Vitamin D and Cardiovascular Disease: Controversy Unresolved
State-of-the-Art Review
Central Illustration
Abstract
Vitamin D deficiency is typically caused by inadequate cutaneous synthesis secondary to decreased exposure to sunlight. Serum levels of 25-hydroxyvitamin D l <20 ng/ml are diagnostic of vitamin D deficiency. Vitamin D has various cardiovascular pleiotropic effects by activating its nuclear receptor in cardiomyocytes and vascular endothelial cells and by regulating the renin-angiotensin-aldosterone system, adiposity, energy expenditure, and pancreatic cell activity. In humans, vitamin D deficiency is associated with the following: vascular dysfunction; arterial stiffening; left ventricular hypertrophy; and worsened metrics of diabetes, hypertension, and hyperlipidemia. It is also linked with worse cardiovascular morbidity and mortality. However, meta-analyses of vitamin D supplementation trials have failed to show clear improvements in blood pressure, insulin sensitivity, or lipid parameters, thus suggesting that the link between vitamin D deficiency and cardiovascular disease may be an epiphenomenon. Ongoing larger randomized trials will clarify whether monitoring and supplementation of vitamin D play roles in cardiovascular protection.
Photosynthesis, Dietary Intake, and Metabolism of Vitamin D
Vitamin D consists of a group of fat-soluble molecules called secosteroids, which are similar to steroids, but with “broken” rings, and that exist in several forms (Figure 1). Its designation as a vitamin is a misnomer given that human skin synthesizes cholecalciferol, or vitamin D3, by the photochemical cleavage of cutaneous 7-dehydrocholesterol, which is most efficient at ultraviolet (UV) wavelengths. The ability to convert 7-dehydrocholesterol into vitamin D in the skin decreases with age and with increasing skin pigmentation or sunscreen use, and it is also affected by seasonal changes, distance from the Equator, and altitude, as well as the degree of ambient pollution and cloud cover. Vitamin D3 is also found naturally in fatty fish, fish oils, and egg yolks and is also industrially manufactured. A second form of vitamin D, ergocalciferol (or vitamin D2) is produced by irradiation of ergosterol, a membrane sterol found in the ergot fungus.
Vitamin D Synthesis and Metabolism
Vitamin D is photosynthesized in the skin and is also acquired by dietary intake. Two hydroxylation steps in the liver and the kidney are required for vitamin D activation, thus forming 1,25-dihydroxyvitamin D. UVB = ultraviolet radiation in the B-wavelength region (320 to 290 nm).
Whether derived from the diet or synthesized cutaneously, vitamins D2 and D3 are biologically inert and require activation by successive hydroxylation steps, first by hepatic mitochondrial and microsomal enzymes, yielding 25-hydroxyvitamin D (25-OH D). This step is loosely regulated, if at all, and excessive intake (i.e., pharmacological preparations) of vitamin D2 or vitamin D3 causes a proportional and unchecked rise in serum 25-OH D levels (1). In contrast, cutaneous synthesis raises serum 25-OH D to a plateau level above which further sun exposure results in spontaneous 25-OH D degradation (2). The second step is catalyzed and tightly regulated by renal 1-α-hydroxylase and yields the hormonal form 1,25-dihydroxyvitamin D (1,25-OH vitamin D or calcitriol). Although 25-OH D may bind and activate the vitamin D receptor (VDR), 1,25-OH vitamin D is by far the most potent vitamin D analogue that mediates most known functions of vitamin D.
The clinical properties of vitamin D have been most extensively studied as an antirachitic factor, including its effects on intestinal and renal handling of mineral ions and regulation of osteoblast activity. Vitamin D deficiency causes a net reduction in intestinal absorption and renal reabsorption of calcium, which, in turn, raises parathyroid hormone (PTH) levels and is accompanied by osteocyte activation and accelerated bone demineralization to maintain eucalcemia. More recently, the identification of fibroblast growth factor 23, a secretory protein expressed in osteoblasts and osteocytes, demonstrated a complex feedback loop along a bone-kidney axis, with pivotal roles in phosphate and vitamin D metabolism. Indeed, elevated fibroblast growth factor 23 is associated with vascular dysfunction, ventricular hypertrophy, and incident CVD and is believed to represent the other side of the same coin as vitamin D deficiency.
