Vitamins: An Evidence-Based Discussion

Educational Objectives

The goal of this program is to improve management of patient vitamins and supplements. After hearing and assimilating this program, the clinician will be better able to:

1. Explain the regulatory process that governs vitamins and supplements.
2. Use evidence-based data to determine whether to prescribe various vitamins to patients to manage or prevent cancer or cardiovascular disease.
3. Identify patients with vitamin D₃ insufficiency vs deficiency.

Summary

Relative risks

Opportunity costs: patients may rely too heavily on vitamins for disease prevention and neglect more beneficial lifestyle behaviors; it is essential to engage in honest conversations with patients about vitamin use and understand patient goals and motivations

Adverse effects: Geller et al (2015) found that ≈23,000 emergency department visits in the United States occur annually due to supplement use; ≈33% of these visits were due to vitamins (micronutrients), which most commonly caused allergic reactions (≈40%) and pill-induced dysphagia (≈41%)

Commercial vitamin synthesis: Crawford et al (2022) found that 43% of supplements contain unlisted ingredients and ≈33% contain substances not listed on the label (which may contribute to allergic reactions)

Vitamin efficacy: vitamin production is unregulated; while the United States Pharmacopeia (USP) label can provide some assurance of quality control, it is not a guarantee of safety or efficacy; therefore, it is important to evaluate evidence for the efficacy of specific vitamins and supplements before recommending them to patients; there has been a shift toward a more integrative approach; the National Institutes of Health changed the name of the National Center for Complementary and Alternative Medicine to the National Center for Complementary and Integrative Health (NCCIH), fostering the belief that natural products and therapies can complement conventional medicine

Regulation of supplements: in the wake of the deaths from L-tryptophan in the 1980s, the Nutrition Labeling and Education Act (NLEA) was passed in 1990 to grant the Food and Drug Association (FDA) the right to regulate food and supplement contents and labels; however, the Dietary Supplement Health and Education Act, passed in 1994, exempts supplements from many of the regulations imposed by the NLEA; thus, supplement labels and contents are not subject to the same standards as those for food and are considered safe unless the FDA can prove otherwise

Supplement use today: data from the 2018 National Health and Nutrition Examination Survey indicate that ≈50% of American adults have taken ≥1 supplement in the prior 30 days, and ≈33% of adults reported that their kids also take supplements; current annual expenditure on supplements in the United States is ≈$40 billion (<10% of the amount spent on prescription drugs)

Background: it is impossible to have an allergy to a vitamin; many vitamins contain an amine compound; 13 human vitamins exist; vitamins A, D, E, and K are fat-soluble vitamins; vitamins B (8 exist) and C are water-soluble vitamins; macronutrients provide calories and are separate from micronutrients

Recommended daily allowance (RDA): neither the amount an average person needs nor a daily goal; RDA represents the amount of a vitamin that is needed by the upper 97^th percentile of the population to avoid developing deficiency; vitamins work inside cells, have long biologic half-lives, and are required in very small doses; eg, the RDA for vitamin D is 600 IU (15 μg); the RDA for vitamin B₁₂ is about one-seventh of the RDA value for vitamin D

Impacts of vitamin A on incidence of lung cancer or cardiovascular disease (CVD): Hennekens et al (1996) — found that 12-yr supplementation with β-carotene (precursor of vitamin A) produced neither harm nor benefit with regard to incidence of lung cancer or CVD; the ATBC cancer prevention study group (1994) — found no reduction in the incidence of lung cancer with α-tocopherol and β-carotene supplementation, though incidence of lung cancer increased in men who took β-carotene; Omenn et al (1996) — found that the combination of β-carotene and vitamin A provided no benefit with regard to the incidence of lung cancer or CVD and indicated a trend of increased lung cancer risk in former smokers or patients exposed to asbestos

Impact of diet on CVD: Kushi et al (1996) — found that dietary intake of vitamin E is inversely associated with risk of death from coronary heart disease among women, but supplemental intake of vitamin E provides no benefit; the PREDIMED trial (Estruch et al, 2018) showed that the Mediterranean diet was associated with ≈25% relative reduction in CV events, though the number of events was small (there was a small absolute benefit)

