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Vitamin and Mineral Supplements for the Primary Prevention of Cardiovascular Disease and CancerUpdated Evidence Report and Systematic Review for the US Preventive Services Task Force

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Importance  Cardiovascular disease and cancer are the 2 leading causes of death in the US, and vitamin and mineral supplementation has been proposed to help prevent these conditions.

Objective  To review the benefits and harms of vitamin and mineral supplementation in healthy adults to prevent cardiovascular disease and cancer to inform the US Preventive Services Task Force.

Data Sources  MEDLINE, PubMed (publisher-supplied records only), Cochrane Library, and Embase (January 2013 to February 1, 2022); prior reviews.

Study Selection  English-language randomized clinical trials (RCTs) of vitamin or mineral use among adults without cardiovascular disease or cancer and with no known vitamin or mineral deficiencies; observational cohort studies examining serious harms.

Data Extraction and Synthesis  Single extraction, verified by a second reviewer. Quantitative pooling methods appropriate for rare events were used for most analyses.

Main Outcomes and Measures  Mortality, cardiovascular disease events, cancer incidence, serious harms.

Results  Eighty-four studies (N=739 803) were included. In pooled analyses, multivitamin use was significantly associated with a lower incidence of any cancer (odds ratio [OR], 0.93 [95% CI, 0.87-0.99]; 4 RCTs [n=48 859]; absolute risk difference [ARD] range among adequately powered trials, −0.2% to −1.2%) and lung cancer (OR, 0.75 [95% CI, 0.58-0.95]; 2 RCTs [n=36 052]; ARD, 0.2%). However, the evidence for multivitamins had important limitations. Beta carotene (with or without vitamin A) was significantly associated with an increased risk of lung cancer (OR, 1.20 [95% CI, 1.01-1.42]; 4 RCTs [n=94 830]; ARD range, −0.1% to 0.6%) and cardiovascular mortality (OR, 1.10 [95% CI, 1.02-1.19]; 5 RCTs [n=94 506] ARD range, −0.8% to 0.8%). Vitamin D use was not significantly associated with all-cause mortality (OR, 0.96 [95% CI, 0.91-1.02]; 27 RCTs [n=117 082]), cardiovascular disease (eg, composite cardiovascular disease event outcome: OR, 1.00 [95% CI, 0.95-1.05]; 7 RCTs [n=74 925]), or cancer outcomes (eg, any cancer incidence: OR, 0.98 [95% CI, 0.92-1.03]; 19 RCTs [n=86 899]). Vitamin E was not significantly associated with all-cause mortality (OR, 1.02 [95% CI, 0.97-1.07]; 9 RCTs [n=107 772]), cardiovascular disease events (OR, 0.96 [95% CI, 0.90-1.04]; 4 RCTs [n=62 136]), or cancer incidence (OR, 1.02 [95% CI, 0.98-1.08]; 5 RCTs [n=76 777]). Evidence for benefit of other supplements was equivocal, minimal, or absent. Limited evidence suggested some supplements may be associated with higher risk of serious harms (hip fracture [vitamin A], hemorrhagic stroke [vitamin E], and kidney stones [vitamin C, calcium]).

Conclusions and Relevance  Vitamin and mineral supplementation was associated with little or no benefit in preventing cancer, cardiovascular disease, and death, with the exception of a small benefit for cancer incidence with multivitamin use. Beta carotene was associated with an increased risk of lung cancer and other harmful outcomes in persons at high risk of lung cancer.

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Article Information

Corresponding Author: Elizabeth O’Connor, PhD, Kaiser Permanente Evidence-based Practice Center, The Center for Health Research, Kaiser Permanente Northwest, 3800 N Interstate Ave, Portland, OR 97227 (Elizabeth.OConnor@kpchr.org).

Accepted for Publication: August 30, 2021.

Author Contributions: Dr O’Connor had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: O’Connor, Evans, Ivlev, Rushkin, Lin.

Acquisition, analysis, or interpretation of data: O’Connor, Evans, Ivlev, Rushkin, Thomas, Martin.

Drafting of the manuscript: O’Connor, Evans, Ivlev.

Critical revision of the manuscript for important intellectual content: Ivlev, Rushkin, Thomas, Martin, Lin.

Statistical analysis: O’Connor, Ivlev.

Obtained funding: O’Connor, Lin.

Administrative, technical, or material support: Evans, Rushkin, Thomas, Martin.

Supervision: Evans, Lin.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was funded under contract HHSA-290-2015-00007-I, Task Order 6, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).

Role of Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We gratefully acknowledge the following individuals for their contributions to this project: Tina Fan, MD, MPH, and Howard Tracer, MD, at the Agency for Healthcare Research and Quality; current and former members of the US Preventive Services Task Force who contributed to topic deliberations; the National Cancer Institute and the National Heart, Lung, and Blood Institute for providing federal partner review of the draft report; and Nadia Redmond, MSPH, Jill Pope, BA, and Melinda Davies, MAIS, for technical and editorial assistance at the Center for Health Research. USPSTF members, peer reviewers, and those commenting on behalf of partner organizations did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 5 content experts (Erin LeBlanc, MD, MPH, Kaiser Permanente Center for Health Research; Edward Giovannucci, MD, ScD, Harvard University; Stephanie Weinstein, PhD, National Cancer Institute; Catharine Ross, PhD, Penn State University; JoAnn Manson, MD, DrPH, MPH, Harvard University) and 2 federal partners, the National Heart, Lung, and Blood Institute and the National Cancer Institute. Comments were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF Recommendation Statement. It did not undergo additional peer review after submission to JAMA.

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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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