Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studiesBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g1903 (Published 01 April 2014) Cite this as: BMJ 2014;348:g1903
- Rajiv Chowdhury, cardiovascular epidemiologist1,
- Setor Kunutsor, PhD candidate1,
- Anna Vitezova, PhD candidate2,
- Clare Oliver-Williams, PhD candidate1,
- Susmita Chowdhury, research associate3,
- Jessica C Kiefte-de-Jong, postdoctoral scientist2,
- Hassan Khan, cardiovascular epidemiologist1,
- Cristina P Baena, assistant professor4,
- Dorairaj Prabhakaran, professor5,
- Moshe B Hoshen, professor6,
- Becca S Feldman, professor6,
- An Pan, assistant professor78,
- Laura Johnson, lecturer9,
- Francesca Crowe, nutritional epidemiologist10,
- Frank B Hu, professor7,
- Oscar H Franco, professor2
- 1Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
- 2Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
- 3Public Health Genomics Foundation, Cambridge, UK
- 4Pontifícia Universidade Católica do Paraná, Brazil
- 5Centre for Chronic Disease Control, New Delhi, India
- 6Clalit Research Institute and Chief Physician’s Office, Clalit Health Services, Israel
- 7Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, US
- 8National University of Singapore, Republic of Singapore
- 9School for Policy Research, University of Bristol, UK
- 10Cancer Epidemiology Unit, University of Oxford, Oxford, UK
- Correspondence to: R Chowdhury or O H Franco
- Accepted 27 February 2014
Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances.
Design Systematic review and meta-analysis of observational studies and randomised controlled trials.
Data sources Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators.
Study selection Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes.
Data extraction Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849 412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30 716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics.
Results In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods.
Conclusions Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.
We thank the following study investigators for helping us with tabular information on vitamin D: Lily Lui, Warren Browner, Joe Ix, Tobias Larsson, Johan Sundstrom, Winfried Marz, Marcus Kleber, Jukka Marniemi, Natasha Wiebe, CARE Study Investigators, Peter Willeit, Francesca Tentori, and Kamyar Kalantar-Zadeh.
Contributors: SK, AV, CO-W, SC, and JCK-deJ contributed equally to this work. RC and OHF conceived the study. SK and RC did the analyses. RC, SK, CO-W, SC, and HK searched the literature and extracted the data. RC and OHF wrote the manuscript. JCK-deJ, SK, AV, CPB, DP, MBH, BSF, AP, LJ, FC, FBH, and OHF contributed to the initial revision of the manuscript. LJ contributed to the critical revision of the manuscript before publication. OHF is the guarantor.
Funding: None. AV, JCK-deJ, and OHF work in ErasmusAGE, a centre for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc, and AXA. Nestlé Nutrition (Nestec Ltd), Metagenics Inc, and AXA had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding authors) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: Not needed.
Transparency declaration: The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
Data sharing: No additional data available.
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