No measurable benefit from supplements in the VITAL trial

Two sets of results from a major trial focused on the use of supplements to prevent cancer and heart disease are published today in the New England Journal of Medicine.

In the so-called VITamin D and OmegA-3 TriaL (VITAL), > 25,000 U.S. men and women with no prior history of cancer, heart disease, or stroke were randomized to treatment in one of four different arms of the trial:

  • Dietary supplements of vitamin D3 (i.e., calciferol) at a dose of 2000 IU/day (Arm A)
  • A placebo comparable to the dietary supplements of vitamin D3 (Arm B)
  • Dietary supplements of omega-3 — also known as marine n-3 — fatty acids (Omacor® fish oil) at a dose of 1 g/day (Arm C)
  • A placebo comparable to the dietary supplements of omega-3 fatty acid (Arm D)

The goal was to see if, compared to a placebo, daily use of either supplement reduced the future risk of developing cancer or serious heart disease (including stroke) within the ensuing 5 years. Many of the details of the trial protocol can be found on the web site.

Men enrolled into the trial had to be ≥ 50 years of age; women had to be ≥ 55 years of age (and no, we don’t know why the women has to be 5 years older than the men, but it probably has something to do with the ages at men and women are most likely to be diagnosed with serious cardiovascular disorders or with the most common forms of cancer).

We should probably also be clear up front that this 5-year time fame is (arguably) relatively short. Whether funding has been made available to follow these patients for any longer is unknown to your sitemaster. He would like to think that it has been, but he suspects that it has not, given the current levels of funding of the National Cancer Institute and the National Institutes of Health.

The two major sets of results of this study are published today in two papers, both by Manson et al. The first of the two papers reports data on the effects of the omega-3 or marine n−3 fatty acid supplement. The second paper reports data on the effects of the vitamin D supplement (calciferol). There are also two editorials commenting on these data: one by Kastelein and Stoes (entitled “FISHING for the miracle of eicosapentaenoic acid“) addresses the omega-3 fatty acid data; the second, by Keaney and Rosen (“VITAL signs for dietary supplementation to prevent cancer and heart disease“) is focused on the vitamin D data.

Here is the bottom line.

  • The VITAL trial enrolled 25,871 people, of whom 5,106 (19.7 percent) self-identified as black
  • The patients were followed for an average (median) of 5.3 years.

In the first paper, Manson et al. report that

  • Major cardiovascular events occurred in
    • 386 participants in Arm A of the trial
    • 419 participants in Arm B of the trial
  • This difference was not statistically significant (hazard ratio [HR] = 0.92; P = 0.24).
  • Invasive cancer was diagnosed in
    • 820 participants in Arm A of the trial
    • 797 participants in Arm B of the trial
  • This difference was, again, not statistically significant (HR = 1.03; P = 0.56).
  • None of the secondary trial endpoints were statistically significant.
  • No excess risks of bleeding or other serious adverse events were observed.

The authors conclude that

Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo.

In the second paper, Manson et al. similarly report that

  • Major cardiovascular events occurred in
    • 396 participants in Arm C of the trial
    • 409 participants in Arm D of the trial
  • This difference was not statistically significant (hazard ratio [HR] = 0.97; P = 0.69).
  • Invasive cancer was diagnosed in
    • 793 participants in Arm C of the trial
    • 824 participants in Arm D of the trial
  • This difference was also not statistically significant (HR = 0.96; P = 0.47).
  • None of the secondary trial endpoints were statistically significant (specifically including risk for death from prostate cancer).
  • No excess risks of hypercalcemia or other adverse events were identified.

In this case the authors conclude that:

Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo.

Theses results would seem– at least at first sight — to be pretty cut and dried: taking vitamin D or a fish oil supplement at the doses used in this study for a period of 5 years has no impact on risk for cancer or serious heart disease.

Of course there is also a different way to look at these data, which is to interpret them as indicating that: taking vitamin D or a fish oil supplement at the doses used in this study for a period of 5 years has no impact on risk for cancer or serious heart disease — but taking one or both of these supplement appears to have no significant risk for side effects either, and maybe they are beneficial if you take one or both of them for 10 years, or 20 years, or whatever!

We are sure that it is possible to quibble with all sorts of things about these two studies, and that some people will do so. On the other hand, it would appear that people who take these dose levels of these agents for just 5 years may have been wasting a good deal of their money if they were under the impression that using these supplements in this way was going to lower their risk for cancer or serious heart disease.

