Clinical trials of vitamin D supplementation and cardiovascular disease: A synthesis of the evidence

The evidence linking vitamin D deficiency with increased risk of cardiovascular disease (CVD) extends back to 1970s when case control studies showed lower circulating concentrations of 25-hydroxyvitamin D [25(OH)D] in myocardial infarction cases compared with controls, which was strengthened by the identification of a vitamin D receptor in cardiac muscle in 1980s. Cohort studies published in the 2000s provided stronger evidence (by measuring 25(OH)D concentrations before the onset of CVD) and confirmed the inverse association between circulating 25(OH)D concentrations and CVD risk. However, concerns remained about possible residual confounding as the reason for the inverse association. This stimulated the initiation of several large scale randomized controlled trials (RCTs) of vitamin D supplementation with CVD as a pre-specified outcome. Results from these studies have been combined with findings from earlier RCTs in a recent meta-analysis undertaken on behalf of the US Endocrine Society. In 14 RCTs with 80,547 participants aged 50-74 years, vitamin D supplementation did not protect against CVD when compared to placebo: risk ratio 1.00 (95 % confidence interval 0.93-1.08). This result did not vary by study quality (risk of bias), gender, calcium co-administration, vitamin D dose or trial setting (community or residential care). This finding is consistent with recent mendelian randomization studies which have not detected a beneficial effect associated with genetically predicted 25(OH)D in people with vitamin D deficiency. Overall, the current evidence indicates that vitamin D does not prevent CVD.