ReviewVitamin D supplementation and lipid profile: What does the best available evidence show?
Introduction
Vitamin D has traditionally been associated with bone health and, together with calcium, is increasingly becoming popular for the prevention and treatment of osteoporosis. Recently, both calcium and vitamin D have been suggested to exert effects on the cardiovascular (CV) system, however the existing evidence is highly controversial. The effects of calcium on the CV system have been reviewed elsewhere and although findings of different studies are conflicting, calcium supplements should be prescribed with caution as significant adverse CV effects have been reported with high intake [1].
The determination of the presence and nature of effects of vitamin D on the CV system is particularly important for a number of reasons. Firstly, hypovitaminosis D is a global health problem with detrimental consequences and notably, according to a recent Workshop Consensus for Vitamin D Nutritional Guidelines, approximately 50% of the elderly population in North America and 60% in the rest of the world have insufficient levels of vitamin D, partly due to reduced outdoor activity, global dimming and decreases in the skin synthesis of vitamin D with age [2], [3]. Large proportions of younger populations also have unsatisfactory vitamin D concentrations. If the correlation between hypovitaminosis D and CV events that were recently reported by epidemiological pooled analysis of prospective studies is true, vitamin D supplementation will function dually both to neutralize inadequate vitamin D levels and the direct metabolic consequences and as a prevention tool of the number one cause of death, CV disease [2], [4], [5]. Conversely, should the evidence strongly suggest adverse effects of the vitamin on the CV system, its use will be restricted where possible and replaced by safer alternatives.
The present review specifically discusses the relationship between vitamin D and serum lipid profile, focusing on evidence deriving from all RCTs identified in the literature.
The vitamin D receptor (VDR) has been historically considered as the only means by which calcitriol achieves its functions, which were thought to be exclusively endocrine and related to mineral metabolism. The VDR initially couples with retinoic X receptor to form a heterodimer, which subsequently binds to vitamin D response elements in the promoter regions of target genes. Recent data, however, has shown that the VDR is expressed in a number of tissues leading to various effects such as immunomodulation and enhancement of cellular proliferation and differentiation. Interestingly, vitamin D regulates around 3% of the genome with numerous effects and functions. Finally, a cytoplasmic form of the VDR has also been identified that responds rapidly or non-genomically to calcitriol and is thought to be involved in cellular calcium handling and other processes [6], [7], [8].
The identification of VDR expression in endothelial cells, vascular smooth muscle cells and cardiac myocytes strongly reinforced the presence of a relation linking vitamin D and the CV system, without, however, implying the nature of this association. Potential effects have been proposed on factors including, but not limited to, blood pressure, serum lipids, CV events, CV death, cardiac work and cardiometabolic syndromes [8].
Although the major source of vitamin D is synthesis in the skin secondary to ultraviolet (UV) B irradiation, it can also be acquired through dietary consumption. Vitamin D may exist in the form of vitamin D2 (ergocalciferol), which derives from the UV irradiation of ergosterol (found in plants and fungi), or vitamin D3 (cholecalciferol) that is produced after UVB irradiation of 7-dehydrocholesterol in the skin of animals. Both are thought to be prohormones as they are biologically inactive and only after a two-step hydroxylation process in the liver and kidneys do they yield the active hormone 1,25-dihydroxyvitamin D (calcitriol). Synthetic supplements exist in both D2 and D3 forms and even though both are eventually converted to the biologically active metabolite, recent data suggested a difference in their efficacy in raising serum 25-OH D, which is the established marker of vitamin D status [9].
In fact, a large meta-analysis of RCTs indicated that vitamin D3 supplements may be more efficacious in elevating serum 25-OH D compared to vitamin D2 supplements, as a statistically significant difference was reported. The favoring of vitamin D3 was evident even with small daily doses and less frequent administration as a bolus at higher dosages [9].
Additionally, a Cochrane meta-analysis investigating the effects of vitamin D supplementation on all-cause mortality found that only vitamin D3 supplementation seems to decrease mortality, while vitamin D2, calcitriol and alfacalcidol had no statistically significant effect on mortality [10].
The exact reasons underlying this difference are still unclear, however these results must be taken seriously into consideration for the future manufacture and use of vitamin D supplements [9].
Each individual may be characterized as vitamin D deficient, insufficient or sufficient based on serum 25-OH D levels. The limit for deficiency is set at a value (20 ng/ml) below which PTH levels become suppressible when challenged with pharmacologic doses of vitamin D and sufficiency is above the value (30 ng/ml) where PTH levels reach their lowest and intestinal calcium absorption is at its maximum. Hence deficiency is <20 ng/ml, sufficiency >30 ng/ml and insufficiency in-between (21–29 ng/ml) [2]. In order for sufficient levels to be achieved, at least 1000 International Units (IU) of vitamin D2 or D3 are thought to be required daily in cases where sun exposure is either absent or inadequate (e.g. winter, sunscreen use) [2].
Section snippets
Vitamin D and CV events
Before discussing the potential CV effects of the vitamin, a concise section summarizing its reported association with CV events is worthwhile, as possible links with CV mortality and events may be more important than correlations to CV parameters. In overview, despite the existence of a few studies that report neutral findings, the protective properties of vitamin D in terms of CV events and all-cause mortality are evident in the literature [10], [11], [12], [13], [14], [15].
A prospective
Vitamin D and lipid profile – randomized controlled trials
Despite the promising data of the observational studies, RCTs fail to indicate a causal association between vitamin D consumption and a favorable lipid profile. Out of 19 RCTs found in the literature up to date, only 1 demonstrated beneficial effects of vitamin D supplementation on serum lipid levels, while, importantly, the only meta-analysis identified, reported statistically significant adverse outcomes in some parameters [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46]
Paradox
Even though the associations noted in observational studies are well established, a causal effect has not yet been proven and a paradox exists: promising findings of observational studies versus discouraging results of interventional studies.
Reasonable explanations have been suggested to provide an explanation to this discrepancy: insufficient activity is a known risk factor for unfavorable lipid profiles, therefore dyslipidemia may be the result of reduced outdoor activity; these people may
Vitamin D, calcium and PTH: which is to blame?
Whenever either of the three is studied, at least a brief mention of the other two should be ideally made. Vitamin D, being one of the calcitropic hormones, is closely related to calcium as well as parathyroid hormone (PTH) and the serum concentrations of all three are directly correlated with each other. Vitamin D supplementation increases serum 25-OH D, which is converted into calcitriol. The latter, in turn, has an impact on both serum calcium (increases) and PTH levels (decrease), both of
Conclusion
The relationship between vitamin D and lipids in humans is a topic that has not been adequately investigated and trustworthy evidence does not yet exist. In spite the fact that some of the mechanisms by which vitamin D may decrease serum cholesterol have been proven in mice after molecular analyses, doubts still remain about their applicability to humans.
Despite the beneficial properties of high serum vitamin D concentrations in terms of the lipid profile shown in the observational studies,
Conflict of interest statement
The authors report no relationships that could be construed as a conflict of interest.
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