A Prospective Randomized Controlled Trial of the Effects of Vitamin D Supplementation on Cardiovascular Disease Risk

University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
PLoS ONE (Impact Factor: 3.23). 05/2012; 7(5):e36617. DOI: 10.1371/journal.pone.0036617
Source: PubMed


Vitamin D (VitD) supplementation has been advocated for cardiovascular risk reduction; however, supporting data are sparse. The objective of this study was to determine whether VitD supplementation reduces cardiovascular risk. Subjects in this prospective, randomized, double-blind, placebo-controlled trial of post-menopausal women with serum 25-hydroxyvitamin D concentrations >10 and <60 ng/mL were randomized to Vitamin D3 2500 IU or placebo, daily for 4 months. Primary endpoints were changes in brachial artery flow-mediated vasodilation (FMD), carotid-femoral pulse wave velocity (PWV), and aortic augmentation index (AIx). The 114 subjects were mean (standard deviation) 63.9 (3.0) years old with a 25-hydroxyvitamin D level of 31.3 (10.6) ng/mL. Low VitD (<30 ng/mL) was present in 47% and was associated with higher body-mass index, systolic blood pressure, glucose, CRP, and lower FMD (all p<0.05). After 4 months, 25-hydroxyvitamin D levels increased by 15.7 (9.3) ng/mL on vitamin D3 vs. −0.2 (6.1) ng/mL on placebo (p<0.001). There were no significant differences between groups in changes in FMD (0.3 [3.4] vs. 0.3 [2.6] %, p = 0.77), PWV (0.00 [1.06] vs. 0.05 [0.92] m/s, p = 0.65), AIx (2.7 [6.3] vs. 0.9 [5.6] %, p = 0.10), or CRP (0.3 [1.9] vs. 0.3 [4.2] mg/L, p = 0.97). Multivariable models showed no significant interactions between treatment group and low VitD status (<30 ng/mL) for changes in FMD (p = 0.65), PWV (p = 0.93), AIx (p = 0.97), or CRP (p = 0.26).In conclusion, VitD supplementation did not improve endothelial function, arterial stiffness, or inflammation. These observations do not support use of VitD supplementation to reduce cardiovascular disease risk.

Trial Registration NCT00690417

Trial Registration NCT01049048

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    • "Murdoch et al. (2012) observed no impact of vitamin D supplementation on the incidence of upper respiratory tract infections [25]. Gepner et al. (2012) observed reduced cardiovascular disease risk in postmenopausal women with vitamin D supplementation [26]. Few studies have, however, evaluated whether interactions between genetic variants in the VDR and vitamin D status could confound disease association in diverse populations. "
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    ABSTRACT: Polymorphisms of the vitamin D receptor gene (VDR) have been associated inconsistently with various diseases, across populations of diverse origin. The T(f) allele of the functional SNP FokI, in exon 2 of VDR, results in a longer vitamin D receptor protein (VDR) isoform, proposed to be less active. Genetic association of VDR with disease is likely confounded by ethnicity and environmental factors such as plasma 25(OH)D3 status. We hypothesized that VDR expression, VDR level and transactivation of target genes, CAMP and CYP24A1, depend on vitamin D, ethnicity and FokI genotype. Healthy volunteers participated in the study (African, n = 40 and White, n = 20). Plasma 25(OH)D3 levels were quantified by LC-MS and monocytes cultured, with or without 1,25(OH)2D3. Gene expression and protein level was quantified using qRT-PCR and flow cytometry, respectively. Mean plasma 25(OH)D3 status was normal and not significantly different between ethnicities. Neither 25(OH)D3 status nor 1,25(OH)2D3 supplementation significantly influenced expression or level of VDR. Africans had significantly higher mean VDR protein levels (P<0.050), nonetheless transactivated less CAMP expression than Whites. Genotyping the FokI polymorphism by pyrosequencing together with HapMap data, showed a significantly higher (P<0.050) frequency of the CC genotype in Africans than in Whites. FokI genotype, however, did not influence VDR expression or VDR level, but influenced overall transactivation of CAMP and 1,25(OH)2D3-elicited CYP24A1 induction; the latter, interacting with ethnicity. In conclusion, differential VDR expression relates to ethnicity, rather than 25(OH)D3 status and FokI genotype. Instead, VDR transactivation of CAMP is influenced by FokI genotype and, together with ethnicity, influence 1,25(OH)2D3-elicited CYP24A1 expression. Thus, the expression and role of VDR to transactivate target genes is determined not only by genetics, but also by ethnicity and environment involving complex interactions which may confound disease association.
    PLoS ONE 06/2013; 8(6):e67663. DOI:10.1371/journal.pone.0067663 · 3.23 Impact Factor
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    • "Our negative results are in line with recent reviews, meta-analyses, and large studies regarding serum lipids and vitamin D supplementation [16] [17] [18], and we have previously concluded in an editorial that it is questionable if more such studies are needed [19]. With a few exceptions [20] most intervention studies have not been able to show an effect on glucose metabolism [21] [22], and similarly, most studies on vitamin D effects on inflammatory markers have also been negative [22] [23] [24]. "
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    ABSTRACT: Data were pooled from four randomized clinical trials with vitamin D performed in Tromsø with weight reduction, insulin sensitivity, bone density, and depression scores as endpoints. Serum lipids, glycated hemoglobin (HbA1c), and high sensitivity C-Reactive Protein, (HS-CRP) were measured at baseline and after 6-12 months of supplementation with vitamin D 20 000 IU-40 000 IU per week versus placebo. A total of 928 subjects who completed the interventions were included. At baseline the mean serum 25-hydroxyvitamin D (25(OH)D) level in those given vitamin D was 55.9 (20.9) nmol/L and the mean increase was 82.4 (40.1) nmol/L. Compared with the placebo group there was in the vitamin D group at the end of the studies a slight, but significant, increase in HbA1c of 0.04%, an increase in HS-CRP of 0.07 mg/L in those with serum 25(OH)D < 50 nmol/L, and in those with low baseline HDL-C and serum 25(OH)D < 50 nmol/L a slight decrease serum HDL-C of 0.08 mmol/L (P < 0.05). No serious side-effects were seen. In conclusion, in subjects without vitamin D deficiency, there is no improvement in serum lipids, HbA1c, or HS-CRP with high dose vitamin D supplementation. If anything, the effect is negative.
    03/2013; 2013(6, supplement):348705. DOI:10.1155/2013/348705
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    ABSTRACT: In the last 3 years, more evidence accumulated that vitamin D (vitD)deficiency associates with cardiovascular disease (CVD) and risk factors. The association with higher cardiovascular (CV) mortality was stronger than with nonfatal CVD events. A higher incidence of type 2 diabetes was also shown. Many factors related to lifestyle (physical activity in particular) influence both vitD levels and CVD, and may contribute to explain these observational data. Whether the association between vitD and CVD is causal can only be established through randomized controlled trials (RCTs), and to date the results of the randomized trials, which were not designed for investigating CV outcomes, do not support the association data. Answers on the effects of vitD supplementation on primary and secondary prevention of CV may be found in the specifically designed ongoing RCTs. In the mean time, low vitamin D levels should be regarded as a marker of unhealthy lifestyle, requiring a more aggressive attempt at modifying individual lifestyle.
    Current Atherosclerosis Reports 09/2012; 14(6). DOI:10.1007/s11883-012-0281-9 · 3.42 Impact Factor
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