Selenium was thought to have a role in cardiovascular disease (CVD) owing to its antioxidant properties; however, evidence from observational studies and randomized controlled trials (RCTs) has been inconsistent and controversial. We thus conducted a meta-analysis to assess the discrepancies between observational and randomized trial evidence.
We searched MEDLINE and EMBASE for eligible prospective studies regarding the relationship between selenium and CVD up to 15 December 2013 and finally included 16 prospective observational studies and 16 RCTs. Random effects model was used to estimate the pooled relative risk (RR). Generalized least-squares trend test and restricted cubic spline model were performed to assess a linear and a nonlinear dose–response relationship.
Our meta-analysis of prospective studies showed a nonlinear relationship of CVD risk with blood selenium concentrations across a range of 30–165 μg/l and a significant benefit of CVD within a narrow selenium range of 55–145 μg/l. Our meta-analyses of RCTs showed that oral selenium supplements (median dose: 200 μg/day) for 2 weeks to 144 months significantly raised the blood selenium concentrations by 56.4 μg/l (95% confidence interval (CI): 40.9, 72.0 μg/l), whereas oral selenium supplements (median: 100 μg/day) for 6 to 114 months caused no effect on CVD (RR=0.91; 95% CI: 0.74, 1.10).
Our meta-analysis in prospective studies demonstrated a significant inverse association between selenium status and CVD risk within a narrow selenium range and a null effect of selenium supplementation on CVD was observed in RCTs. These findings indicate the importance of considering selenium status, dose and safety in health assessment and future study design.
Selenium exerts its biological functions on redox signaling, antioxidant defense, immune response and thyroid hormone function mainly via selenium-dependent glutathione peroxidases (GPx) and other selenoproteins.1, 2, 3, 4 Adequate intake of selenium may be beneficial for cardiovascular disease (CVD), cancer and other chronic diseases.5, 6 Food is the primary source of selenium contents in the human body; however, dietary selenium intake varies widely and primarily depends on the soil on which crops and fodder are grown.7 Selenium was added to various dietary supplements as a popular supplement,5 although the prevention effects on CVD have not been confirmed.
There is a long-standing interest in the CVD research community regarding the potential yet unproven benefits or risks of selenium intake on the development and progression of CVD. There were largely divergent results between the observational studies and randomized controlled trials (RCTs). Earlier retrospective case–control studies showed that the blood selenium concentrations of CVD patients were lower than those of the healthy population, indicating an inverse correlation.8, 9 A significant inverse association between selenium status and risk of coronary heart disease was reported in a meta-analysis of 25 observational studies,8 yet there has been little research on whether there is a threshold effect for the relationship between selenium concentrations and CVD events. Individual observational studies have shown inconsistent findings and have not fully considered the possible nonlinear relationship. In addition, influence by other antioxidants cannot be ruled out in observational studies. Well-designed and well-conducted RCTs, as the most reliable design strategy, can avoid most of the biases inherent in observational studies and help evaluate a possible causal relation. However, a few randomized trials have evaluated the effects of selenium on cardiovascular outcomes10, 11, 12, 13 and showed no obvious benefits from selenium for CVD. In addition to heterogeneity in intervention periods and selenium formula and dosage, these individual trials are limited by statistical power for addressing specific thresholds of circulating selenium concentrations for optimal cardiovascular health. Previously, neither meta-analysis of six RCTs8 for selenium-containing supplements nor a meta-analysis of 12 RCTs for selenium supplements alone14 showed significant protective effect on cardiovascular end points. Both the meta-analyses focused on testing the selenium-CVD hypothesis but did not specifically address the dose-dependent relationship. There is still disagreement between observational studies and RCTs, which largely hindered a consistent conclusion to be drawn.
To maximize statistical power and to reduce sampling bias from individual studies, we conducted a meta-analysis of available prospective data from both observational studies and RCTs. Specifically, our study aimed to provide a comprehensive evaluation of the full spectrum of variation in baseline selenium concentrations and its dose–response relationship with incident CVD in prospective observational studies, and to determine whether any differences in selenium biomarkers by selenium supplementation could account for CVD risk in RCTs.
