Our meta-analysis of prospective observational studies showed an inverse association between baseline circulating 25(OH)-vitamin D and risk of CVD with considerable heterogeneity between studies. Comparing the lowest versus the highest categories of 25(OH)-vitamin D concentration, the pooled RR for total CVD was 1.52 (95% CI: 1.30-1.77). The increment of CVD risk with decreasing 25(OH)-vitamin D was generally linear over the range of 25(OH)-vitamin D from 20 to 60 nmol/L, with a modest and marginally significant pooled RR of 1.03 (95% CI: 1.00-1.06) per 25 nmol/L decrement in 25(OH)-vitamin D. These associations remained significant when the analyses were restricted to the studies that excluded participants with baseline CVD and had better controlled for confounding.
A large body of evidence from laboratory studies suggest that vitamin D potentially has beneficial effects on cardiovascular risk factor profiles and development of CVD.3-7 Population studies have shown favorable associations of circulating vitamin D with CVD risk factors
, particularly hypertension,43
impaired glucose tolerance or type 2 diabetes,44
In clinical studies, circulating 25(OH)-vitamin D was low in patients with myocardial infarction,8
, and peripheral arterial disease.10
Despite of the promising data from cross-sectional and case-control studies, results of prospective studies on the association between baseline 25(OH)-vitamin D and subsequent incidence of CVD events remain inconsistent. Our systematic review of literature, in line with earlier reviews,17, 18
found that the majority, albeit not all, prospective studies support an association between low circulating 25(OH)-vitamin D and increased risk of CVD events. The pooled RRs demonstrated a strong, highly significant, inverse association. Although there is considerable heterogeneity between individual studies, stratified analysis found that the inverse association was generally consistent in various subgroups except for the duration of follow-up. A stronger association was found in studies with <10 years follow-up than those with longer follow-up. This finding may reflect greater changes in 25(OH)-vitamin D over longer periods of time, or the competing risks for fatal and non-fatal diseases in older populations.
Some previous studies have suggested a possible non-linear association between 25(OH)-vitamin D and risk of CVD, with a threshold effect or even a U-shaped relation.11, 16
Due to the limited data and the heterogeneity between studies, especially with respect to categories of 25(OH)-vitamin D used, specific CVD outcomes, and confounders adjusted for, the optimal levels of 25(OH)-vitamin D for cardiovascular health has yet to be determined. To resolve this uncertainty, we examined the dose-response association and found that to be generally linear for 25(OH)-vitamin D ranging from 20 to approximately 60 nmol/L. The magnitude of linear association over the broad spectrum of 25(OH)-vitamin D was only modest: the pooled RR for CVD per 25 nmol/L decrement in 25(OH)-vitamin D was 1.03 when all studies were included, and 1.07 when limited to the studies that excluded participants with baseline CVD and had better controlled for confounding. The linear association appeared relatively stronger when combining data from 10 studies that reported the RR of CVD in association with continuous 25(OH)-vitamin D, presumably due to difference in data source, levels of 25(OH)-vitamin D, and modeling strategy. When we specifically evaluated the individual studies with extreme circulating 25(OH)-vitamin D levels, we found that the lowest category of 25(OH)-vitamin D studied was <25 nmol/L; in 3 studies11, 25, 41
that reported the results, all showed significant associations between low 25(OH)-vitamin D and increased risk of CVD. On the other hand, 8 studies12, 16, 31-35, 38
included 25(OH)-vitamin D >65 nmol/L in the comparison group versus a higher reference, with one study examining multiple categories well above 85 nmol/L;35
six found no significant change in the risk of CVD, suggesting a possible threshold effect.
Since our meta-analysis is based on observational study data, the result is subject to potential bias in all observational studies. Although potential confounders such as age, BMI, and physical activity have been adjusted for in individual studies, residual confounding cannot be ruled out. Causality underlying the observed association and the effect of vitamin D supplement on cardiovascular health cannot be addressed in our analysis and remain to be determined in future studies. Preliminary findings from clinical trials have suggested that vitamin D supplementation may reduce cardiovascular mortality46
or CVD event rate,47
supporting a possible role of vitamin D in CVD prevention. Nevertheless, existing trial data are insufficient and inconclusive. There is suggestive evidence that a moderate to high vitamin D exposure may be needed for prevention of CVD.48
It should be noted that the Women’s Health Initiative (WHI) Calcium-Vitamin D trial, in which 36,282 postmenopausal women were assigned to take calcium (1000 mg/d) plus vitamin D3
(400 IU/d) or placebo for 7 years, found no reduction in CHD or stroke incidence with combined calcium and vitamin D supplement.49
One of the most plausible reasons is that the vitamin D dose used in the WHI was too low that it did not change circulating vitamin D levels significantly.49
Although randomized trials are important to establish the causality of vitamin D-CVD relation, their inferences are commonly linked with a single dose of vitamin D that yields a narrow change rather than a full spectrum of 25(OH)-vitamin D. Our meta-analysis of prospective observational studies allows an evaluation on the dose-response association between vitamin D and CVD risk over a broad range of 25(OH)-vitamin D level, which will not only complement findings from ongoing randomized trials but also help to inform future trials that test the effect of vitamin D supplements on CVD regarding the optimal doses.
This meta-analysis has several potential limitations. First, because our analyses were based on published studies, publication bias is a concern. However, a visual inspection of plot and formal tests indicated no evidence of substantial publication bias. Second, some individual studies that reported very strong associations may have influenced the meta-analysis results. Nevertheless, our sensitivity analyses showed that the pooled RR was similar after removing the studies with high RRs. Third, the optimal 25(OH)-vitamin D for cardiovascular health may differ by race/ethnicity. However, since virtually all existing studies were conducted among predominantly Caucasian cohorts, we were unable to assess race/ethnicity specific associations between vitamin D and CVD, even after combining data in this meta-analysis. Finally, the potential bias in each individual study and high heterogeneity between studies preclude definitive conclusions.
Despite of the controversy on causation, improving vitamin D status has been proposed as one promising strategy for CVD prevention. Given the high prevalence of vitamin D insufficiency in the general U.S. population, the potential public health impact of vitamin D improvement would be substantial. Current dietary guidelines for vitamin D by IOM20
that recommend 600 IU/day for persons 1 to 70 years of age and 800 IU/day for persons over 70 years, corresponding to a circulating 25(OH)-vitamin D of 50 nmol/L or more assuming minimal sun exposure, are solely based on the beneficial effect of vitamin D on bone health. The IOM report concluded that evidence was insufficient to demonstrate that vitamin D protects against CVD and called for additional research to elucidate this association. Our meta-analysis based on existing literature showed that low levels of circulating 25(OH)-vitamin D are associated with an increased risk of CVD. The dose-response curve between 25(OH)-vitamin D and CVD risk indicated that the association was generally linear across the range of 25(OH)-vitamin D from 20 to 60 nmol/L with a marginally significant trend. More prospective studies and randomized clinical trials are needed to further clarify the association between 25(OH)-vitamin D higher than 60 nmol/L and CVD risk and to assess the causality of observed associations.