Cross-sectional studies have reported consistent associations between lower vitamin D status and prevalent cardiometabolic outcomes (1
). In longitudinal observational studies, reviewed here, lower vitamin D status was associated with increased risk of incident hypertension and possibly cardiovascular disease, but the strengths of associations were attenuated compared to cross-sectional studies. The evidence from longitudinal studies of type 2 diabetes was sparse. In trials, there was no statistically significant effect of vitamin D supplementation on diastolic or systolic blood pressure, glycemic, or cardiovascular outcomes. However, there was a suggestion of lower systolic blood pressure (by 2 mm Hg, statistically nonsignificant) with vitamin D supplement use. Further data are necessary to adjudicate this observation.
There are several plausible mechanisms of how vitamin D may modify risk of cardiometabolic outcomes. Vitamin D may have direct (via vitamin D receptor activation) and indirect (via calcium homeostasis regulation) effects on various mechanisms related to type 2 diabetes pathophysiology, including impaired pancreatic beta cell function and insulin resistance (1
). Regarding cardiovascular outcomes, vitamin D regulates the renin-angiotensin system (46
), suppresses proliferation of vascular cell smooth muscle (47
), ameliorates insulin resistance (18
) improves endothelial cell-dependent vasodilation (48
), inhibits anticoagulant activity (50
) and myocardial cell hypertrophy (51
), and may modulate macrophage activity (54
) and cytokine generation (34
Several possible reasons may explain the lack of apparent concordance between the cross-sectional, longitudinal observational, and randomized studies. The inverse association between vitamin D status and cardiometabolic outcomes may be confounded by a variety of factors. First, vitamin D status is an excellent marker of good health, including positive associations with young age, normal body weight, and a healthy lifestyle (56
) and negative associations with smoking, parental history of myocardial infarction, and alcohol intake (2
). Second, lower vitamin D status may reflect chronic non-specific illness. Therefore, the inverse association seen in cross-sectional studies may be due to reverse causation. Third, additional components in foods rich in vitamin D (e.g., fish or fortified dairy products) may have direct effects on cardiometabolic disease or, alternatively, foods rich in vitamin D may replace other foods that increase risk of cardiometabolic disease (e.g., fortified milk replacing sweetened drinks) (57
). Finally, observational studies have used single measurements of serum or plasma 25(OH)D as a proxy of vitamin D status, which may not reflect long-term vitamin D status.
The Women’s Health Initiative, which is the largest trial on vitamin D and calcium supplementation to-date, reported no statistically significant effects for all cardiometabolic outcomes examined. However, this trial used a relatively small dose of vitamin D (400 IU/day), had difficulties with compliance over 7 years, and allowed participants in both intervention groups to take supplemental vitamin D. Based on dose and compliance, the effect of supplementation on 25(OH)D concentration in the Women’s Health Initiative trial has been estimated it to be only 5 nmol/L (58
), an increment very unlikely to be associated with any change in risk of cardiometabolic outcomes based on data from the observational studies.
The optimal 25(OH)D concentration is currently under review by the Institute of Medicine. For a variety of skeletal and non-skeletal outcomes, it has been proposed that 25(OH)D concentration <25 nmol/L defines vitamin D deficiency, while a level >75 nmol/L is associated with improved bone and non-bone related outcomes (59
). In the longitudinal observational studies, any decreased risk of cardiometabolic outcomes was seen only among those with a moderate 25(OH)D concentration (62–87 nmol/L) compared to those with relatively low levels (25–37 nmol/L). In several studies, an apparent threshold was seen where risk of cardiovascular disease did not decrease further with 25(OH)D concentration >50 nmol/L (24
), indicating that vitamin D deficiency may increase risk but higher 25(OH)D concentration may not necessarily lower risk proportionately. These data suggest that clinically significant effects of improving vitamin D status on cardiometabolic outcomes may be seen only among those with vitamin D deficiency. Higher levels of 25(OH)D concentration (>250 nmol/L) have been recommended by some to optimize outcomes; however, there is a complete lack of longitudinal data (observational or trials) to support such a recommendation.
Our study has certain limitations based on the quality of the published studies included in the review. In the observational studies, the outcome was ascertained by self-report or from national registry data. A positive self-report is generally quite accurate in epidemiologic studies (60
) and most of the included studies validated the outcome. However, early-stage cardiometabolic outcomes may have been undiagnosed and therefore missed and not included in the analyses. There was also substantial heterogeneity among studies, especially in vitamin D thresholds or doses analyzed, specific outcomes, and confounders adjusted for. Importantly, not all studies adjusted for sun exposure. Finally, study participants were mostly whites aged approximately 40 to 70 years old, thus limiting the applicability to other racial groups and life stages.
In conclusion, a lower vitamin D status was possibly associated with higher risk of incident hypertension and cardiovascular disease, but the association with diabetes-related outcomes remains unclear. As a whole, trials showed no statistically significant effect of vitamin D supplementation on cardiometabolic outcomes. The available data are inadequate to support the contention that cardiometabolic outcomes can be improved by raising vitamin D intake or serum or plasma 25(OH)D concentrations. It is therefore imperative that adequate randomized trials are conducted in well-defined populations (e.g. pre-diabetes, pre-hypertension, whites vs. non-whites) to test the potential role of vitamin D in primary prevention or therapy. Vitamin D remains a promising, though unproven, new element in the prevention and management of cardiometabolic disease.