Subjects and methods
Data source and searches
We searched MEDLINE and EMBASE databases for all relevant articles on selenium and CVD published up to 15 December 2013. We used the search terms including ‘selenium‘, ‘selenite‘, ‘selenate‘, ‘cardiovascular disease‘, ‘myocardial infarction‘, ‘stroke‘, ‘peripheral arterial disease‘, ‘mortality‘, ‘coronary heart disease‘, ‘ischemic heart disease‘, ‘sudden cardiac arrest‘, ‘cardiovascular risk‘, ‘hypertension‘, ‘cholesterol‘, ‘hypercholesterolemia‘, ‘hyperlipidemia‘, ‘diabetes‘, ‘arteriosclerosis‘ and ‘hypertriglyceride‘. The search was restricted to English language only and to adults.
We chose the articles based on the following inclusion criteria: (1) original studies (not reviews, meeting abstracts, editorials, letters or commentaries); (2) adult human studies; (3) prospective study design (for example, prospective cohort, nested case–control, case–cohort) or RCTs; (4) prospective studies that provided the relative risk (RR) estimation between baseline circulating or toenail selenium concentration and CVD incidence or mortality; and (5) RCTs with selenium-containing supplements (selenium alone or a combination with other vitamins or minerals), which provided available data of selenium dose and CVD incidence or mortality and/or circulating concentrations of selenium or selenium protein GPx activity. We also manually searched bibliographies from recent reviews and retrieved articles for additional studies. Finally, a total of 16 articles of prospective observational studies and 16 articles of RCTs were included in this meta-analysis.
Two investigators (XZ and CL) independently selected the articles and extracted the data. Any discrepancies were resolved by consensus. Information extracted from articles included population source, study design, follow-up period, sample size, subject characteristics (age and sex), selenium biomarkers, CVD end points, selenium forms and dose (RCTs). When results were available on different subpopulations in the same cohort1, 3, 10, 15, 16, 17 and single RCT,18, 19 we considered each subpopulation as an independent study in the meta-analysis (basic study characteristics were described in Supplementary Table 1 for prospective studies and in Supplementary Table 2 for RCTs).
Of 16 prospective observational studies, most of them (14) provided RRs or hazard ratios and 95% confidence intervals (CIs) for the relationship between baseline selenium concentrations and CVD events. Two articles provided RRs for selenium concentrations, as a continuous variable was not included in the analysis owing to uncertain comparison scales.20, 21 We alternatively calculated crude RRs in the studies that only provided exact numbers of events16, 17 and chose RRs estimated from the models fully adjusted for major confounders as main results in the articles with several estimation models.
We analyzed observational studies and RCTs, respectively, and estimated the pooled RRs by DerSimonian and Laird’s random-effect model in which each study was weighted by the inverse of sum of within-study plus between-study variance.22 Between-study heterogeneity was tested by Cochrane’s Q statistic, I2 and H statistics, respectively. The percentages of I2 around 25 (I2=25), 50 (I2=50) and 75% (I2=75) indicate low, medium and high heterogeneity, respectively. An H statistics <1.2 indicates little heterogeneity and an H >1.5 raises caution regarding notable heterogeneity. We used Begg’s adjusted rank correlation test and Egger’s regression asymmetry test to test publication bias.23, 24
For observational studies, we also explored differences of the pooled RRs from baseline measurements, including sex (women, men or mixed), age (<60 years and ⩾60 years), sample size (<1000 and ⩾1000), covariance adjustment (body mass index and smoking) and CVD end points (CVD, coronary heart disease, MI and stroke).
