVD endpoints have also yielded inconclusive findings (Brown 2001; Hercberg 2004;Korpela 1989; Kuklinski 1994; You 2001).

There is some evidence of potential adverse effects of selenium supplementation. Recent findings from observational studies and randomised controlled trials have raised concerns that high selenium exposure may lead to adverse cardio-metabolic effects, at least in selenium-replete populations, such as an increased risk of diabetes, hypertension and hyperlipidemia (Laclaustra 2009;Stranges 2007; Stranges 2010b). For example, in a post-hoc analysis of the NPC trial in the Eastern US (Stranges 2007), supplementation with selenium alone (200 μg/day as high-selenium yeast) increased the risk of type 2 diabetes compared to placebo, particularly in men and in participants with high baseline plasma selenium (hazard ratio of 2.70 in the highest tertile of plasma selenium, i.e. >121.6 ng/ml). In addition, the recent Cochrane review examining the effect of selenium for the prevention of cancer also highlighted the potential adverse effects of selenium supplementation notably gastrointestinal upset, alopecia, and an increased risk of Type 2 diabetes (Dennert 2011).

Description of the intervention

The intervention to be examined in this review is selenium supplementation as a single ingredient. Selenium is a key component of a number of selenoproteins involved in essential enzymatic functions such as redox homeostasis, thyroid hormone metabolism, immunity and reproduction (Burk 2002; Papp 2007). Because of the potential of these selenoproteins to protect against oxidative stress, significant expectations were raised for the prevention of several chronic diseases commonly associated with oxidative stress including cancer, CVD, and type 2 diabetes (Combs 1998; Neve 1996; Rayman 2000).

How the intervention might work

In theory, potential CVD benefits of selenium supplements are supported by the ability of selenoproteins such as glutathione peroxidase (GPx) and selenoprotein S to combat the oxidative modification of lipids, inhibit platelet aggregation and reduce inflammation (Blankenberg 2003; Brigelius-Flohe 2003; Curran 2005;Gao 2006; Neve 1996; Salonen 1988; Sattler 1994; Vunta 2007). However, selenium has a narrow therapeutic window and there is considerable inter-individual variability in terms of metabolic sensitivity and optimal selenium intake (Whanger 1996). Part of the inconsistencies in the effect of selenium supplements on cardiometabolic outcomes in different studies might be explained by the variability of selenium status and selenium intake across countries and population subgroups (Rayman 2009; Stranges 2010a). In this view, the association between selenium and cardio-metabolic outcomes is likely to be U-shaped with potential harm occurring at selenium levels both below and above the physiological range for optimal activity of selenoproteins. For example, recent findings from the UK PRECISE Pilot trial among 501 elderly volunteers with relatively low selenium status showed that supplementation with selenium alone at 100 and 200 mg/d significantly decreased total and non-HDL cholesterol concentrations, and that the ratio of total-to-HDL cholesterol decreased progressively with increasing selenium doses (Rayman 2011).

Why it is important to do this review

Use of selenium enriched foods, supplements and fertilizers has increased markedly in recent years in the US and other Western countries (Broadley 2006; Millen 2004; Rayman 1997), because of the perception that the anti-oxidant properties of selenium could potentially reduce the risk of cancer, CVD and other chronic diseases. Given the recent findings on potential adverse effects of high selenium exposure (Laclaustra 2009; Stranges 2007; Stranges 2010b), from a public health perspective the relationship between selenium status and CVD health should be clarified in order to help guide consumers in their choices of nutritional supplements and enriched food products. There has been no published systematic review on the effect of selenium only supplements on the primary prevention of CVD.

OBJECTIVES

The primary objective is to determine the effectiveness of selenium only supplementation for the primary prevention of CVD. We will also determine potential adverse effects of selenium only supplementation on major CVD risk factors, such as blood pressure, blood lipids and type 2 diabetes. Results will be stratified by baseline selenium status and country where possible, as well as by selenium dosage.

