Cooper Cardiologist Shares Key VITAL Trial Vitamin D Takeaways
There seems to be no end to the confusion and controversy about the reported health benefits of supplements. This is certainly true for vitamin D and omega-3 fatty acids. The VITAL (VITamin D and OmegA-3 TriaL) study was designed in 2010 with the goal of providing the final word regarding the impact of these supplements on the prevention of cancer and cardiovascular disease. It is no surprise that the results of this study were announced in November 2018 with great fanfare, including a presentation at the annual American Heart Association meeting with the simultaneous publication of the results in the prestigious New England Journal of Medicine.
If you relied on the headlines as your sole source of information about the VITAL study, you were probably inclined to throw your vitamin D and omega-3 fatty acid supplements in the trash. Unfortunately, the headlines missed some vital information regarding the important findings of this newsworthy clinical trial.
In brief, the VITAL study was a randomized, placebo-controlled trial, enrolling almost 26,000 men (≥ 50 years of age) and women (≥ 55 years of age) who were treated with either vitamin D3 (50 mcg ( 2000 IU) per day) or placebo and marine n−3 (also called omega-3) fatty acids (1 gram per day) or placebo for the prevention of cancer and cardiovascular disease. This is called a two-by-two factorial design.
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$26.98 Add to cartThese participants were followed for a median of 5.3 years. This means half were followed for more, and half were followed for less than 5.3 years. From my perspective, the use of medians is not a very intuitive way of describing follow-up. I think it is more helpful to know the range of follow-up was 3.8 to 6.1 years.
The primary endpoints were:
- Invasive cancer of any type
- Major cardiovascular events (a combination of myocardial infarction (heart attack), stroke or death from cardiovascular causes)
Vitamin D Results of the VITAL Study Impact on Cancer
Prevention of Cardiovascular Disease Related to Vitamin D Levels
In participants who took 50 mcg (2,000 IU) of vitamin D daily, there was no reduction in the risk of developing major cardiovascular events. The authors of the study note an important caveat to this finding. In prior observational studies, vitamin D levels less than 20 ng/mL were associated with higher cardiovascular risk. In this study, the average baseline value of vitamin D (i.e., at the start of the study) was 31 (lower limits of the normal range). Less than 13 percent of the study participants had a vitamin D level < 20 at the start of the study. Because few participants had a very low level of vitamin D, it was unlikely that a statistically significant reduction in cardiovascular risk would be demonstrated in this study.
Prevention of Cancer Associated with Vitamin D Levels Clarification
This study concluded that supplementation with vitamin D did not result in a lower incidence of invasive cancer compared with a placebo. “Incidence of invasive cancer” means new cases of cancer diagnosed during the duration of the study.
Recall that participants in this study were followed for 3.6 to 6.1 years, with half followed for less than five years. Can we really test whether any intervention reduces the risk of developing cancer in a study with this short length of follow-up? For most cancers, the answer is no.
Cancers begin as just one cancer cell. This single cancer cell doubles to become two cancer cells, then two cells double to become four cancer cells and so on. The doubling time can vary depending on many factors, such as the type of tumor and the ability of the patient’s body to resist cancer; it can range from days to years, averaging three to four months.
A single cell needs 30 doublings to reach a (generally) detectable size (1 cm, 0.4 inches or a billion cells). For example, if a cancer has a doubling time of three months, it will take 90 months (7.5 years) for the cancer to be detectable by an imaging test or physical examination. In one study of different types of lung cancers, the average doubling time was 303 days for adenocarcinomas and only 70 days for small cell lung cancer. Thus, the time from cancer initiation to detection could be as long as 25 years and as short as six years. So, it is highly likely that most, if not all, of the “newly diagnosed” cancers identified in the study were already present but not yet detected.
Vitamin D and Cancer Behavior and Possible New Connections
So, with a relatively short follow-up time, this study cannot realistically provide much information about truly preventing cancer. However, several findings from this study may shed some light on the impact of vitamin D on cancer behavior once it is already present (but not yet detected).
