Are Clinical Trials Misleading?

Written by Dr. Steve Chaney on . Posted in clinical trials

Is Most Of What You’ve Been Told About Vitamins Wrong?

Author: Dr. Stephen Chaney

 

man searching with magnifying glassI am a scientist and a professor. I taught medical students for 40 years. I believe in evidence based medicine. Why would I tell you that many of the clinical trials about the impact of individual nutrients on your health are misleading?

Let me start by sharing a story that I used to tell every new graduate student in my lab. The story goes like this: There is this drunk on the sidewalk, on his hands and knees under a lamppost, just groping around. A policeman comes up to him and says, “What are you doing?” The drunk says, “I’m looking for my housekeys.” The policeman gets down on his hands and knees and he looks too, and finally he says, “I can’t find them anywhere. Are you sure you lost them here?” To which the drunk relies, “Nope, I lost them over there, but the light’s better here.”

The point I was trying to make is that we can only do experiments where the light is good. But the questions we sometimes want to ask are over in the corner, where we can’t really shine the light on it directly. It’s often difficult to look in the right place and/or to ask the right questions.

That’s particularly the case with holistic approaches because holistic approaches, by their very nature, are multi-factorial. You have multiple variables that you’re trying to change at one time. For example, you might want to optimize weight, exercise, vitamins, minerals, and essential fatty acids if you’re trying to look at a healthy lifestyle.

But, in the 21st-century, studies generally focus on individual nutrients or individual drugs in an intervention, placebo-controlled trial. This is considered the “Gold Standard” for evidence based medicine. However, it’s very difficult to evaluate holistic approaches with that kind of study.

 

The Whole Is Greater Than The Parts

internationally renowned expert sessionOne of the examples that I love to use, because it really made an impression on me as a young scientist, occurred at an International Cancer Symposium I attended more than 30 years ago.

I attended a session in which an internationally renowned expert was giving his talk on colon cancer. He said, “I can show you, unequivocally, that colon cancer risk is significantly decreased by a lifestyle that includes a high-fiber diet, a low-fat diet, adequate calcium, adequate B-vitamins, exercise and weight control. But I can’t show you that any one of them, by themselves, is effective.”

The question that came to me as I heard him speak was: “What’s the message that a responsible scientist or responsible health professional should be giving to their patients or the people that they’re advising?” You’ve heard experts saying: “Don’t worry about the fat” “Don’t worry about calcium.” “Don’t worry about B-vitamins.” “Don’t worry about fiber.” “None of them can be shown to decrease the risk of colon cancer.”

Is that the message that we should be giving people? Or should we really be saying what that doctor said many years ago – that a lifestyle that includes all those things significantly decreases the risk of colon cancer?

 

Are Clinical Trials Misleading?

 

clinical trialsA recent paper about how to best evaluate the relationships between nutrition and disease (Shao et al, European Journal of Nutrition, DOI: 10.1007/s00394-017-1460-9) caught my attention. This paper, written by a team of 10 international experts, was a summary of key findings from a recent international meeting of the Council for Responsible Nutrition.

The paper started out by reviewing the strengths of clinical studies in which the effect of a single intervention on a health outcome is evaluated in a double-blind, placebo controlled clinical study; something they referred to as a reductionist approach.

  • A reductionist approach is ideal for evaluating the effect of drug candidates on disease outcomes. That is because:
    • Everyone in the study already has the disease.
    • The drug is meant to be used by itself.
    • It is easy to measure outcomes. The drug either has an effect on the disease, or it doesn’t.
  • A reductionist approach has also been valuable in defining the role of nutrients in preventing deficiency diseases. That is because, in the words of the authors:
    • “A simple cause-effect relationship exists between a particular nutrient and a specific deficiency disease.
    • Symptoms of a specific nutrient deficiency can be explained in terms of the role played by the respective nutrient.
    • Providing the nutrient in the diet can prevent, and in many cases, reverse, the deficiency disease.”

