The current issue of Annals of Internal Medicine groups together three generally well-done studies on the topic of multivitamins and chronic disease prevention with what could be described as a sensationalistic, headline-grabbing editorial. The editorial, entitled Enough is Enough: Stop Wasting Money on Vitamin and Mineral Supplements, serves as a call to action for medical professionals to actively advise against the routine use of vitamin and mineral supplements and for researchers to cease any further, futile research into the potential benefits of supplements in the general population. 

What's your take on the current science and discussion on multivitamin use?

Do the recent data provided in Annals really tip the discussion from what we have become used to—“not enough evidence to recommend for or against”—to a finite conclusion that supplements are ineffective and dangerous? Does this represent a major transition in the state of nutritional science or just another blip in a long history of conflicting research and opinion that confuses medical professionals and health-conscious consumers alike?  One of the studies’ authors seems to agree that the editorial is overstated. “It drives me crazy that they say ‘enough is enough,’” says Dr. John Gaziano from Harvard, as reported in USA Today, “when there’s only been one large study of (standard) multivitamins and it’s ours.” Let’s briefly discuss the main conclusions from each of the three trials without hyperbolae.

Vitamin and Mineral Supplements in the Primary Prevention of Cardiovascular Disease and Cancer: An Updated Systematic Evidence Review for the US Preventive Services Task Force

This is a systematic review of the available evidence for the benefits and harms of vitamin and mineral supplements in the primary prevention of cardiovascular disease (CVD) and cancer in generally healthy adults. The authors are careful to point out that the results from this analysis do not apply to the targeted use of nutrients in nutritionally deficient or otherwise at-risk individuals. The review included only four available randomized control trials (RCTs). Of these, the two larger trials, representing 27,658 subjects over a follow up period of more than 10 years, yielded moderately positive results in cancer prevention among men.  There were no effects on cardiovascular disease or cancer risk among women. The remaining two RCTs, representing 949 subjects over a one- to three-year period, did not report on cardiovascular disease or cancer incidence.  In evaluating the available studies on single or paired nutrient interventions, the authors point out that the data were “scant and heterogeneous and showed no clear evidence of benefit or harm.”

Long-Term Multivitamin Supplementation and Cognitive Function in Men

Goldstein and colleagues assessed cognitive performance within the context of the Physicians’ Health Study II, a long-term randomized, double-blind, placebo-controlled trial of multivitamin use in a population of male physicians. Previous results from this same study have demonstrated modest overall protection against cancer and cataracts and no benefits in CVD prevention.  Cognitive assessments were conducted on 5947 subjects by telephone interview, and up to four total assessments per subject were completed over a 12 year period. No differences in primary or secondary measures of cognitive performance between the multivitamin and placebo groups were found. Although all subjects experienced some change in assessment score from baseline to final assessment, it is unclear whether these time-dependent changes were significant or represented a clinically-relevant degree of typical age-related cognitive decline.

The authors conclude, in part, that the population was highly educated and well-nourished and that the doses of vitamins used may have been too low to yield benefits in this population. Further, the authors suggest that more studies are needed to clarify whether multivitamin supplementation may be of benefit in individuals with less optimal nutritional status and that such an assessment is particularly important in the aging population, as older individuals are at risk for nutritional deficiencies due to reduced micronutrient intake and the altered absorption and metabolic requirements of vitamins.

Oral High-Dose Multivitamins and Minerals After Myocardial Infarction

As opposed to the assessment of primary prevention, above, this study evaluated whether a multivitamin is effective for the secondary prevention of cardiovascular events in a population with a history of myocardial infarction (heart attack). A total of 1708 subjects aged 50+ were evaluated at 134 academic and clinical sites in the US and Canada and followed for up to 60 months (mean intervention period was 31 months).  Primary endpoints of interest were death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. There was a positive 11 percent relative reduction in cardiac events in the multivitamin group compared to the placebo group, although this trend did not reach statistical significance. Notably, the authors discuss the severe limitations of the study in terms of statistical power. The study was designed for an effect size of a 25 percent reduction in events, which was quite optimistic. Further, the population size was further reduced by considerable non-adherence and withdrawal (another aspect of the study, reported separately, required intravenous chelation therapy, which could be expected to increase dropout rates). 

In the current study, a multivitamin did not reduce CVD events, but there was a positive trend such that a study with more subjects and a longer observation period is indicated. Finally, the authors reported a significant interaction of multivitamins with statin use in which subjects not receiving a statin saw a greater positive effect of multivitamin therapy than those also receiving a statin.  The authors caution against applying this result clinically without further study. 

Conclusions

In general, the Enough is Enough editorial ignores positive data where they do exist, overemphasizes the potential harms of supplement usage by regurgitating a few well-known negative trials such as those on high-dose β-carotene and vitamin E (not multivitamins, mind you, but isolated nutrients), and fails to acknowledge the widespread nutritional inadequacies in the general population. While the authors do make an attempt to focus their criticisms on the limitations of supplements in well-nourished populations, where probably everyone can agree potential benefits would be minimized, they seem to have an impaired view on the current nutritional status of Americans and discount (or at least marginalize the importance of) any potential benefits in at-risk subgroups. 

So, is the case closed? No. More studies are needed. And as the data suggest, it is time to move nutritional research away from a one-size-fits-all public health approach to one in which targeted nutritional interventions become part of a personalized approach to medicine.