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A look at the recent Lancet review study

Posted on: December 6, 2013   by  Brant Cebulla

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A new study has come out in the journal the Lancet, and we have received many emails requesting that we address it. The study is this one:

Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. The Lancet Diabetes & Endocrinology 06 December 2013

The study type was a review; so it is not primary research, rather secondary research that sorts through and gathers all the research published to date.

Although the title of the paper claims that it was a systematic review, it’s not exactly a systematic review in the classic evidence-based medicine sense. Systematic reviews address a specific question (called a PICO question), asking how an exposure (like vitamin D) relates to an outcome (like cancer) or outcomes (like cancer and cardiovascular disease, etc.). That’s not what this paper did; there’s no clearly defined PICO question or questions.

What this paper did was collect all the prospective cohort studies to date that looked at vitamin D’s relationship to a disease. And they collected all randomized controlled trials to date that looked at vitamin D’s relationship to a disease. So in all, they examined studies that covered a plethora of diseases. They wanted to know the following:

  • What kind of results are prospective cohort studies showing? Prospective cohort studies are observational, not controlled trials.
  • What kind of results are randomized controlled trials showing?
  • Is there a gap between what these observational studies are showing and what the randomized controlled trials are showing?
  • If there is a gap, why is there a gap? Can we develop a hypothesis why there is a gap?

So they searched PubMed and Embase for prospective cohorts and randomized controlled trials. They had various criteria for whether or not to include a study in their analysis. One notable inclusion criteria for randomized control trials was that trials had to use doses of at least 2,000 IUs of vitamin D and participants had to start below a level of 20 ng/ml before they started the trial.

In all, they found 290 prospective cohort studies and 172 randomized controlled trials.

Here’s what they found:

  • In general, prospective cohort studies showed more robust results than the randomized controlled trials.
  • Many specific diseases that prospective cohort studies showed promise for, didn’t have the same kind of promise and proof from randomized controlled trials.
  • Randomized controlled trials were generally considered failures for their lack of significant improvement in target outcomes. To give an arbitrary example, if a randomized controlled trial assessed 15 different outcomes (like multiple cardiovascular health markers, for example) and only had 3 significant outcome improvements, the authors’ general attitude was that vitamin D was not beneficial (more on this later).
  • The type of outcome in randomized controlled trials that best matched the results of the prospective cohort studies was all-cause mortality. In other words, randomized controlled trials generally show that vitamin D protects against all-cause mortality, just like prospective cohort studies do.

The researchers concluded that since randomized controlled trials don’t perfectly match prospective cohort studies, then vitamin D deficiency must be linked to diseases via reverse-causality or confounding factors. An example of reverse causality is the following:

  • Vitamin D deficiency doesn’t cause depression; depression causes vitamin D deficiency because it causes people to stay indoors.

An example of a confounding factor:

  • Vitamin D deficiency doesn’t cause depression; a lack of UV exposure causes depression and a lack of UV exposure causes vitamin D deficiency.

The above examples are arbitrary examples, so please don’t take either statement to be necessarily true.

While it could be the case that vitamin D deficiency is a victim of reverse-causality or confounding factors and vitamin D interventions won’t prevent or treat some diseases, we’re not at the point in research to make that call. Here’s why:

To date, randomized controlled trials have been mostly small and exploratory. We’re not exactly sure how vitamin D affects the body. We think we’re very likely not getting enough, but how that affects us, we’re still trying to figure it out.

Since the randomized controlled trials we have setup to date are mostly exploratory, our trials will always look like failures to a certain extent. We’re not sure what kind of markers vitamin D will affect, so we list many markers as outcomes we’re interested in. In these trials, when vitamin D only improves 20% of the markers, some researchers say vitamin D is no good. Other researchers will say, “We’ve discovered which markers vitamin D is good for.”