We used the method proposed by Greenland and Longnecker25 to assess the linear relationship of selenium concentrations and CVD risk. To explore a possible nonlinear trend, we first graphically examined the shape of the relationship by using LOWESS smoothed curve and quadratic curve; second, we applied the two-stage random-effect dose–response meta-analysis method proposed by Orsini with three fixed knots at 10th, 50th and 90th percentiles for the distributions of reported circulating selenium concentrations across all included studies.26, 27 The concentration values of each category were determined as the median or mean concentrations if available; otherwise, we calculated the means or midpoints of the lower and upper bounds instead. If there was an open lower or upper bound, it was estimated by one known bound minus or plus the other half width of the adjacent category.
For RCTs, the pooled RRs for the overall effect of selenium supplementation on CVD events were calculated. We then examined whether sample size (<1000 and ⩾1000), trial duration (⩽5 years and >5 years), selenium supplements (selenium alone and a combination of selenium with other antioxidants), supplemental dose (⩽100 μg/day and 200 μg/day) and selenium formulation (bio-selenium and all others) modified the association. Changes in blood selenium concentrations in response to supplementation were derived, respectively, in six trials with ⩽100 μg/day supplements and four trials with 200–300 μg/day supplements. We calculated the weight mean difference of circulating selenium concentrations comparing the treatment with the placebo groups.
All analyses were performed using the STATA software (version 13, STATA Corp., College Station, TX, USA). Statistical significance was defined as two-tailed α<0.05.
A total of 16 prospective studies involving 35 607 participants and 4421 incident CVD cases were included in this meta-analysis (Figure 1). Of them, 11 were cohort studies and six were nested case–control studies. Most studies (13 studies) were population-based and three were health-professional populations.13, 28, 29 Biospecimen tissues for selenium concentrations included serum (13 studies), erythrocyte (one study),30 plasma (one study)29 and toenail (two studies).13, 28
Of all 16 trials, 37 572 participants (range: 23–17 448; median: 351) took the median dose of 100 μg/day (range: 75–300 μg/day) selenium supplements for 2 weeks to 114 months duration (median: 12 months). Of all trials, 14 used a placebo-controlled double-blinded design and two used an open-label design.31, 32 Selenium formulation included l-selenomethionine,33, 34, 35 sodium selenite36, 37 and selenium-enriched yeast.33, 38 One study did not report form information.39 Of all included trials, nine trials estimated RRs of CVD mortality or incidence (Supplementary Table 2), 10 trials reported information of selenium biomarkers and only 3 trials33, 39, 40 provided both.
Selenium concentrations and CVD events in prospective observational studies
By combining evidence from 16 studies, the pooled RR for the highest (median: 101.5 μg/l) versus the lowest category (median: 53.7 μg/l) of baseline blood (serum/plasma/erythrocyte) selenium concentrations was 0.87 (95% CI: 0.76, 0.99), indicating a significant but modest association between baseline selenium concentrations and CVD risk (Figure 2). Neither publication bias nor between-study heterogeneity was statistically significant. In stratified analyses (Table 1), sex, follow-up duration, sample size, specimen type, adjustment for body mass index or smoking and baseline selenium concentrations did not seem to materially modify the inverse association. The inverse associations were more evident among those studies with lower median or mean baseline selenium concentrations (<106 μg/l; RR, 0.77; 95% CI: 0.61, 0.96) than those with higher concentrations (⩾106 μg/l; RR, 0.93; 95% CI: 0.80, 1.10), but the interaction was not significant (P=0.14). In addition, there was no evidence for a significant relationship between toenail selenium concentrations and CVD on the basis of two studies (Figure 2).
The overall dose–response relationship was assessed across a range of selenium concentrations between 30 μg/l and 165 μg/l. For each 25 μg/l increment in circulating selenium concentrations, the pooled RR was estimated to be 0.89 (95% CI: 0.84, 0.95). The analysis modeled by restricted cubic spline suggested a reasonably nonlinear relationship between circulating selenium and CVD risk (Supplementary Figure 1). The curve showed that selenium concentrations were significantly associated with a lower risk of CVD at a range from 55 to 145 μg/l with a nadir at 125 μg/l as compared with low selenium concentrations (median: 53.7 μg/l; Figure 3). The association was null when it exceeded 145 μg/l. Evidence was insufficient to examine the relationship between selenium concentration and CVD risk when the selenium concentration exceeded 150 μg/l.