However, the authors went on to say that the use of the reductionist approach to study effect of nutrients on optimal health or holistic approaches to health often has led to misleading results. They characterized these studies as often “leading down a rabbit hole.”

For example, the authors said: “In an effort to uncover the magic bullet, scientists inappropriately studied nutrients in a drug-like context. Unlike drugs, nutrients do not function in isolation and have beneficial effects on multiple tissues and organ systems.”

The authors concluded by saying that if we want to truly understand the role of nutrients on health outcomes, we need to focus on holistic studies in which the effect of multiple nutrients on multiple health outcomes are evaluated.

 

Clinical Trials That Have Mislead Us

 

I realize that the report I just described is conceptual. It’s difficult to wrap your mind around. To better understand how clinical trials employing a reductionist approach can often mislead us, let’s look at some specific examples comparing holistic studies to reductionist studies.

dash dietHealthy diets: Healthy diets have a significant impact on health, but it is not possible to show that individual components of those diets are beneficial: In previous issues of “Health Tips From the Professor,” I have discussed the Mediterranean and DASH diets. I have shared studies showing that the Mediterranean diet dramatically reduces the risk of heart disease, diabetes, cognitive decline, and some forms of cancer. However, you would be hard pressed to show that individual components of the Mediterranean diet have a significant impact on these health outcomes.

Similarly, the DASH diet is as effective as drugs at controlling blood pressure (Moore et al, Hypertension, 38: 155-158, 2001 ). Other than sodium restriction, you would also be hard pressed to show that the individual components of the DASH diet exert a significant effect on blood pressure.

Supplements That Are Going to Kill You: Individual nutrients can sometimes have adverse effects on your health. Those reports generate a lot of negative press, but the adverse effects usually disappear when those nutrients are consumed along with nutrients that complement their effect on whole body metabolism.

Here are two examples of the negative press that you may have heard about the dangers of supplementation, but what the studies actually showed is that a holistic approach to supplementation was superior to supplementation with individual supplements.

For example, there was something called the Iowa Women’s Health Study that got some negative press in 2011 (Mursu et al, Archives of Internal Medicine, 171:1625-1633, 2011). This is one of those studies that led to headlines saying: “Vitamins can kill you.”

The study did show a slight increase in mortality in people who consumed high-dose vitamin B6 or high-dose folic acid by themselves. But in that same study, people who were taking high-dose B complex containing both B6 and folic acid in balance had no increase in mortality.

Another example is vitamin E and prostate cancer. You probably saw the headlines, which said: “Vitamin E increases the risk of prostate cancer.” Those headlines were based on a study published in the Journal of American Medical Association in 2011 (J Klein et al, Journal of the American Medical Association, 306: 1549-1556, 2011). However, in that same study the people who were taking vitamin E and selenium (two nutrients that work together synergistically) had no increase in cancer risk.

There is a good biochemical rationale for those results. Vitamin E converts some reactive oxygen species to peroxides, which are quite dangerous themselves. Selenium is part of an enzyme that converts peroxides to water. Together, vitamin E and selenium convert reactive oxygen species (free radicals) to something that is completely harmless. By itself, vitamin E does only half the job.

Holistic Approaches to Supplementation: The same appears to be true if you look at holistic approaches to supplementation rather than holistic approach to supplementationsupplementing with individual nutrients. A study done by Dr. Gladys Block and published in Nutrition Journal in 2007 (Block et al, Nutrition Journal 2007,6:30 doi: 10.1186/1475-2891-6-30) looked at a holistic approach to supplementation for the very first time.

She compared people who were taking multiple supplements, typically a multivitamin, extra antioxidants, extra B vitamins, carotenoids, fish oil and probiotics; people who were taking only a multivitamin; and people who were using no supplements whatsoever over a 20-year period.

