Abstract
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Vitamin supplements have been alternately ignored, hyped as the panacea for long life, scorned as quackery and occasionally studied scientifically. Despite uncertainty and conflicting evidence, use of dietary supplements is increasing among US adults, with approximately 40% reporting multivitamin and mineral (MVM) use and more than 50% using dietary supplements of any kind. Therefore, after all this time, money and effort, why do we not have more definitive answers regarding the benefit/harm profiles?
Here, we are considering supplements for adults containing MVMs with approximately 20 or more vitamins and minerals, usually at levels close to the reference daily intake (RDI). Generalizations to younger individuals and women of child-bearing age should not be made.
There are a number of reasons why studies of MVM disagree, including varying study designs, different populations studied and different hypotheses being tested. Another complicating factor is that MVM is a ‘black box‘. We cannot know which of the many ingredients are responsible for any effect we might find nor can we know if no effect is found, whether one ingredient may block another or whether some ingredients are at nonoptimal dosage. Complicating the picture further is the existence of many different formulations, each aimed at different segments of the population, with wide variations in dose. For example, the dose of vitamin B12, is 100% RDI in the one-a-day brand for adults, 417% RDI in Centrum® Silver® (Pfizer, NY, USA) for adults, 833% RDI in Centrum Silver for women older than 50 years of age, and 1667% RDI for men older than 50 years of age.
MVMs are not regulated by the US FDA in the same way that drugs and foods are, thus there is no standardization of the number, dosage or quality of the ingredients of MVMs. It is not feasible to conduct clinical trials of each ingredient separately or even of the many different formulations of MVMs.
Most of the studies investigating MVMs for primary prevention have been observational studies conducted in generally healthy adults. The Women's Health Initiative (WHI) study of 161,606 postmenopausal women followed for a median of 8 years, found no effect of MVM supplements on either cardiovascular disease (CVD) or cancer [1], nor did a large prospective study of a million adult Americans [2], which found that CVD mortality was similar in users and nonusers of MVM alone, but risks were 15% lower in users of MVM in combination with vitamins A, C or E. Cancer mortality in male smokers was increased with MVM alone or in combination users, but decreased in male current nonsmokers. No associations were found in women. A meta-analysis of observational studies investigating MVM use and breast cancer incidence [3] found no association overall, and all except one study [4], demonstrated no harm. A systematic review of 15 studies found no pattern of associations of MVM and disease by sex, smoking status or frequency of use, and concluded that MVMs do not increase CVD, cancer or mortality and may provide a modest protective benefit [5]. Another systematic review of 26 studies [6,7] found that most of the studies investigated single nutrients or functionally related nutrient pairs, with only two studies investigating the efficacy of MVMs on cancer and CVD [8–10], and only one of these included women [10]. In general, it was concluded that there is no harm to vitamin supplements, with two studies on MVM demonstrating some protective effect with regard to cancer in men [11].
One problem with these studies is that, while they may have enough power to test the null hypothesis of no effect in the whole population, they often do not have sufficient power to look at specific subgroups, such as older people who may have less than an adequate diet. Nor do they examine possible interactions of MVM with specific aspects of diet. Are MVMs more useful in people who are frail, for example, or who changed their diet from adulthood to old age? This is yet to be investigated.
Another issue with observational studies is that those who take MVM may be healthier in other aspects of life which would, at least in part, explain any small benefits seen. Randomized trials do not have these biases. Since individuals are assigned randomly to either treatment group, known and unknown confounders are balanced across the two groups if the trial is large enough. One of the two randomized trials, the SU.VI. MAX study, was a primary prevention trial conducted in 13,017 French adults aged 35–60 years and treated for 7.5 years [10]. However, they used a combination of only five antioxidant ingredients, so it was not a complete MVM. This trial found a protective effect of low-dose antioxidants against cancer and all-cause mortality in men (relative risk: 0.69 [9% CI: 0.53–0.91] and 0.63 [95% CI: 0.42–0.93], respectively), but not in women.
