The Short-Term Effects of Vitamin D Repletion on Cholesterol: A Randomized, Placebo-Controlled Trial
Arteriosclerosis, Thrombosis, and Vascular Biology
Abstract
Objective—
Vitamin D deficiency is common and associated with dyslipidemia. However, it is unclear whether oral vitamin D supplementation improves the lipid profile. Therefore, we conducted a randomized, placebo-controlled trial to determine the short-term effects of vitamin D repletion on the lipid profile.
Methods and Results—
One hundred fifty-one vitamin D−deficient (25-hydroxyvitamin D <20 ng/mL) adults with elevated risk for cardiovascular disease were randomized to receive either 50 000 IU of vitamin D3 weekly for 8 weeks or placebo. The primary outcome was the change in small low-density lipoprotein (LDL) particle number. Secondary outcomes included changes in other nuclear magnetic resonance−based and chemical lipid fractions. Vitamin D failed to improve the lipid profile. Compared with the placebo, vitamin D repletion did not change small LDL particle number (mean change, +18 nmol/L; 95% CI [−80 to +116 nmol/L]; P=0.63). There were also no changes in the chemical lipid profile: total cholesterol (+5.8 mg/dL, 95% CI [−1.4 to +13.0 mg/dL], P=0.14); LDL cholesterol (+3.8 mg/dL, 95% CI [−2.5 to +10.2 mg/dL], P=0.13); high–density lipoprotein cholesterol (+0.4 mg/dL 95% CI [−1.6 to +2.6 mg/dL], P=0.71); and triglycerides (+7.9 mg/dL 95% CI [−6.5 to +22.3 mg/dL]). In the vitamin D repletion group, exploratory multivariate regression analysis demonstrates that changes in LDL cholesterol were positively correlated with the changes in serum calcium (P<0.001) and inversely with the changes in serum parathyroid hormone (P=0.02).
Conclusion—
In contrast to the association between low 25-hydroxyvitamin D levels and dyslipidemia, correcting vitamin D deficiency in the short-term does not improve the lipid profile. Repletion of 25-hydroxyvitamin D levels raised serum calcium levels and decreased serum parathyroid hormone levels. These expected physiological responses to vitamin D therapy were correlated with a significant increase in LDL cholesterol.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01008384.
Introduction
Vitamin D is primarily generated in the skin, in response to direct absorption of ultraviolet B radiation. Vitamin D can also be obtained through fortified foods and oral supplements. In the liver, vitamin D is hydroxylated to form 25-hydroxyvitamin D [25(OH)D]. The serum level of 25(OH)D is the standard criterion for determining whole-body vitamin D status. Clinical strata of 25(OH)D levels are defined as follows: <20 ng/mL (deficient), 20 to 30 ng/mL (insufficient), and >30 ng/mL (sufficient).1,2 However, the optimal level of 25(OH)D remains to be defined. Indeed, a recent report from the Institute of Medicine concluded that higher 25(OH)D levels are not consistently associated with greater benefit and that levels ≥20 ng/mL may be sufficient.3
The classic actions of vitamin D influence mineral metabolism and include suppressing parathyroid hormone (PTH) production and increasing gut calcium absorption.4,5 In addition, vitamin D has pleiotropic actions, and vitamin D signaling is operational in many tissues, including the cardiovascular system.6,7 Epidemiologic studies have shown an association between 25(OH)D deficiency and worse cardiovascular health.8–10 However, whether 25(OH)D is a mere biomarker of health or whether 25(OH)D deficiency has a causal role in disease remains unclear. This distinction is especially important when deciding whether or not to target low 25(OH)D levels for repletion.
Blood cholesterol levels are strong predictors of cardiovascular risk.11 Elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol levels are independent risk factors for adverse cardiovascular events. LDL cholesterol levels are typically not measured directly but rather calculated from the Friedewald equation and reflect cholesterol that is neither HDL cholesterol nor very-low-density lipoprotein cholesterol. An alternate way of measuring LDL is through NMR lipoprotein analysis. In some populations, the concentration of small, dense LDL particles can add to the prognostic value of the standard, chemical lipid profile.12
Although there is epidemiologic evidence associating high 25(OH)D levels with a healthier lipid profile, there are no randomized, placebo-controlled trials that have tested the effect of correcting vitamin D deficiency on the lipid profile.13 We previously conducted an analysis of a large, national, community-based laboratory database to infer how changes in 25(OH)D levels may affect the lipid profile.14 We established strong cross-sectional associations between higher 25(OH)D levels and lower total cholesterol, lower LDL cholesterol, higher HDL cholesterol, and lower triglycerides. However, longitudinal analysis showed that increasing 25(OH)D levels from the deficient to sufficient range had a neutral effect on the lipid profile—increased total and HDL cholesterol but no change in LDL cholesterol and triglycerides. Although we could not determine the precise source of repletion, >80% of the increase in 25(OH)D levels was in the form of 25(OH)D2 and, thus, exogenous. We have extended these findings by performing a randomized, double-blind, placebo-controlled trial to determine the short-term effect of vitamin D3 repletion on the lipid profile.
