The use of dietary supplements in the United States (US) continues to grow, and today approximately one-half of American adults reports using them.¹ Whereas some dietary supplements are indicated for the treatment of specific nutritional deficiencies or health disorders (e.g., calcium supplementation in patients with osteoporosis), a growing number are advertised as promoting cardiovascular health despite a lack of supporting scientific evidence. Manufacturers of dietary supplements are prohibited from claiming that their products treat disease, but these precautions are easy to miss in advertisements or product labeling, contributing to widespread misperceptions regarding the efficacy and safety of dietary supplements. However, given their pervasive use, cardiovascular team members should be informed about dietary supplements, and particularly those that patients may be taking for cardiovascular health.

Risks Posed by Dietary Supplements

Dietary supplements are not held to the same regulatory rigor as prescription medications in the US, thus studies evaluating their safety and efficacy are not required before they can be marketed to consumers. Many supplements contain pharmaceutical ingredients, but often at a much lower potency than what is contained in drug products approved by the US Food and Drug Administration (FDA). Although some of these ingredients may produce salutary effects, it is unclear what potentially adverse effects they or other ingredients in the product may have. Indeed, dietary supplements are thought to contribute to over 23,000 visits to the emergency department in the US annually.²

Risks may be especially problematic in special populations (e.g., older patients, patients with hepatic or renal impairment), which are part of the evaluation process for prescription drugs but not dietary supplements. Additionally, without regulatory oversight by the FDA, dietary supplements are not formally evaluated for drug-food and drug-drug interactions, which can pose a risk to patients who take prescription medications. The lack of manufacturer oversight also limits the extent to which the potency, purity, and quality of products can be assured, although some manufacturers voluntarily submit their products to undergo testing by the United States Pharmacopeia (USP) or other organizations involved in ensuring good manufacturing practices (GMP).

Dietary Supplements Commonly Promoted for Cardiovascular Health

Below are examples of dietary supplements commonly promoted for cardiovascular health, as well as a brief overview of what is known about their efficacy to date.

Fish Oil (Omega-3 Fatty Acids)

Fish oil contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), although the percentage of each varies by formulation. Fish oil is effective for reducing serum triglyceride concentrations, but it is unclear whether this confers an improvement in cardiovascular risk. Even more controversial is whether fish oil reduces the risk of cardiovascular disease (CVD) despite improving surrogate markers for CVD, such as serum lipid concentrations. Although earlier trials indicated that fish oil may exert cardioprotective effects, a meta-analysis of recent trials failed to find a significant reduction in outcomes.³ A meta-analysis of patients with established CVD also failed to find a benefit.⁴ The discrepancy between older and contemporary trials may suggest that fish oil exerts only a mild benefit in CVD, which has been overshadowed by more modern interventions (e.g., statins). Fortunately, omega-3 fatty acids have been shown to be relatively safe, although they can increase the risk of bleeding and should be used with caution in patients taking aspirin or anticoagulants.

Niacin

Niacin or Vitamin B3 has been shown to reduce total cholesterol and low-density lipoprotein concentrations (LDL-C), although it does so less effectively than statins and has not been associated with comparable reductions in cardiovascular events. Although niacin also decreases triglycerides and increases high-density lipoprotein concentrations (HDL-C), these effects have not conferred improvements in cardiovascular outcomes among patients receiving statins.⁵ Moreover, its use for this purpose increases the risk of adverse effects, including impaired glucose control, gastrointestinal disturbances, and musculoskeletal effects.⁶ Although niacin may still have a role in patients with challenging dyslipidemias, its use should be limited to clinicians who specialize in this area. Of note, inositol hexanicotinate (IHN) or "flush free" niacin does not demonstrate lipid-lowering properties and should not be used for this purpose. Additionally, sustained-release formulations have been associated with an excess risk of hepatotoxicity.⁷