The PHS II randomized controlled trial was the only trial of a common commercially available multi-ingredient MVM (Centrum Silver), but only included men [8,9]. After 11 years of treatment in 14,641 men, there was no effect on CVD overall, however, there was a 39% reduction in heart attack deaths (hazard ratio: 0.61 [95% CI: 0.38–0.995]; p < 0.05) [8], a reduction in overall cancer and a 12% reduction in all cancer, excluding prostate cancer (hazard ratio: 0.88 [% CI: 0.79–0.98]; p < 0.02) [9]. There are no placebo-controlled, randomized clinical trials of MVM in women.
A different question is whether MVMs may be useful for secondary prevention. The WHI conducted a study of nearly 8000 postmenopausal women aged 50–79 years at baseline, who had invasive breast cancer and were followed for an average of 7 years after their breast cancer diagnosis [12]. Deaths from breast cancer were 30% lower in the women who used MVM at baseline than in those who did not (hazard ratio: 0.70; 95% CI: 0.55–0.91). This highly robust association persisted after multiple different adjustments for potential confounding, including propensity score matched analyses. Perhaps women using MVMs had more nutritional reserves and were better prepared to withstand the insult of breast cancer.
Interestingly, the PHS in men also found in prespecified analyses, that the effects of daily use of MVM in reducing cancer was greater in men for secondary versus primary prevention of cancer, particularly for epithelial cell cancers [9]. This finding has been neglected, but it certainly supports the WHI finding of the protective effect of MVMs with regard to breast cancer mortality in women diagnosed with invasive breast cancer. In the WHI study, most of women were taking MVMs before their diagnosis. There were too few women who first began taking MVMs after diagnosis to draw any conclusions regarding this group. Of course no woman knows she is going to be diagnosed with breast cancer, so the question is whether women should take MVMs in general, since they appear to do no harm, but should they get breast cancer, they may be protected against breast cancer death.
“…the high cost of multivitamins and minerals is not a good argument, since it is considered personal discretionary spending and it is up to consumers to decide whether their money is better spent on soft drinks, which in contrast to the multivitamins and minerals, do cause harm…”
Arguments against the general use of MVMs are that they may not be effective for primary prevention and that they are a waste of money. In regard to effectiveness, many task forces on the subject state that there is not enough evidence for or against MVMs. With regard to the waste of money issue, the Office of Dietary Supplements of the NIH (MD, USA) reports that, in 2011, approximately US$5.2 billion was spent on MVMs [13]. In comparison, US$65 billion was spent on soft drinks (National Soft Drinks Association, DC, USA [14]). Therefore, the high cost of MVMs is not a good argument, since it is considered personal discretionary spending and it is up to consumers to decide whether their money is better spent on soft drinks, which in contrast to the MVMs, do cause harm (via increased risk of diabetes and obesity). However, consumers should be able to make informed choices.
Unfortunately, there are several important gaps in knowledge regarding MVMs, which are, admittedly, difficult to study. First of all, we should know a lot more about which subgroups might benefit from MVM by age and nutritional status. Second, we do not have any clinical trials on efficacy of MVM in women, particularly in older women. This is sorely needed. Third, there has been virtually no adequate study of secondary prevention. In addition to the WHI study, we need studies of survivors of breast cancer in other populations, as well as survivors of lung cancer, myocardial infarction and other conditions. There are many existing large cohort studies in which such analyses could be undertaken, and even though they are observational studies, we need confirmation of the WHI results in reducing breast cancer mortality in postmenopausal women with invasive breast cancer.
Thus, in our view, MVMs do no harm, may be protective for certain women and there is no compelling argument against taking them. We note that this view does not apply to certain single vitamins, some of which are beneficial (e.g., vitamin D) and some of which are harmful (e.g., vitamin A or β-carotene in smokers). However, what is strongly needed is a clinical trial of MVMs in women and the analysis of pooled observational cohorts to identify subgroups for whom MVMs would be most useful.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.