Vitamin D Supplementation Doesn’t Prevent Major Diseases: Results from the VITAL Trial
A major prospective National Institutes of Health (NIH)-funded trial known as the VITAL trial involved 25,871 participants from the general population in order to determine how well daily dietary supplements helped reduce the risk of developing cancer, heart disease, and stroke in people with no prior history of these conditions. The study found that vitamin D3 (cholecalciferol), at a dose of 2000 international units per day over a median 5.3 years, did not result in a lower incidence of invasive cancer or major cardiovascular events compared to placebo.
The vitamin D trial results can be accessed at: Manson JE et al. “Vitamin D supplements and prevention of cancer and cardiovascular disease.” New Eng J Med 2019; 380:33-44.
The term VITAL stands for The Vitamin D and Omega-3 Trial. The vitamin D portion of the trial was conducted in concert with the omega-3 fatty acid study.
The authors prefaced the study by stating that supplemental vitamin D has been viewed in recent years as a potential strategy for preventing cancer and cardiovascular disease. For example, other studies have shown lower rates of death from cancer in regions with greater sun exposure compared with areas with less sun exposure. Inferences were drawn, as the major source of vitamin D is through synthesis in the skin via ultraviolet rays from sunlight. In addition, observational studies have shown associations between low serum levels of vitamin D and increased risks of cancer and cardiovascular disease.
The authors cited a lack of data from large-scale randomized trials (involving 10,000 or more participants) of vitamin D in moderate or high doses designed with cancer and cardiovascular disease as primary outcomes.
The U.S. Preventive Services Task Force concluded that there were insufficient data to evaluate the effectiveness for supplementation with vitamin D for the prevention of cancer and cardiovascular diseases. (See U.S. Preventive Services Task Force recommendation statement – Ann Intern Med 2014; 160:558-64.) Prior to that conclusion, the Institute of Medicine had previously called for new trials of vitamin D in amounts at least twice the recommended dietary allowance for bone health to clarify new benefits in addition to bone health. (See Institute of Medicine. “Dietary reference intakes for calcium and vitamin D.” Washington D.C. National Academies Press, 2011.)
The VITAL trial was designed to address these knowledge gaps regarding vitamin D supplementation.
VITAL was a randomized, double-blind, placebo-controlled trial to test the benefits and risks of vitamin D3 (cholecalciferol) at a dose of 2000 international units in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States.
Participants were recruited throughout the United States and the groups were balanced according to sex and with a goal to include at least 5,000 African-American participants. Participants were required to limit the use of vitamin D from all supplemental sources to 800 international units per day.
Questionnaires were used at baseline to collect data on risk factors for cancer, cardiovascular disease, and other conditions. From there, annual questionnaires were used to collect data on adherence to and potential side effects of the trial agents.
The primary endpoints were major cardiovascular events consisting of heart attack, stroke, or death from cardiovascular causes and invasive cancer of any type. Secondary cancer endpoints were colorectal, breast, and prostate cancers, as well as death from cancer. Secondary cardiovascular endpoints were an expanded composite of major cardiovascular events plus coronary revascularization.
A total of 25,871 participants underwent randomization:
- 51% were women
- Mean age of participants was 67.1 years
- The cohort included 20% black participants, 71% non-Hispanic whites; the rest were members of other racial or ethnic groups
A total of 15,787 participants had blood samples analyzed:
- Mean 25-hydroxyvitamin D level at baseline was 30.8 nanogram per milliliter
- After one year of supplementation with vitamin D3, the mean 25-hydroxyvitamin D blood level was close to or above 40 nanogram per milliliter
- During the median follow-up of 5.3 years, invasive cancer of any type developed in 793 vitamin D participants and 824 placebo participants
- No significant differences between the two groups were observed with regard to the incidence of breast, prostate, or colorectal cancer
- During a median follow up of 5.3 years, a major cardiovascular event occurred in 396 participants in the vitamin D group and in 409 in the placebo group
- Total myocardial infarction occurred in 169 vitamin D group and in 176 placebo group
- Total stroke occurred in 141 vitamin D group and in 149 placebo group
- Death from cardiovascular disease occurred in 152 vitamin D group and in 138 placebo group (HR 0.96; CL 0.96-1.21)
Death from any cause
- 978 deaths from any cause
- 485 deaths in vitamin D group; 493 deaths in placebo group
The authors cited two trials of high-dose vitamin D which had been completed. One 4-year trial evaluated vitamin D 2000 international units daily plus calcium 1,500 mg against placebo for cancer prevention in 2,303 women in Nebraska and showed a “suggestive” but nonsignificant 30% lower incidence of cancer. (Lappe J, et al. JAMA 2017; 317:1234-43.)
The other, a 3.3-year Vitamin D Assessment Study (VIDA), tested monthly vitamin D (100,000 international units) against placebo for prevention of cancer in 5,110 participants in New Zealand. It showed no benefit on cancer outcomes for Vitamin D. (Scragg R, et al. JAMA Oncol 2018; July 19.) However, given the long latency for cancer development, extended follow-up is necessary to fully ascertain potential preventive effects of vitamin D on cancer development.
The authors stated that the observed lack of benefit of vitamin D supplementation for cancer and cardiovascular outcomes is consistent with results of previous published trials. They again cite the VIDA trial, which showed that rate of cancer was not lower among participants who received monthly administration of high-dose vitamin D than among those receiving placebo. And neither this current VITAL trial nor VIDA showed that vitamin D was associated with a reduced rate of death from any cause.
In summary, this VITAL trial showed that daily supplementation with 2000 international units of vitamin D for 5 years among healthy adults in the United States did not reduce the incidence of cancer or major cardiovascular events.
In an accompanying editorial by Keaney and Rosen (Keaney JF Jr., Rosen CJ. “VITAL signs for dietary supplementation to prevent cancer and heart disease.” N Eng J Med 2019; 380:91-93), the commentators stated that the VITAL trial was the largest and longest of any to test whether Vitamin D supplementation could prevent cardiovascular disease or cancer. Despite the negative findings, there is still uncertainty about cancer prevention with vitamin D. Vitamin D consistently suppresses cell proliferation in vitro, which translates into potential in vivo anticancer efficacy. Also, the Nebraska trial showed a suggestive preventive effect, with a 30% lower incidence of cancer with vitamin D and calcium supplementation.
However according to the editorial, in the absence of new compelling data, it is prudent to conclude that dietary supplementation of vitamin D by the general population does not protect against cardiovascular events or cancer.
Richard L. Wynn, BS Pharm, PhD, is professor of pharmacology at the Baltimore College of Dental Surgery, Dental School, University of Maryland Baltimore.
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