Impacts of vitamin E and supplementation on CVD: the Heart Outcomes Prevention Evaluation-2 (HOPE-2) study (Lonn et al, 2006) did not find any benefit from supplementation of folic acid or homocysteine; the HOPE-TOO trial (Lonn et al, 2005) did not note benefit from vitamin E supplementation; the British Heart Protection Study (Collins et al, 2003) noted no reduction in mortality with antioxidant supplementation

Impacts of vitamin supplementation on hospitalized patients: the LOVIT trial (Lamontagne et al, 2022) found that intravenous vitamin C was associated with a higher risk for mortality of adult patients with sepsis, vs placebo, and baseline vitamin C level were nonpredictive of benefit

Recommendations: in 2013, a comprehensive meta-analysis of vitamins and supplements published by the US Preventive Services Task Force (USPSTF) recommended discontinuation of the use of vitamin and mineral supplements for the prevention of cancer and CVD

Vitamin D: the Endocrine Society guidelines (Holick et al, 2011) state that patients with vitamin D <20 mg/dL are considered deficient, and those with vitamin D levels between 20 and 30 mg/dL are considered insufficient; Rosen et al (2012) contested Holick et al (2011) and noted that for most adults, bone health optimization was achieved by vitamin D₃ levels of 12 to 14 mg/dL (ie, levels of 20 and 30 mg/dL are unnecessary for bone health); the VITAL trial (Manson et al, 2019) found no association between vitamin D₃ supplementation and decreased incidence of cancer or CVD; subanalysis revealed no prediction of additional benefit for patients considered to have vitamin D₃ deficiency or insufficiency vs normal baseline levels; LeBoff et al (2022) found that vitamin D₃ supplementation did not reduce risk of bone fracture, and low baseline vitamin D₃ level did not predict additional benefit from supplementation

Resources: the USPSTF website provides their own subanalyses on individual supplements; the Cochrane Library provides access to meta-analyses on individual vitamins and multivitamins; the NCCIH website has fact sheets for dietary supplements as well as for vitamins and minerals

Readings

Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330(15):1029-1035. doi:10.1056/NEJM199404143301501. View article; Boughanem H, Kompella P, Tinahones F, et al. An overview of vitamins as epidrugs for colorectal cancer prevention. Nutr Rev. 2023;81(4):455-479. doi:10.1093/nutrit/nuac065. View article; Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018;378(25):e34. doi:10.1056/nejmoa1800389. View article; Fernandez-Barres, S, Martin N, Canela T, et al. Dietary intake in the dependent elderly: evaluation of the risk of nutritional deficit. J Hum Nutr Diet. 2016;29(2):174-184. doi:10.1111/jhn.12310. View article; Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334(18):1145-1149. doi:10.1056/nejm199605023341801. View article; Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. doi:10.1210/jc.2011-0385. View article; Kushi LH, Folsom AR, Prineas RJ, et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996;334(18):1156-1162. doi:10.1056/nejm199605023341803. View article; Lamontagne F, Masse MH, Menard J, et al. Intravenous vitamin C in adults with sepsis in the intensive care unit. N Engl J Med. 2022;386(25):2387-2398. doi:10.1056/nejmoa2200644. View article; LeBoff M, Chou S, Ratliff K, et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-309. doi:10.1056/NEJMoa2202106. View article; Lonn E, Bosch J, Arnold M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354(15):1567-1577. doi: 10.1056/NEJMoa060900. View article; Manson JE, Cook NR, Lee I-Min, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33-44. doi:10.1056/nejmoa1809944. View article; O’Dwyer DD, Vegiraju S. Navigating the maze of dietary supplements: regulation and safety. Top Clin Nutr. 2020;35(3):248-263. doi:10.1097/tin.0000000000000207. View article; Omenn G, Goodman G, Thornquist M, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155. doi:10.1056/NEJM199605023341802. View article.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Williams was recorded at the 54th Annual Primary Care Summer Review, held February 6-10, 2023, in Portland, OR, and presented by Oregon Health and Science University. For information on upcoming CME activities from this presenter, please visit https://ohsu.edu/school-of-medicine/cpd. Audio Digest thanks the speakers and the Oregon Health and Science University for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

FP712001

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.