The results were dramatic. The holistic supplement users had one-third the prevalence of angina, heart attacks and congestive heart failure and one-quarter the prevalence of diabetes compared to the other two groups. In contrast, reductionist studies looking at the effect of those nutrients individually have generally been inconclusive.

So just like a holistic approach to health, a holistic approach to supplementation appears to be superior to using individual supplements. This is a small study, but it is an example of the kinds of studies that need to be done in the future, if we are to truly understand the role of holistic approaches for optimizing our health.

 

The Bottom Line

Studies in which the effect of a single intervention on health outcomes is evaluated in a double-blind, placebo-controlled clinical study is considered the “Gold Standard” for evidence based medicine. A recent report has questioned the value of this kind of study in defining the impact of holistic approaches on health outcomes.

  • The authors concluded that the “Gold Standard” of clinical studies, which they referred to as a reductionist approach:
    • Was ideal for evaluating the effect of drugs on preventing or treating diseases.
    • Has been well suited for evaluating the role of individual nutrients in preventing deficiency diseases.
    • Was not well suited for evaluating the role of holistic approaches on health outcomes.
    • Was not well suited for evaluating the role of nutrients for promoting optimal health.
  • The authors concluded by saying that if we want to truly understand the role of nutrients on health outcomes, we need to focus on holistic studies in which the effect of multiple nutrients on multiple health outcomes are evaluated.
  • I shared three examples illustrating cases in which holistic approaches were more accurate than reductionist studies:
    • Healthy diets have a significant impact on health, but it is not possible to show that that individual components of those diets are beneficial.
    • Individual nutrients can sometimes have adverse effects on your health, but the adverse effects disappear when those nutrients are consumed along with nutrients that complement their effect(s) on whole body metabolism.
    • A holistic approach to supplementation can have a significant, beneficial effect on health outcomes, but it is difficult to show any benefit from individual nutrients included in that holistic approach to supplementation.
  • For more details, read the article above.

 

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.

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Comments (2)

  • Alayne Campbell

    |

    Very informative, A good yardstick to measure by.

    How do I get a copy of your suggestions for those on kemotherapy?

    Reply

    • Dr. Steve Chaney

      |

      Dear Alayne,
      I am not a medical doctor, so I do not comment on specific medical cases. If you are talking about nutritional supplements, a general rule of thumb is to space supplements and chemotherapy drugs so that they are not present in the bloodstream at the same time. This usually involves a day or two window on either side of chemotherapy during which supplements are not taken. For more specific recommendations, consult your doctor and/or your pharmacist.
      Dr. Chaney

      Reply

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Latest Article

Does Magnesium Optimize Vitamin D Levels?

Posted February 12, 2019 by Dr. Steve Chaney

The Case For Holistic Supplementation

Author: Dr. Stephen Chaney

 

Does magnesium optimize vitamin D levels?

magnesium optimize vitamin dOne of the great mysteries about vitamin D is the lack of correlation between vitamin D intake and blood levels of its active metabolite, 25-hydroxyvitamin D. Many people who consume RDA levels of vitamin D from foods and/or supplements end up with low blood levels of 25-hydroxyvitamin D. The reason(s) for this discrepancy between intake of vitamin D and blood levels of its active metabolite are not currently understood.

Another great mystery is why it has been so difficult to demonstrate benefits of vitamin D supplementation. Association studies show a strong correlation between optimal 25-hydroxyvitamin D levels and reduced risk of heart disease, cancer, and other diseases. However, placebo-controlled clinical trials of vitamin D supplementation have often come up empty. Until recently, many of those studies did not measure 25-hydroxyvitamin D levels. Could it be that optimal levels of 25-hydroxyvitamin D were not achieved?

The authors of the current study hypothesized that optimal magnesium status might be required for vitamin D conversion to its active form. You are probably wondering why magnesium would influence vitamin D metabolism. I had the same question.

