In December, the Annals of Internal Medicine (AIM) published 3 studies evaluating the effects of multivitamin supplementation on chronic disease prevention.1–3 These studies were accompanied by an alarming editorial: “Enough Is Enough: Stop Wasting Money on Vitamin and Mineral Supplements.”4 The authors of the editorial claim that the results of the 3 studies, along with previous trials, indicate “no substantial health benefit” of multivitamins and call for an end to further research on multivitamins for chronic disease prevention in well-nourished populations. The authors conclude 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 3 studies that were purportedly the basis for the editorial are examined below.
1. Long-term multivitamin supplementation and cognitive function in men: a randomized trial
Grodstein F, O'Brien J, Kang JH, et al.
In this large, randomized, double-blind, placebo-controlled trial, the effects of long-term multivitamin supplementation on cognitive function in later life were evaluated in male physicians aged 65 years or older from the Physicians’ Health Study (PHS) II. Cognitive function was the final outcome to be reported from PHS II. Previous results from this study have shown that long-term multivitamin supplementation reduced the risk for cancer and cataracts but did not impact cardiovascular disease outcomes.
In the cognitive substudy, participants completed an initial cognitive assessment, followed by 3 waves of follow-up over a total period of 12 years. Cognition was evaluated by a validated telephone interview and included a battery of tests. Subjects received an active multivitamin or a multivitamin placebo daily. There were no significant differences in the change in cognitive function over follow-up between the multivitamin and placebo groups, as assessed by the global score of cognition and in secondary analyses of verbal memory and individual test results. This study benefited from high follow-up and adherence, as well as a large study population (N=5,947). The authors noted, however, that subjects in the PHS II “may have been too well-nourished to observe benefits of supplementation” and that “further research is needed in other populations, such as those with nutrient deficiencies, to determine whether there are cognitive benefits specific to daily multivitamin use.”
2. Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial
Lamas GA, Boineau R, Goertz C, et al.
This study was part of the multicenter TACT (Trial to Assess Chelation Therapy) study and assessed the effects of high-dose oral multivitamins and multiminerals (MVMM) on the secondary prevention of cardiovascular events (total death, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina) in patients who had previously experienced myocardial infarction. A non-significant 11% reduction in cardiovascular events was reported in the MVMM group compared to the placebo group during the 55-month follow-up. This study is tempered by a significant nonadherence and withdrawal in both treatment groups (likely due to the regimen of 6 large caplets daily and the burden of combining an oral vitamin regiment with intravenous chelation therapy), as well as the reduced statistical power given that the study was designed to detect a 25% relative reduction in the primary endpoint, which the authors conceded may have been “overly optimistic” for oral vitamins. Importantly, the authors stated that there was “No evidence suggest[ing] harm from vitamin therapy in any category of adverse events.”
3. 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
Fortmann SP, Burda BU, Senger CA, et al.
This systematic review was conducted to assess the evidence for the benefits and harms of vitamin and mineral supplements in nutrient-sufficient adults for the primary prevention of cardiovascular disease (CVD) and cancer. The studies assessed the effectiveness or safety of supplements in the primary prevention of cancer, CVD, or all-cause mortality in healthy, nourished adults. In the multivitamin portion of the analysis (multivitamins were defined by the authors as combinations of 3 or more vitamins and minerals), 5 large, good-quality studies were included, 2 of which reported lower cancer incidence in men taking a multivitamin for more than 10 years. These 2 large trials were the PHS-II and the Supplementation in Vitamins and Mineral Antioxidants Study (SU.VI.MAX). PHS-II enrolled only male participants. The SU.VI.MAX trial included women, but did not find a benefit for this subgroup. Multivitamin intervention did not have an effect on CVD events in the reviewed studies. The authors came to the same conclusion as authors of other similar reviews, which is that there are a limited number of rigorous randomized controlled trials that have assessed the efficacy of multivitamins for cancer and heart disease.
Analysis and Clinical Implications
Clinicians with expertise in nutrition are not surprised by the notion that MVMM supplements are not meant to be a panacea for chronic disease prevention. Multivitamins are 1 component of a healthy lifestyle and are a safe and effective way to fill nutrient gaps that are not met through diet alone.
From a clinical standpoint, MVMM supplementation provides a safe way to correct these nutrient shortfalls while working with individuals to improve dietary intake of nutrients.
While the authors of the editorial are correct in concluding that there is not enough rigorous evidence to support that an MVMM alone will prevent chronic disease or death, it is misguided and scientifically inaccurate to overinterpret this to mean that there is no benefit to taking an MVMM or that this line of investigation should stop. Government research shows that Americans have frank nutrient gaps. In fact, recent data show that a large portion of Americans fall below the estimated average requirement (EAR) for certain nutrients, specifically vitamins A, C, D, and E and magnesium and calcium, even when nutrient intake from diet, fortified foods, and supplements is considered.5 Intake of some nutrients is low enough to be a public health concern. These include potassium, dietary fiber, calcium, and vitamin D, along with iron, folate, and vitamin B12 for specific population groups.6 From a clinical standpoint, MVMM supplementation provides a safe way to correct these nutrient shortfalls while working with individuals to improve dietary intake of nutrients.
The authors of the editorial ignore the established benefits of MVMM supplementation in filling nutrient gaps. Furthermore, the available research indicates that the case is not closed on the potential for additional benefits from vitamin and mineral supplements. The TACT multivitamin study showed a promising trend in cardiovascular event–reduction with MVMM supplementation that warrants additional research. Although the PHS II substudy published in AIM did not show a benefit of multivitamin supplementation on cognitive function, 2 other recently published arms of PHS II showed reductions in the risk of cancer7 and cataracts.8 These are real, demonstrated benefits that should not be ignored. It is also important to note that these benefits were shown in a well-nourished population, and the potential benefit in a population with nutrient inadequacies has yet to be examined. If MVMM can contribute to reducing the burden of significant diseases such as cancer or cataract in a well-nourished population, this is icing on the cake.
The editorial by Guallar et al missed a critical point discussed in the accompanying manuscripts it covers. Fortmann et al make a compelling observation in their systematic review of the evidence for the benefits and harms of vitamin and mineral supplements in nutrient-sufficient adults for the primary prevention of CVD and cancer. While these authors concur that there is insufficient evidence to conclude that a MVMM prevents cancer or heart disease, they note that their review focuses on randomized controlled trials—a study design used primarily to evaluate drug therapy. The authors state, “This design might not be ideally suited to evaluate nutrients.” The limitations of this study design for researching nutrition include the influence of baseline nutritional status, lack of a nutrient-free placebo group, and small effect size. This report by Fortmann et al serves as the basis for the US Preventive Services Task Force (USPSTF) recommendations. The USPSTF reaches a more balanced conclusion regarding the future of nutrition research than do the authors of “Enough is Enough.” Instead of slamming the door on additional research, as Guallar et al have suggested, the USPSTF concludes that “there are significant challenges to studying nutrient supplementation using methods similar to those used in studying pharmaceutical interventions. New and innovative research methodologies for examining effects of nutrients that account for the unique complexities of nutritional research but maintain rigorous designs should be explored.”