Following chronic and severe vitamin D deficiency, frank hypocalcemia ensues, but patients rarely present with the acute symptoms (e.g., tingling or tetany) that are classically observed following surgical resection of parathyroid glands, as this usually develops over an extended period. Rather, isolated vitamin D deficiency commonly manifests as a constellation of vague, local, or diffuse musculoskeletal aches and pains, accompanied by low serum calcium and phosphorus and elevated alkaline phosphatase and PTH levels. The diagnosis is confirmed by low serum 25-OH D levels.
Vitamin D Status: Deficiency Versus Insufficiency
The most suitable metabolite for assessment of vitamin D status is serum 25-OH D, given its long half-life (weeks vs. hours for 1,25-OH vitamin D) and its reflection of both dietary intake and cutaneous synthesis. Serum 25-OH D levels >12 ng/ml are generally required to maintain 1,25-OH vitamin D within its narrow physiological range and to suppress PTH, and most current guidelines agree that levels <20 ng/ml are inadequate for maintaining bone health and are therefore diagnostic of vitamin D deficiency. However, a consensus is yet to be reached regarding an optimal level for maintaining nonskeletal health and reaping possible cardiovascular and cancer preventive benefits. Although some consider levels >20 ng/ml to be sufficient, others categorize levels between 20 and 29 ng/ml as vitamin D insufficiency and/or even diagnose vitamin D deficiency at any level <30 ng/ml.
Vitamin D Deficiency and Cardiovascular Diseases: Epidemiology
Population studies demonstrate an unequivocal association between vitamin D deficiency and the prevalence of many chronic morbid conditions, including cardiovascular disease (CVD) and its risk factors. Notable examples include the third National Health and Nutrition Examination, as well as large European cohorts that showed a cross-sectional inverse relationship between 25-OH D levels and the prevalence of hypertension, insulin resistance, frank type 2 diabetes mellitus (DM), and dyslipidemia, despite careful adjustment for potential confounders. Moreover, vitamin D deficiency has been implicated as an independent risk factor for the prospective development of CVD or its risk factors, as well as incident all-cause and CVD morbidity and mortality in several cohort studies that followed hundreds of thousands of subjects for nearly 2 decades (3).
Vitamin D and CVD: Mechanisms
Epidemiological studies linking vitamin D status and CVD risk were paralleled by experimental studies elucidating mechanisms by which vitamin D deficiency may confer increased CVD risk (Central Illustration). Both the VDR and 1-α-hydroxylase, which converts vitamin D into the hormonal 1,25-OH vitamin D form, are found in cardiovascular tissues, and experimental models lacking VDR highlight its tissue-specific activity. For example, VDR knockout results in increased ventricular mass and atrial natriuretic peptide levels and dyshomeostasis of cardiac metalloproteinases and fibroblasts, thereby promoting formation of a fibrotic extracellular matrix and leading to ventricular dilation and impaired electromechanical coupling (4,5).
Mechanisms by Which Vitamin D Deficiency May Confer Cardiovascular Risk
Potential effects of vitamin D metabolism on the cardiovascular system are divergent, but they share common initial steps of nuclear and plasma membrane vitamin D receptor (VDR) activation. 1,25-OH vitamin D = 1,25-dihydroxyvitamin D; ANP = atrial natriuretic peptide; Ca2+ = calcium cation; MMP = matrix metalloproteinases; RAS = renin-angiotensin system; RXR = retinoid-X receptor; VDRE = vitamin D response elements (promoter region of target genes); VEGF = vascular endothelial growth factor; VSMC = vascular smooth muscle cell.
Endothelial cells also express VDR, which is up-regulated under stress; VDR activation modulates response elements in the vascular endothelial growth factor (VEGF) promoter and affects calcium influx across the cell membrane, as well as endothelium-dependent vascular smooth muscle contractions and vascular tone in hypertensive models (6). Importantly, the role of 1,25-OH vitamin D as a negative regulator of the renin-angiotensin-aldosterone system (RAAS) was demonstrated in VDR knockout models (7). Other potential consequences of impaired vitamin D metabolism on human vasculature include exacerbation of atherogenesis and acceleration of arterial calcification. For example, the established antilymphoproliferative properties of vitamin D extend to regulation of monocyte or macrophage differentiation and the concomitant response to and secretion of inflammatory cytokines (7–10). This action, in turn, may determine monocyte infiltration and cholesterol retention in the vascular wall.
