Supplements: Science and Skepticism

Summarized by Robert W. Griffith, MD
March 13, 2006

Introduction

Many popular treatments based on supplements have recently taken hits on their credibility. Saw palmetto for benign prostatic hypertrophy, vitamin D and calcium for osteoporosis, glucosamine and chondroitin for osteoarthritis, melatonin for sleeplessness, echinacea for the common cold, ginseng for memory loss, and so on. The damage has mostly come from the results of well-conducted controlled clinical studies, reported in reputable medical journals. Also there have been reports in recent months of large studies discounting the benefits of low-fat and soy diets for cardiovascular health, and omega-3 fatty acids for preventing cancer.

What's going on?

Why are all these negative results appearing at this time? It seems probable that a lot of clinical studies started in the late 90s or a little later are now coming to fruition. And the disappointing balance of the results is not too surprising, considering the somewhat rigid study designs employed.

One should remember that modern clinical trial design has emerged in response to the desire to 'prove' that a treatment is effective and safe. National drug regulatory bodies such as the FDA are largely responsible for evaluating the evidence obtained. And physicians, who are trained as scientists, have embraced these designs, which call for adequate numbers of subjects to satisfy statistical concerns, careful criteria for patient inclusion, random distribution of subjects to active or control treatments, 'blinding' to ensure absence of bias in observers, etc.

In reporting results, the researcher can usually only describe a treatment as effective if there is a statistically significant difference between the benefits seen compared with those seen using a placebo - i.e. no treatment at all. And this is where most of the trouble starts.

Activity vs. placebo

In testing new drugs, it's quite common to find that a so-called 'placebo-response' is seen in around 30% of the subjects. This means that, for instance, one in three people with depression given a dummy tablet will report it as effective in relieving their symptoms. This applies to many, if not most, medical conditions that can't be well measured, as well as some that can. One might think that the rate of wound closure would be strictly objective - the gap could be measured each day. However, wound closure has been shown to be slower in patients who have emotional strife with their partners. Treatment with a placebo might well influence their response to such strife, and hence the wound-healing rate.
It's extremely difficult to exclude people who may have a placebo response from a clinical trial, so one tries to overcome this by including an adequate number of patients, and find differences that are statistically significant. The next problem is that statistical significance may not be clinically relevant. Think of an antidepressant that's successful in 40% of patients compared with a 30% placebo responder rate. That means the drug may itself only help one in ten of the patients taking it - three in ten would have got a response with a placebo.
Old-time practitioners knew this when they prepared arrays of placebo medications - colored bitter-tasting water in elegant sealing-wax wrapped bottles. Modern-day marketers know it when they sell items like "Coral Calcium', 'CortiSlim', or 'HeadOn'.

Severity of the disease plays a role

Proponents of supplements point out that their effectiveness is usually coupled with absolute safety. But note that supplements are often taken to prevent the development of, or worsening of, a condition, not to provide a cure. And their champions are among the first to recognize that serious conditions require more serious treatment - surgery for appendicitis, stenting for coronary artery disease, or chemotherapy for cancer. For the most part, supplements are sold for conditions that don't kill, or only kill slowly.

Standards of effectiveness

The FDA sets high standards for new drugs - statistically significant effectiveness, well-defined safety, and so on. This means that drugs that have been approved have passed these standards, and published studies will be mostly 'positive'. (Admittedly there's a bias which tends to preclude publication of negative findings for candidate drugs in development - the candidates are often unlikely to be approved and the results won't ever be of interest on a wide scale.) Most supplements, not being approved drugs, have not undergone this level of evaluation. When modern clinical trial designs are used in testing them, it's no wonder that many fail; they are at the same developmental level as candidate drugs, where many often fail, too.

In the absence of positive clinical trials, most supplement use is based on recommendations from friends, relatives, or pharmacists. Media advertisements, too, play quite a role, as do advocates reached through the Internet - often patient support groups.

It's not very likely that you'll get a recommendation for supplements from your physician (except perhaps for a multivitamin or calcium). She/he has been educated in the need for applying Evidentiary Medicine, and for most supplements this evidence just isn't there.

Individuals vs. the many

Clinical trials carry results from many patients and reduce them to an average - which is then compared to another average from, say, the placebo. How about the individual patient? Anyone can claim "I'm not Mr. Average". And, of course, an average is made up of many individuals, some of whom will have very high, others very low results. When your doctor is treating you, you want to make sure she/he is treating you, and not a statistic.

Supplement manufacture

Manufacturers don't have to provide FDA with evidence that supplements are effective or safe; however, they are not permitted to market unsafe or ineffective products. And supplements are not required to be standardized in the United States, which means they can vary in their content from batch-to-batch. If you have any doubts about the quality or safety of a product, contact the manufacturer and ask for information on its established safety and effectiveness.

What to do?

Remember that a positive study is often followed by a negative one, and vice-versa. Scientists always insist that a study should provide reproducible results before we attach too much importance to them. So if you are taking supplements and they are working for you, and they aren't too expensive, why not carry on? Just make sure your doctor knows about them when he prescribes medications, as they can interact with drugs and other supplements, sometimes in a bad way.

Source

• - see links below -

Related Links
NIH: Office of Dietary Supplements
The Savvy Supplement User
Tips for Older Dietary Supplement Users

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