Does Vitamin D Supplementation Lower Incidence of Cancer, CVD Events?

Researchers recently found that vitamin D supplementation did not lower the incidence of invasive cancer or cardiovascular events.

The study, a nationwide, randomized, placebo-controlled trial, was conducted by a research team led by, JoAnn Manson, MD, DrPH, and colleagues. The researchers sought to better understand whether vitamin D supplementation reduces the risk of cancer or cardiovascular disease compared with placebo. The primary endpoints of the study included invasive cancer of any type and major cardiovascular events, and the secondary endpoints included site-specific cancers, death from cancer, and additional cardiovascular events.

According to the findings, vitamin D supplementation did not lower the risk of either primary endpoint. More specifically: 

• 167 participants were diagnosed with cancer during the median follow-up; and,
• 805 participants experienced a major cardiovascular event.

To better understand the benefit of vitamin D supplementation for invasive cancer or cardiovascular events as well as the overall study findings, Pharmacy Learning Network spoke with Dr Manson.  

Please tell us a little bit about yourself.

I am an endocrinologist and a clinical trial researcher. I serve as chief of the division of preventive medicine at Brigham and Women's Hospital, professor of medicine at Harvard Medical School and professor of epidemiology at the Harvard Chan School of Public Health.

Can you briefly discuss the objective of your study?

The vitamin D and omega-3 trial (VITAL) is a large-scale randomized clinical trial, nearly 26,000 men and women nationwide, testing the role of vitamin D 2,000 IUs a day, and omega-3 fatty acids one gram a day in the primary prevention of cardiovascular disease and cancer.

We tested these two supplements in a factorial design, which means that we were able to test both interventions efficiently in the same trial, with 4 different treatment groups, to look at independent and joint effects. VITAL is a completed placebo-controlled, double-blinded trial with an average duration of 5.3 years.

What are the benefits and cons of vitamin D supplementation?

Our findings for vitamin D were that the overall results were neutral but there was a promising signal for a reduction in cancer death in the group receiving of vitamin D compared to the group receiving placebo.

We did not see a significant reduction in the primary endpoint of total invasive cancer or major cardiovascular events. We had the two co-equal primary endpoints related to cancer and to cardiovascular disease, and the results were not statistically significant.

However, for the pre-specified secondary endpoint of cancer death, we did see a borderline significant 17 percent reduction with vitamin D and after limiting the analysis to those in the trial for at least two years to account for cancer latency, we saw a statistically significant 25 percent reduction in cancer death.

However, overall the trial results were not statistically significant and particularly for cardiovascular disease, we really did not see a signal for benefit even when we looked at those who started out with low vitamin D blood levels at baseline, such as below 20 nanograms per ml.

We were not able to see a clear benefit among those who started out with lower levels. This is a volunteer population, so the average blood levels at baseline were not deficient in most of our participants.

Were you surprised at all by the findings of the study?

There had been some previous clinical trials suggesting that vitamin D might reduce cancer death, and so it was gratifying to see that signal again in the VITAL trial, and we’ve recently completed a meta-analysis of cancer findings in all completed trials.

In this new meta-analysis, we included cancer death as an endpoint, and adding in VITAL, and we do see overall a statistically significant 13 percent reduction, hazard ratio 0.87, for cancer death looking at all of these randomized trials in aggregate. Reduction in cancer death seems to be where the greatest signal is for a vitamin D benefit.

The trials in aggregate do not show a clear reduction in cancer incidence, which may take even longer follow up, or in cardiovascular events. Now, it may be that vitamin D affects tumor biology, and it has the effect of making a tumor less invasive, less aggressive, and less likely to metastasize.

Therefore, even in a five-year trial you might see a reduction in cancer death because many people will already have undiagnosed cancer or preclinical tumors, and vitamin D might be affecting their biology to make these tumors less likely to result in metastasis and death.

This possibility needs further study. I think it looks promising, but based on the VITAL trial which generally has null or neutral results, we certainly would not recommend that everyone run out and start taking moderate or high doses of vitamin D. We think it's important to advise against mega-dosing with very high doses, such as 10,000 IUs a day or higher --- these are doses that have not been well-tested in the long term.

We believe that those who are already taking vitamin D supplements, especially if it's at a moderate dose or similar to what was tested in VITAL, it would be reasonable to continue taking the supplements if they're doing well.

We didn't see adverse events, we did not see high blood calcium levels or other side effects or serious adverse events with 5.3 years of vitamin D supplementation at a dose of 2,000 IUs a day. We were able to document safety over 5 years, but there just wasn't substantial benefit observed for the primary outcomes.

Finally, is there anything else you would like to add?

I do want to add that VITAL has 23 ancillary studies, so stay tuned for much more research to be published from VITAL. We'll be publishing on the effects of the these supplements on diabetes, cognitive function, mood, depression, infections, lung diseases, bone health, autoimmune diseases, and many other outcomes.

Regarding the omega-3 intervention, we did see a signal for a lower risk of heart attack with omega-3s vs placebo, although overall there was not a significant reduction in the primary endpoint of major cardiovascular events or cancer with this supplement either.

Reference:

Manson JE, Cook NR, Lee I, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease [published online January 3, 2019]. N Engl J Med. 2019; 380:33-44
doi: 10.1056/NEJMoa1809944