Vitamin D is viewed as a promising supplement by the medical, public health, and lay communities, potentially offering many health benefits. But enthusiasm for a new intervention too often gets far ahead of the evidence, as was the case with beta-carotene, selenium, folic acid, and vitamins C and E.
Despite the enthusiasm for vitamin D, there have been no large-scale primary prevention trials that have had either cardiovascular disease or cancer as a prespecified primary outcome. Previous randomized trials of vitamin D have focused primarily on osteoporosis, fracture, falls, and physical function. Although the investigators often reported their findings on vitamin D and cardiovascular disease or cancer, these outcomes were generally secondary or tertiary end points that were not prespecified. These studies should be viewed as hypothesis-generating rather than hypothesis-testing. The increasing prevalence of use of vitamin D supplements underscores the need for rigorous and conclusive evidence from randomized clinical trials that have cardiovascular disease and cancer as primary outcomes.
This article will explain the rationale for a large-scale, randomized clinical trial to evaluate the role of vitamin D in the prevention of cardiovascular disease and cancer. It will also describe the biological mechanisms and currently available evidence relating vitamin D to potential health benefits. Finally, the design, dosage considerations, and logistics of the Vitamin D and Omega-3 Trial (VITAL) will be presented.
EVIDENCE IS MOUNTING FOR VITAMIN D’S BIOLOGICAL IMPORTANCE
Vitamin D is undoubtedly important to health: not only is it produced endogenously, but at least 500 genes have been identified with vitamin D response elements. The vitamin D receptor is found in nearly all cells in the body, and the 1-alpha-hydroxylase enzyme is present in many tissues. Some studies suggest that almost 10% of the human genome may be at least partially regulated by vitamin D.
From Hajjar V, et al. Does vitamin D deficiency play a role in the pathogenesis of chronic heart failure? Do supplements improve survival? Cleve Clin J Med 2010; 77:290–293. Figure 1.
Although we know vitamin D is important, what our optimal intake and our blood level of 25-hydroxyvitamin D3 should be are key unknowns.
RECOMMENDATIONS FOR VITAMIN D INTAKE
During winter, late fall, and early spring, people who live above the 37th parallel (geographically, about one-half of the contiguous United States) do not get enough ultraviolet B energy from the sun to make all the vitamin D they need, even if they spend several hours outside every day. In addition, dark skin pigmentation serves as a sun block, as do sunscreens.
The Institute of Medicine (IOM) provided guidelines for vitamin D intake in 1997 and, most recently, in 2010. However, these guidelines are based on the amount of vitamin D required for bone health and do not address the amount that may be of benefit for prevention of cancer and cardiovascular disease. The latter outcomes are not addressed because the IOM committee believed that evidence was insufficient to determine the role of vitamin D in the prevention of cardiovascular disease, cancer, and other chronic diseases. Thus, current IOM guidelines, which generally recommend less than 1,000 IU of vitamin D daily, are relevant to bone health but not necessarily to other health outcomes. More research is needed to understand whether the guidelines should be modified for the prevention of other chronic diseases.
Moreover, whether or not everyone should be screened for 25-hydroxyvitamin D3 blood levels is controversial. Most experts agree that a level less than 20 ng/mL is deficient or insufficient. Conversely, potentially harmful are levels 150 ng/mL or more (> 375 nmol/L), which entail the risk of hypercalcemia, vascular soft tissue calcification, and hyperphosphatemia.
People do not reach toxic levels with ultraviolet light exposure because the amount of 25-hydroxyvitamin D3 synthesis is well regulated. Dietary supplements, however, can bring about toxic levels, and patients taking high doses need to be monitored carefully. The level that should be considered optimal is controversial and requires further study.