Selenium supplementation and CVD events in RCTs
Our meta-analysis of nine RCTs showed that oral selenium supplements (75–300 μg/day, median: 100 μg/day) for 6 to 114 months (median: 60 months) did not significantly decrease the incidence of CVD events (RR=0.91; 95% CI: 0.74, 1.10) as compared with the placebo groups (Table 2). There was a weakly significant between-study heterogeneity (P for Cochran Q-test=0.07, H statistics=1.4 (1.0, 2.0) and I2 =45 (0, 75)). The Begg’s funnel plot showed that the smaller RRs with small s.e. tended to be near the null effect line, and larger RRs with large s.e. tended to be under the horizontal line. This indicated the presence of publication bias in favor of small trials with positive findings (Egger test, P=0.03; Begg’s test P=0.10). In the stratified analyses (Table 2), smaller trials with shorter trial durations tended to report positive results; the pooled RR was 0.42 (95% CI, 0.24, 0.73) for small trials (<1000) with a duration⩽5 years, and 1.02 (95% CI, 0.93, 1.11) for large trials (⩾1000) with a duration >5 years (P for interaction=0.002). In addition, differences in mean ages of participants, study area, selenium formulation, supplemental doses and CVD end points did not appear to change the risk of CVD by selenium supplementation. The pooled RR was 0.78 (95% CI: 0.49, 1.26) for six trials with a dose of ⩽100 μg/day (only one is 75 μg/day41, 42) and 0.91 (95% CI: 0.69, 1.21) for three trials with 200 μg/day selenium intake (Figure 4).
Selenium biomarker concentrations in response to selenium supplementation
Our meta-analysis of 10 RCTs showed that oral selenium supplements (median dose: 200 μg/day) for 6.5 months (range: 2 weeks to 144 months) significantly raised the blood selenium concentrations by 56.4 μg/l from a median baseline selenium concentration of 98.5 μg/l (95% CI for weighted mean differences: 40.9, 72.0 μg/l). Different formulations of selenium supplements had nonsignificant effects on the circulating selenium concentrations, and thus we pooled all trials with different formulations of supplements to address the following dose–response relationship. A steep linear relationship between supplemental duration and selenium concentration changes was observed for a dose of 100 μg/day before the 9-month supplementation (Supplementary Figure 2). A similar relationship was shown for dose of 200 μg/day before 13 months after supplementation and then a plateau change between 90 and 110 μg/l was reached. However, there are not enough data to address the plateau for the dose of 100 μg/day.
As the cardiovascular health by selenium is thought to be through antioxidant function of GPx, we have additionally examined available data from five RCTs to character a time course of percentage changes of GPx activity in blood after selenium supplementation. Percentage changes of GPx activity increased abruptly at 1–2 weeks after oral selenium supplement and then reached the maximal levels at 12 weeks (Supplementary Figure 3).
Our meta-analysis of prospective observational studies provided some evidence of a possible nonlinear, most likely U-shaped, relationship between baseline selenium concentrations and CVD. Within a narrow range from 55 to 145 μg/l, selenium concentrations were associated with a significantly lower risk of CVD. We found no evidence for significant effect modifications by sex, follow-up duration, sample size, specimen type, baseline selenium concentrations and adjustment for body mass index or smoking. Our meta-analysis of RCTs showed no evidence for an overall effect of oral selenium supplements on CVD events with a 44% elevation of selenium concentrations. Neither selenium formulation nor dose (100 μg/day or 200 μg/day) modified this effect. In addition, evidence for publication bias indicated that smaller RCTs with positive results may largely account for this significant effect on CVD by selenium supplementation, as previously reported.
