COMMENTARY

Vitamin D: Insights Into Relationship With CVD and All-Cause Mortality

JoAnn E. Manson, MD, DrPH

Disclosures

April 18, 2017

Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital. I would like to talk about vitamin D, which has been in the news again, this time with two recent randomized clinical trials of high-dose vitamin D supplementation. One trial of vitamin D for cardiovascular disease prevention was published in JAMA Cardiology,[1] and a trial on vitamin D for cancer prevention was published in JAMA.[2] In addition, a large-scale meta-analysis of the relationship between the 25-hydroxyvitamin D blood level and mortality was published in PLoS One.[3]

Cardiovascular disease prevention. The cardiovascular disease prevention randomized trial[1] was done in New Zealand and included about 5000 participants. There was no clear evidence for a benefit of high-dose vitamin D supplementation, given as a monthly bolus dose, in terms of cardiovascular endpoints. The baseline average 25-hydroxyvitamin D blood level in this trial was 26 ng/mL, so this was a generally replete population.

Cancer prevention trial. In the cancer prevention trial,[2] which was conducted among about 2300 women in Nebraska, there was no significant reduction in the risk for cancer with 2000 IU daily of vitamin D supplementation. The mean blood level of 25-hydroxyvitamin D at baseline was 32 ng/mL, even higher than in the New Zealand trial. Both populations were generally replete and had blood levels that were already higher than what the National Academy of Medicine considers sufficient.[4]

Vitamin D and mortality. The meta-analysis of 25-hydroxyvitamin D levels and mortality outcomes may provide some insights into why these trials of vitamin D supplementation showed no results or significant benefits. In the meta-analysis, which included more than 26,000 participants from a large European consortium, there was a suggestion of a threshold effect for all-cause mortality. Once participants were at a 25-hydroxyvitamin D blood level of about 20 ng/mL (50 nmol/L, because the ratio between the two measurement units is 2.5:1), there was no clear evidence of greater reduction in all-cause mortality as the vitamin D level increased. For cardiovascular mortality, there appeared to be a threshold association at about 30 mg/mL, beyond which there is no clear evidence for greater benefit.

The good news is that several additional randomized trials of vitamin D supplementation will be completed and published within the next 1-1.5 years. Two of these trials are very large: the VITAL trial in the United States, with 26,000 participants; and the D-Health trial in Australia, with 20,000 participants. These trials and others that will be completed soon will be able to stratify by baseline 25-hydroxyvitamin D level and/or by intake of vitamin D and provide some indication of whether supplementation results differ according to the baseline vitamin D status of the participants. They will also be able to stratify by body mass index, and the VITAL trial will stratify by race/ethnicity.

Stay tuned for the results of these ongoing randomized clinical trials. In the meantime, there appears to be no clear evidence that high-dose vitamin D supplementation will reduce the risk for cardiovascular disease or cancer, and also no clear evidence that getting to very high blood levels of 25-hydroxyvitamin D will reduce the risk for these chronic diseases.

Thank you so much for your attention. This is JoAnn Manson.

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