Vitamin D and CVD: Clinical Evidence
Vitamin D, arterial stiffness, and hypertension
The unequivocal cross-sectional and prospective inverse relationship between vitamin D deficiency and elevated blood pressure (BP) suggests involvement of vitamin D metabolism in the pathogenesis of hypertension. A cause-and-effect relationship is hypothesized on the basis of the key modulating effects of vitamin D on the RAAS axis whereby vitamin D deficiency may promote sustained RAAS activation, whereas sufficient levels may afford “endogenous” proximal inhibition.
For example, studies in normotensive and hypertensive subjects revealed an inverse relationship between vitamin D metabolites and plasma renin activity, regardless of baseline renin levels or salt intake, whereas dietary salt loading in vitamin D–deficient hypertensive subjects resulted in an exaggerated BP increase that was proportional to increases in 1,25-OH vitamin D and baseline renin levels (11–14). Moreover, administration of high-dose cholecalciferol therapy (15,000 IU/day for 1 month) in obese, hypertensive patients resulted in a significant increase in renal plasma flow and a decrease in mean arterial pressure. Infusion of angiotensin following cholecalciferol therapy resulted in a greater decline in renal plasma flow and higher aldosterone secretion when compared with pre-treatment infusions, akin to the well-known findings of increased tissue sensitivity to angiotensin following RAAS antagonist therapy (15,16).
Unopposed activation of the RAAS and generation of angiotensin promote arterial stiffening and endothelial dysfunction that precede and contribute to the development of hypertension and are also predictors of CVD risk (17). We previously reported increased arterial stiffness and vascular dysfunction with lower 25-OH D levels in 554 healthy subjects, independent of potential confounders (18). These findings were reproduced in the British Multi-Ethnic Study and Baltimore Longitudinal Study of Aging and were also reported in post-menopausal women, patients with diabetes, and patients with rheumatologic conditions, peripheral arterial disease, and renal insufficiency (19–25). Although significant improvements in vascular function were evident with passive normalization of vitamin D status in our cohort at 6 months, and with vitamin D therapy in asymptomatic black adolescents and diabetic subjects, meta-analyses of few randomized trials examining vascular function concluded that vitamin D therapy has no significant effects on arterial stiffness or endothelial function (Table 1) (26–34).
| First Author, Year (Ref. #) | Number of RCTs (Number of Patients) | Patient Population | Follow-Up, months | Conclusions | |
|---|---|---|---|---|---|
| Endothelial dysfunction, arterial stiffness | Rodríguez, 2016 (27) | 13 (607) | HTN, DM, CKD, PAD, PCOS, older | 2–12 | Nonsignificant decreases in pulse wave velocity and augmentation index (effect size: −0.1 m/s and −0.15; p = 0.17 and 0.08, respectively) |
| Joris, 2015 (26) | 9 (658) | DM, HTN, HIV, CVA, African Americans | 2–12 | No effect on brachial artery flow-mediated dilation (0.15%; p = 0.41) | |
| Stojanović, 2015 (28) | 8 (529) | DM, CKD, HIV, CVA, menopausal women | 2–4 | No effect on brachial artery flow-mediated dilation (1%; p = 0.09) | |
| HTN, arterial BP | Beveridge, 2015 (33) | 46 (4,541) | Healthy, DM, HTN, older, CKD, HIV, HF | 1–18 | No significant systolic (−0.5 mm Hg; p = 0.27) or diastolic (0.2 mm Hg; p = 0.38) BP changes compared with placebo |
| Qi, 2016 (34) | 8 (917) | Non-CKD, pre-HTN, HTN, African Americans | 3–84 | No significant systolic (−0.08 mm Hg; p = 0.2) or diastolic (0.09 mm Hg; p = 0.155) BP changes compared with placebo | |
| Insulin resistance and type 2 DM | Jamka, 2015 (58) | 12 (1,181) | Overweight, pre-DM adolescents and adults | 3–13 | No effect on glucose concentration (−0.1 mmol/l; p = 0.25) or HOMA-IR index (0.04; p = 0.86) |
| Seida, 2014 (59) | 35 (43,407) | Healthy, obese, pre-DM/DM, CKD | 2–84 | No effect on measures of insulin resistance, progression to DM, or incidence of adverse events. | |