The authors pointed out that:

  • Magnesium status affects the activities of enzymes involved in both the synthesis and degradation of 25-hydroxyvitamin D.
  • Some clinical studies have suggested that magnesium intake interacts with vitamin D intake in affecting health outcomes.
  • If the author’s hypothesis is correct, it is a concern because magnesium deficiency is prevalent in this country. In their “Fact Sheet For Health Professionals,” the NIH states that “…a majority of Americans of all ages ingest less magnesium from food than their respective EARs [Estimated Average Requirement]; adult men aged 71 years and older and adolescent females are most likely to have low intakes.” Other sources have indicated that magnesium deficiency may approach 70-80% for adults over 70.

If the author’s hypothesis that magnesium is required for vitamin D activation is correct and most Americans are deficient in magnesium, this raises some troubling questions.

  • Most vitamin D supplements do not contain magnesium. If people aren’t getting supplemental magnesium from another source, they may not be optimally utilizing the vitamin D in the supplements.
  • Most clinical studies involving vitamin D do not also include magnesium. If most of the study participants are deficient in magnesium, it might explain why it has been so difficult to show benefits from vitamin D supplementation.

Thus the authors devised a study (Q Dai et al, American Journal of Clinical Nutrition, 108: 1249-1258, 2018 ) to directly test their hypothesis.

 

How Was The Study Designed?

magnesium optimize vitamin d studyThe authors recruited 180 volunteers, aged 40-85, from an ongoing study on the prevention of colon cancer being conducted at Vanderbilt University. The duration of the study was 12 weeks. Blood was drawn at the beginning of the study to measure baseline 25-hydroxyvitamin D levels. Three additional blood draws to determine 25-hydroxyvitamin D levels were performed at weeks 1, 6, and 12.

Because high blood calcium levels increase excretion of magnesium, the authors individualized magnesium intake based on “optimizing” the calcium to magnesium ratio in the diet rather than giving everyone the same amount of magnesium. The dietary calcium to magnesium ratio for most Americans is 2.6 to 1 or higher. Based on their previous work, they considered an “ideal” calcium to magnesium ratio to be 2.3 to 1. The mean daily dose of magnesium supplementation in this study was 205 mg, with a range from 77 to 390 mg to achieve the “ideal” calcium to magnesium ratio. The placebo was an identical gel capsule containing microcrystalline cellulose.

Two 24-hour dietary recalls were conducted at baseline to determine baseline dietary intake of calcium and magnesium. Four additional 24-hour dietary recalls were performed during the 12-week study to assure that calcium intake was unchanged and the calcium to magnesium ratio of 2.3 to 1 was achieved.

In short this was a small study, but it was very well designed to test the author’s hypothesis.

 

Does Magnesium Optimize Vitamin D Levels?

 

does magnesium optimize vitamin d levelsThis was a very complex study, so I am simplifying it for this discussion. For full details, I refer you to the journal article (Q Dai et al, American Journal of Clinical Nutrition, 108: 1249-1258, 2018).

The most significant finding was that magnesium supplementation did affect blood levels of 25-hydroxyvitamin D. However, the effect of magnesium supplementation varied depending on the baseline 25-hydroxyvitamin D level at the beginning of the study.

  • When the baseline 25-hydroxyvitamin D was 20 ng/ml or less (which the NIH considers inadequate), magnesium supplementation had no effect on 25-hydroxyvitamin D levels.
  • When the baseline 25-hydroxyvitamin D was 20-30 ng/ml (which the NIH considers the lower end of the adequate range), magnesium supplementation increased 25-hydroxyvitamin D levels.
  • When the baseline 25-hydroxyvitamin D level approached 50 ng/ml (which the NIH says may be “associated with adverse effects”), magnesium supplementation lowered 25-hydroxyvitamin D levels.

