Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies

Abstract

Background: Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25-hydroxy-vitamin D (25[OH]-vitamin D) levels for potential cardiovascular health benefits remain unclear.

Methods and results: We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6123 CVD cases in 65 994 participants were included for a meta-analysis. In a comparison of the lowest with the highest 25(OH)-vitamin D categories, the pooled relative risk was 1.52 (95% confidence interval, 1.30-1.77) for total CVD, 1.42 (95% confidence interval, 1.19-1.71) for CVD mortality, 1.38 (95% confidence interval, 1.21-1.57) for coronary heart disease, and 1.64 (95% confidence interval, 1.27-2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose-response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below ≈60 nmol/L, with a relative risk of 1.03 (95% confidence interval, 1.00-1.06) per 25-nmol/L decrement in 25(OH)-vitamin D.

Conclusions: This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations.

Figures

Figure 1

Study Search and Selection Flow Diagram. Search terms for vitamin D included vitamin D, 25hydroxy-vitamin D, 1,25dihydroxy-vitamin D, calcidiol, and calcitriol. Search terms for cardiovascular disease (CVD) included cardiovascular disease, ischemic heart disease, coronary artery disease, cardiovascular mortality, myocardial infarction, and stroke. Initial search results were further limited to English-language articles, human studies, and studies of adults 18 years. In each box, the sum of studies in all categories may exceed the total number because of overlapping classification.

Figure 2

A Random-Effect Meta-Analysis of 19 Independent Studies. Adjusted relative risk (RR) and 95% confidence interval (CI) of total cardiovascular events (including myocardial infarction, stroke, and cardiovascular death) was estimated comparing the lowest category versus the highest category of baseline circulating 25(OH)-vitamin D concentration. Squares indicate RR in each study. The size of the square is proportional to the precision of the RR (inverse of its variance). Horizontal line represents the 95% CI. The pooled RR and 95% CI are indicated by the unshaded diamond.

Figure 3

Dose-response Association between Circulating 25(OH)-vitamin D and Risk of Cardiovascular Disease in 16 Prospective Studies. The analysis was conducted using a fractional polynomial spline regression. Circles indicate relative risk (RR) in each study. The size of the circle is proportional to the precision of the RR (inverse of its variance). The grey shaded region shows the 95% CIs around the regression line. The method described by Greenland and Longnecker for the dose-response analysis was used to compute the linear trend from the correlated RRs and 95% CIs across categories of 25(OH)-vitamin D.