| Hypercholesterolemia and dyslipidemia | Wang, 2012 (64) | 12 (1,346) | Healthy, obese, DM, CVA | 1–36 | Statistically significant increase in LDL cholesterol of 3.2 (95% CI: 0.6 to 5.9) mg/dl, but not total/HDL cholesterol or triglycerides |
| Elamin, 2011 (38) | 12 (2,267) | Healthy, older, pre-DM/DM, hyperlipidemia | 6–72 | No significant effect on LDL (0.1 mg/dl; 95% CI: −0.24 to 0.07; p = 0.27) or triglycerides (0.04 mg/dl; 95% CI: −0.11 to 0.03; p = 0.25 | |
| Cardiovascular morbidity and mortality | Bolland, 2014, (55) | 8 (46,431) | Post-menopause, pre-DM, osteoporosis | 2–60 | No effect on incidence of myocardial infarctions, ischemic heart disease, or cerebrovascular accidents |
| Bjelakovic, 2014 (71) | 56 (47,814) | Older women, osteoporosis | 2–72 | Small relative risk reduction in all-cause mortality with only cholecalciferol (vitamin D3) administration |
Similarly, randomized trials examining BP changes with vitamin D supplementation and/or replacement have been generally disappointing. For example, in 455 vitamin D–deficient patients with pre-hypertension or stage I hypertension, a study group expected to benefit the most from vitamin D replacement, 6 months of daily high-dose (4,000 IU) versus low-dose (400 IU) cholecalciferol did not differ in their effects on the primary endpoint, which was the 24-h systolic BP (−0.8 vs. −1.6 mm Hg; p = 0.71). It is worth mentioning that this study did not include a placebo arm, and there was a modest BP reduction in both groups (35).
An Austrian trial in 188 hypertensive subjects with 25-OH D levels <30 ng/ml found no significant antihypertensive effects in those subjects randomized to 2,800 IU/day of cholecalciferol compared with placebo (treatment effect: −0.4 mm Hg; p = 0.712) (36). In contrast, systolic BP in 238 black subjects with hypertension was lowered by 0.7, 3.5, and 4 mm Hg following 3 months of winter cholecalciferol supplementation with 1,000, 2,000, and 4,000 IU/day, respectively, compared with placebo (+0.6 mm Hg; p < 0.04). In this study, every 1 ng/ml increase in 25-OH D level was associated with a 0.2 mm Hg reduction in systolic BP, but not diastolic BP (37).
Several meta-analyses and systematic reviews of trials largely designed to investigate skeletal effects of vitamin D therapy reported varied conclusions on its BP effects. An analysis of data from 46 such trials concluded that vitamin D supplementation is ineffective in lowering BP and should not be used as an antihypertensive agent. Overall, there were either no changes or only small reductions in BP in most studies, with specific subgroups, including subjects with hypertension, those with baseline deficiency, and blacks, appearing to derive modest benefits (Table 1) (37–42).
A commonly overlooked but major complicating factor in determining the effects of vitamin D on BP is that exposure to UV light also causes reductions in BP, independent of vitamin D photosynthesis. Significant hypotensive effects of erythemal and pre-erythemal doses of UV irradiation have been demonstrated in both normotensive and hypertensive subjects (43–45). These effects are likely to be the result of overall decreases in vascular resistance with diffuse skin vasodilation, and this “photorelaxation” is thought to be partly mediated by increased nitric oxide release in cutaneous vascular beds (46,47). However, whether normalizing vitamin D deficiency by photosynthesis affects arterial pressure differently from oral supplementation remains unknown.
Vitamin D and DM
Experimental evidence highlights mechanisms by which vitamin D may influence glycemic control. These mechanisms include modulation of pancreatic RAAS activity and regulation of calcium ion traffic across β-cells that directly affect insulin synthesis and secretion. Furthermore, vitamin D deficiency results in aberrant immune responses that precipitate an inflammatory milieu and subsequent insulin resistance (48–50). However, discrepancies in experimental and clinical evidence underscore knowledge gaps in determining the relationship between vitamin D metabolism and glycemic control (50).
