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

Do Omega-3s Lower Blood Pressure in Young, Healthy Adults?

Posted August 14, 2018 by Dr. Steve Chaney

What Is The Omega-3 Index And Why Is It Important?

Author: Dr. Stephen Chaney

 

Do omega-3s lower blood pressure in healthy adults?

omega-3s lower blood pressure young adultsThe literature on the potential health benefits of omega-3s is very confusing. That’s because a lot of bad studies have been published. Many of them never determined the omega-3 status of their subjects prior to omega-3 supplementation. Others relied on dietary recalls of fish consumption, which can be inaccurate.

Fortunately, a much more accurate measure of omega-3 status has been developed and validated in recent years. It’s called the Omega-3 Index. Simply put, the Omega-3 Index is the percentage of EPA and DHA compared to 26 other fatty acids found in cellular membranes. Using modern technology, it can be determined from a single finger prick blood sample. It is a very accurate reflection of omega-3 intake relative to other fats in the diet over the past few months. More importantly, it is a measure of the omega-3 content of your cell membranes, which is a direct measure of your omega-3 nutritional status.

A recent extension of the Framingham Heart Study reported that participants with an Omega-3 Index >6.8% had a 39% lower risk of cardiovascular disease than those with an Omega-3 Index <4.2% (WS Harris et al, Journal of Clinical Lipidology, 12: 718-724, 2018 ). Although more work needs to be done, an Omega-3 Index of 4% or less is generally considered indicative of high cardiovascular risk, while 8% or better is considered indicative of low cardiovascular risk. For reference, the average American has an Omega-3 Index in the 4-5% range. In Japan, where fish consumption is much higher and cardiovascular risk much lower, the Omega-3 Index is in the 9-11% range.

Previous studies have suggested that omega-3 fatty acids lower blood pressure to a modest extent. Thus, it is not surprising that more recent studies have shown an inverse correlation between Omega-3 Index and blood pressure. However, those studies have been done with older populations, many of whom had already developed high blood pressure.

From a public health point of view, it is much more interesting to investigate whether it might be possible to prevent high blood pressure in older adults by optimizing omega-3 intake in a young, healthy population, most of whom had not yet developed high blood pressure. Unfortunately, there were no studies looking at that population. The current study was designed to fill that gap.

 

How Was The Study Done?

omega-3s lower blood pressure young healthy adultsThe current study (M.G. Filipovic et al, Journal of Hypertension, 36: 1548-1554, 2018 ) was based on data collected from 2036 healthy adults, aged 25-41, from Liechtenstein. They were participants in the GAPP (Genetic and Phenotypic Determinants of Blood Pressure) study. Participants were excluded from the study if they had been diagnosed with high blood pressure and were taking medication to lower their blood pressure. They were also excluded if they had heart disease, chronic kidney disease, other severe illnesses, obesity, sleep apnea, or daily use of non-steroidal anti-inflammatory medications.

Blood samples were collected at the time of their enrollment in the study and frozen for subsequent determination of Omega-3 Index. Blood pressure was also measured at their time of enrollment in two different ways. The first was a standard blood pressure measurement in a doctor’s office.

For the second measurement they were given a wearable blood pressure monitor that recorded their blood pressure over 24 hours every 15 minutes during the day and every 30 minutes while they were sleeping. This is considered more accurate than a resting blood pressure measurement in a doctor’s office because it records the variation in blood pressure, while you are sleeping, while you are exercising, and while you go about your everyday activities.

 

Do Omega-3s Lower Blood Pressure In Young, Healthy Adults?

omega-3s lower blood pressure young adults equipmentNone of the participants in the study had significantly elevated blood pressure. The mean systolic and diastolic office blood pressures were 120±13 and 78±9 respectively. The average Omega-3 Index in this population was 4.6%, which is similar to the average Omega-3 Index in the United States.

When they compared the group with the highest Omega-3 Index (average = 5.8%) with the group with the lowest Omega-3 Index (average = 4.6%):

  • The office measurement of systolic and diastolic blood pressure was decreased by 3.3% and 2.6% respectively
  • While those numbers appear small, the differences were highly significant.
  • The 24-hour blood pressure measurements showed a similar decrease.
  • Blood pressure measurements decreased linearly with increasing Omega-3 Index. [In studies of this kind, a linear dose-response is considered an internal validation of the differences observed between the group with the highest Omega-3 Index and the group with the lowest Omega-3 Index.]

The authors concluded: “A higher Omega-3 Index is associated with statistically significant, clinically relevant, lower systolic and diastolic blood pressure in normotensive, young and healthy individuals. Diets rich omega-3 fatty acids may be a strategy for primary prevention of hypertension.”