Subjects and Methods
Subjects
Men and women between the ages of 18 and 85 years were recruited and underwent a screening visit at which nonfasting lipid profiles, 25(OH)D, high-sensitivity C-reactive protein, serum creatinine, and glucose values were measured. A medical history, including current medications and tobacco use, as well as height and weight measurements, was also performed. Estimated glomerular filtration rate was calculated using the 4-variable modification of diet in renal disease equation.15 Inclusion criteria were 25(OH)D level ≤20 ng/mL and at least 1 of the following cardiovascular risk factors: body mass index >30 kg/m2, HDL <40 mg/dL for men or <50 mg/dL for women, hsCRP >2 mg/L, glomerular filtration rate 30 to 59 mL/min per 1.73 m2, a history of coronary artery disease, diabetes mellitus, or a 10-year Framingham risk score >10%. We excluded subjects who were taking >400 IU of ergocalciferol or cholecalciferol, or any dose of activated vitamin D (1,25-dihydroxyvitamin D or its analogues) within 1 month, as well as subjects with triglycerides >400 mg/dL, serum calcium >10.5 mg/dL, serum phosphorus >5.5 mg/dL, a change in any lipid therapy within 1 month, or an glomerular filtration rate <30 mL/min per 1.73 m2. All visits took place at the Rockefeller University Hospital. The research protocol was approved by Rockefeller University’s Institutional Review Board. This study was listed on ClinicalTrials.gov (Identifier NCT01008384).
Study Visits and Intervention
Subjects were required to fast for 8 hours before the study visits. At the first study visit, a medical history was taken and subjects underwent venipuncture to determine 25(OH)D, calcium, PTH, lipid, and hsCRP levels. After blood was drawn, subjects ingested the first dose of study drug under direct observation and were given a study diary to record days/times of study drug doses. The study drug was either vitamin D3 10 000 units or placebo (The BTR Group, Pittsfield, IL). Subjects were provided with an 8-week supply of medication and were instructed to take 5 pills each Monday, without specifying a time of day or in relation to meals. After 1 week, subjects were contacted by phone to determine whether any adverse events had occurred. Subjects returned to Rockefeller University Hospital 4 weeks after the first study visit and underwent venipuncture to determine 25(OH)D, calcium, phosphorus, PTH, and lipid levels. Interim compliance was assessed through pill counts and review of the study diary. The final study visit took place 8 weeks after the first study visit, where 25(OH)D, calcium, phosphorus, PTH, lipid, and hsCRP levels were measured and pill counts and study diaries were reviewed.
Randomization
Eligible participants were assigned to the 2 study groups such that for every 6 subjects, 3 were randomly assigned to the vitamin D repletion and the other 3 were assigned to the placebo. Thus, subjects were grouped in blocks of 6 with random 1:1 allocation. Randomization and intervention assignment was performed by the Rockefeller University Hospital pharmacist. Study personnel remained blinded to subject allocation until results for the end points were available and entered into a composite database for analysis.
End Points
The primary end point was a change in small LDL particle number, determined by nuclear magnetic resonance (NMR) lipid profiling (Liposcience, Raleigh, NC). Pilot studies (n=22) conducted by our group showed that vitamin D repletion raised small LDL particle number by 13% (P=0.04), whereas LDL cholesterol levels only increased by 5.8% (P=NS). Therefore, we chose the change in small LDL particle number as the primary end point. Based on the pilot data for this metric, we estimated a sample size of 150 subjects to achieve a power of 80% to demonstrate a difference in the primary end point between the groups with a 2-tailed α<0.05.