12 Responses

  1. At least with respect to the Vitamin D arm the VITAL trial has some significant issues with respect to design and implementation. Based on one outdated study, the goal of the trial was to raise the serum vitamin D level to 40 ng/ml, which has been shown by several studies to be the minimum level to achieve health benefits. The published study only presented actual data on achieved serum levels at the first year of the 5+ year study. Serum levels were reported for only 6.4% of the participants, with the mean 25(OH)D serum level raised from 20.8 to 41.8 ng/ml, again the known lower limit for positive health effects. So, little information on the actual effect of the supplementation on the serum levels of 25(OH)D.

    Furthermore, the protocol’s supplementation dose, 2,000 IU/day was too low to raise serum levels of 25(OH)D to an effective level. An ongoing study with over 7,300 participants by the Vitamin D Council has shown that to raise the average serum 25(OH)D from 20 to a more effective 50 ng/ml would required a daily dose of 8,000 IU. So, all the media hype about the poorly designed VITAL study showing no positive benefits of vitamin D supplementation seems to be rather inappropriate.

    The actual conclusion should be that the study showed that inadequate vitamin D supplementation achieving minimal serum levels of 25(OH)D does not lower cancer risks. Unfortunately the inappropriate conclusions of the VITAL study are likely to deter a more meaningful clinical trial.

  2. There were also similar findings from a study in New Zealand and from the Mendelian randomization study.

  3. Should it be: women had to be ≥ 55?

  4. Yes. You are correct, and I have changed this above. Thank you!

  5. californiatrailnevada,

    See the NZ trial I referenced — they gave a 200,000 IU loading dose followed by 100,000 IU monthly. It still had no effect. (Don’t forget that it is stored in fat and the liver.) Serum vitamin D levels are controlled by biochemical processes (just as other steroids are) — just taking more won’t necessarily increase serum levels. There was also no difference in prostate cancer incidence in men who had very low serum vitamin D in men due to genetic abnormalities. There does not seem to be a dose effect.

  6. Omega 3s were well below what is considered a therapeutic dose.

  7. Thanks!

    It appears the the Mendelian study based its conclusions on a limited set of genetic defects related to the cancers. The abstract of the New Zealand study is more compelling but I’d like to see the actual paper ….

  8. californiatrailnevada pretty much explains my regard for an appropriate level of 25(OH)D before writing vitamin D off. Knowledgeable medical oncologists have recommended sufficient dosage to reach a better level of 75 ng/ml, and that usually takes 8,000 to 9,000 IU daily over several months to come into that level, after which a daily dose of 4,000 to 5,000 IU will likely maintain that level. We should look at vitamin D for its effect on overall health in addition to our regard for the prostate cancer patient.

  9. Further to my response, above: A few years back I did some research and study of the importance of vitamin D3 for men diagnosed with prostate cancer. I ended up compiling the information in this article. Since this article was compiled a few years ago, some of the reference URLs within it have expired for access, yet the information which was referenced remains reliable.

  10. Chuck, thanks for the additional references. The New Zealand study Allen mentions sounds interesting. I’d like to see the actual paper instead of the abstract. The references you cite are those I am familiar with and they clearly suggest the the VITAL study used inadequate dosages of the D3 supplements and had target serum levels below the generally recommended serum levels for health and cancer benefits. Their study protocol is available. An example of the study’s failure to fully evaluate the available research on vitamin D is the protocol’s limit of total vitamin D3 intake (VITAL supplied plus other dietary sources); “to ensure total supplemental vitamin D intake does not exceed the current safety limit [i.e., NOAEL] of 4000 IU/d set by the EC SCF).” Setting the “safety limit” for vitamin D3 to 4,000 IU/day is absolute nonsense! A very unfortunate result of this poorly conducted study will be that the resultant press coverage will result in decreased intake of vitamin D for the general population and will discourage funding for needed better research on the issues.

  11. Doug-

    A secondary analysis of SELECT trial men (see here or here) found that men at the high end of serum omega-3s had increased risk of prostate cancer and of aggressive prostate cancer. Why would anyone risk it?

    “This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.”

  12. Doug and Maack1:

    Your confirmation bias is showing. You ignore higher level of evidence for lower level of evidence, and write off large, well-done randomized clinical trials (like the NZ RCT) that don’t conform to your intuitions. That is not a good model to set for others.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: