Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: Antioxidants have been promoted for cardiovascular disease (CVD) risk reduction and for the prevention of cancer. Our preliminary analysis suggested that only when selenium was present were antioxidant mixtures associated with reduced all-cause mortality.

Objective: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effect of selenium supplementation alone and of antioxidant mixtures with or without selenium on the risk of CVD, cancer, and mortality.

Methods: We identified studies using the Cochrane Library, Medline, and Embase for potential CVD outcomes, cancer, and all-cause mortality following selenium supplementation alone or after antioxidant supplement mixtures with and without selenium up to June 5, 2020. RCTs of ≥24 wk were included and data were analyzed using random-effects models and classified by the Grading of Recommendations, Assessment, Development, and Evaluation approach.

Results: The meta-analysis identified 9423 studies, of which 43 were used in the final analysis. Overall, no association of selenium alone or antioxidants was seen with CVD and all-cause mortality. However, a decreased risk with antioxidant mixtures was seen for CVD mortality when selenium was part of the mix (RR: 0.77; 95% CI: 0.62, 0.97; P = 0.02), with no association when selenium was absent. Similarly, when selenium was part of the antioxidant mixture, a decreased risk was seen for all-cause mortality (RR: 0.90; 95% CI: 0.82, 0.98; P = 0.02) as opposed to an increased risk when selenium was absent (RR: 1.09; 95% CI: 1.04, 1.13; P = 0.0002).

Conclusion: The addition of selenium should be considered for supplements containing antioxidant mixtures if they are to be associated with CVD and all-cause mortality risk reduction. This trial was registered at https://www.crd.york.ac.uk/PROSPERO/ as CRD42019138268.

Keywords: all-cause mortality; antioxidants; cardiovascular disease; meta-analysis; selenium; supplements.

FIGURE 1

Search summary. Flow diagram outlining the search strategy used to identify publications that report RCT data on antioxidant supplementation and risk of CVD, cancer, and all-cause mortality. The publications are from database inceptions to June 5, 2020, of single RCTs identified by searching Cochrane, Medline, and Embase and by manual searches. Titles and abstracts were reviewed in the first stage of screening while full-manuscript review was done in the second stage. CHD, coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction, RCT, randomized controlled trial.

FIGURE 2

Sensitivity analysis of antioxidant supplementation and CVD mortality risk for studies with and without selenium. The diamond represents the pooled risk estimate. Interstudy heterogeneity was tested using the Cochran Q statistic (χ²) at a significance level of P < 0.10 and quantified by the I² statistic. An I² value ≥50% is considered to indicate substantial heterogeneity. All results are presented as risk ratios with 95% confidence intervals, using the Mantel-Haenszel method with a random-effects model. NNT for antioxidant supplementation and CVD mortality risk for studies with selenium is 264. The 2 antioxidant groups are significantly different (P  = 0.01; I² = 84.3%). ASAP, Antioxidant Supplementation in Atherosclerosis Prevention; CLIPS, Critical Leg Ischaemia Prevention Study; CVD, cardiovascular disease; HATS, HDL-Atherosclerosis Treatment Study; HPS, Heart Protection Study Collaborative Group; M-H, Mantel-Haenszel; MVP, Multivitamins and Probucol Study Group; NNT, number needed to treat; PHS, Physicians’ Health Study; REACT, Roche European American Cataract Trial; SELECT, Selenium and Vitamin E Cancer Prevention; SIT, Shadong Intervention Trial; WAVE, Women's Angiographic Vitamin and Estrogen.

FIGURE 3

Sensitivity analysis of antioxidant supplementation and all-cause mortality risk for studies with and without selenium. The diamond represents the pooled risk estimate. Interstudy heterogeneity was tested using the Cochran Q statistic (χ²) at a significance level of P < 0.10 and quantified by the I² statistic. An I² value ≥50% is considered to indicate substantial heterogeneity. All results are presented as risk ratios with 95% confidence intervals, using the Mantel-Haenszel method with random-effects model. *Jacobson et al., 2000—data retrieved from meta-analysis (21). NNT for antioxidant supplementation and all-cause mortality risk for studies with selenium is 226. NNH for antioxidant supplementation and all-cause mortality risk for studies without selenium is 115. The 2 antioxidant groups are significantly different (P = 0.0002; I² = 92.8%). AREDS, Age-Related Eye Disease Study; ASAP, Antioxidant Supplementation in Atherosclerosis Prevention; ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CARET, Carotene and Retinol Efficacy Trial; CLIPS, Critical Leg Ischaemia Prevention Study; HATS, HDL-Atherosclerosis Treatment Study; HPS, Heart Protection Study Collaborative Group; M-H, Mantel-Haenszel; MINVITOAX, Mineral Vitamin Antioxidant; MVP, Multivitamins and Probucol Study Group; NNH, number needed to harm; NNT, number needed to treat; PHS, Physicians’ Health Study; REACT, Roche European American Cataract Trial; SELECT, Selenium and Vitamin E Cancer Prevention; SIT, Shadong Intervention Trial; SU.VI.MAX, Supplémentation en Vitamines et Minéraux AntioXydants study; WACS, Women's Antioxidant Cardiovascular Study; WAVE, Women's Angiographic Vitamin and Estrogen.

FIGURE 4

Forest plot showing antioxidants (with and without selenium) by smoking and health status and all-cause mortality. *Jacobson et al., 2000—data retrieved from meta-analysis (21). The diamond represents the pooled risk estimate. Interstudy heterogeneity was tested using the Cochran Q statistic (χ²) at a significance level of P < 0.10 and quantified by the I² statistic. An I² value ≥50% is considered to indicate substantial heterogeneity. All results are presented as risk ratios with 95% confidence intervals, using the Mantel-Haenszel method with random-effects model. The difference between studies with and without selenium among the healthy (low-risk) group was significant (P = 0.01; I² = 83.4%) while the difference within the higher risk group was not significant (P = 0.54; I² = 0%), and there were no studies in the highest risk category (smokers) with selenium in the antioxidant mix. AREDS, Age-Related Eye Disease Study; ASAP, Antioxidant Supplementation in Atherosclerosis Prevention; ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CARET, Carotene and Retinol Efficacy Trial; CLIPS, Critical Leg Ischaemia Prevention Study; HATS, HDL-Atherosclerosis Treatment Study; HPS, Heart Protection Study Collaborative Group; M-H, Mantel-Haenszel; MINVITOAX, Mineral Vitamin Antioxidant; MVP, Multivitamins and Probucol Study Group; PHS, Physicians’ Health Study; REACT, Roche European American Cataract Trial; SELECT, Selenium and Vitamin E Cancer Prevention; SIT, Shadong Intervention Trial; SU.VI.MAX, Supplémentation en Vitamines et Minéraux AntioXydants study; WACS, Women's Antioxidant Cardiovascular Study; WAVE, Women's Angiographic Vitamin and Estrogen.

FIGURE 5

The opposing activity of supplemental antioxidants and selenium and zinc on the endogenous antioxidant system. GPx, glutathione peroxidase; SOD, superoxide dismutase.