These kinds of exploratory randomized controlled trials have paved the way for large randomized controlled trials now finally underway. These trials include:

Name Place Participants Amount of vitamin D Outcomes Year of results
VITAL USA 20,000 2,000 IU/day Cancer and heart disease 2017
FIND Finland 18,000 1,600 IU or 3,200 IU/day Cancer, heart disease and diabetes 2020
VIDAL UK 20,000 60,000 IU/month Longevity and others 2020

When these trials conclude, we will better be able to compare prospective cohort studies and randomized controlled trials. But not until then. The reason is, these much larger trials will have robust enough data to look at simpler, more clinical outcomes, like cancer incidence, stroke incidence, as opposed to just having to look at markers for health.

And just because randomized controlled trials haven’t shown robust results like prospective cohort studies have yet, doesn’t mean there should be any “new doubts” on vitamin D. It is likely that not all randomized controlled trials will show the same benefits in vitamin D as prospective cohort studies do. If randomized controlled trials failed for nine out of every ten diseases, would you not take vitamin D? No, you still would, for prevention or treatment against every tenth disease.

The argument for supplementation and good sun exposure habits has always been that hunter-gatherers have much higher vitamin D levels than those living in developed countries. The logic is not based on observational outcome evidence. This remains the logic behind the pro-vitamin D crowd until the large randomized controlled trials above are published in 5-10 years.

Lastly, if you get in a debate over the merit of this study with friends or colleagues, don’t let them tell you this was a well-designed systematic review! As mentioned to start, this review didn’t have a PICO question for one, and for two, its methodology for searching for studies was not comprehensive because they did not use all the search terms they needed to for vitamin D. As a result, I’ve already noticed they didn’t include a very promising small randomized controlled trial by Derakhshandi H et al on multiple sclerosis and vitamin D. For a more comprehensive and thorough search term, see our post on methodology here.

17 Responses to A look at the recent Lancet review study

  1. Mark Richards

    An article in Medscape takes things a step further.

    “Some supplementation if an individual’s vitamin-D concentration falls below a “sufficiency” threshold of 75 nmol/L continues to be recommended — an ill-advised practice, Dr. Autier asserted.”

    Two questions:

    1. Why advise against supplementation when it does no harm?
    2. What is this review paper intended to accomplish and who does it benefit?

  2. Tom Weishaar

    Another thing that has to be teased out of reports of randomized controlled trials is whether the individuals in the treatment group actually took their vitamin D supplements. If they don’t adhere to taking the supplement, of course there won’t be any difference between the two groups. If the research question is whether it’s worth recommending that patients take a vitamin D supplement (“intention-to-treat”), then this is the correct way to do it.

    But if the question is whether increasing vitamin vitamin D levels has a positive biological effect, then those who run RCTs have to take ensure and report on adherence.

  3. Brant Cebulla

    Mark,

    I think researchers always want their research to have quite a bit of clinical influence — it’s one of the reasons why they’re in research. So often when media picks up their study, they almost always make a “what does this mean for the patient” kind of statement. Or, the media will specifically ask the researchers this question, and they will get cornered into saying something in the realm. You will notice even in animal model studies, researchers often get carried away with “patients should now do this _______” kind of statements.

    More than likely Autier et al already felt there wasn’t sufficient evidence to date for vitamin D supplementation, before carrying out the review. So, with how they crafted their paper, it was good opportunity for the group to come out and say, “Stop supplementing.”

    Who does it benefit — since it wasn’t a classic systematic review, I think the researchers really wanted to put their theory of reverse-causality and confounding factors out there (although not an original theory for vitamin D). That way, in 5-10 years, if the large-scale RCTs don’t show benefit (I think they will), this group will be there to say, “I told you so.”

  4. Ron Carmichael

    Even with the three large studies underway (mentioned above) there is a striking lack of assurance of “natural” blood levels being attained by the doses in the study. Rather than a iu/kg body weight dose, it appears that researchers cannot get away from a notion that proving a negative (by sub-therapeutic dosage levels) will result in meaningful, actionable, outcomes.Giving a fixed dose regardless of body weight is sub-optimal, I would think. Perhaps most researchers don’t want to “rock the boat” of the established “knowledge” that D is just for preventing rickets…

  5. Dr William Grant

    The authors work at the International Prevention Research Institute in Lyon, France
    http://www.i-pri.org/
    A few days ago, there were many files at their website including one labeled “Partners”. Many of the big companies from Big Pharma were among the partners. For some reason, none of the links beyond the home page work now (Dec. 11, 8:00 pm, PST).