METHODS

Criteria for considering studies for this review

Types of studies

Randomised controlled trials

Types of participants

Adults of all ages from the general population and those at high risk of CVD. This review will focus on the effects of selenium supplementation on the primary prevention of CVD. We will exclude those who have experienced a previous myocardial infarction (MI), stroke, revascularisation procedure (coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA)), those with angina, or angiographically defined coronary heart disease (CHD).

Types of interventions

The intervention will be selenium only supplementation as a single ingredient. Multivitamin/mineral preparations including selenium will be excluded, as it would be impossible to disentangle selenium-specific effect from those derived by other micronutrients. Baseline selenium status is likely to influence the effect of selenium supplementation on cardiovascular outcomes (Rayman 2009; Stranges 2010a), so results will be analysed by baseline selenium status and country where possible, as well as by selenium dosage and duration of the intervention.

Trials will only be considered where the comparison group is placebo or no intervention. We will focus on follow-up periods of 6 months or more as these are most relevant for public health interventions.

Types of outcome measures

Primary outcomes

Major CVD end-points: CVD, non-fatal myocardial infarction (MI), non-fatal stroke, and revascularization procedures (CABG or PCTA).

Secondary outcomes
  • -

    Total mortality

  • -

    CHD composite end-point: fatal CHD, non-fatal MI, or CABG or PCTA

  • -

    Stroke composite end-point: fatal and non-fatal stroke

  • -

    Peripheral artery disease

  • -

    Type-2 diabetes*

  • -

    Changes in levels of blood pressure and blood lipids

* This outcome will be used as a potential side-effect of selenium. Other adverse effects will be noted and data will be collected on costs where available.

Search methods for identification of studies

Electronic searches

The following electronic databases will be searched: MEDLINE, EMBASE, PsycINFO, CINAHL, the Web of Science (Science Citation Index Expanded (SCI-EXPANDED), Social Sciences Citation Index (SSCI), Conference Proceedings Citation Index - Science (CPCI-S)) and the Cochrane Library (including the Cochrane Central Register of Controlled Trials (CENTRAL) and NHS Centre for Reviews and Dissemination (CRD) databases Health Technology Assessment (HTA), Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database (NEED)).

Medical subject headings (MeSH) or equivalent and text word terms will be used. The Cochrane sensitive-maximising RCT filter will be used Lefebvre 2011. There will be no language restrictions. Searches will be tailored to individual databases. The search strategy for MEDLINE is shown in Appendix 1.

Searching other resources

In addition, reference lists of reviews and retrieved articles will be checked for additional studies.

We will search the metaRegister of controlled trials (mRCT) (www.controlled-trials.com/mrct), Clinicaltrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/) for ongoing trials.

Citation searches will be performed on key articles. Google Scholar will also be used to search for further studies. Experts in the field will be contacted for unpublished and ongoing trials. Authors will be contacted where necessary for additional information.

Data collection and analysis

Selection of studies

From the searches, the title and abstract of each paper will be reviewed by two reviewers (KR, LH) and potentially relevant references retrieved. Following this initial screening, the full text reports of potentially relevant studies will be obtained, and two reviewers (KR, LH) will independently select studies to be included in the review using predetermined inclusion criteria. In all cases disagreements about any study inclusions will be resolved by consensus and a third reviewer will be consulted if disagreement persists.

Data extraction and management

Data will be extracted independently by two reviewers (KR, LH) using a proforma and chief investigators will be contacted to provide additional relevant information if necessary. Details of the study design, participant characteristics, study setting, intervention (including dose and duration), and outcome data including details of outcome assessment, adverse effects, and methodological quality (randomisation, blinding, attrition) will be extracted from each of the included studies. Disagreements about extracted data will be resolved by consensus and a third reviewer will be consulted if disagreement persists.

Assessment of risk of bias in included studies

Risk of bias will be assessed by examining the quality of the random sequence generation and allocation concealment, description of drop-outs and withdrawals (including analysis by intention-to-treat), blinding (participants, personnel and outcome assessment) and selective outcome reporting (Higgins 2011). The risk of bias in included studies will be assessed independently by two reviewers (KR, LH).