NMR lipid profiles were determined after all subjects had completed the study. Secondary end points included changes in other NMR lipid parameters, the standard lipid profile, and hsCRP levels. Aside from the NMR-based measurements, all testing was performed by the Memorial Sloan Kettering Cancer Center clinical laboratory concurrent with study visits. 25(OH)D levels were determined using the Diasorin LIASON automated chemiluminescent immunoassay. Lipid profiles were measured using an enzyme-based Siemens platform, where LDL was calculated in accordance with the Friedewald equation.16
Statistical Analysis
Comparisons between the vitamin D repletion and placebo groups were made using the Mann−Whitney U test. Comparisons for the within-group changes were made using paired Student t tests. Correlations were assessed by calculating Pearson correlation coefficients. Multivariate analysis was performed using stepwise linear regression models using the following inputs: (baseline) age, 25(OH)D, calcium, PTH, LDL and HDL cholesterol, triglycerides, phosphorus, hsCRP, glucose; (response) Δ25(OH)D, ΔHDL, Δtriglycerides, Δcalcium, ΔPTH, Δphosphorus, ΔhsCRP, Δglucose. χ2 analysis was used for noncontinuous variables. P values <0.05 were considered to be significant, except for assessing univariate correlation coefficients. For these, the Bonferroni correction was applied for testing 7 parameters associated with ΔLDL cholesterol, with a resultant significance threshold of P<0.007. For the 2 parameters associated with the change in LDL particle number, a significance threshold of <0.025 was used. Statistical analyses were conducted using Tibco S+ software (version 8.2).
Results
Baseline characteristics of the 151 subjects who completed the study are shown in Table 1. Subjects were recruited between October 2009 and May 2011. The subjects were well matched with respect to age, sex, race, 25(OH)D, and lipid levels. Consistent with the physiological response of increased PTH to vitamin D deficiency, mean baseline PTH levels (≈60 pg/mL) were at the high end of the normal range (12–65 pg/mL) for both groups.
Vitamin D Repletion Group (n=76) | Placebo Group(n=75) | P Value | |
---|---|---|---|
Age, y | 48.4±11.3 | 47.4±12.8 | 0.45 |
Women, % | 45 | 45 | 0.94 |
Blacks, % | 45 | 47 | 0.80 |
25(OH)D, ng/mL | 13.4±5.3 | 14.1±5.7 | 0.45 |
Calcium, mg/dL | 9.0±0.3 | 9.1±0.4 | 0.06 |
PTH, pg/mL | 61±32 | 60±35 | 0.72 |
Total cholesterol, mg/dL | 189.3±33.4 | 184.2±38.0 | 0.31 |
HDL cholesterol, mg/dL | 50.8±14.9 | 49.3±12.7 | 0.94 |
LDL cholesterol, mg/dL | 116.6±29.0 | 111.8±34.0 | 0.18 |
Triglycerides, mg/dL | 109.5±62.8 | 115.8±54.2 | 0.15 |
Small LDL particles, nmol/L | 780±487 | 816±421 | 0.49 |
Total LDL particles, nmol/L | 1267±425 | 1267±387 | 0.89 |
Total HDL particles, nmol/L | 30 836±6837 | 31 884±5992 | 0.18 |
Total VLDL particles, nmol/L | 57.7±34.4 | 57.4±29.9 | 0.91 |
hsCRP, mg/L | 6.0±6.3 | 6.0±6.8 | 0.60 |
Fasting glucose, mg/dL | 105.6±32.3 | 105.3±28.8 | 0.81 |
Creatinine, mg/dL | 1.0±0.2 | 1.0 ± 0.2 | 0.47 |
25(OH)D indicates 25-hydroxyvitamin D; PTH, parathyroid hormone; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; hsCRP, high-sensitivity C-reactive protein. Data are shown as mean values±SD.
After 4 and 8 weeks of therapy, mean 25(OH)D levels were significantly higher than baseline in the vitamin D repletion group (37.0±9.5 and 43.0±12.3 ng/mL, respectively; P<0.0001 versus baseline for both; Figure 1). In contrast, the 25(OH)D levels remained unchanged in the placebo group (14.5±5.8 and 14.6±6.2 ng/mL, 4 and 8 weeks, respectively; P=NS for both versus baseline). After 4 weeks, 79% of the subjects in the vitamin D repletion group had 25(OH)D levels ≥30 ng/mL, and this proportion increased to 88% at the final study visit 8 weeks later. Therefore, most subjects who received vitamin D had sufficient 25(OH)D levels for the majority of the treatment period. Serum calcium levels increased by 0.12 mg/dL in the vitamin D group relative to the placebo group (P=0.04) but remained below the upper limit of normal (10.5 mg/dL) for all subjects throughout the study, ranging between 8.0 and 10.1 mg/dL. PTH values decreased by an average 18±25 pg/mL in the vitamin D repletion group (P<0.0001 versus baseline) but were unchanged in the placebo group (−3±24 pg/mL, P=0.28; ΔPTH for vitamin D versus placebo, P<0.001).

