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

JoAnn E. Manson, MD, DrPH


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.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.