What are the questions that the VITAL study intended to address?
DR. MANSON: Most previous studies of these dietary supplements have been observational, and we were interested in testing, in a large-scale randomized clinical trial setting, the effects of vitamin D and omega-3 fatty acid (FA) supplements on the risks of major chronic diseases, including cancer and cardiovascular disease. We wanted to have a “usual risk” population that was representative of the general public, age 50 and older and at typical risk of cancer and cardiovascular disease. All of the participants were free of these conditions at baseline.[1,2]
Q: Could you tell us about the details of the study design?
DR. MANSON: The study included nearly 26,000 US men and women. The men were age 50 and older and the women were 55 and older, with racial and ethnic diversity. As I mentioned, the participants were free of cardiovascular disease and cancer at baseline. The duration of the trial was a median of 5.3 years, so this trial was longer than many of the previous randomized trials with these supplements. We used what is called a factorial design, which enabled us to look at the independent and joint effects of the two dietary supplements. Vitamin D was given at a dose of 2,000 international units (IUs), and the omega-3 FAs (which were in the form of a prescription medication called Lovaza in the United States) had 1 gram a day of the marine omega-3 FAs EPA [eicosapentaenoic acid] and DHA [docosahexaenoic acid].
Q: What were the major results? Were any of the findings particularly surprising?
DR. MANSON: The main results of the trial focused on the primary prespecified endpoints, which were total cancer incidence and major cardiovascular events (a composite of myocardial infarction, stroke, and cardiovascular mortality). There was not a significant reduction with either of the agents. With the omega-3 FAs, there were some promising findings for myocardial infarction. For vitamin D, we saw no significant reduction in total cancer incidence, but we did see a signal for a reduction in cancer death. During the overall treatment period of 5.3 years, we saw a statistically non-significant 17% reduction in cancer death, with a hazard ratio of 0.83. However, we had planned to account for a latency period by doing some analyses that excluded early follow-up. In an analysis that excluded the first 2 years of follow-up, we did see a signal for a reduction in cancer deaths that was statistically significant, a 25% reduction, as well as a non-significant 6% reduction in cancer incidence with vitamin D. And why might there be a reduction in cancer death but not cancer incidence?
This has been found in previous randomized clinical trials, including meta-analyses of earlier trials. There’s some evidence from laboratory and clinical studies that shows that vitamin D might modify tumor biology, such that it makes cancers less invasive and less likely to metastasize. This could lead to a reduction in the likelihood of death from cancer within a 5.3-year period, but not affect the initiation of cancer, which is a very long-term process. For the omega-3 FAs, we did not see any reduction in cancer incidence or cancer mortality. We did see some promising findings for myocardial infarction, a secondary prespecified endpoint—a 28% reduction. We also saw a hint that after excluding early follow-up and accounting for the latency period, there was a borderline increase in cancer incidence of 13% with the omega-3 FAs, which is statistically non-significant, but we plan to watch this closely over time in case any further increase in cancer incidence emerges. There was no increase in cancer deaths with the omega-3 FA supplementation.
In regard to vitamin D, it was not surprising that the signal was more for a reduction in cancer death than cancer incidence because that had been suggested by earlier randomized trials as well. However, we were surprised that there was a signal for a greater reduction in cancer among the participants who were average weight or lower. Those who were within a normal weight range did appear to benefit from vitamin D in terms of a reduction in cancer, but those who were overweight or obese did not. This suggests that perhaps the individuals who have a higher weight may need a larger dose of vitamin D or else they may have a type of resistance, similar to insulin resistance, with decreased bioactivity of vitamin D. This result needs further exploration, but it was very interesting and surprising to see such an interaction with body mass index for vitamin D and cancer.
Q: How do you interpret the VITAL study results and are there other similar trials that are ongoing or being planned, or is this trial unique?
DR. MANSON: There are other trials on vitamin D, but most are smaller or have tested lower doses. There is a large trial in Australia that has close to 20,000 participants, and the results should be reported over the next 2 years. Smaller trials on these supplements will report results over the next few years. Overall, the randomized clinical trials on vitamin D analyzed in meta-analyses have not suggested a reduction in the incidence of cancer, but have suggested a reduction in cancer mortality, so our findings are consistent with these meta-analyses. As the largest vitamin D trial, we should be able to contribute to additional meta-analyses and the updated results are likely to suggest an even stronger signal regarding cancer death. The longer follow-up of our study will be of great benefit. With the omega-3 FAs, there have been very few long-term randomized trials looking at cancer as a prespecified endpoint, so I think we will have important information from the longer follow-up of the VITAL trial.
Reducing Cancer Risk Through Diet
Nutrition guidance and choices can play a fundamental role in helping adults reduce their risks for cancer and other chronic diseases. A common thread throughout the nutrition research over many years is that eating a balanced, whole-foods diet is beneficial in disease risk reduction and, at the same time, highly unlikely to present health hazards. Consuming foods such as fish, olive oil, nuts, and seeds is a safe, effective, practical (and, many claim, delicious) way to get essential nutrients and fats.
Omega-3 fatty acids (FAs), in particular, have been proven to be beneficial. Back in 1991, one study determined that a fish oil diet inhibits colon cancer in mice. Several studies have revealed the benefits of omega-3 FA supplementation in women with breast and gynecological cancers,[2-4] and a 2016 study showed the connection between consuming fish twice weekly and longevity.