A previous meta-analysis of prospective observational studies reported a similar inverse association between coronary heart disease and selenium concentrations, although the influence of other antioxidants cannot be ruled out in observational studies.8 Selenium status may possibly affect this relationship,8 and this relationship might be discernible only in a population with lower selenium concentrations. The narrow selenium range of CVD reduction (55 to 145 μg/l) reported by our meta-analysis was similar to the range of adequate selenium levels at 60–140 μg/l, as previously reported.6 Owing to limited data, we only addressed the nonlinear relationship when selenium concentration did not exceed 150 μg/l. Further studies for the exact boundary of this relationship are warranted.
The nonlinear associations might be influenced by many potential factors, such as sample size, duration, specimen types and baseline selenium status. Adjustment for body mass index and smoking did not change the strength of the associations, although they were potential confounders.43, 44 The median level of blood selenium from observational studies included in our meta-analysis was 102.8 μg/l, which was slightly lower than that in a nationally representative sample of the US population from the NHANES 2003–2004 (136.4±19.9 μg/l).45 The source of biospecimen for assessment may modify this association.45, 46, 47, 48 However, there was a small number of studies that assayed biospecimen samples other than serum. In addition, we were unable to exclude the nonlinear association that might be caused by statistical fluctuation owing to relatively low power. In addition, several lines of evidence seem to support the hypothesis of the nonlinear relationship between selenium and CVD. For instance, a randomized controlled pilot trial of 501 old persons with low selenium status found that a low dose of selenium supplementation had a significant effect on decreasing total and non-high-density lipoprotein cholesterol concentrations, whereas the effect was nonsignificant for a high-dose supplementation (300 μg/day).3 Similarly, a 57% higher risk of diabetes was observed in the highest quintile of serum selenium (147.0 μg/l) compared with the lowest quintile (105.9 μg/l) in the NHANES III.49 Taken together, it seems reasonable to speculate that high selenium concentrations may be related to elevating levels of some intermediate CVD risk factors, including dyslipidemia and type 2 diabetes, and may thus diminish the inverse association and even lead to possibly increased risk of CVD risk. Nevertheless, few prospective studies have specifically assessed this hypothesis.
Our meta-analysis of RCTs found that oral selenium supplements had no significant effect on CVD, which was consistent with previous meta-analyses.8, 14 Publication bias in previous RCTs may possibly explain the observed significant results in some individual trials. In particular, most large trials with longer durations reported null findings and thus suggested that substantial publication bias due to selective publication of small trials with positive results is likely.
The null effect of selenium supplementation on CVD risk was also complicated by the significant between-study heterogeneity in selenium dosage, formula, duration and combinations of supplements. Selenium dosage varied across individual RCTs. These differences might have contributed to differential results and led to difficulties in estimating the true effect of optimal dose of selenium supplements. Our results clearly show that oral selenium supplements, either a dose of 100 or 200 μg/day, significantly increases selenium concentrations and thereby can replete selenium status in the human body. It should be noted that circulating selenium after 12 weeks of selenium supplementation was significantly elevated by at least 50 μg/l compared with placebo and it increased by 150 μg/l above a median baseline concentration of 100 μg/l. The median of circulating selenium concentration was 123.6 μg/l, with an interquartile range from 113.7 to 134.7 μg/l in a nationally representative sample of the US general populations aged ⩾20 years, a US National survey data of NHANES III (1988–1994) with 7129 participants.50 In the present study, the median circulating level of all 10 included trials was 97 μg/l (interquartile range: 90–108 μg/l) at baseline, which was slightly lower than the levels of NHANES III. After oral selenium supplementation (with a median dose of 200 mg/day for a median duration of 6 months), circulating selenium concentrations increased to a median level of 150 μg/l (interquartile range: 135–225.7 μg/l), which was apparently higher than the estimated levels and ranges from NHANES III data. On the basis of the above available evidence, it seems reasonable to conclude that significantly elevated selenium concentrations, by taking selenium supplements were most likely above the range of 55–145 μg/l and may not be optimal for CVD health. The trial duration might be another potential source of heterogeneity. We observed a significant difference between subgroups of duration⩽5y and>5y and a time-dependent change of serum selenium in response to supplementation, although such a difference might be caused by chance owing to small sample sizes in subgroups.
