Alternative Medicines and Supplements for the Primary Prevention of Cardiovascular Disease and Cancer

Cardiology Review® Online, August 2014, Volume 30, Issue 4

The use of various dietary supplements by patients will probably continue, so medical practitioners must be able to advise patients about potential harms and benefits.

Thomas F. Whayne Jr. MD, PhD

Review

Moyer VA, on behalf of US Preventive Services Task Force. Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160(8):558-564.

The use of various dietary supplements by patients will probably continue, so medical practitioners must be able to advise patients about potential harms and benefits.

Alternative medication and supplement use by patients is a reality that medical practitioners must become familiar with. Various studies have shown that usage of alternative medications and supplements in association with prescription medications is shockingly high. One point-of-care survey of 458 patients in 1999 reported that 45% of patients were using alternative medications and dietary supplement with their prescription medications.1In 1997, an estimated 15 million US adults were taking herbal supplements and/or high-dose vitamins concurrently with their prescription medications.2

Study Design

On behalf of (and as a 2014 update of) the 2003 US Preventive Services Task Force (USPSTF), Virginia Moyer, MD, MPH, reviewed evidence regarding the effectiveness of multivitamin or mineral supplements in the general adult population of the United States for primary prevention of cardiovascular (CV) disease and cancer.3The assessment made by the USPSTF involved healthy adults generally 50 years or older, without any documented specific nutritional needs. The assessment definitely did not apply to pregnant or about-to-become pregnant women, chronically ill or hospitalized patients with established nutritional deficiency, or children. The USPSTF reported that the burden of disease in 2011 showed that CV disease accounted for 23.7% of all deaths and that cancer accounted for 22.8% of all deaths in the United States.3However, in an updated systematic evidence review for the United States in 2013, the USPSTF found limited evidence to back up any benefit from the use of vitamin and mineral supplements in decreasing the incidence of CV disease or cancer, with only 2 trials showing a borderline-significant benefit on cancer in men from multivitamin supplements and no effect on CV disease.4The majority of studies from this updated 2013 review had a duration of 10 years or fewer.4The USPSTF concluded that there is inadequate evidence for any effectiveness of multivitamin supplements or for most single or paired vitamins or minerals for the prevention of CV disease or cancer, and therefore the balance of benefits and harms is indeterminate.3

There were, however, sufficient data to estimate net benefit for 2 individual vitamin supplements: beta carotene and vitamin E. For beta carotene, there appears to be a significantly increased risk for lung cancer in patients using tobacco; for vitamin E supplementation, no net benefit was detected.3In 2003, the USPSTF considered that there was insufficient evidence to recommend for or against the use of vitamin A, vitamin C, vitamin E, multivitamin plus folic acid, or antioxidant combinations to prevent CV disease or cancer. The current USPSTF update looked at additional evidence on supplements, and concluded that there were no benefits shown, including for vitamin D, calcium, selenium, and folic acid. In addition, there is new evidence that increased the certainty of a lack of benefit for vitamin E in preventing CV disease or cancer.3

The reported general lack of benefit of alternative medications and supplements is also supported by other organizations, which include an independent consensus panel of the National Institutes of Health,5the Academy of Nutrition and Dietetics,6and the American Cancer Society.7Based on the most rigid evidence-based medicine, it can at most be considered that multivitamin supplements, other supplements, and alternative medications may be useful in the attainment of recommended levels of some nutrients, but the emphasis must continue to be on a well-balanced diet.

Commentary

Doubts Remain, but patients still take supplements and alternative medicines

The clinical guideline described by Moyer on behalf of the USPSTF casts much doubt on alternative medications and dietary supplements consisting of vitamins and/or minerals.3Nevertheless, the clinical reality is that the use of various dietary supplements by patients will probably continue. Therefore, it is essential that medical practitioners be aware of the available evidence-based medicine in order to assess and advise of any possible benefit and, even more importantly, counsel against potentially harmful supplements. In a 2010 individual review of the relevance of alternative medications to CV disease, including some food components, it was found that the following could be considered beneficial: coenzyme Q10 (CoQ), nuts, olive oil, omega fatty acids, policosanol, red wine, red yeast rice, soy protein, and plant sterols and stanols.8The following were determined to be safe but ineffective: acai berry, antioxidant vitamins (A, beta carotene, and E), ayurvedic medicine, B vitamins, homocysteine, cinnamon, Cordyceps sinensis, garlic, gingko biloba, guggul (guggulipid), kava, lecithin, St. John’s wort, and vitamin C, whereas chelation therapy was assessed to be harmful.8Only beta carotene is treated differently by Moyer and the USPSTF from this earlier assessment, with apparent harm associated with beta carotene use in the form of increased lung cancer risk in patients with a history of tobacco use.3

Despite concerns about the lack of benefit of supplements, CoQ as a supplement warrants specific discussion and assessment in regard to statin myopathy. The status of CoQ appears to have been established as a functional element in cell membranes with an additional antioxidant role. It also assists in the regeneration of redox capacity, and plays an important role in the control of membrane channels. The biosynthesis of CoQ occurs in mitochondria and the endoplasmic reticulum of cells; this biosynthesis has been shown to be inhibited by statins.9Because of these associations and the inhibition of CoQ biosynthesis by statins, interest has been created in the possibility of prevention or, at least, a decrease in the symptoms of myopathy associated with statin usage. In a study of lovastatin administered in very high doses up to 45 mg/kg/d for 7 days in patients with solid-tumor cancers, Thiebault et al reported reductions in ubiquinone (CoQ) serum concentrations of up to 49%.10They found that myopathy was the dose-limiting toxicity, and that treatment with ubiquinone was associated with reversal of the myopathy caused by very high-dose lovastatin, and that it prevented the development of this toxicity in a group of 56 patients. This finding has raised interest in CoQ as a supplement to decrease statin-associated myopathy despite its lack of proven antitumor benefit. Caso et al studied patients receiving statin therapy for increased CV risk who had apparent symptoms of statin myopathy. They randomized the patients in a double-blind manner to receive either CoQ in a dose of 100 mg/d (18 patients) or vitamin E in a dose of 400 IU/d (14 patients).11The patients were followed for 30 days; afterward, the group that had received CoQ appeared to demonstrate a 40% decrease in severity of muscle pain (P <.001) with a 38% apparent decrease in interference in daily activities (P <.02). On the other hand, patients in the vitamin E group showed no significant benefit. Unfortunately, although it is much needed, a large, randomized placebo-controlled trial of CoQ is very unlikely to be conducted due to lack of a pharmaceutical company financial incentive.8In addition, the use of CoQ in brief, very high dose statin trials as an investigational management for solid tumors, or in studies with limited numbers of patients taking a statin to decrease CV risk, do not result in evidence-based proof of the value of CoQ to markedly decrease or prevent statin-induced myopathy, which occurs in up to 10.5% of patients.12Nevertheless, CoQ supplementation appears very safe and when previous myopathy associated with a statin has occurred or risk for myopathy is high, consideration of CoQ supplementation appears appropriate pending more definitive proof of benefit.

Vitamin D supplementation is also problematic. A synthesis of data by Holick found that worldwide, 1 billion individuals are probably deficient in vitamin D or at least have an insufficiency.13An association has been shown between vitamin D deficiency and hypertension, elevated plasma triglycerides, insulin resistance, diabetes mellitus, pancreatic beta cell dysfunction, coronary heart disease, myocardial infarction, stroke, congestive heart failure, obesity, peripheral vascular disease, and metabolic syndrome.14There is also an association between vitamin D deficiency and increased statin-associated myopathy, with a decrease in this myopathy with vitamin D supplementation. This finding may be important in CV risk reduction because vitamin D could potentially increase statin medication adherence.15Vitamin D supplementation appears to be very safe, with a safe upper limit for continual supplementation of more than 10,000 IU/d (250 mcg/d),16far beyond any usual long-term usage. Although evidence-based proof of benefit for vitamin D supplementation to decrease CV risk is lacking, the potential CV benefit appears to justify assessment of vitamin D levels, with the clinician left to make a decision involving the individual patient when a significant deficiency is documented.14

