An editorial published in this month’s issue of Circulation examined the evidence for the role of vitamin D in lipid profiles.
Numerous epidemiological studies correlate higher 25(OH)D levels with a decreased risk of cardiovascular disease. For example:
- The Norwegian Tromsø study followed 4,751 participants for 11 years and found that those in the lowest serum 25(OH)D quartile had a 32% greater risk of mortality from cardiovascular disease than those in the highest serum 25(OH)D quartile.
- The Framingham Offspring Study also found a significant inverse association between vitamin D levels and heart disease. Among its 1,739 participants, those with serum 25(OH)D levels <10 ng/mL had a hazard ratio of 1.80 for a cardiovascular event as compared to participants with serum 25(OH)D levels >15 ng/mL.
One possible mechanism proposed for these observations is that vitamin D has a lipid-lowering effect. In general, the observational data show that higher serum 25(OH)D levels are associated with more favorable lipid profiles. However, randomized controlled trials (RCT) are necessary to establish a causal role for vitamin D in heart disease prevention. These trials are costly, time-consuming, and require thousands of subjects to achieve statistically significant results.
The authors of this editorial therefore promote the cost-effective alternative performed by Ponda et al. From a pool of > 4 million laboratory tests, 108,711 individuals were selected who had undergone repeated serum 25(OH)D and lipid testing 4 to 26 weeks apart. In men and women, they found that those with higher serum 25(OH)D levels had lower total cholesterol, LDL cholesterol, and triglycerides and higher levels of HDL cholesterol.
Of these 108, 711 participants, 6,260 had 25(OH)D serum levels <20 ng/mL that had increased to between 30 and 100 ng/mL after the second blood measurement. 81% of the increase in this group was from vitamin D2 supplementation, and no statistically significant improvement in lipid profiles was observed. A group of 2,332 individuals who had blood levels <20 ng/mL at their initial serum 25(OH)D test as well as following the second test served as a control group.
The authors compare these results with the conclusions of the only published meta-analysis involving vitamin D supplementation and lipid profiles, which involved 12 clinical trials and 1,346 participants. The only statistically significant effect reported was a small increase in LDL cholesterol of 3.23 mg/mL. Limitations of the trials included small sample sizes, variations in vitamin D forms and doses, study duration from 8 weeks to 3 years, at baseline the majority of the subjects were not vitamin D deficient, and no studies specified high lipid levels as inclusion criteria.
The authors then attempt to explain the inconsistent results of the meta-analysis with those of the Ponda et al. data. Because the patients who received treatment for vitamin D deficiency were more likely to have a diagnosis of a lipid disorder than the subset of patients that remained vitamin D deficient, they speculate that the physicians of these patients would also have advised some form of treatment for their hyperlipidemia along with their vitamin D deficiency, and that it was therefore reasonable to expect a positive change in the lipid profile.
Because no such change was observed and the results of the meta-analysis revealed a statistically significant rise in LDL cholesterol with vitamin D supplementation, the authors go so far as to suggest that the study design of Ponda et al. potentially masked an effect of vitamin D on lipid profiles. This concern, coupled with the data from observational studies showing the greatest benefit of vitamin D on cardiovascular health occurs with 25(OH)D serum levels above 15 ng/mL, led the authors to conclude that further RCT’s examining the effect of vitamin D supplementation on lipid levels should be restricted to individuals that are both vitamin D deficient and hyperlipidemic.
At present, supplementation with vitamin D does not appear to improve serum lipid profiles. However, the Ponda et al. data cited by the authors utilized D2 supplementation, as did roughly a third of the trials included in the meta-analysis. It is possible that D3 supplements or UV radiation could yield different results, or that improvement in the lipid profile is not the mechanism by which vitamin D and UV exposure have been shown to reduce the risk of cardiovascular disease.