Is it all just fishful thinking?

The use of dietary supplements is common in the U.S., with some estimates stating that over half^[1] of adults regularly consume supplements of some kind. Fish oil is the most common^[2] non-vitamin and non-mineral supplement taken in the U.S., with consumers citing improved heart health^[3] as their main motivation for taking it. Many epidemiological studies^[4][5] have demonstrated that a high intake of fish^[6] or omega-3^[7] (n-3) fatty acids is associated with a decreased risk of cardiovascular diseases (CVDs) or risk factors for the diseases. However, this effect has largely not been demonstrated^[8] in human clinical trials, as most trials show n-3s to have a neutral effect with respect to a reduction in clinical events. One large, early trial to investigate n-3s and clinical events was the GISSI-Prevenzione trial^[9] which appeared to clearly demonstrate the benefit of around 300 milligrams of eicosapentaenoic acid (EPA) and 600 milligrams of docosahexaenoic acid (DHA) daily with regard to sudden death, total mortality, cardiovascular mortality, and coronary heart disease mortality for people who had suffered a recent heart attack. The main outcomes of the trial are shown in Figure 1. Since then, however, several trials have been conducted^[10] showing inconsistent results, bringing the cardioprotective effects of omega-3 into doubt. Moreover, the participants of the trials were participants with a history of cardiac issues, such as coronary heart disease or a recent myocardial infarction, so the implication of omega-3 supplementation for the general population is equally unclear.

Vitamin D supplementation is also common, with reported usage of vitamin D supplements (excluding from multivitamins) increasing^[1] from 5.1% in 1999 to 19% in 2012. The most common reason cited for taking vitamin D was to improve bone health^[3]. However, there have been many reports suggesting that vitamin D might reduce the risk of cancer as well. For example, activation of vitamin D receptors appears to reduce liver inflammation and fibrosis in mice and in human tissue samples^[11]. Recent reviews^[12][13] of preclinical and epidemiological studies indicates that vitamin D plays a role in anticancer signaling by reducing cell proliferation, reducing inflammation, and increasing apoptosis, among other activities. However, human trials have not found much of a clinical effect. For example, the Women’s Health initiative, a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women, found no difference^[14] in rates of colon cancer from the placebo group after seven years of an intervention with 400 IU per day of vitamin D3. One limitation of this study was that the 400 IU dose of vitamin D3 may have been too low to have an obvious clinical effect. A more recent trial^[15] of 2,303 postmenopausal women remedied this limitation by giving participants 2000 IU of vitamin D3 plus calcium per day for four years to see if there was any difference in any types of invasive cancer. The results did not reach statistical significance, but there appeared to be a statistically nonsignificant trend suggesting that vitamin D plus calcium may reduce the risk of cancer. A potential confounder to some of these trials is that they use both vitamin D and calcium supplementation, and calcium alone has been linked to reduced^[16] cancer risk and improved^[17] cancer survival. So, how can we really know what effect the vitamin D alone may have?

To address the concerns regarding methodological limitations in previous trials such as a small study population or low doses of the supplements, there was a need for a study like the VITamin D and OmegA-3 TriaL (or VITAL) to examine the cardiovascular and cancer impact of vitamin D and omega-3 fatty acids with a large, diverse population of healthy volunteers.

Although observational evidence suggests fish oil and vitamin D protect against maladies like cancer or cardiovascular disease, evidence regarding supplementation with these nutrients from human clinical trials has been inconsistent. The study under review, VITAL, aims to address the limitations of past trials in this area.