There were no significant differences in the changes in lipid parameters either within or between groups after 8 weeks of treatment for standard, chemical-based (Table 2), and NMR-based (Table I in the online-only Data Supplement) lipid measurements. There were also no changes in the chemical lipid profile after 4 weeks of treatment (Table II in the online-only Data Supplement).
Change in Vitamin D Repletion Group(n=75) | P Value | Change in Placebo Group(n=76) | P Value | Intergroup Difference [95% CI] | P Value | |
---|---|---|---|---|---|---|
Total cholesterol | +1.2±21.0 (+0.6) | 0.63 | −4.6±23.9 (−2.5) | 0.10 | +5.8 [−1.4 to +13.0] | 0.14 |
LDL cholesterol | −0.3±18.6 (−0.3) | 0.88 | −4.1±20.8 (−3.7) | 0.09 | +3.8 [−2.5 to +10.2] | 0.13 |
HDL cholesterol | +0.3±6.4 (+0.6) | 0.71 | −0.2±6.6 (−0.4) | 0.84 | +0.4 [−1.6 to +2.6] | 0.71 |
Triglycerides | +6.1±50.0 (+5.3) | 0.29 | −1.8±39.0 (−1.6) | 0.70 | +7.9 [−6.5 to +22.3] | 0.43 |
LDL indicates low-density lipoprotein; HDL, high-density lipoprotein. Data are shown as mean values±SD and (percentage change).
Because there was a strong response of vitamin D repletion on the biomarkers of calcium and PTH, we determined through exploratory analyses whether this physiological response to vitamin D was associated with changes in LDL cholesterol (Table 3). Indeed, increases in serum calcium and decreases in PTH levels were significantly correlated with increases in LDL cholesterol. These relationships were absent in the placebo group (Figure 2). To account for potential confounding factors, we constructed a stepwise multivariate regression model for changes in LDL cholesterol in the vitamin D group (Tables 4 and 5). Consistent with the strong univariate relationships, changes in calcium and PTH remained significant, independent predictors of changes in LDL cholesterol (P<0.001 and P=0.016 for Δcalcium and ΔPTH, respectively; ANOVA F-statistic P<1×10−6). In addition, the model explained 44% of the variability in LDL cholesterol levels. Increases in serum calcium and decreases in PTH were also significantly correlated with the increases in LDL particle number: r=0.33 for Δcalcium and r=−0.40 for ΔPTH; P<0.01 for both. Similarly, these relationships remained significant on multivariate analysis (P=0.026 and P=0.006 for Δcalcium and ΔPTH, respectively; ANOVA F-statistic P<1×10−5; Table III in the online-only Data Supplement).
Response Variables | r | P Value |
---|---|---|
ΔCalcium | 0.522 | <0.0001 |
ΔPTH | −0.348 | 0.002 |
ΔTG | −0.268 | 0.02 |
Δ25(OH)D | 0.210 | 0.07 |
ΔHDL cholesterol | 0.198 | 0.09 |
ΔPhosphorus | 0.098 | 0.40 |
ΔhsCRP | 0.075 | 0.50 |
PTH indicates parathyroid hormone; TG, triglycerides; 25(OH)D, 25-hydroxyvitamin D; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein.
Values in bold are statistically significant.
Regression Statistics | |
---|---|
Multiple R | 0.662 |
R2 | 0.438 |
Observations | 75 |
Significance F | <0.000001 |
Coefficients | P Value | |
---|---|---|
ΔCalcium, per mg/dL | 19.855 | <0.001 |
ΔPTH, per pg/mL | −0.201 | 0.016 |
ΔTG, per mg/dL | −0.090 | 0.011 |
Baseline LDL cholesterol | −0.101 | 0.075 |
ΔHDL | 0.513 | 0.083 |
ΔGlucose | −0.116 | 0.127 |
PTH indicates parathyroid hormone; TG, triglycerides; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
Values in bold are statistically significant.

Because vitamin D therapy has also been suggested to be anti-inflammatory, we measured serial hsCRP levels.17 Relative to the control group, there was no change in the mean hsCRP level with vitamin D repletion after 8 weeks (+1.5 mg/L, 95% CI [−0.5 to +3.5 mg/L]; P=0.48).