For example, although human adipocytes express membrane-bound VDR that modulates lipolysis and lipogenesis activity in vitro, VDR-null murine models exhibit a lean phenotype and increased energy expenditure, which are associated with adipose tissue atrophy. Furthermore, models heterozygous for VDR show a similar, albeit less severe phenotype (51). Alternatively, the increased adiposity and body fat mass observed in most insulin-resistant subjects may partly account for the lower 25-OH D levels seen in this population because lipid-soluble vitamin D may be sequestered in adipose tissue, thus decreasing 25-OH D bioavailability (52).
Observational, case control, and prospective evidence strongly suggests that supplementing infants with vitamin D may significantly reduce the future incidence of type 1 DM. Dosage and timing of therapy appear to modulate these protective effects (53). The evidence for type 2 DM is weaker. Results from the Women’s Health Initiative (WHI), in which 33,591 post-menopausal women were randomized to both daily calcium and cholecalciferol (1 g and 400 IU, respectively) or placebo, demonstrated no primary prevention benefit of vitamin therapy in 2,291 incident cases of DM after 7 years of follow-up (54). Although the effect of supplementation on 25-OH D level was not reported in the WHI, this was estimated to be ∼2 ng/ml, given the dosage used and reported compliance, which is thought to be of little clinical consequence (40). Nevertheless, participants with impaired fasting glucose at baseline showed attenuated progression of insulin resistance with vitamin D supplementation on subgroup analysis when compared with those subjects with normal glucose tolerance.
Other major limitations of the WHI study include study subjects’ enrollment in additional dietary and hormonal interventions, dose of vitamin D administered, inclusion of subjects already taking vitamin D supplements, and the exclusion of men (55). Overall, although some smaller and nonrandomized clinical trials show promising improvements in glycemic control with vitamin D therapy in select patient populations (i.e., women with polycystic ovary syndrome or gestational diabetes) (56,57), systematic reviews and meta-analyses of available randomized data demonstrate no beneficial effects of vitamin D supplementation on indexes of glucose metabolism (Table 1) (58,59). This finding is echoed in an Endocrine Society statement emphasizing the lack of solid evidence supporting benefits of vitamin D therapy in DM (50).
Vitamin D and hyperlipidemia
Vitamin D is structurally related to cholesterol and photosynthesis of cholecalciferol is achieved by irradiation of cutaneous 7-dehydrocholesterol, which is a precursor of cholesterol. There is also seasonal variation in plasma lipid levels and lipoprotein composition, whereby higher total cholesterol and low-density lipoprotein (LDL) levels are observed in the winter and reach their nadir during the summer. These cyclical changes remain pronounced despite adjusting for dietary or physical activity changes (60). Although cross-sectional analyses unequivocally confirm an association between optimal vitamin D status and a favorable lipid profile (61,62), the effects of vitamin D supplementation or normalization of its deficiency on serum lipid fractions remain unclear.
The WHI showed that 400 IU of cholecalciferol in addition to 1,000 mg of calcium daily was associated with an ∼4.5 mg/dl decrease in LDL cholesterol compared with placebo (p = 0.03), and higher 25-OH D levels correlated with increased high-density lipoprotein and lower triglyceride levels (p = 0.003 and <0.001, respectively). Conversely, despite a highly significant cross-sectional correlation between optimal 25-OH D levels and a favorable lipid profile in laboratory data from more than 4 million patients, longitudinal analysis of results from ∼110,000 patients, who had repeated 25-OH D and lipid profile assessments within 6 months of initial testing, showed that normalization of vitamin D status by oral supplementation (verified by an increase in total 25-OH D, but not photosynthesized D3) may actually increase total cholesterol by 0.8 mg/dl (p = 0.01), without significant effects on LDL cholesterol (increased by 0.3 mg/dl; p = 0.06) (61).
A subsequent randomized, placebo-controlled clinical trial of short-term oral vitamin D therapy in 151 vitamin D–deficient subjects reported no beneficial effects on lipoprotein composition (63). Furthermore, 2 meta-analyses assessed pooled data for the effect of vitamin D on blood lipids and showed predominantly no beneficial effects, with 1 report even demonstrating a 3.2 mg/dl increase in LDL cholesterol (38,64).