    However, through a Google search, I found this website with a list of partners
    http://www.oncotrack.eu/the-group/consortium/international-prevention-research-institute/
    I copied information about all 20 or so consortium members. They include Bayer HealthCare,
    Eli Lilly, Roche, Pfizer, Merck, Janssen Pharmaceutica, Boehringer Ingelheim International, AstraZeneca and several universities.

    I leave it to the reader to consider whether any of these consortium members would like to see vitamin D supplementation widely accepted.

  6. John

    This study jibes with something I have been chewing on for some time. The web site is called VitaminDCouncil.org and all the articles talk about Vitamin D. Almost everything says Vitamin D, but is that what is really going on? When we look at a group’s Vitamin D levels and find lower disease rates associated with higher D levels, we make a big mistake to continue talking about Vitamin D because it implies causation whether intended or not. I know you have discussed the danger of jumping from association to causation, but sunshine, the engine that produced the Vitamin D AND A LOT OF OTHER THINGS AND CHANGES often goes unmentioned. Where did those Vitamin D levels come from? Almost never from a supplement; almost always from sun exposure. I suspect that is what causes researchers to study the effects of Vitamin D on diseases instead of the effects of sunshine. We don’t give sunshine the billing it deserves. The web site should be sunshine.org or gooutside.org or throwawaythesunscreen.org or researchersneverevenlookedtoseeifavoidingsunshinemighthurtyou.org ( I like that one!). If the researchers would expose the experimental groups to sunshine to test the associations discovered by measuring Vitamin D, I have no doubt that they WOULD support the cohort studies.

    It’s like your earlier discussion of girls with larger feet having higher reading skills (which they really do, but they read better because they are older, and thus have bigger feet). If we were studying foot size in five hundred studies, writing five thousand articles about foot size, naming our web site bigfeet.org, never talking about the real driver of foot size we might expect researchers reading all these papers to choose to operate on girls’ feet to extend them, then test reading skills and be perplexed when they fount no improvement. Foot size is a symptom of aging and Vitamin D levels are a symptom of sun exposure. We should talk sunshine, not Vitamin D or UVA or UVB. Real sunshine is a basket of inputs. The entire radiation spectrum and the fresh air, the bright light; it’s a big package, not one element.

  7. IAW

    To: Dr. Grant
    Thanks for taking the time to do the research and for “pulling the curtain back” so to speak and showing us who funds this group of so called “researchers”!

  8. IAW

    To: John above
    Maybe I interpreted the above incorrectly but I think you are being a little harsh on the Vitamin D Council. Dr. Cannell does promote sunshine, sunlamps and supplements. Where I live, in the wintertime, I can go out in the sun all I want but it is proven that I will not make enough vitamin D to sustain myself in good health. So one cannot just rely on “sunshine” in this day and age unless you live at the equator.

  9. westexas@aol.com

    Building on some of the previous comments, rather than reported dosages versus disease rates and total mortality risk, wouldn’t the key question be circulating, 25(OH)D, Vitamin D blood levels versus disease rates and total mortality risk?

  10. westexas@aol.com

    Fascinating article in the NYT about Big Pharma trying to get as many people as possible on prescription stimulants, for Attention Deficit Disorder:

    http://www.nytimes.com/2013/12/15/health/the-selling-of-attention-deficit-disorder.html?_r=0

    And of course, I think that we are seeing similar attempts regarding statins.

    Incidentally, are you guys going to have any comments on the recent multivitamin study?

    It does seem to me that the medical establishment seems to be quite hostile to supplements, especially Vitamin D, while they seem to think that it’s a swell idea for everyone to get on some kind of long term prescription drug.

