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Cited by 183Antioxidant Activity and Oxidative StressVitamin C and Antioxidants ResearchNutrition and Health Studies

Meta-regression analyses, meta-analyses, and trial sequential analyses of the effects of supplementation with beta-carotene, vitamin A, and vitamin E singly or in different combinations on all-cause mortality: do we have evidence for lack of harm?

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Bjelakovic, Goran, Nikolova, Dimitrinka, Gluud, Christian·2013·PLoS ONE
DOI 10.1371/journal.pone.0074558PMC PMC3765487
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Abstract

BACKGROUND AND AIMS: Evidence shows that antioxidant supplements may increase mortality. Our aims were to assess whether different doses of beta-carotene, vitamin A, and vitamin E affect mortality in primary and secondary prevention randomized clinical trials with low risk of bias. METHODS: The present study is based on our 2012 Cochrane systematic review analyzing beneficial and harmful effects of antioxidant supplements in adults. Using random-effects meta-analyses, meta-regression analyses, and trial sequential analyses, we examined the association between beta-carotene, vitamin A, and vitamin E, and mortality according to their daily doses and doses below and above the recommended daily allowances (RDA). RESULTS: We included 53 randomized trials with low risk of bias (241,883 participants, aged 18 to 103 years, 44.6% women) assessing beta-carotene, vitamin A, and vitamin E. Meta-regression analysis showed that the dose of vitamin A was significantly positively associated with all-cause mortality. Beta-carotene in a dose above 9.6 mg significantly increased mortality (relative risk (RR) 1.06, 95% confidence interval (CI) 1.02 to 1.09, I(2) = 13%). Vitamin A in a dose above the RDA (> 800 µg) did not significantly influence mortality (RR 1.08, 95% CI 0.98 to 1.19, I(2) = 53%). Vitamin E in a dose above the RDA (> 15 mg) significantly increased mortality (RR 1.03, 95% CI 1.00 to 1.05, I(2) = 0%). Doses below the RDAs did not affect mortality, but data were sparse. CONCLUSIONS: Beta-carotene and vitamin E in doses higher than the RDA seem to significantly increase mortality, whereas we lack information on vitamin A. Dose of vitamin A was significantly associated with increased mortality in meta-regression. We lack information on doses below the RDA. BACKGROUND: All essential compounds to stay healthy cannot be synthesized in our body. Therefore, these compounds must be taken through our diet or obtained in other ways [1]. Oxidative stress has been suggested to cause a variety of diseases [2]. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing diseases and death. Despite the fact that a normal diet in high-income countries may provide sufficient amounts of antioxidants [3,4], more than one third of adults regularly take antioxidant supplements [5,6].

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  • The impact of vitamin E supplementation on cardiovascular mortality or prostate cancer is still not settled and clinical intervention studies have shown no benefit.

    “Nonetheless, the impact of vitamin E supplementation on cardiovascular mortality or prostate cancer is still not settled and clinical intervention studies have shown no bene fi t.”

    From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [369]

    The Results (page unavailable) report no significant effect of vitamin E alone on all-cause mortality, and the Conclusions say the evidence does not support antioxidant supplementation in a generally well-nourished population. But the Methods specify that this paper’s only outcome was all-cause mortality; it does not establish whether effects on cardiovascular mortality or prostate cancer remain unsettled or whether intervention studies showed no benefit for those specific outcomes. (LLM, conf=0.85)

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  1. [22]Standing Committee on the Scientific Evaluation of Dietary (1998). Reference Intakes. Food and Nutrition Board, Institute of Medicine Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. In: The National Academies Press pp. 1- 71. PubMed: 231936252084556523115811 20845565
  2. [23]Scientific Committee on Food, Scientific Panel on Dietetic Products, Nutrition and Allergies (2006) Tolerable upper intake levels for vitamins and minerals. In: European Food Safety Authority pp. 1- 480.
  3. [24]the Nordic Cochrane Centre The Cochrane Collaboration (2012) Review Manager (RevMan), version 5.2 Copenhagen [computer program].
  4. [51]Bonelli L, Camoriano A, Ravelli P, Missale G, Bruzzi P, Aste H (1998) Reduction of the incidence of metachronous adenomas of the large bowel by means of antioxidants. In: Proceedings of International Selenium Tellurium Development Association. In: Palmieri Y pp. 91– 94. Scottsdale AZ

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Authors
Bjelakovic, G., Nikolova, D., & Gluud, C.
Affiliations
Copenhagen University Hospital (DK)
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-09-06
Volume
8
Issue
9
Pages
e74558
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0074558
PMC
PMC3765487
OpenAlex
W2081764095
Cited by
183
References
155
Citations by year
2026: 5 · 2025: 9 · 2024: 8 · 2023: 16 · 2022: 13 · 2021: 18 · 2020: 11 · 2019: 18 · 2018: 18 · 2017: 15 · 2016: 18 · 2015: 23 · 2014: 9 · 2013: 1 · 2012: 1
FWCI
12.67
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Gentofte Hospital
  • Rigshospitalet
  • Copenhagen Trial Unit, Centre for Clinical Intervention Research
Topics
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutrition and Health Studies
Keywords
antioxidant supplements, beta-carotene, vitamin A, vitamin E, all-cause mortality, dose-response relationship, recommended daily allowance, vitamin A toxicity, oxidative stress, primary and secondary prevention, randomized controlled trials, trial sequential analysis, meta-regression
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Drug Combinations, Female, Humans, Male, Middle Aged, Mortality, Regression Analysis, Vitamin A, Vitamin E, Randomized Controlled Trials as Topic, beta Carotene, Dietary Supplements

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