Vitamin D and CVD morbidity and mortality
The WHI is the largest randomized trial of vitamin D therapy to date. One year following randomization of 36,282 post-menopausal women to hormonal replacement therapy and/or dietary modifications, participants were asked to participate in a double-blind trial of vitamin D (400 IU/day) in combination with calcium (1 g/day) supplementation. Although designed to investigate skeletal and cancer preventive effects, study investigators pre-specified secondary cardiovascular efficacy endpoints. After 7 years of follow-up, rates of incident myocardial infarction and coronary disease–related death, revascularization, confirmed angina, strokes, and transient ischemic attacks did not differ between the treatment and placebo groups (65).
Major criticisms of this study include the low dose of vitamin D, as well as inclusion of women already taking calcium and vitamin D at doses up to those of the trial’s treatment dosage. In addition, despite mostly balanced baseline characteristics of the treatment and placebo groups, significantly more hypertensive women were part of the active treatment group. Although most vitamin D clinical trials simultaneously administered calcium, accumulating evidence points toward increased risks of cardiovascular events with calcium supplementation without concomitant vitamin D administration (66). Interestingly, post hoc analysis in women not taking vitamin D or calcium at baseline revealed significant decreases in colorectal and breast cancer incidence, but not in fractures or overall mortality rates (55).
A few clinical trials examined the effects of vitamin D supplementation without calcium on cardiovascular health. In a British fracture prevention trial, thrice-yearly administration of a large oral dose of cholecalciferol in 2,686 older subjects (76% men) for 5 years resulted in a nonsignificant trend toward decreased all-cause mortality compared with placebo (67). A smaller randomized vitamin D−only trial also failed to elicit significant changes in conventional cardiovascular risk factors, except for some favorable changes in lipoprotein composition in 265 older women, a change deemed clinically unimportant by the study investigators (68).
A notable recent vitamin D−only trial randomized patients with heart failure on optimal medical therapy to 1 year of cholecalciferol therapy or placebo and found significant improvements in left ventricular dimensions and improvement in ejection fraction (69). In contrast, patients with chronic kidney disease who received the activated (hormonal) vitamin D analogue paricalcitol over 48 weeks did not exhibit any favorable structural or functional left ventricular changes, as assessed by magnetic resonance imaging or echocardiography, compared with subjects receiving placebo (70).
Despite widely variable study groups and dosing strategies, meta-analyses and systematic reviews of available randomized vitamin D trials report similar findings: possible small relative reductions (up to 7%) in overall mortality, but not cardiovascular mortality (38,71,72). Yet different investigators arrived at disparate conclusions; some investigators suggested positive effects in certain subpopulations (e.g., institutionalized, older, or female patients), whereas others reported likely cardiovascular benefits only with cholecalciferol therapy in moderate to high doses (71,73). Other investigators have concluded that there is no significant cardiovascular benefit of vitamin D therapy from the trial evidence to date (38,65).
Vitamin D and CVD: Why the Evidence Falls Short
Most of the controversy regarding vitamin D stems from its cross-sectional relationships with a breadth of important health metrics, which were optimal at 25-OH D levels of ∼30 ng/ml, thus introducing vitamin D “sufficiency” as levels of 25-OH D >30 ng/ml. This cutoff, however, diagnoses vitamin D deficiency (<20 ng/ml) or insufficiency (20 to 30 ng/ml) in nearly 40% to 50% of all adults worldwide. Although the strong association between vitamin D deficiency and incident CVD implies a cause-and-effect relationship, this is complicated by the possibility that low 25-OH D levels may be a result of CVDs, rather than the cause of disease. A key point to consider is that ambient sunlight exposure can maintain physiological vitamin D levels, and ambulatory subjects with normal outdoor exercise activities are likely to have higher 25-OH D levels (from increased sunlight exposure) and lower likelihood of CVD, thus raising the concern that the link between CVD and vitamin D is an epiphenomenon. Indeed, we previously demonstrated an independent correlation between vitamin D status and cardiovascular fitness, measured by cardiopulmonary exercise testing in healthy adults (74).
However, it should be emphasized that most randomized vitamin D therapy trials to date were designed to investigate protective skeletal effects; therefore, subjects’ mean age exceeded 70 years, they were mostly women (≈75%), and many had established CVD or risk factors (71). To date, <60 randomized trials have reported cardiovascular outcomes, and less than one-half of these trials were designed with any a priori cardiovascular endpoints (38,71,75). Additionally, many studies were tertiary prevention trials directed at patients with established morbid conditions, such as end-stage kidney failure, debilitating fractures, and pulmonary tuberculosis (76–78). This, in turn, affects the applicability of conclusions drawn from pooling of available randomized vitamin D therapy studies.
