Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis.

BACKGROUND: Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear. METHODS AND RESULTS: We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level meta-analysis was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial-level meta-analysis, and 24 trials (2051 participants) contributed to individual-participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial-level meta-analysis showed no significant effect of supplementation on macrovascular measures (flow-mediated dilatation, 0.37% [95% confidence interval, -0.23 to 0.97]; carotid-femoral pulse wave velocity, 0.00 m/s [95% confidence interval, -0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues. CONCLUSIONS: Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.

The effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease.

Adequate vitamin D levels may promote cardiovascular health by improving endothelial function and down-regulating inflammation. The objective of this pilot trial was to investigate the effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease (CAD). Using a double-blind placebo wait-list control design, 90 subjects with CAD and vitamin D deficiency (< 20 ng/ml) were randomized 1:1 to 50,000 IU of oral ergocalciferol or placebo weekly for 12 weeks. Endothelial function (reactive hyperemia peripheral arterial tonometry, RH-PAT), circulating adhesion molecules, and pro-inflammatory cytokines were measured at baseline and 12 weeks. The median increase in serum 25-vitamin D from baseline was 26 ± 17 ng/ml in the active group and 4 ± 8 ng/ml in the placebo group (between-group difference = 22 ng/ml, p < 0.001). The median within-subject change in RH-PAT score was 0.13 ± 0.73 with active treatment and -0.04 ± 0.63 with placebo (between-group difference = 0.17, p = 0.44). Within-group and between-group differences in intercellular adhesion molecule levels were greater with placebo (between-group difference = 6 ng/ml, p = 0.048). Vascular cell adhesion molecule levels decreased in both groups by a similar magnitude (median difference between groups = 8.5 ng/ml, p = 0.79). There was no difference between groups in magnitude of reduction in interleukin (IL)-12 (-8.6 ng/ml, p = 0.72) and interferon-gamma (0.52 ng/ml, p = 0.88). No significant differences in blood pressure, e-selectin, high-sensitivity c-reactive protein, IL-6 or the chemokine CXCL-10 were found with treatment. In conclusion, repleting vitamin D levels in subjects with CAD failed to demonstrate any benefits on surrogate markers of cardiovascular health. These results question the role of vitamin D supplementation in modifying cardiovascular disease.

Vitamin D status and risk of cardiovascular events: lessons learned via systematic review and meta-analysis.

Accumulating data linking hypovitaminosis D to cardiovascular (CV) events has contributed to large increases in vitamin D testing and supplementation. To evaluate the merits of this practice, we conducted a systematic review with meta-analysis providing a framework for interpreting the literature associating hypovitaminosis D with increased CV events. Prospective studies were identified by search of MEDLINE and EMBASE from inception to January 2010, restricted to English language publications. Two authors independently extracted data and graded study quality. Pooled relative risks (RR) were calculated using a random effects model. Ten studies met criteria for review and 7 were included in meta-analysis. Pooled RR for CV events using FAIR and GOOD quality studies was 1.67 (95% confidence interval, 1.23-2.28) during an average follow-up of 11.8 years. There was evidence of significant heterogeneity across studies (Q statistics = 16.6, P = 0.01, I = 63.8%), which was eliminated after omitting 2 studies identified by sensitivity analysis (RR, 1.34 [1.08-1.67]; P for heterogeneity =0.33). When restricting analysis to GOOD quality studies (RR, 1.27 [1.04-1.56]), no significant heterogeneity was found (P = 0.602). Systematic review identified significant shortcomings in the literature, including variability in defining vitamin D status, seasonal adjustments, defining and determining CV outcomes, and the use of baseline vitamin D levels. In conclusion, a modest increased risk of CV events associated with hypovitaminosis D is tempered by significant limitations within the current literature. These findings underscore the importance of critical appraisal of the literature, looking beyond reported risk estimates before translating results into clinical practice.