The simplest interpretation of these results is:

  • When vitamin D intake is inadequate, magnesium cannot magically create 25-hydroxyvitamin D from thin air.
  • When vitamin D intake is adequate, magnesium can enhance the conversion of vitamin D to 25-hydroxyvitamin D.
  • When vitamin D intake is too high, magnesium can help protect you by lowering 25-hydroxyvitamin D levels.

The authors concluded: “Our findings suggest that optimal magnesium status may be important for optimizing 25-hydroxyvitamin D status. Further dosing studies are warranted…”

 

What Does This Study Mean For You?

magnesium optimize vitamin d for youThis was a groundbreaking study that has provided novel and interesting results.

  • It provides the first evidence that optimal magnesium status may be required for optimizing the conversion of vitamin D to 25-hydroxyvitamin D.
  • It suggests that optimal magnesium status can help normalize 25-hydroxyvitamin D levels by increasing low levels and decreasing high levels.

However, this was a small study and, like any groundbreaking study, has significant limitations. For a complete discussion of the limitations and strengths of this study I refer you to the editorial (S Lin and Q Liu, American Journal of Clinical Nutrition, 108: 1159-1161, 2018) that accompanied the study.

In summary, this study needs to be replicated by larger clinical studies with a more diverse study population. In order to provide meaningful results, those studies would need to carefully control and monitor calcium, magnesium, and vitamin D intake. There is also a need for mechanistic studies to better understand how magnesium can both increase low 25-hydroxyvitamin D levels and decrease high 25-hydroxyvitamin D levels.

However, assuming the conclusions of this study to be true, it has some interesting implications:

  • If you are taking a vitamin D supplement, you should probably make sure that you are also getting the DV (400 mg) of magnesium from diet plus supplementation.
  • If you are taking a calcium supplement, you should check that it also provides a significant amount of magnesium. If not, change supplements or make sure that you get the DV for magnesium elsewhere.
  • I am suggesting that you shoot for the DV (400 mg) of magnesium rather than reading every label and calculating the calcium to magnesium ratio. The “ideal” ratio of 2.3 to 1 is hypothetical at this point. A supplement providing the DV of both calcium and magnesium would have a calcium to magnesium ratio of 2.5, and I would not fault any manufacturer for providing you with the DV of both nutrients.
  • If you are taking high amounts of calcium, I would recommend a supplement that has a calcium to magnesium ratio of 2.5 or less.
  • If you are considering a magnesium supplement to optimize your magnesium status, you should be aware that magnesium can cause gas, bloating, and diarrhea. I would recommend a sustained release magnesium supplement.
  • Finally, whole grains and legumes are among your best dietary sources of magnesium. Forget those diets that tell you to eliminate whole food groups. They are likely to leave you magnesium-deficient.

Even if the conclusions of this study are not confirmed by subsequent studies, we need to remember that magnesium is an essential nutrient with many health benefits and that most Americans do not get enough magnesium in their diet. The recommendations I have made for optimizing magnesium status are common-sense recommendations that apply to all of us.

 

The Case For Holistic Supplementation

 

magnesium optimize vitamin d case for holistic supplementationThis study is one of many examples showing that a holistic approach to supplementation is superior to a “magic bullet” approach where you take individual nutrients to solve individual problems. For example, in the case of magnesium and vitamin D:

  • If you asked most nutrition experts and supplement manufacturers whether it is important to provide magnesium along with vitamin D, their answer would likely be “No”. Even if they are focused on bone health, they would be more likely to recommend calcium along with vitamin D than magnesium along with vitamin D.
  • If your doctor has tested your 25-hydroxyvitamin D levels and recommended a vitamin D supplement, chances are they didn’t also recommend that you optimize your magnesium status.
  • Clinical studies investigating the benefits of vitamin D supplementation never ask whether magnesium intake is optimal.