    As some of you might say, “Do ya think?”

  11. westexas@aol.com
  12. Robin@SunSeekersUSA.com

    Westexas … I am convinced that you are correct:
    “It does seem to me that the medical establishment seems to be quite hostile to supplements, especially Vitamin D, while they seem to think that it’s a swell idea for everyone to get on some kind of long term prescription drug.”

    The Maryland Indoor Tanning Assoc. met with a branch of the AMA called MedChi last year … The CEO off handedly mentioned that his group was going to submit a legislative bill to ban the sale of supplements in any establishment selling prescription drugs. It was clear to us that the purpose was to eliminate the choice or even idea of supplements and have people focus on doctor prescribed pharmaceutical drugs.

    The AMA (and many branches including the AADA) along with big pharma are who spearhead the “war on Indoor Tanning” and, the use of Sunblock. Since indoor tanning and the sun naturally produce Vitamin D3, it makes complete sense that they would work to make supplements and especially Vitamin D look irrelevant and useless. Gotta keep people afraid of the sun in order to sell sunblock.

    “Do ya think?”
    In my experience of dealing with MedChi and cohorts, there is no doubt in my mind that it is a conspiracy. Let us not forget about the AMA vs Chiropractic … http://en.wikipedia.org/wiki/Wilk_v._American_Medical_Association

  13. Rita and Misty

    It would be helpful (I think) if there were a vitamin D knowledgeable dermatologist (or two…or three..or four…or….or…) to speak on this matter.

    I know that there are vitamin D knowledgeable physicians and researchers within this vitamin D community. Perhaps if you would each outreach to one dermatologist (or two…or three..or four..or…or), there might be a domino effect of knowledge regarding the necessity of sunshine and vitamin D.

    Mainstream medicine is a closed sphere. Change must come from within, initiated by those physicians and researchers brave (enough) to speak on such a controversial subject.

    Good luck.

  14. Robin@SunSeekersUSA.com

    Rita and Misty, just to name a few doctors and researchers with a background in Dermatology.
    1. Dr. Michael Holick, Ph.D., MD. – Director of General clinical research Center and Professor of Medicine, Dermatology, Physiology, and Biophysics at Boston University Medical Center has written several books as well as published many reports on the subject of Vitamin D.
    2. Dr. Bernard Ackerman, M.D. Director emeritus of the Ackerman Academy of Dermatopathology in New York, and a professor of dermatology and pathology of Downstate University Medical Center in Brooklyn, N.Y.
    3. Dr. Arthur R. Rhodes is a professor of dermatology of Rush Medical College, Chicago

    I suggest a couple of books:
    The UV Advantage by Michael f. Holick
    Solar Power for Optimal Health by Dr. Marc Sorenson
    Sunshine and Vitamin d by Frank Murray

  15. Rita and Misty

    These are great doctors.

    I hope they are mentoring others to carry on their work.

    The journey is long, and we have far to go….

    If the vitamin D community truly believes that outreach occurs person-by-person, I encourage every vitamin D knowledgeable physician and/or researcher to touch the life of just one vitamin D ignorant physician and/or researcher.

  16. Rita and Misty

    Please let me add to my above message (because I’m wordy):

    And, do your outreach personally…be certain that s/he not only understands but agrees, and then encourage her/him to join the VDC. This might require (more than) several attempts on your part. 😉

    The Domino Effect.

    Good luck.

    🙂

  17. foodhospital

    The partners who collaborate within iPRi, the International Prevention Research Institute, can be found here http://www.i-pri.org/about/partners/

    I would like to point to a piece by Steve Hickey, Damien Downing and Robert Verkerk
    ‘Designed to fail: a trial without meaning ‘
    http://www.anh-usa.org/designed-to-fail-a-trial-without-meaning/

    and to
    ‘Cookbook Science a half-baked approach to natural health’ by Steve Hickey and Robert Verkerk
    http://www.anh-europe.org/files/090108_Cookbook-science_final_0.pdf

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