Measures of treatment effect

Data will be processed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Dichotomous outcomes will be expressed as odds ratios or relative risks, and 95% confidence intervals (CI) will be calculated for each study. For continuous variables net changes will be compared (i.e. intervention group minus control group differences) and a weighted mean difference (WMD) or standardised mean difference (SMD) and 95% CIs will be calculated for each study.

Assessment of heterogeneity

For each outcome tests of heterogeneity will be carried out (using the chi-squared test of heterogeneity and I2 statistic). In the situation of no heterogeneity a fixed effect meta-analysis will be performed. If substantial heterogeneity is detected the reviewers will look for possible explanations for this (e.g. participants and intervention). If the heterogeneity cannot be explained, the reviewers will consider the following options: provide a narrative overview and not aggregate the studies at all, or use a random effects model with appropriate cautious interpretation.

Subgroup analysis and investigation of heterogeneity

If there are sufficient trials, results will be stratified according to baseline selenium status and country, and selenium dosage.

Sensitivity analysis

Sensitivity analyses will be carried out excluding studies of low methodological quality. If there are sufficient trials, funnel plots and tests of asymmetry (Egger 1997) will be undertaken to assess possible publication bias.

ACKNOWLEDGEMENTS

No acknowledgements at the protocol stage.

SOURCES OF SUPPORT

Internal sources

  • Warwick Medical School, University of Warwick, UK.

External sources

  • NIHR Cochrane Programme Grant, UK.

APPENDICES

Appendix 1. MEDLINE search strategy

MEDLINE (OVID)

  1. Selenium/

  2. exp Selenium Compounds/

  3. selen*.tw.

  4. selepen.tw.

  5. 80Se.tw.

  6. SeO3.tw.

  7. SeO4.tw.

  8. or/1-7

  9. exp Cardiovascular Diseases/

  10. cardio*.tw.

  11. cardia*.tw.

  12. heart*.tw.

  13. coronary*.tw.

  14. angina*.tw.

  15. ventric*.tw.

  16. myocard*.tw.

  17. pericard*.tw.

  18. isch?em*.tw.

  19. emboli*.tw.

  20. arrhythmi*.tw.

  21. thrombo*.tw.

  22. atrial fibrillat*.tw.

  23. tachycardi*.tw.

  24. endocardi*.tw.

  25. (sick adj sinus).tw.

  26. exp Stroke/

  27. (stroke or stokes).tw.

  28. cerebrovasc*.tw.

  29. cerebral vascular.tw.

  30. apoplexy.tw.

  31. (brain adj2 accident*).tw.

  32. ((brain* or cerebral or lacunar) adj2 infarct*).tw.

  33. exp Hypertension/

  34. hypertensi*.tw.

  35. peripheral arter* disease*.tw.

  36. ((high or increased or elevated) adj2 blood pressure).tw.

  37. exp Hyperlipidemias/

  38. hyperlipid*.tw.

  39. hyperlip?emia*.tw.

  40. hypercholesterol*.tw.

  41. hypercholester?emia*.tw.

  42. hyperlipoprotein?emia*.tw.

  43. hypertriglycerid?emia*.tw.

  44. exp Diabetes Mellitus/

  45. diabet*.tw.

  46. or/9-45

  47. 8 and 46

  48. randomized controlled trial.pt.

  49. controlled clinical trial.pt.

  50. randomized.ab.

  51. placebo.ab.

  52. drug therapy.fs.

  53. randomly.ab.

  54. trial.ab.

  55. groups.ab.

  56. 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55

  57. exp animals/not humans.sh.

  58. 56 not 57

  59. 47 and 58

HISTORY

Protocol first published: Issue 2, 2012

Footnotes

DECLARATIONS OF INTEREST

None known.

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  • * Indicates the major publication for the study

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