The VITamin D and OmegA-3 TriaL (VITAL) at Brigham and Women’s Hospital (BWH) is an ongoing research study in 25,875 men and women across the U.S. investigating whether taking daily dietary supplements of vitamin D3 (2,000 IU) or omega-3 fatty acids (Omacor® fish oil, 1 gram) reduces the risk for developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. Funded by the National Institutes of Health, the trial will also assess the nutrients’ effects on diabetes, cognitive function, and other conditions.
VITAL is a randomized, double-blind, placebo-controlled trial of Vitamin D and omega-3 fatty acids that is following a multiethnic population for five years. To date, there have been no previous large randomized trials of supplemental vitamin D in high enough doses to produce meaningful changes in circulating vitamin D levels and designed to assess its effects on cancer and CVD.
“Vitamin D and omega-3 fatty acids look promising in observational studies but there’s a great need for large-scale randomized trials that assess cause and effect relationships,” said JoAnn Manson, MD, DrPH, Chief, Division of Preventive Medicine at BWH and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School.
Participants are divided into four groups: vitamin D (2000 IU/day of vitamin D₃ cholecalciferol) plus omega-3s (1g/day); vitamin D plus placebo omega-3s; omega-3s plus placebo vitamin D; and placebos for both. “We’re looking at the independent effects of vitamin D and omega-3 supplements, and the design allows us to separate the effects of the two interventions,” said Dr. Manson.
The vitamin D dose is based on what was most promising in earlier research and provided the best balance of efficacy and safety. The current Institute of Medicine (IOM) RDA for adults aged 50-70 is 600 IU/day and adults over 70 is 800 IU/day, which is based on strong evidence that this amount is sufficient to maintain bone health in the North American population. However, accumulating data suggest that vitamin D intakes above these RDAs may confer optimal health benefits. For example, systemic reviews and meta-analyses have raised new questions about the effects of supplemental vitamin D alone on fracture risk and bone health outcomes. One review of studies of serum 25-hydroxyvitamin D in relation to various outcomes, including colorectal cancer, falls, fractures, physical functioning, and dental health found that optimal 25(OH)D levels were above 75 nmol/L, rather than the 50 nmol/L level recommended by the IOM.
The omega-3 dose of 1g/day (which includes the marine fatty acids eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) is recommended by the American Heart Association (AHA) for people with CVD and has been demonstrated to be beneficial, with minimal side effects, in large secondary prevention trials but has not been previously tested in primary prevention.
In some laboratory research, Vitamin D has demonstrated an anti-inflammatory effect that is important in CVD and cancer. When vitamin D is supplemented within the cell culture, it affects the cancer cell’s ability to proliferate and may make the cancer less likely to metastasize. Studies have also shown that vitamin D’s anti-inflammatory properties may lead to favorable effects on blood pressure, cholesterol, and glucose tolerance.
Omega-3 fatty acids have also shown considerable promise for the prevention of CVD in laboratory and observational studies; large randomized secondary prevention trials have also found CVD benefits, including lowering risk of irregular heart rhythms, as well as decreasing blood clotting and inflammation. The data on omega-3’s effects on the primary prevention of CVD and cancer, however, are inconclusive.
VITAL’s primary aim is to test whether vitamin D or omega-3 fatty acid supplementation reduces the risk for total cancer and major CVD events (myocardial infarction, stroke and cardiovascular mortality). It is also looking at whether these nutrients reduce the risk for specific cancers, including colorectal, breast and prostate; total cancer mortality; cardiovascular mortality, and coronary revascularization; and the individual components of the primary cardiovascular endpoint, particularly CVD mortality. Study objectives also include testing whether vitamin D or omega-3 fatty acid supplementation reduces fracture risk and benefits bone structure.
The trial is exploring whether vitamin D3 and marine omega- 3 fatty acid supplementation exhibit synergistic or additive effects on the risk for total cancer, major CVD events, and the secondary endpoints, and whether their effects on cancer and CVD risk vary by baseline blood levels of these nutrients, race/skin pigmentation (for vitamin D3), and body mass index (BMI) (for vitamin D3). Testing the effects of vitamin D on African-Americans is particularly important since they are at higher risk of vitamin D deficiency as well as certain cancers, including prostate, cardiovascular events and mortality from cancer and CVD. VITAL is assessing whether supplementation can reduce these health disparities.
With funding from the National Institutes of Health (NIH), the trial is also assessing the effects of these nutrients on diabetes, high blood pressure, respiratory conditions, and other outcomes in a group of 1,050 Boston-area participants who are undergoing detailed testing, including a two-hour glucose tolerance test, and bone imaging to measure body composition, bone mineral density, and bone structure, at Brigham and Women’s. “We are very interested in the question of the effects of supplementation on diabetes, cognitive function, mood/depression, bone health, autoimmune conditions, and other outcomes, which are being addressed in ancillary studies,” said Dr. Manson.
“These studies also will clarify whether high-dose, supplemental vitamin D is effective in the primary prevention of fractures, with major impacts on clinical and public health guidelines,” explained Meryl S. LeBoff, MD, Chief, Calcium Bone Section, Division of Endocrinology, Diabetes and Hypertension and a Professor of Medicine at Harvard Medical School.
Additional trials of vitamin D and/or omega-3 supplementation are in progress worldwide. If they and VITAL have positive results, “the clinical implications will be substantial if the results demonstrate that 2000 IU/d of vitamin D confers greater benefits than 600 to 800 IU/d, then the population will need supplementation and/or increased food fortification, as current diets do not provide that amount. The findings may influence public policy and nutritional guidelines. Vitamin D could become a standard supplement for CVD and cancer prevention just as folic acid supplementation is recommended during pregnancy to prevent birth defects,” said Dr. Manson.