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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Is Our Microbiome Affected By Exercise?

Posted November 6, 2018 by Dr. Steve Chaney

Microbiome Mysteries

Author: Dr. Stephen Chaney

is our microbiome affected by exerciseIn a recent post,  What is Your Microbiome and Why is it Important,  of “Health Tips From The Professor” I outlined how our microbiome, especially the bacteria that reside in our intestine, influences our health. That influence can be either good or bad depending on which species of bacteria populate our gut. I also discussed how the species of bacteria that populate our gut are influenced by what we eat and, in turn, influence how the foods we eat are metabolized.

I shared that there is an association between obesity and the species of bacteria that inhabit our gut. At present, this is a “chicken and egg” conundrum. We don’t know whether obesity influences the species of bacteria that inhabit our gut, or whether certain species of gut bacteria cause us to become obese.

Previous studies have shown that there is also an association between exercise and the species of bacteria that inhabit our gut. In particular, exercise is associated with an increase in bacteria that metabolize fiber in our diets to short chain fatty acids such as butyrate. That is potentially important because butyrate is a primary food source for intestinal mucosal cells (the cells that line the intestine). Butyrate helps those cells maintain the integrity of the gut barrier (which helps prevent things like leaky gut syndrome). It also has an anti-inflammatory effect on the immune cells that reside in the gut.

However, associations don’t prove cause and effect. We don’t know whether the differences in gut bacteria were caused by differences in diet or leanness in populations who exercised regularly and those who did not. This is what the present study (JM Allen et al, Medicine & Science In Sports & Exercise, 50: 747-757, 2018 ) was designed to clarify.  Is our microbiome affected by exercise?

 

How Was The Study Designed?

is our microbiome affected by exercise studyThis study was performed at the University of Illinois. Thirty-two previously sedentary subjects (average age = 28) were recruited for the study. Twenty of them were women and 12 were men. Prior to starting the study, the participants filled out a 7-day dietary record. They were asked to follow the same diet throughout the 12-week study. In addition, a dietitian designed a 3-day food menu based on their 7-day recall for the participants to follow prior to each fecal collection to determine species of gut bacteria.

The study included a two-week baseline when their baseline gut bacteria population was measured, and participants were tested for fitness. This was followed by a 6-week exercise intervention consisting of three supervised 30 to 60-minute moderate to vigorous exercise sessions per week. The exercise was adapted to the participant’s initial fitness level, and both the intensity and duration of exercise increased over the 6-week exercise intervention. Following the exercise intervention, all participants were instructed to maintain their diet and refrain from exercise for another 6 weeks. This was referred to as the “washout period.”

VO2max (a measure of fitness) was determined at baseline and at the end of the exercise intervention. Stool samples for determination of gut bacteria and concentrations of short-chain fatty acids were taken at baseline, at the end of the exercise intervention, and again after the washout period.

In short, this study divided participants into lean and obese categories and held diet constant. The only variable was the exercise component.

 

Is Our Microbiome Affected By Exercise?

is our microbiome affected by exercise fitnessThe results of the study were as follows:

  • Fitness, as assessed by VO2max, increased for all the participants, and the increase in fitness was comparable for both lean and obese subjects.
  • Exercise induced a change in the population of gut bacteria, and the change was comparable in lean and obese subjects.
  • Exercise increased fecal concentrations of butyrate and other short-chain fatty acids in the lean subjects, but not in obese subjects.
  • The exercise-induced changes in gut bacteria and short-chain fatty acid production were largely reversed once exercise training ceased.

The authors concluded: “These findings suggest that exercise training induces compositional and functional changes in the human gut microbiota that are dependent on obesity status, independent of diet, and contingent on the sustainment of exercise.” [Note: To be clear, the exercise-induced changes in both gut bacteria and short-chain fatty acid production were independent of diet and contingent on the sustainment of exercise. However, only the production of short-chain fatty acids was dependent on obesity status.]

 

What Does This Study Mean For You?

is our microbiome affected by exercise gut bacteriaThere are two important take home lessons from this study.

  • With respect to our gut bacteria, I have consistently told you that microbiome research is an emerging science. This is a small study, so you should regard it as the beginning of our understanding of the effect of exercise on our microbiome rather than conclusive by itself. It is consistent with previous studies showing an association between exercise and a potentially beneficial shift in the population of gut bacteria.

The strength of the study is that it shows that exercise-induced changes in beneficial gut bacteria are probably independent of diet. However, it is the first study to look at the interaction between obesity, exercise and gut bacteria, so I would interpret those results with caution until they have been replicated in subsequent studies.

  • With respect to exercise, this may be yet another reason to add regular physical activity to your healthy lifestyle program. We already know that exercise is important for cardiovascular health. We also know that exercise increases lean muscle mass which increases metabolic rate and helps prevent obesity. There is also excellent evidence that exercise improves mood and helps prevent cognitive decline as we age.

Exercise is also associated with decreased risk of colon cancer and irritable bowel disease. This effect of exercise has not received much attention because the mechanism of this effect is unclear. This study shows that exercise increases the fecal concentrations of butyrate and other short-chain fatty acids. Perhaps, this provides the mechanism for the interaction between exercise and intestinal health.

 

The Bottom Line

A recent study has reported that:

  • Exercise induces a change in the population of gut bacteria, and the change was comparable in lean and obese subjects.
  • Exercise causes an increase in the number of gut bacteria that produce butyrate and other short-chain fatty acids that are beneficial for gut health.
  • These effects are independent of diet, but do not appear to be independent of obesity because they were seen in lean subjects but not in obese subjects.
  • The exercise-induced changes in gut bacteria and short-chain fatty acid production are largely reversed once exercise training ceases.

The authors concluded: “These findings suggest that exercise training induces compositional and functional changes in the human gut microbiota that are dependent on obesity status, independent on diet, and contingent on the sustainment of exercise.”

For more details and my interpretation of the data, 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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