Discussion
We conducted a randomized, double-blind, placebo-controlled trial to determine whether vitamin D repletion exerts an effect on the lipid profile. Over an 8-week period, despite effective vitamin D repletion, there was a failure to improve either the standard or NMR−based lipid profile. As measured by a decrease in serum PTH and an increase in serum calcium, the vitamin D repletion group did show significant end-organ responses to vitamin D therapy. These physiological responses were also significantly associated with an increase in LDL cholesterol. Therefore, high-dose oral supplementation in an at-risk population may have an adverse effect on cardiovascular risk for those individuals who have the strongest biological response to vitamin D. Likewise, the benefit inferred from cross-sectional associations of higher 25(OH)D levels and a healthier lipid profile is not replicated by short-term vitamin D repletion.
Vitamin D deficiency is highly prevalent in the general population, and even more so in patients with cardiovascular disease.8,9 Further, low 25(OH)D levels are associated with worse cardiovascular outcomes.10 However, adequately controlled, prospective studies of vitamin D repletion to determine an effect on cardiovascular morbidity and mortality are lacking.18 Even for surrogate cardiovascular biomarkers, such as blood lipids, few clinical trials have studied the effect of vitamin D supplementation, and these trials were inconclusive.19–28 We had previously reported on the incongruence of the vitamin D/lipid relationship when contrasting cross-sectional to longitudinal data.14 By analyzing a community-based laboratory data repository in a cross-sectional manner, we found that 25(OH)D levels >30 ng/mL compared with <20 ng/mL were associated with a markedly healthier lipid profile. However, in the same population of patients assessed longitudinally, raising 25(OH)D levels in the short-term had no effect on lipids. However, no randomized, placebo-controlled trial has studied the effect of vitamin D repletion, targeting 25(OH)D deficiency, with an adequate dose of vitamin D to achieve sufficient 25(OH)D levels. Although large trials of vitamin D supplementation are underway that use higher doses of vitamin D than prior studies, they still do not specifically target vitamin D deficiency.29
Vitamin D deficiency is clinically defined by the serum level of 25(OH)D and low levels correlate with biomarkers of mineral metabolism, such as elevations in PTH. However, there is considerable variation in the end-organ response to vitamin D, and there is still significant controversy over the definition of normal 25(OH)D levels.3,30 We found that the biological effects of vitamin D repletion, namely a decrease in PTH and increase in serum calcium, were strongly and independently associated with a rise in LDL cholesterol and LDL particle number. Indeed, stratifying subjects by change in serum calcium with vitamin D therapy shows that those with an above-median response compared with those with a below-median response had an increase in LDL cholesterol of 15.4 mg/dL. A similar subgroup analysis of the placebo group shows no relationship.
Our trial presents new data to guide clinical practice. In stark contrast to the strong cross-sectional associations between higher 25(OH)D levels and each component of the lipid profile, our clinical trial failed to show any effect of vitamin D repletion on lipids.14 Further, the effect estimate for changes in LDL cholesterol was opposite that predicted by association. Indeed, qualitatively, there was a higher frequency of subjects in the vitamin D group who had an increase in LDL cholesterol levels compared with placebo at both 4 weeks (52% versus 36%) and 8 weeks (55% versus 37%). However, the optimal time frame for achieving repletion is unknown, and the long-term effects of vitamin D repletion on the lipid profile are unclear. However, the uncoupling between our randomized clinical trial data and the cross-sectional associations of higher 25(OH)D levels should spark caution towards inferred benefits of vitamin D supplementation on the lipid profile.
Epidemiologic and observational studies suggest that vitamin D may play a role in cardiovascular health and disease distinct from calcium and PTH homeostasis. However, definitive data from large, prospective clinical trials are lacking. Previous studies of other nutritional supplements have shown that such trials may be necessary before accepting supplementation as universal practice to avoid potential harm. Without the availability of outcomes data, an important step before embracing supplementation is to confirm that biomarkers of cardiovascular risk associated with vitamin D deficiency that were identified in cross-sectional studies do in fact respond to vitamin D therapy. Our study challenges the notion that vitamin D repletion ameliorates dyslipidemia and raises the possibility that vitamin D supplements may worsen the lipid profile for some patients.
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© 2012 American Heart Association, Inc.
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Received: 14 March 2012
Accepted: 23 July 2012
Published online: 4 September 2012
Published in print: October 2012
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This work was supported, in part, by grant no. 8 UL1 TR000043 from the National Center for Advancing Translational Sciences, National Institutes of Health.
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