2019 JAMA Cardiology Meta-Analysis of Vitamin D and Cardiovascular Disease Risk

• A recent meta-analysis published in the June 2019 issue of JAMA Cardiology concluded that vitamin D supplementation is not associated with a reduced incidence of major cardiovascular events including myocardial infarction, stroke, CVD mortality, or all-cause mortality.
• There are several factors that limit the applicability of these findings:
  • The majority of trials included in this meta-analysis used low-dose vitamin D (~1,000 IU/day);
  • Most randomized clinical trials (RCTs) included in this meta-analysis were not designed specifically to measure cardiovascular outcomes and therefore caution must be used when evaluating the merits of results generated from endpoints not pre-specified and/ or from trials not designed to investigate these endpoints;
  • Serum levels of 25-hydroxyvitamin D after supplementation were either not measured or not recorded/ extracted from the included trials to assess for response; this analysis did not provide information on participants' vitamin D blood levels following supplementation;
• The results of this meta-analysis do not contradict Life Extension's longstanding position that vitamin D supplementation to target a blood level of about 50 to 80 ng/mL is an important component of any health regimen. Life Extension continues to strongly suggest that most individuals supplement with vitamin D as need to maintain healthy levels of about 50 – 80 ng/mL.

The meta-analysis, titled "Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83,000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis" concludes that supplementing with vitamin D does not offer any significant benefit or protection from cardiovascular outcomes.¹ The meta-analysis included 21 RCTs and measured various adverse cardiovascular events. The paper argues that much of the positive literature surrounding vitamin D only offers correlative evidence, not causative, and when the RCTs are pooled for analysis, there is no significant protection offered by vitamin D supplements.

However, there are several flawed aspects of this meta-analysis. First, most of the studies used doses of vitamin D much lower than may be required to substantially affect serum 25-hydroxyvitamin D levels. Many of the studies used doses of 1,000 IU/day or lower, with only a few studies utilizing doses up to 4,000 IU/day. This is a problem as many people require higher doses of vitamin D in order to achieve serum levels associated with protective benefits. Overweight and obese individuals may require even higher doses. Daily doses in excess of 6,000 IU may be required to achieve serum levels above 40 ng/ml in some individuals.² Thus, the amount of supplemental vitamin D studied here is likely not enough to raise serum levels a sufficient amount to see benefit.

Another flaw of this meta-analysis is that the authors do not report serum 25-hydroxyvitamin D levels after supplementation, only baseline levels (prior to supplementation). We therefore cannot know whether the participants in these clinical trials ever achieved serum levels high enough to see benefit—and based on their low doses, many of them likely did not achieve these levels. A meta-analysis of how serum levels after supplementation affect risk would give a better indication.

Additional limitations of the meta-analysis are listed in the paper itself: most of the included trials were not designed to measure cardiovascular outcomes and are therefore inadequate to draw definitive conclusions from regarding CVD. The authors of the meta-analysis also lacked patient-level data and consequently could not perform subgroup analysis in many areas of interest.

Many sources support the protective effects of vitamin D and increased serum 25-hydroxyvitamin D levels. Meta-analyses of observational studies have shown that levels of serum 25-hydroxyvitamin D are inversely correlated with risk of CVD events, hypertension, and all-cause mortality.^3-6 In one meta-analysis including 18 studies, each 16 ng/ml increase in serum 25-hydroxyvitamin D reduced the risk of hypertension by 26%.⁴ Another meta-analysis of 73 cohort studies (n = 849,412) and 22 RCTs (n = 30,716) concluded that higher serum vitamin D levels were associated with lower risk of mortality (from cancer, CVD, and more), and intervention with supplements significantly reduced the risk of mortality.⁵

Vitamin D supplements (in doses sufficient to raise serum 25-hydroxyvitamin D to approximately 50 – 80 ng/mL) remain a fundamental component of any well-rounded health and longevity regimen.

References

1. Barbarawi M, Kheiri B, Zayed Y, et al. Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis. JAMA Cardiology. 2019.
2. Kimball SM, Mirhosseini N, Holick MF. Evaluation of vitamin D3 intakes up to 15,000 international units/day and serum 25-hydroxyvitamin D concentrations up to 300 nmol/L on calcium metabolism in a community setting. Dermato-endocrinology. 2017;9(1):e1300213.
3. Gaksch M, Jorde R, Grimnes G, et al. Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium. PloS one. 2017;12(2):e0170791.
4. Burgaz A, Orsini N, Larsson SC, Wolk A. Blood 25-hydroxyvitamin D concentration and hypertension: a meta-analysis. J Hypertens. 2011;29(4):636-645.
5. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ (Clinical research ed). 2014;348:g1903.
6. Zhang R, Li B, Gao X, et al. Serum 25-hydroxyvitamin D and the risk of cardiovascular disease: dose-response meta-analysis of prospective studies. The American journal of clinical nutrition. 2017;105(4):810-819.