Moreover, any beneficial or protective effects of vitamin D therapy will likely be evident only in clinical trials recruiting at least thousands of patients, particularly for hard endpoints such as cardiovascular mortality. For softer endpoints, such as serum lipids, where cross-sectional data show an ∼5% difference between those subjects with optimal 25-OH D levels (>30 ng/ml) and individuals with vitamin D deficiency (<20 ng/ml), as many as 4,000 subjects would need to be enrolled in a clinical trial of vitamin D repletion to show 3% to 5% lipid lowering with a power of 0.8 and significance of 0.05 (79).
2018: A defining year for the vitamin D controversy?
Eagerly awaited results from the randomized, placebo-controlled VITAL (VITamin D and Omega-3 triAL) will demonstrate whether cholecalciferol supplementation (2,000 IU/day), with or without omega-3 fatty acids, affects the incidence of CVD, stroke, and cancer in ∼25,000 healthy, middle-aged U.S. adults. The mean treatment period is projected at 5 years, with a similar follow-up period, and recruitment was completed in March of 2014, with an anticipated last follow-up date later this year. Baseline 25-OH D levels will be measured in the majority of VITAL subjects, thus allowing for subgroup analysis in deficient subjects, and repeat measurements will be performed in 6,000 participants on follow-up (80).
Results will likely be unveiled in 2018, which the vitamin D believers hope to mark for another public health victory for vitamin D supplementation nearly a century after its discovery as a cure for rickets. This large study and hundreds of other ongoing clinical trials will soon provide much-needed evidence to determine the relationship between vitamin D and CVD.
Evaluation of Vitamin D Status and Management of Vitamin D Deficiency: Current Guidelines
The advent of tandem mass spectrometry after liquid chromatography and serum extraction allowed for accurate and reproducible 25-OH D measurement and became the gold standard for assessment of vitamin D status. The threshold below which PTH increases varied in different cross-sectional studies, ranging from 12 to 40 ng/ml, but vitamin D supplementation suppresses PTH only when 25-OH D levels are <20 ng/ml, and 1,25-OH vitamin D levels are almost invariably normalized when serum 25-OH D levels are >20 ng/ml. However, optimal intestinal calcium absorption is thought to occur at serum 25-OH D levels near 30 ng/ml, although fracture risks in the older population start to increase at levels <20 ng/ml.
There is no disagreement on the importance of recognizing and treating severe vitamin D deficiency (25-OH D <12 ng/ml), and almost all experts would consider treating subjects with 25-OH D levels <20 ng/ml. It also should be emphasized that the cardiovascular benefits of vitamin D therapy in patients with chronic kidney disease and hyperparathyroidism have been long recognized, including BP reduction, improved electrolyte imbalances, and overall reduced cardiovascular mortality rates in patients undergoing hemodialysis (81,82).
However, there is no consensus on whether 25-OH D levels of 30 ng/ml or higher compared with 20 ng/ml provide additional health benefits in the general population, with the Endocrine Society guidelines advocating for the higher 25-OH D levels on the one hand and the Institute of Medicine asserting the absence of data to establish the basis of these recommendations on the other (Figure 2). Another major point of disagreement is defining “at-risk” populations for routine assessment of vitamin D status, and the Institute of Medicine criticized the large, unnecessary cost of testing that comes with the Endocrine Society’s broad definition. The 2 bodies, nevertheless, agree that vitamin D is essential for skeletal health and that there is no convincing evidence linking vitamin D with CVD or overall mortality benefits. There is also agreement that no need exists to screen the general population routinely for vitamin D deficiency, and the dietary reference intakes established by the Institute of Medicine are also consistent with the Endocrine Society recommendations for the general populations.
Categories of Vitamin D Status According to the Institute of Medicine Versus the Endocrine Society
∗Treatment with vitamin D3 or D2. †Including recommended daily allowance. 25-OH D = 25-hydroxyvitamin D.
Populations at risk for vitamin D deficiency
The following groups are at a higher risk of developing vitamin D deficiency: individuals with decreased cutaneous production of vitamin D as a result of increasing age, darker skin pigmentation, clothing, or behaviors that limit sun exposure (for religious, cultural, or health reasons); those chronically deprived of sun exposure secondary to geography, debilitation, work schedule, location, imprisonment, or skin disease; and patients with disorders limiting absorption of fat-soluble vitamins and those receiving specific therapies (corticosteroids; several antiepileptic, antifungal, and antiviral medications). To guide replacement therapy, measurement of 25-OH D levels should be performed whenever deficiency is suspected.
