Supplements: Flushing your money down the toilet in expensive urine

I remember during medical school that more than one of my faculty used to have a regularly repeated crack that the only thing that taking vitamin supplements could do for you was to produce expensive pee. My first year in medical school was nearly thirty years ago now; so it’s been a long time. During the nearly three decades since I first entered medical school, I have yet to see any evidence to persuade me otherwise. If you eat a well-rounded diet, you don’t need vitamin supplementation. Of course, none of that stops the supplement manufacturers from trying to convince us that taking multivitamins and various single vitamin supplements is absolutely critical for health and that they can even cure diseases. There’s even a form of alternative medicine quackery whose basic premise is that, if a little bit of vitamins is good, a lot more is better. That branch of quackery is known as orthomolecular medicine.

So it was with some amusement that I watched the festivities this week as the Annals of Internal Medicine published multiple studies and an editorial taking the supplement industry to task. The editorial, entitled Enough Is Enough: Stop Wasting Money on Vitamin and Mineral Supplements, was unusually blunt and harsh for a peer-reviewed journal, so much so that it provoked news stories with headlines like How the vitamin industrial complex swindled America:

Questions about the health benefits of vitamin supplements have been percolating in the medical establishment for decades — even as the multivitamin industry has grown to a multi-billion powerhouse in the U.S. This week, the respected journal the Annals of Internal Medicine put its well-heeled foot down.

“We believe that the case is closed — supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful,” the journal said in an editorial. “These vitamins should not be used for chronic disease prevention. Enough is enough.”

Here’s Dr. Edgar Miller of Johns Hopkins Bloomberg School of Public Health, one of the editorial’s five co-authors: “What will protect you is if you spend the money on fruits, vegetables, nuts, beans, low fat dairy, things like that,” Miller tells CBS News. “Exercising would probably be a better use of the money.” The only exceptions are folic acid for pregnant women and, possibly, vitamin D — the studies are mixed on its benefits and risks.

And, from the editorial itself:

Other reviews and guidelines that have appraised the role of vitamin and mineral supplements in primary or secondary prevention of chronic disease have consistently found null results or possible harms (5, 6). Evidence involving tens of thousands of people randomly assigned in many clinical trials shows that -carotene, vitamin E, and possibly high doses of vitamin A supplements increase mortality (6, 7) and that other antioxidants (6), folic acid and B vitamins (8), and multivitamin supplements (1, 5) have no clear benefit.

Despite sobering evidence of no benefit or possible U.S. adults from 30% between 1988 to 1994 to 39% between 2003 to 2006, while overall use of dietary supplements increased from 42% to 53% (9). Longitudinal and secular trends show a steady increase in multivitamin supplement use and a decline in use of some individual supplements, such as -carotene and vitamin E. The decline in use of -carotene and vitamin E supplements followed reports of adverse outcomes in lung cancer and all-cause mortality, respectively. In contrast, sales of multivitamins and other supplements have not been affected by major studies with null results, and the U.S. supplement industry continues to grow, reaching $28 billion in annual sales in 2010. Similar trends have been observed in the United Kingdom and in other European countries.

The large body of accumulated evidence has important public health and clinical implications. Evidence is sufficient to advise against routine supplementation, and we should translate null and negative findings into action. The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided. This message is especially true for the general population with no clear evidence of micronutrient deficiencies, who represent most supplement users in the United States and in other countries (9).