That’s because most doctors and nutrition experts still think of nutrients as “magic bullets.” I cover holistic supplementation in detail in my book “Slaying The Supplement Myths.”  Other examples that make a case for holistic supplementation that I cover in my book include:

  • A study showing that omega-3 fatty acids and B vitamins may work together to prevent cognitive decline. Unfortunately, most studies looking at the effect of B vitamins on cognitive decline have not considered omega-3 status and vice versa. No wonder those studies have produced inconsistent results.
  • Studies looking at the effect of calcium supplementation on loss of bone density in the elderly have often failed to include vitamin D, magnesium, and other nutrients that are needed for building healthy bone. They have also failed to include exercise, which is essential for building healthy bone. No wonder some of those studies have failed to find an effect of calcium supplementation on bone density.
  • A study reported that selenium and vitamin E by themselves might increase prostate cancer risk. Those were the headlines you might have seen. The same study showed Vitamin E and selenium together did not increase prostate cancer risk. Somehow that part of the study was never mentioned.
  • A study reported that high levels of individual B vitamins increased mortality slightly. Those were the headlines you might have seen. The same study showed that when the same B vitamins were combined in a B complex supplement, mortality decreased. Somehow that observation never made the headlines.
  • A 20-year study reported that a holistic approach to supplementation produced significantly better health outcomes.

In summary, vitamins and minerals interact with each other to produce health benefits in our bodies. Some of those interactions we know about. Others we are still learning about. When we take high doses of individual vitamins and minerals, we create potential problems.

  • We may not get the full benefit of the vitamin or mineral we are taking because some other important nutrient(s) may be missing from our diet.
  • Even worse, high doses of one vitamin or mineral may interfere with the absorption or enhance the excretion of another vitamin or mineral. That can create deficiencies.

The same principles apply to our diet. I mentioned earlier that whole grains and legumes are among the best dietary sources of magnesium. Eliminating those two foods from the diet increases our risk of becoming magnesium deficient. And, that’s just the tip of the iceberg. Any time you eliminate foods or food groups from the diet, you run the risk of creating deficiencies of nutrients, phytonutrients, specific types of fiber, and the healthy gut bacteria that use that fiber as their preferred food source.

The Bottom Line

 

A recent study suggests that optimal magnesium status may be important for optimizing 25-hydroxyvitamin D status. This is one of many examples showing that a holistic approach to supplementation is superior to a “magic bullet” approach where you take individual nutrients to solve individual problems. For example, in the case of magnesium and vitamin D:

  • If you asked most nutrition experts and supplement manufacturers whether it is important to provide magnesium along with vitamin D, their answer would likely be “No.”  Even if they are focused on bone health, they would be more likely to recommend calcium along with vitamin D than magnesium along with vitamin D.
  • If your doctor has tested your 25-hydroxyvitamin D levels and recommended a vitamin D supplement, chances are he or she did not also recommend that you optimize your magnesium status.
  • Clinical studies investigating the benefits of vitamin D supplementation never ask whether magnesium intake is optimal. That may be why so many of those studies have failed to find any benefit of vitamin D supplementation.

I cover holistic supplementation in detail in my book “Slaying The Supplement Myths” and provide several other examples where a holistic approach to supplementation is superior to taking individual supplements.

In summary, vitamins and minerals interact with each other to produce health benefits in our bodies. Some of those interactions we know about. Others we are still learning about. Whenever we take high doses of individual vitamins and minerals, we create potential problems.

  • We may not get the full benefit of the vitamin or mineral we are taking because some other important nutrient(s) may be missing from our diet.
  • Even worse, high doses of one vitamin or mineral may interfere with the absorption or enhance the excretion of another vitamin or mineral. That can create deficiencies.

The same principles apply to what we eat. For example, whole grains and legumes are among the best dietary sources of magnesium. Eliminating those two foods from the diet increases our risk of becoming magnesium deficient. And, that’s just the tip of the iceberg. Any time you eliminate foods or food groups from the diet, you run the risk of creating deficiencies.

For more details about the current study and what it means to you read the article above.

 

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.

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