title: 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?
abstract: OBJECTIVE
  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].
authors.affiliation: The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark ; Department of Internal Medicine, Gastroenterology and Hepatology, Medical Faculty, University of Nis, Niš, Serbia.
authors.forename: Goran
authors.initials: G
authors.lastname: Bjelakovic
authors.forename: Dimitrinka
authors.initials: D
authors.lastname: Nikolova
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019587:Dietary Supplements / Q000009:adverse effects*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D014801:Vitamin A / Q000009:adverse effects*; D014810:Vitamin E / Q000009:adverse effects*; D019207:beta Carotene / Q000009:adverse effects*
chemical_list: D004338:Drug Combinations; D019207:beta Carotene; D014801:Vitamin A; D014810:Vitamin E
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