So what are the studies that led to this amazingly honest and scientifically justified? They consist of two good studies and the only part of a bad study that I believe. I’ll explain. First up is a randomized study out of Brigham and Women’s Hospital in Boston that examined the question of whether vitamin supplementation can improve cognition in older men. It’s known as the Physicians’ Health Study II (PHS II), which is a large-scale, randomized, double-blind, placebo-controlled trial testing the long term effects of multivitamins in the prevention of chronic disease. The study presented here is a substudy of the main study looking at cognitive function. The study has a 2 x 2 x 2 x 2 factorial design and tests vitamin E, β-carotene, ascorbic acid, and a multivitamin in male physicians aged 50 or older. Randomization occurred back in 1997, and, when all was said and done, after continuing participants from PHS I were joined by newer recruits, there were 2,980 subjects receiving multivitamin and 2,967 receiving placebo. Endpoints were assessed using the Telephone Interview for Cognitive Status (TICS), which is a telephone adaptation of the Mini-Mental State Examination (26); immediate and delayed recalls of the East Boston Memory Test (EBMT) to assess verbal memory; the delayed recall of a 10-word list in the TICS to test verbal memory; and a category fluency task. The primary prespecified outcome of the cognitive substudy was a composite score of global cognition (i.e., an average of all cognitive tests). Investigators created the composite global score by standardizing results of each cognitive test using Z scores and averaging them. Because verbal memory is strongly associated with risk for Alzheimer disease, investigators also assessed a secondary outcome of a verbal memory composite score.

To make a long story short, the results of this study, too, were resoundingly negative. There was no statistically significant effect on any of the outcomes measured, and in fact none of them even came close to being statistically significant. Given the number of outcomes examined, that in itself is about as negative a study as negative can be. This left the poor investigators scrambling to explain their negative results. (Remember, no one does a test this large expecting it to be completely negative like this.) They go on and on about how maybe because these were all highly educated men, effect sizes were much smaller and how they were all in general adequately nourished. Of course, that’s exactly the point. For normal, adequately nourished people, vitamin and mineral supplementation produces no detectable benefits in general. It’s only for certain targeted nutritional deficiencies where supplementation can help, and in some cases nutritional supplementation can be harmful.

The next study is a systematic review of the evidence with respect to whether multivitamin supplementation has an effect on all cause mortality, cancer, and cardiovascular disease by the U.S Preventative Services Task Force, the same group that reevaluated screening mammography guidelines four years ago. Basically, the USPSTF reviewed three primary prevention trials of multivitamin supplements and 24 trials of single or paired vitamins that randomly assigned more than 400,000 subjects. The studies were found using a search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects, which encompassed the time period from January 2005 to 29 January 2013, supplemented with manual searches. Two investigators independently selected and reviewed fair- and good-quality trials for benefit and fair- and good-quality trials and observational studies for harms. Only studies that were conducted among community-dwelling adult subjects in developed countries who were not malnourished and had no chronic disease were included.

If you look at the Forest plots in Figures 2 and 3, which examine the unadjusted relative risk for cardiovascular disease and cancer, respectively, at the longest followup, you’ll see that they are about as overwhelmingly negative as can be, with virtually all the studies having error bars that overlap zero. (Unfortunately, this is the only article that’s not behind a pay wall; so you can look at the Forest plot yourself. The results for cardiovascular disease were particularly negative. For cancer, there was a study suggesting selenium and calcium might have protective effects against cancer, while there was one suggesting that folic acid supplementation might increase the risk of cancer. All of these studies’ effects were barely statistically significant, and the rest were all consistent with the null hypothesis; i.e., no effect. This led the USPSTF reviewers to conclude that “results of vitamin supplementation trials have been disappointing at best, despite having a solid mechanistic basis,” further stating that they found no evidence that nutritional doses of vitamins or minerals on cardiovascular disease, cancer, or all-cause mortality.

Finally, the third study is the most infamous of all, the Trial to Assess Chelation Therapy (TACT) study. Regular readers will recall that I’ve written about this one many times as a misbegotten and unethical waste of $30 million of taxpayer money. You probably only recall this study as testing chelation therapy as a treatment for cardiovascular disease, but recall that it was a 2 x 2 factorial design that tested these groups:

  • Chelation plus high oral high dose vitamin and mineral supplement
  • Chelation placebo plus oral high dose vitamin and mineral supplement
  • Chelation plus oral high dose vitamin and mineral supplement placebo
  • Chelation placebo plus oral high dose vitamin and mineral supplement placebo