Co-enzyme Q10

Co-enzyme Q10 (CoQ10), also known as ubiquinone or ubidecarenone, is a fat-soluble antioxidant synthesized endogenously and involved in a variety of metabolic processes. Supplementation with CoQ10 has been touted for reducing statin-associated muscle symptoms (SAMS); however, recent evidence has shown CoQ10 to have no apparent impact on SAMS.^8,9 CoQ10 has also been studied in heart failure for its promising effects on myocardial contractility and exercise performance. However, these trials have shown mixed results and have been subject to significant flaws in methodology.^10,11 Current guidelines do not recommend addition of CoQ10 in patients with heart failure.¹²

Vitamin D

Vitamin D deficiency has been shown to have a strong association with CVD, but it is unknown whether vitamin D deficiency contributes to the pathogenesis of CVD or if it is merely a surrogate marker for comorbidities that contribute to CVD.¹³ Available evidence is contradictory and current recommendations do not support vitamin D supplementation solely for cardiovascular health.¹⁴ Supplementation with vitamin D3 has been specifically studied in heart failure patients, showing a modest increase in left ventricular hemodynamic function but failing to influence exercise capacity or other clinical endpoints.^15,16

Magnesium

Magnesium is commonly prescribed for patients who develop hypomagnesemia as a consequence of diuretic therapy, but it has also been evaluated for a variety of other cardiovascular conditions, including arrhythmias, coronary artery disease, and myocardial infarction. Although correcting hypomagnesemia can reduce the risk of arrhythmias in high-risk patients, its effects on other cardiovascular conditions remains inconclusive.¹⁷ Some epidemiologic studies indicate that low serum magnesium concentrations may increase the risk of CVD, whereas others have failed to show an association.^18,19

Red yeast rice

Red yeast rice is a fermented rice product that may contain monacolin K, an HMG-CoA reductase inhibitor identical to the active ingredient in lovastatin. In the late 1990s, the FDA prohibited red yeast rice products in the US from containing more than trace amounts of monacolin K and began taking legal action against manufacturers whose products were in violation of these regulations. Nonetheless, due to limitations in the agency's ability to inspect manufacturers of dietary supplements, some products may still contain more than trace amounts of monacolin K as well as the toxin citrinin.²⁰ Red yeast rice products that conform to FDA regulations often consist of proprietary blends of other ingredients that lack proven efficacy in the treatment of dyslipidemia.

Antioxidant vitamins (A and E)

Contrary to the lack of rigorous evaluation for most dietary supplements, vitamin A (beta-carotene) and vitamin E (alpha-tocopherol) have been studied in large, robust clinical trials.^21,22 Both were believed to lower the risk of cancer and CVD, but neither of these effects was observed when compared to placebo. In addition, long-term vitamin E supplementation has been associated with an increased risk of heart failure in patients with pre-existing vascular disease or diabetes.²³

Garlic

Garlic supplementation has been promoted for modifying cardiovascular risk factors, including hyperlipidemia and hypertension. The active compounds in garlic and their effective doses are ill-defined, and the data available to support the use of garlic are severely limited due to methodological flaws.²⁴

Resveratrol

Resveratrol is a naturally occurring plant compound with purported cardioprotective effects attributed to its antioxidant-like properties and salutary impact on serum lipid concentrations and blood pressure. It is believed to be the active component in red wine that confers cardiovascular benefits in observational analyses. However, in controlled clinical trials, supplementation with resveratrol does not alter CVD risk factors or clinical outcomes.²⁵

Flaxseed

Flaxseeds contain phytoestrogens as well as alpha-linolenic acid, an omega-3 fatty acid. Some formulations have been associated with improvements in surrogate markers for CVD, such as total cholesterol and LDL-C, whereas others have produced inconsistent results.²⁶ Similar findings exist for its potential effects on blood pressure. To date, no evidence suggests flaxseed has an impact on cardiovascular outcomes.

Recommendations for Practitioners

Dietary supplements are frequently consumed by patients due in part to the sense of empowerment and control over health they provide.²⁷ Although patients should be encouraged to actively participate in their care, these motivations should be driven towards dietary and lifestyle interventions associated with improvements in cardiovascular outcomes (e.g., limiting sedentary habits, exercising, and avoiding tobacco products). When non-pharmacologic therapies are insufficient for preventing or treating CVD, drug therapy may be warranted. Although prescription medications are generally the safest and most evidence-based approach, ongoing and future research may substantiate the role of certain dietary supplements for the treatment of CVD. For this reason, practitioners should remain up-to-date on the most current literature in this area. Table 1 contains a list of complementary and alternative medicine (CAM) resources for practitioners to use as a reference.

