Vitamin D3 effects on lipids differ in statin and non-statin-treated humans: superiority of free 25-OH D levels in detecting relationships

Abstract

Context: Inverse associations between 25-OH vitamin D levels and cardiovascular morbidity and mortality have been reported.

Objectives: Our goals were to 1) investigate effects of correcting inadequate D status on lipids, 2) determine whether free 25-OH D is better correlated with lipids than total 25-OH D.

Design: A randomized, double-blind placebo-controlled trial was performed.

Setting: Participants resided in the general community.

Participants: Adults with inadequate D status were randomized to D3: 14 men, 12 women, age 60 ± 8 years (mean ± SD) or placebo: 12 men, 11 women: 59 ±12 years.

Intervention: Responses to 12-week oral vitamin D3 titrated (1000-3000 IU/d) to achieve 25-OH D levels ≥25 ng/mL were compared to placebo.

Main outcome measures: Measurements were 25-OH D (tandem mass spectometry), free 25-OH D (direct immunoassay), lipids (directly measured triglyceride, cholesterol, and subfractions; plant sterols and cholesterol synthesis precursors), and safety labs before and after 6 and 12 weeks D3 or placebo. Data were analyzed by repeated measures ANOVA and linear regression.

Results: Vitamin D3 was titrated to 1000 IU/d in 15/26 (58%), to 2000 IU/d in 10, and 3000 IU/d in one patient. D3 had no effect on cholesterol or cholesterol subfractions except for trends for decreases in atorvastatin-treated patients (cholesterol, P = .08; low-density lipoprotein [LDL] cholesterol, P = .05). Decreased campesterol concentrations (P = .05) were seen with D3 but not placebo in statin-treated patients. Relationships between total 25-OH D and lipids were not detected, but inverse linear relationships were detected between free 25-OH D and triglycerides (P = .03 for all participants [n = 49], P = .03 in all statin-treated [n = 19], and P = .0009 in atorvastatin-treated [n = 11]), and between free 25-OH D and LDL cholesterol (P = .08 overall, P = .02 in all statin-treated, and P = .03 for atorvastatin-treated), and total cholesterol (P = .09 overall; P = .04 for all statin-treated, and P = .05 for atorvastatin-treated).

Conclusions: Vitamin D lipid-lowering effects appear limited to statin-treated patients and are likely due to decreased cholesterol absorption. Relationships between lipids and D metabolites were only detected when free 25-OH D was measured, suggesting the superiority of determining free 25-OH D levels compared to total 25-OH vitamin D levels when analyzing biologic responses.

Trial registration: ClinicalTrials.gov NCT00723385.

Figures

Figure 1.

Mean (± SE) cholesterol responses to daily oral vitamin D3 administration (solid circles connected by solid lines) or placebo (open circles connected by dashed lines) at baseline, after at least 6 weeks (mid-study), and at least 12 weeks (study end) in atorvastatin-treated participants (upper panel) and responses of LDL cholesterol (lower panel). Differences in responses were significant (P < .05).

Figure 2.

Mean (± SE) campesterol responses (upper panel) and lathosterol responses (lower panel) to daily oral vitamin D3 administration (solid circles connected by solid lines) or placebo (open circles connected by dashed lines) at baseline and study end for statin-treated participants are presented. Differences in campesterol responses between the D3-treated vs placebo-treated approached significance (P = .05).

Figure 3.

Relationships between free 25-OH vitamin D concentrations and cholesterol (total), triglycerides, and LDL cholesterol are presented for the D3-supplemented group at baseline (open circles and dotted lines) and at the end of supplementation (closed circles and solid lines) (left panels) and for the placebo group at baseline (open triangles and dotted lines) and at the end of the study (closed triangles and solid lines) (right panels). Regression results are presented with baseline values above the 0 point and relationships at study end toward the right of each panel. Significant relationships existed after D3 supplementation for LDL cholesterol (P < .007) and approached significance for total cholesterol (P < .08). At no time points were significant relationships detected in the placebo-treated subjects, likely due to the narrow range of free 25-OH D concentrations. No significant relationships at any time were detected for total 25-OH vitamin D concentrations and lipids (data not shown).

Figure 4.

Relationships between circulating free 25-OH vitamin D concentrations and triglycerides, LDL cholesterol, and total cholesterol are shown for the HMG-CoA reductase inhibitor (statin) -treated participants: atorvastatin data (solid circles), simvasatin (open circles), and lovastatin (inverted triangles). Significant inverse relationships were detected between free 25-OH vitamin D concentrations and triglycerides, LDL cholesterol, and cholesterol concentrations (results are presented within the figures for atorvastatin-treated participants; see text for additional details).