There’s a lot of basic science work showing vitamin D can:
- Slow the growth of cancer cells
- Stimulate cell death
- Reduce blood vessel growth to tumors
- Decrease inflammation
- Stimulate the body’s immune system to fight cancer
Thus, vitamin D may decrease tumor invasiveness and the likelihood of tumor metastases leading to a reduced risk of death from cancer.
Vitamin D and Death from Cancer: Rates and Connections
These basic science findings about vitamin D and cancer growth were supported by the results of the Vital study regarding the impact of vitamin D on death from cancer. The rate of death was not proportional during the duration of the study; this means the rate of death each year was not the same. More than one-third of the cancer deaths occurred in the first two years of the study. These participants who died early clearly had aggressive cancers once diagnosed or cancers diagnosed at an advanced stage
When the authors analyzed the data without the early cancer deaths during the first two years of follow-up, they found that participants who took vitamin D had a 25 percent reduced risk of dying from cancer. So even though cancer was present, it was less likely to progress as rapidly, resulting in death. These findings suggest that Vitamin D supplementation could prolong life in the presence of cancer.
In a subgroup analysis in the VITAL study, participants with a normal body mass index (BMI) < 25 who were treated with vitamin D were significantly less likely to be diagnosed with a new cancer during the study (almost a 25% reduction in risk) suggesting a slowing of tumor growth. This benefit was extinguished at higher BMI levels. It is well known that excess weight is associated with an increased risk of multiple cancer types; this benefit of vitamin D at the current supplement dose appears to be extinguished at higher weights.
Few Vitamin D Measurements Made on Treatment
Finally, one very important criticism of this trial was the failure to measure vitamin D levels throughout the study in a large number of participants to confirm vitamin D levels were staying constant in the placebo group and were increasing in the vitamin D group.
About 60 percent of participants had blood samples that could be analyzed to measure baseline vitamin D levels at the start of the study.
However, only 6 percent (1,644 out of almost 26,000 participants) had blood samples that could be analyzed for vitamin D levels during the study (at one year).
- Vitamin D Group: Mean vitamin D levels increased from 30 ng/ml to 42 ng/ml at one year
- Placebo Group: No significant change
Ultimately, we have no idea what the vitamin D levels were in the treatment group at the end of the study period.
Participants received study capsules in the mail. The mean rate of adherence to the trial regimen (the percentage of participants who reported taking at least two-thirds of the trial capsules) was:
- Vitamin D Group: 82.0 percent
- Placebo Group: 80.3 percent
So, those participants who were technically following the study protocol (“adherent”) could miss one out of every three study medications.
Furthermore, about one in five participants took less than two-thirds of the study medications. I was very disappointed this study only had measured vitamin D levels on 6 percent of the participants at one time period (one year). Who knows what the vitamin D levels were in study participants at the two-, three-, four- or five-year mark?
Above All, Do No Harm
Finally, it was reassuring to see there were no significant differences between the two groups (vitamin D treatment and placebo) with respect to incident diagnoses of hypercalcemia, kidney stones or gastrointestinal symptoms.
Key Takeaways About the VITAL Trial Vitamin D Findings
- With a follow-up period of just 3.6 to 6.1 years, this was not a cancer prevention study. It was a cancer detection study to determine whether vitamin D use slowed cancer growth sufficiently to reduce the detection of the cancer using standard cancer detection modalities in clinical practice.
- Vitamin D use was associated with a 25 percent reduction in cancer detection in those participants with a normal BMI but not in overweight or obese participants.
- Vitamin D use was associated with a 25 percent reduction in the cancer death when the first two years of follow-up were excluded (those participants diagnosed with aggressive or advanced cancer at the start of the study).
- These findings are consistent with basic science research showing vitamin D may decrease cancer growth, invasiveness and the tendency for cancer to spread to distant sites.
Overall, it’s important to remember to talk with your physician before starting any new supplements.
Dr. Nina Radford is the Director of Clinical Research and a cardiologist at Cooper Clinic. She also wrote a review and key takeaways of the Omega arm of the VITAL study.