Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials
Authors: Sathish C Pichika
Melanie Paquette
Cyril W C Kendall
John L Sievenpiper
Edward L Giovannucci
Darshna Patel
David Kitts
David J A Jenkins
Tom Tsirakis
Sonia Blanco Mejia
Sandhya Sahye-Pudaruth
Meaghan Kavanagh
Journal: American Journal of Clinical Nutrition (2020)
Discipline: CLINICAL MEDICINE
Keywords: all-cause mortality; antioxidants; cardiovascular disease; meta-analysis; selenium
Affiliations: Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada, Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Toronto, Ontario, Canada, Clinical Nutrition Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada, Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, Ontario, Canada, Food Nutrition and Health, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada, Department of Nutrition and Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada, Department of Mathematics and Statistics, University of Windsor, Windsor, Canada

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. 

Retracted: No

PubPeer comments:
 # Effects of antioxidants on mortality may be heterogeneous Jenkins et al. calculated that u201cantioxidants without seleniumu201d increased all-cause mortality by RR = 1.09 whereas u201cantioxidants with seleniumu201d decreased mortality by RR = 0.90 in Fig. 3 of [1]. The test of heterogeneity between the two sets of randomized trials gave P = 0.0002. Jenkins assumed that the effect of antioxidants is sufficiently uniform such that pooling 19 trials investigating diverse u201cantioxidants without seleniumu201d gives a meaningful overall average effect for the general community. This may be an unjustified assumption, however. Two particularly large trials in the u201cantioxidants without seleniumu201d group administered beta-carotene and both found statistically significant harm from beta-carotene [2,3]. There is no justification to assume that the average effect of beta-carotene is the same as the average effect of all other antioxidants, for which no similar harms have been demonstrated. Furthermore, there is little, if any, evidence that beta-carotene is a physiologically relevant antioxidant [4,5]. Thus, trials with beta-carotene should not be included if the goal is to estimate the effects of physiologically relevant antioxidants. Jenkins referred to the ATBC Study [3], but failed to mention the evidence from the ATBC Study that vitamin E and beta-carotene may have interaction in their effects on mortality in some groups of people [6], and that the effects of vitamin E on all-cause mortality vary by age and dietary vitamin C intake [7,8]. When there is evidence of heterogeneity in the effects between antioxidants, and even within single antioxidants [6-10], it is scientifically unsound to calculate one single estimate of RR = 1.09 increase in all-cause mortality, and give an impression that the estimate is meaningful for all non-selenium antioxidants for all people. A fundamentally important goal in modern biomedicine is specificity. The strength of a randomised trial is that the difference between the trial groups can be specifically attributed to the intervention that was tested. When trials with different antioxidants are pooled together, there is u201capples and orangesu201d problem. It is not evident whether the effect applies to any specific antioxidant. Instead, the pooled estimate can be meaningless. Comparison of randomized trials that have been carried out in different contexts with different antioxidant mixtures is observational research. The variation in participants, in contexts and in the non-selenium antioxidants may explain the differences between the two groups as well as the inclusion or exclusion of selenium in the mixtures. Although the question about possible benefits of selenium is interesting, Jenkinsu2019 meta-analysis is uninformative about the answer. 1. Jenkins DJA, Kitts D, Giovannucci EL, Sahye-Pudaruth S, Paquette M, Blanco Mejia S, Patel D, Kavanagh M, Tsirakis T, Kendall CWC, Pichika SC, Sievenpiper JL. Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2020;112(6):1642-1652. https: doi.org 10.1093 ajcn nqaa245 http: www.ncbi.nlm.nih.gov pmc articles pmc7727482 2. https: doi.org 10.1056 nejm199605023341802 https: escholarship.org uc item 0mr2057n 3. http: dx.doi.org 10.1001 jama.290.4.476 4. http: dx.doi.org 10.1111 j.1753-4887.2000.tb07810.x 5. http: dx.doi.org 10.1016 S0306-9877(97)90286-3 6. https: doi.org 10.1017 jns.2020.3 http: www.ncbi.nlm.nih.gov pmc articles pmc7082716 7. https: dx.doi.org 10.1093 aje kwn413 https: www.ncbi.nlm.nih.gov pmc articles PMC2661323 8. https: doi.org 10.3389 fnut.2020.00036 http: www.ncbi.nlm.nih.gov pmc articles pmc7136753 9. https: doi.org 10.3177 jnsv.64.374 10. https: doi.org 10.1017 S0007114516003408 ,