There is little concern that a person will consume excess omega-3 fat from dietary sources, as compared with getting too much from supplements. As Manson points out, “mega-dosing”—or ingesting more than necessary of any given supplement, whether omega-3 FAs, vitamin D, or others—can pose dangers.
Although vitamin D is not found naturally in many foods, most adults can maintain adequate serum levels with appropriate sun exposure and/or dietary supplementation. Populations that seem to be at risk for low vitamin D include older adults, those who are home-bound or otherwise primarily indoors, persons with darker complexions such as African Americans, and those who are obese. Research suggests low vitamin D levels are associated not only with cancer and cardiovascular disease, but also diabetes, hypertension, metabolic syndrome, and cognitive decline. Mechanisms and causal relationships are still being elucidated. Nonetheless, it is safe to say that awareness of an individual’s serum vitamin D levels, and supplementing to prevent or correct a deficiency, is prudent. The bottom line is to get enough, but not too much, of any nutrient—ideally from foods, but from careful supplementation instead, if necessary.
Financial Disclosure: Ms. Anselmo has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Linder MA. A fish oil diet inhibits colon cancer in mice. Nutr Cancer. 1991;15:1-11.
2. Corsetto PA, Cremona A, Montorfano G, et al. Chemical–physical changes in cell membrane microdomains of breast cancer cells after omega-3 PUFA incorporation. Cell Biochem Biophys. 2012;64:45-59.
3. Rahman M, Veigas M, Williams PJ, Fernandes G. DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA. Breast Cancer Res Treat. 2013;141:341-52.
4. Khadge S, Thiele GM, Sharp JG, et al. Long-chain omega-3 polyunsaturated fatty acids decrease mammary tumor growth, multiorgan metastasis and enhance survival. Clin Exp Metastasis. 2018;35:797-818.
5. Gubbi S, Barzilai N, Crandall J, et al. The role of dietary patterns and exceptional parental longevity in healthy aging. Nutr Healthy Aging. 2017;4:247-54.
Ms. Anselmo has specialized in oncology nutrition since 2007. She is a Registered Dietitian Nutritionist at the Evelyn H. Lauder Breast Center of Memorial Sloan Kettering Cancer Center, New York, New York.
Q: What are the clinical implications of these results?
DR. MANSON: In terms of guidance regarding who should take supplements and who should not, we feel that we were able to demonstrate the safety over 5.3 years of this dose of vitamin D (2,000 IUs per day) and 1 gram per day of omega-3 FAs. We did not see significant side effects—there was no increased risk of hypercalcemia with this dose of vitamin D and no increased risk of bleeding with the omega-3 FAs. For patients who are already taking these supplements in similar doses, we don’t think the VITAL trial provides a strong reason for stopping these dietary supplements. However, we do think that it is important to caution against mega-dosing on these supplements because much higher doses of vitamin D have been linked to hypercalcemia and higher doses of omega-3 FAs can increase bleeding risk. This is an important warning, because there are individuals taking extremely high doses of these supplements.
For the omega-3 FAs, we did find that those who had lower fish consumption tended to benefit the most in terms of cardiovascular disease and heart attack risk. So, if someone has a very low fish intake despite encouragement to increase their consumption, and they’re at elevated risk for heart disease, they may be a candidate for an omega-3 FA supplement. However, we are not encouraging routine use of these supplements. Mostly we’re saying, stay tuned and we will have additional results in the next 6 to 12 months from several ancillary studies, as mentioned earlier, and we’ll have longer-term follow-up of the cohort. Some of the signals we saw may strengthen or weaken with longer follow-up. Both the longer-term follow-up and the ancillary studies will be very helpful in informing decision making. We expect that medical and public health authorities, over time, may look at the results from VITAL and other recent randomized trials, and assess whether the clinical guidelines for the use of these dietary supplements should be updated.
Q: What’s next for this study? You mentioned further follow-up. Are there additional analyses that you and your colleagues are now conducting, and are the participants still being followed to track outcomes?
DR. MANSON: We will be continuing to follow the participants for at least 2 years post-intervention. The treatment period ended December 31, 2017, and we will follow for an additional 2 years to see if any of these signals, such as the trend for a reduction in cancer death with vitamin D, will become stronger or weaker over time. We will also see if a significant reduction in cancer incidence emerges over time. Additionally, we will keep an eye on the omega-3 findings in relation to cancer. We plan to apply for a renewal grant and follow the participants for even longer, hopefully for at least 4 to 5 more years after this 2-year time point, allowing us to account more fully for latency of cancer and to have greater statistical power to look at the relationship between these dietary supplements and cancer.
We also have several ancillary studies that may help to inform the benefit-risk profile of these supplements. For example, we are looking at effects on diabetes, cognitive function, depression, and autoimmune diseases, and also testing their effect on numerous biomarkers, including telomere length and metabolomics, that may be of relevance to cancer, cardiovascular disease, and other chronic diseases.
Financial Disclosure: The VITAL study is supported by the National Institutes of Health, but study supplements were provided by Pharmavite and Pronova BioPharma/BASF Pharma.
1. Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2018 Nov 10. [Epub ahead of print]
2. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018 Nov 10. [Epub ahead of print]