Treatment of vitamin D deficiency
A practice guideline statement by the Endocrine Society recommends treatment of vitamin D–deficient subjects with 25-OH D <19 ng/ml by oral administration of 50,000 IU/week of either vitamin D2 or D3 for 8 weeks, followed by daily maintenance doses between 1,500 and 2,000 IU. Both loading and maintenance doses may be much higher in those with increasing risks for the development or recurrence of vitamin D deficiency. Concurrent calcium supplementation is also a key component of effective treatment, and a preventive strategy should always address underlying causes, if possible (83).
In addition to maintaining sufficient serum 25-OH D levels, patients with end stage renal and/or hepatic diseases that impair vitamin D activation and result in hypocalcemia, as well as patients with secondary hyperparathyroidism or hypoparathyroidism, require activated vitamin D therapy (e.g., 1,25-OH vitamin D at 0.25 and 0.5 μg/day). Although patients with granulomatous disorders and dysregulated 1,25-OH vitamin D production may require vitamin D replacement, 25-OH D levels >30 ng/ml can worsen the associated hypercalcemia. Careful monitoring of vitamin D status and of serum and urinary calcium is therefore necessary in these patients.
Routine assessment and preventive measures in the cardiac patient
On the basis of the available clinical evidence to date, routine screening or assessment of vitamin D status is not recommended. Measurement of vitamin D metabolites is justified in patients with risk factors for decreased production, intake, or activation of vitamin D, irrespective of cardiac risk factors. Although vitamin D deficiency is prevalent, noninstitutionalized individuals who maintain moderate sun exposure will probably not benefit from additional supplementation, especially in areas of lower latitude, nor will younger individuals who are physically active, with a normal body mass index, and fairer skin complexions, for which casual exposure of the face, arms, and legs (as little as 10 to 15 min, thrice weekly) results in cutaneous production of sufficient amounts of vitamin D.
Although UV irradiation causes direct DNA damage and is now an established skin carcinogen, the incidence of nonmelanoma skin cancer heavily depends on skin tone (blacks have one-eightieth the lifetime risk compared with Caucasians). Moderate sun exposure should therefore not be discouraged in at-risk individuals with darker skin pigmentation, particularly in areas of higher geographic latitude. Even in sunny locations, expanding urbanization and concomitant air pollution, together with increasing concerns of skin malignancies and resultant sun-avoidant behavior, all adversely contribute to the high prevalence of vitamin D deficiency.
In healthy individuals, prevention of vitamin D deficiency can be readily achieved by a combination of casual sunlight exposure and consumption of fatty fish or fish oils, in addition to fortified foods and/or supplements. Although the current recommended dietary allowance of vitamin D in the United States ranges between 400 and 800 IU/day, as much as 2,000 IU/day may be needed to maintain sufficient 25-OH D levels (≥30 ng/ml) in adults at risk for deficiency. Given that most diets generally provide less daily vitamin D intake, pharmacological supplementation with vitamin D2 or D3 is therefore often required, particularly in locations where few foods are fortified with vitamin D or in individuals with risk factors for deficiency.
Conclusions
Vitamin D deficiency is a highly prevalent condition. It is associated with most CVD risk factors and with CVD morbidity and mortality. Despite a large body of experimental, cross-sectional, and prospective evidence that implicates vitamin D deficiency in the pathogenesis of CVD, the causality of this relationship remains to be established. Most importantly, CVD endpoint trials of vitamin D therapy are needed to support vitamin D therapy for cardiovascular protection.
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Abbreviations and Acronyms
| 1,25-OH vitamin D | 1,25-dihydroxyvitamin D (calcitriol) |
| 25-OH D | 25-hydroxyvitamin D |
| BP | blood pressure |
| CVD | cardiovascular disease |
| DM | diabetes mellitus |
| LDL | low-density lipoprotein |
| PTH | parathyroid hormone |
| RAAS | renin-angiotensin-aldosterone system |
| UV | ultraviolet |
| VDR | vitamin D receptor |
Footnotes
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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