 

What Does This Mean For You?

omega-3s lower blood pressure young adults questionPerhaps I should first comment on the significance of the relatively small decrease in blood pressure observed in this study.

  • These were young adults, all of whom had normal or near normal blood pressure.
  • The difference in Omega-3 Index was rather small (5.8% to 4.6%). None of the participants in the study were at the 8% or above that is considered optimal.
  • Liechtenstein is a small country located between Switzerland and Spain. Fish consumption is low and omega-3 supplement consumption is rare.

Under these conditions, even a small, but statistically significant, decrease in blood pressure is remarkable.

We should think of this study as the start of the investigation of the relationship between omega-3 status and blood pressure. Its weakness is that it only shows an association between high Omega-3 Index and low blood pressure. It does not prove cause and effect.

Its strength is that it is consistent with many other studies showing omega-3 fatty acids lower blood pressure. Furthermore, it suggests that the effect of omega-3s on blood pressure may also be seen in young, healthy adults who have not yet developed high blood pressure.

Finally, the authors suggested that a diet rich in omega-3s might reduce the incidence of high blood pressure by slowing the age-related increase in blood pressure that most Americans experience. This idea is logical, but speculative at present.

However, the GAPP study is designed to provide the answer to that question. It is a long-term study with follow-up examinations scheduled every 3-5 years. It will be interesting to see whether the author’s prediction holds true, and a higher Omega-3 Index is associated with a slower increase in blood pressure as the participants age.

 

Why Is The Omega-3 Index Important?

 

The authors of this study said: “The Omega-3 Index is very robust to short-term intake of omega-3 fatty acids and reliably reflects an individual’s long-term omega-3 status and tissue omega-3 content. Therefore, the Omega-3 Index has the potential to become a cardiovascular risk factor as much as the HbA1c is for people with diabetes…” That is a bit of an overstatement. HbA1c is a measure of disease progression for diabetes because it is a direct measure of blood sugar control.

In contrast, Omega-3 Index is merely a risk factor for cardiovascular disease. However, if it is further validated by future studies, it is likely to be as important for predicting cardiovascular risk as are cholesterol levels and markers of inflammation.

However, to me the most important role of Omega-3 Index is in the design of future clinical studies. If anyone really wants to determine whether omega-3 supplementation reduces cardiovascular risk, high blood pressure, diabetes or any other health outcome they should:

  • Start with a population group with an Omega-3 Index in the deficient (4-5%) range.
  • Supplement with omega-3 fatty acids in a double blind, placebo-controlled manner.
  • Show that supplementation brought participants up to an optimal Omega-3 Index of 8% or greater.
  • Look at health outcomes such as heart attacks, cardiovascular deaths, hypertension, stroke, or depression.
  • Continue the study long enough for the beneficial effects of omega-3 supplementation to be measurable. For cardiovascular outcomes the American Heart Association has stated that at least two years are required to obtain meaningful results.

These are the kind of experiments that will be required to give definitive, reproducible results and resolve the confusion about the health effects of omega-3 fatty acids.

 

The Bottom Line

 

An accurate measure of omega-3 status has been developed and validated in recent years. It’s called the Omega-3 Index. Simply put, the Omega-3 Index is the percentage of EPA and DHA compared to 26 other fatty acids found in cellular membranes.

Although more work needs to be done, an Omega-3 Index of 4% or less is generally considered indicative of high cardiovascular risk while 8% or better is considered indicative of low cardiovascular risk.

Previous studies have shown an inverse correlation between Omega-3 Index and blood pressure. However, these studies have been done with older populations, many of whom had already developed high blood pressure.

From a public health point of view, it is much more interesting to investigate whether it might be possible to prevent high blood pressure in older adults by optimizing omega-3 intake in a young, healthy population, most of whom had not yet developed high blood pressure. Until now, there have been no studies looking at that population.

The study described in this article was designed to fill that gap. The participants in this study were ages 25-41, were healthy, and none of them had elevated blood pressure.

When the group with the highest Omega-3 Index (average = 5.8%) was compared with the group with the lowest Omega-3 Index (average = 4.6%):

  • Both systolic and diastolic blood pressure were decreased
  • Blood pressure measurements decreased linearly with increasing Omega-3 Index.

The authors concluded: “A higher Omega-3 Index is associated with statistically significant, clinically relevant, lower systolic and diastolic blood pressure in normotensive, young and healthy individuals. Diets rich omega-3 fatty acids may be a strategy for primary prevention of hypertension.”

Let me translate that last sentence into plain English for you. The authors were saying that optimizing omega-3 intake in young adults may slow the age-related increase in blood pressure and reduce the risk of them developing high blood pressure as they age. This may begin to answer the question “Do omega-3s lower blood pressure in young, healthy adults?”

Or even more simply put: Aging is inevitable. Becoming unhealthy is not.

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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