In addition, available evidence indicates that the role of selenium in human health is primarily owing to its presence in selenoproteins, including antioxidant enzyme GPx, although the exact mechanisms have not yet been fully elucidated. The hypothesis of selenium and CVD is supported by the ability of GPx to combat the oxidative modification of lipids and to reduce platelet aggregation.5 The findings from our meta-analysis of GPx activity may explain disparate results between observational studies and RCTs for cardiovascular health by selenium. Our meta-analysis of GPx activity showed that 12-week selenium supplementation caused a maximal increment in GPx activity by 12%. However, it remains uncertain whether increment is sustained in the long-term period and contributes to the effects of selenium on CVD, owing to limited numbers of RCTs with available data on GPx activity.
There is also a concern on the effect of selenium forms of supplements on circulating selenium concentrations. Evidence supported that the bioavailability of organic selenium is superior to that of inorganic selenium because inorganic selenium may increase the oxidant stresses.51 Owing to limited power, it is difficult to tease out the effect of selenium forms in our study. Besides, differences in study population, intervention periods, CVD events and selenium status might have decreased overall statistical power for testing the hypothesis whether selenium intake from various supplements exerts any beneficial effect on CVD events.
Our meta-analysis has several limitations. First, the observational nature of prospective studies included in our analysis cannot rule out residual confounding, although the consistency of our results across multiple strata and sensitivity analyses minimizes the likelihood that residual confounding explains the findings. Second, all included observational studies used a single measurement of selenium at baseline, which is not a time-integrated measure of selenium status and thereby affect the association. Third, substantial between-study heterogeneity could influence the accuracy in the pooled estimates. Nevertheless, the strength and the direction of the associations were essentially unchanged after excluding the studies with extreme values. Fourth, as in any meta-analysis, publication bias is possible, although we attempted to retrieve all relevant data. Fifth, the benefits of selenium may only present in the deficient population. Owing to sparse data, we have insufficient statistical power to clearly illustrate this hypothesis. In addition, we have low power to explore the differential effects between selenium supplements alone and combined selenium supplements. Finally, limited data from existing prospective studies and RCTs provided insufficient power to detect potential sources of heterogeneity and interactions. In addition, we cannot completely exclude the possibility that changes in treatment compliance for all the trials included and differential serum selenium concentrations in response to supplementation may affect the explanation for our observed differences between treatment and placebo, especially when relevant information was unavailable and trial duration was long.
Our meta-analysis of 16 prospective observational studies suggested a nonlinear relationship between baseline blood selenium concentrations and risk of incident CVDs; the significant benefit range of selenium concentration was limited from 55 to 145 μg/l. Our meta-analysis of nine RCTs found no overall effect of oral selenium supplements on CVD, with significantly elevated selenium concentrations at a mean level of ~154 μg/l, which was above the upper limit of the observed beneficial range (145 μg/l). Our findings thus indicated a need for future long-term RCTs with optimal selenium supplemental dose and safety considerations. At present, available evidence is not conclusive to support the widespread use of selenium or selenium-containing supplements for CVD prevention.
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The study was supported by the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative Grant (Drs XZ and YS). We are thankful for the excellent advice and guidance from Dr Wanzhu Tu, from the Department of Biostatistics at the Indiana University School of Medicine, who served as statistical consultant for this study.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website
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Zhang, X., Liu, C., Guo, J. et al. Selenium status and cardiovascular diseases: meta-analysis of prospective observational studies and randomized controlled trials. Eur J Clin Nutr 70, 162–169 (2016). https://doi.org/10.1038/ejcn.2015.78
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