It is hoped that there will be increased study and information on multivitamins, individual supplements, and alternative medications use to guide the medical practitioner. However, this will be a slow process due to lack of support for randomized clinical trials of multivitamins and supplements. Each patient will have to be assessed individually and made a partner in any decision on supplementation, based on the available evidence. Fortunately, most supplements involve very little risk.

References

1. Peng CC, Glassman PA, Trilli LE, Hayes-Hunter J, Good CB. Incidence and severity of potential drug-dietary supplement interactions in primary care patients: an exploratory study of 2 outpatient practices. Arch Intern Med. 2004;164(6):630-636.

2. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280(18):1569-1575.

3. Moyer VA, on behalf of US Preventive Services Task Force. Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive services Task Force recommendation statement. Ann Intern Med. 2014;160(8):558-564.

4. Fortmann SP, Burda BU, Senger CA, Lin JS, Whitlock EP. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: an updated systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159(12):824-834.

5. National Institutes of Health State-of-the-Science Panel.National Institutes of Health State-of-the-Science Conference Statement: multivitamin/mineral supplements and chronic disease prevention. Am J Clin Nutr. 2007;85(1):257S-264S.

6. Marra MV, Boyar AP. Position of the American Dietetic Association: nutrient supplementation. J Am Diet Assoc. 2009;109(12):2073-2085.

7. Kushi LH, Doyle C, McCullough M, et al. American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin. 2012;62(1):30-67.

8. Whayne TF, Jr. What should medical practitioners know about the role of alternative medicines in cardiovascular disease management? Cardiovasc Ther. 2010;28(2):106-123.

9. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol. 2007;49(23):2231-2237.

10. Thibault A, Samid D, Tompkins AC, et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res. 1996;2(3):483-491.

11. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007;99(10):1409-1412.

12. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients: the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403-414.

13. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.

14. Whayne TF, Jr. Vitamin D: popular cardiovascular supplement, but benefit must be evaluated. Int J Angiol. 2011;20(2):63-72.

15. Ahmed W, Khan N, Glueck CJ, et al. Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Transl Res. 2009;153(1):11-16.

16. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007;85(1):6-18.

About the Author

Thomas F. Whayne, Jr., MD, PhD, has been professor of medicine in the Division of Cardiovascular Medicine at the University of Kentucky since April l998. Prior to that he spent 2 years at the Ohio State University, followed by 5 years at the Oklahoma Medical Research Foundation and the University of Oklahoma. Subsequently, he was in private practice in Lexington, KY, for 21 years before joining the University of Kentucky. Dr Whayne graduated from the University of Pennsylvania School of Medicine in 1963, followed by a residency in Internal Medicine at New York Hospital—Cornell Medical Center. His cardiovascular training was at the University of California—San Francisco, where he was awarded a PhD in Biochemistry in 1970. Dr Whayne is board certified in both cardiovascular disease and internal medicine. His patient practice is limited to cardiovascular medicine, with major interests in the aggressive treatment of coronary atherosclerosis, blood lipid disorders, and the reduction of cardiovascular risk factors. His research interests include lipoprotein metabolism and innovative cardiovascular medical therapies. Dr Whayne has published over 100 articles including 17 in the Spanish language and he has given over 70 international presentations in Spanish in Spanish-speaking countries. Dr Whayne has received fellowships in several professional organizations including the American College of Cardiology, the American College of Physicians, the American Heart Association, the Philadelphia College of Physicians, and the International College of Angiology.