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Original Investigation
June 2017

Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study A Randomized Clinical Trial

Author Affiliations
  • 1School of Population Health, The University of Auckland, Auckland, New Zealand
  • 2Department of Public Health & General Practice, The University of Otago, Christchurch, New Zealand
  • 3Department of Public Health, University of Cambridge, Cambridge, England
  • 4Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Cardiol. 2017;2(6):608-616. doi:10.1001/jamacardio.2017.0175
Key Points

Question  Does monthly high-dose vitamin D supplementation prevent cardiovascular disease?

Findings  In a randomized clinical trial that included 5108 participants from the community, the cumulative incidence of cardiovascular disease for a median follow-up period of 3.3 years was 11.8% among participants given 100 000 IU of vitamin D3 monthly and 11.5% among those given placebo.

Meaning  Monthly high-dose vitamin D supplementation did not prevent cardiovascular disease and should not be used for this purpose.


Importance  Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D.

Objective  To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population.

Design, Setting, and Participants  The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis.

Interventions  Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years).

Main Outcomes and Measures  The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis.

Results  Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes.

Conclusions and Relevance  Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study.

Trial Registration  clinicaltrials.gov Identifier: ACTRN12611000402943