This allowed Gervasio Lamas, MD, a professor of clinical medicine at the Columbia University Division of Cardiology and now Chairman of Medicine at Mount Sinai Medical Center, who is the PI of TACT, to look at whether high dose vitamin and mineral supplementation had any effect on cardiovascular disease. Recall that the original results of the study showed no benefit in any individual endpoint from the witches’ brew of chelation therapy with or without high dose vitamin supplementation. For the composite endpoint used, there was similarly no benefit in everyone except one group: Diabetics. As I put it, normally this sort of finding would lead to the recommendation that chelation therapy should not be used in anyone without diabetes because the best evidence we have from TACT is that it’s resoundingly ineffective. Also, as I explained, the “benefit” observed in diabetics is likely due to confounders. Perhaps I’ll have to write about that further, as, seeking to divide the study into as many MPUs (minimal publishable units) as possible, Lamas recently published a paper on the diabetics in TACT.

In the meantime, I’ll remain “shrill and brutish” about TACT and point out that the most recent MPU from TACT found nothing even resembling a statistically significant effect of the high dose vitamin supplementation on the same composite endpoint consisting of time to death from any cause, reinfarction, stroke, coronary revascularization, or hospitalization for angina, or any of the individual endpoints. This left Lamas lamenting that you can’t conclude for sure much of anything because so many patients either didn’t adhere to the regimen or dropped out of the trial. Nearly half the patients discontinued the vitamin therapy, and 17% withdrew from the study. Still, this MPU from TACT is about as negative as negative can be.

None of this is surprising.

Of course, the supplement industry is large and has powerful advocates; so its allies were not going to take this lying down. The responses are at best disingenuous and, in one case, hilariously over the top. For instance, Cara Welch, Sr VP of Scientific & Regulatory Affairs for Natural Products Association (NPA), says:

The intention of supplements is to supplement the diet. Don’t expect supplements to cure the common cold or prevent cancer, but they are part of the puzzle of a healthy lifestyle.

In the same article, Steve Mister, President and CEO of the Council for Responsible Nutrition (CRN), laments:

The editorial demonstrates a close-minded, one-sided approach that attempts to dismiss even the proven benefits of vitamins and minerals. It’s a shame for consumers that the authors refuse to recognize the real-life need for vitamin and mineral supplementation, living in a fairy-tale world that makes the inaccurate assumption that we’re all eating healthy diets and getting everything we need from food alone. We would not suggest that vitamin supplements are a panacea for preventing chronic disease, but we hope the authors would agree that there is an appropriate place for supplements. Given that government research repeatedly demonstrates that the typical consumer diet is falling short on critical nutrients, vitamin supplements are an appropriate option to meet those needs.

Hilariously, on the same page is a sponsored link claiming that a supplement called Immmuno-LP20 can stimulate the immune system and fight off colds and infections. ‘Nuff said. Well, almost. These two spokespersons are being disingenuous at best and at worst are lying. Of course, the supplement industry claims all sorts of health benefits for vitamin supplementation that go beyond just claiming they are a “part of the puzzle of a healthy lifestyle.” I’ve lost track of how many times I’ve seen such claims.

My favorite response, however, comes from—you guessed it!—Mike Adams. No one—and I mean no one—brings home the crazy like Mike, and this is no exception. He was quick off the mark to post a characteristic rant of his, Mainstream media attacks multivitamins in yet another example of quack science catapulted into the news by pharma interests. It’s replete with cries of “pharma shill!” and dire insinuations of conspiracy to suppress “natural” cures. You really have to read the whole thing. If you’re a connoisseur of crankery, as I am, you won’t regret it, as it’s enormously entertaining in the way that only Mike Adams can be.

The key objections that Adams has to the entire series of articles in Annals are quite predictable, and involve the aforementioned conspiracies and everyone being in the pay of big pharma. Oh, and let’s not forget the alleged “double standard”:

The answer is because this scrutiny is reserved solely for nutritional supplements. In today’s distorted system of quack medicine, junk science and pro-pharma propaganda, medications never have to be proven effective to be promoted and hyped. There is no scientific evidence whatsoever, for example, that chemotherapy prevents the progression of cancer (chemo actually causes more cancer), or that statin drugs enhance lifespan. There is no evidence whatsoever that ADHD drugs create healthy children or that antidepressants cure depression. Yet all these drugs are heavily hyped by medical journal (i.e. “drug journals”) and the mainstream media without regard for their disastrous lack of efficacy and safety.