Many patients do not disclose dietary supplement usage to cardiovascular team members. In fact, in studies evaluating dietary supplement use in patients with CVD, up to 92% of clinicians were unaware that their patients were taking supplements.²⁸ Although this lack of awareness is multifactorial, some patients intentionally choose not to disclose supplement consumption for fear of disapproval. Others misperceive that supplements are not drugs, and unless directly asked, do not feel the need to report it to health care providers. Therefore, it is imperative that practitioners question patients regarding use of dietary supplements in order to prevent potentially inappropriate or harmful therapy.

Although practitioners should discourage patients from taking dietary supplements that lack evidence to support their use, some patients may elect to take them anyway. For these individuals, the following key points may reduce potential harm:

• Counsel patients to only use products that are independently verified by a third party for purity, quality, and GMP (e.g., USP, National Sanitation Foundation [NSF]).
• Encourage patients to talk with their pharmacist about potential drug-drug interactions with their prescription medications.
• Encourage patients to minimize supplement consumption.
• Monitor for potential adverse effects.
• Counsel patients on using evidence-based resources to learn about the supplements they consume (Table 1).

In summary, the growing use of dietary supplements among adults in the US warrants greater awareness among cardiovascular team members. Although many products are promoted for their potential cardiovascular benefits, few have demonstrated them in controlled clinical trials. Nonetheless, patients may still inquire about dietary supplements or take them despite recommendations to the contrary, requiring that cardiovascular team members openly discuss them with patients, document them in the medical record, and understand their potential risks.

Table 1

Complementary and Alternative Medicine Resources for Practitioners	Website
National Center for Complementary and Integrative Health	https://nccih.nih.gov/
Natural Medicines Comprehensive Database	https://naturalmedicines.therapeuticresearch.com/
BMC Complementary and Alternative Medicine Open Access Journal	https://bmccomplementalternmed.biomedcentral.com/
Evidence-based Complementary and Alternative Medicine Open Access Journal	https://www.hindawi.com/journals/ecam/
FDA: Dietary Supplements	http://www.fda.gov/Food/DietarySupplements/default.htm
MedlinePlus: Complementary and Alternative Medicine	https://medlineplus.gov/complementaryandintegrativemedicine.html

References

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5. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
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16. Witte KK, Byrom R, Gierula J, et al. Effects of Vitamin D on cardiac function in patients with chronic HF: the VINDICATE study. J Am Coll Cardiol 2016;67:2593-603.
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18. Guasch-Ferré M, Bulló M, Estruch R, et al. Dietary magnesium intake is inversely associated with mortality in adults at high cardiovascular disease risk. J Nutr 2014;144:55-60.
19. Xu T, Sun Y, Xu T, Zhang Y. Magnesium intake and cardiovascular disease mortality: a meta-analysis of prospective cohort studies. Int J Cardiol 2013;167:3044-7.
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23. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;293:1338-47.
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Keywords: Anticoagulants, Arrhythmias, Cardiac, Biomarkers, Blood Pressure, Cardiovascular Diseases, Cholecalciferol, Cholesterol, Comorbidity, Coronary Artery Disease, Diabetes Mellitus, Dietary Supplements, Docosahexaenoic Acids, Drug Interactions, Dyslipidemias, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Fish Oils, Flax, Garlic, Heart Failure, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Hypertension, Life Style, Lipoproteins, HDL, Lipoproteins, LDL, Magnesium, Myocardial Infarction, Neoplasms, Niacin, Pharmacists, Phytoestrogens, Prescription Drugs, Product Labeling, Risk Factors, United States Food and Drug Administration, Vitamin A, Vitamin D, Vitamin D Deficiency, Vitamin E, Vitamins, alpha-Linolenic Acid, alpha-Tocopherol, beta Carotene, Primary Prevention, Secondary Prevention

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