Excuse me a minute, while I wipe the flecks of spittle off of my glasses. So intense is Adams’ crazy that they’re flying out of my computer screen as I read his screed. Of course, I’ve addressed many of these very topics, particularly how chemotherapy actually does work, contrary to Adams’ lies, does work. In any case, this is a classic case of projection, because the real double standard is with respect to supplements. Thanks to the DSHEA of 1994, the law that hamstrings the FDA with respect to regulating health claims about supplements, supplements are regulated as food, not medicine, which means that the standards are lower, and antivaccinationists can even get away with claiming an industrial chelator is a nutritional supplement, at least for a while. All we’re left with, then, are claims by Adams that no drug has ever reversed any disease? Really? Antibiotics do a damned good job of curing pneumonia and numerous other bacterial infections. Chemotherapy can cure some cancers. Adams also angrily dismisses any sort of disease management, such as the use of antihypertensive drugs, as not “curing” the condition, which is besides the point. Until there is a “cure,” management is often quite helpful. How many millions of people have avoided heart attacks and strokes because cheap antihypertensives keep their blood pressure under control? How many diabetics haven’t lost limbs or vision because of glucose control due to insulin or oral hypoglycemic medicines? Adams posits a false dichotomy, where either a treatment completely reverses a disease process or it’s useless. Sorry, but things are not black and white.

Perhaps the most hilarious part of Adams’ “argument,” such as it is, is this:

To make sure these multivitamin studies fail to produce positive results, these studies are universally structured so that they are based on cheap, low-grade, synthetic vitamins and inorganic minerals. Not coincidentally, these brands of low-grade multivitamins are actually manufactured by companies owned by pharmaceutical interests. They really do have a financial incentive to make multivitamins look bad, and so their multivitamin formulations are intentionally designed to fail.

Which makes no sense. Pharma makes lots of money selling supplements, and the cost of developing vitamin supplements is nowhere near what it takes to develop a new drug, as the massive clinical studies needed to win FDA approval aren’t necessary. Supplements are thus nearly pure profit, which is why drug companies and large commercial interests have jumped into the business. As usual, Adams is completely wrong. If anything, pharmaceutical companies have every incentive to want the studies published in Annals to be positive studies, because that would translate into increased sales and increased profits. Hilariously, one of the supplements used in these studies, the Centrum Silver used in PHS II, is manufactured by Pfizer, and, as Scott Gavura points out, the vitamin combinations used in TACT were chosen by naturopaths and “natural” health practitioners themselves. Do you really think Pfizer wants a study concluding that taking its Centrum Silver does no good for seniors? Oh, and Adams’ Pinto analogy made me almost spit up my coffee on my MacBook Pro as I typed this. Read it for yourself. You won’t regret it. Probably.

Basically, the hilarious thing is that Adams’ whine boils down to the naturalistic fallacy, namely the claim that nutrients derived naturally from food products is better. Ironically, that’s exactly what the editorial in Annals said in essence, namely that for most people in developed countries who are adequately nourished through food (who, by the way, make up the vast majority of supplement users), vitamin and mineral supplements are unnecessary and do not prevent chronic disease. The message from the evil medical cabal portrayed by Adams is to get your nutrition from your food. The evil medical cabal also recommends elsewhere to consume a diet high in vegetables and fruits.

I can’t help but finish by noting another thing Adams says:

If you want to take supplements, invest in high-end, quality supplements based on food concentrates or food extracts. Nutrients derived from real food tend to be far healthier than synthetic nutrients.

Again, that’s exactly what the editorial says, that nutrients derived from real food are good enough such that supplementation is unnecessary. However, note the first part of what Adams says: Invest in “high-end” supplements. Those “high-end” supplements are also the highest profit supplements. I’m guessing that’s going to be the next supplement cabal retort to science: Don’t use those cheap, pharma-produced supplements. They aren’t the real supplements. Use our high-end, natural supplements instead. They’re the real deal.

Next step: Continue to profit!