In order to bring you the best possible user experience, this site uses Javascript. If you are seeing this message, it is likely that the Javascript option in your browser is disabled. For optimal viewing of this site, please ensure that Javascript is enabled for your browser.
Did you know that your browser is out of date? To get the best experience using our website we recommend that you upgrade to a newer version. Learn more.

We use cookies to optimise the design of this website and make continuous improvement. By continuing your visit, you consent to the use of cookies. Learn more

Nutraceuticals : what they are and how they work

An article from the E-Journal of the ESC Council for Cardiology Practice

Nutraceuticals represent a new opportunity in the prevention and treatment of cardiovascular disease. Their effective action and high safety level offer a bright prospect for the future in both the healthy and the unhealthy. Manufacturing industries have well understood this chance. Nevertheless, as health providers, before their widespread use can be recommended, we need clear terms of sale and also some support from large clinical outcome trials with respect to their efficacy and safety in terms of cardiovascular prevention.

Prevention


The portmanteau word "nutraceutical" was coined by Dr. S. DeFelice in 1989 from the terms "nutrition" and "pharmaceutical". Today, nutraceutical is a term commonly used in marketing to describe any product derived from food sources that provide extra health benefits in addition to the basic nutritional value found in food (1). Such products typically will claim to prevent chronic diseases, improve health, delay the aging process and/or increase life expectancy. Due to minimal international regulation in the area, various types of products can fall under the nutraceutical category and there may be overlap between these and herbals, dietary supplements and functional foods.

I - Products that are not labeled nutraceuticals but that may have this function

1) Herbals

Herbalism is a traditional medicinal or folk medicine practice based on the use of plants and plant extracts. Herbalism is also referred to as botanical medicine, medical herbalism, herbal medicine, herbology and phytotherapy. An herbal is "a collection of descriptions of plants put together for medicinal purposes" (2). For over 100 years, doctors have regularly used herbals such as digitalis lanata or atropa belladonna in clinical practice. Today many other herbals are marketed as heart healthy; they include CoQ10, garlic, fenugreek, magnesium, ginger, grape seed extract, l-carnitine, extract vitamins, flax seed oil, and ginko bilobe. But herbals are drugs and all herbal supplements can have side effects that range from mild to severe. Herbs can also interact with other herbs, drugs and foods.

2) Dietary Supplements

According to the Dietary Supplement Health and Education Act of 1994 (DSHEA) (3) a dietary supplement is a product other than tobacco "intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, an amino acid, a mineral, an herb or other botanical".
A dietary substance is for use by man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract, or combinations of these ingredients. Moreover a dietary supplement: 1) is intended for ingestion in pill, capsule, tablet, or liquid form 2) is not represented for use as a conventional food or as the sole item of a meal or diet 3) is labeled "dietary supplement".
The "dietary ingredients" in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars and metabolites. Dietary supplements can also be extracts or concentrates, and may be found in forms such as tablets, capsules, softgels, gelcaps, liquids or powders. Under DSHEA rules, the dietary supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is marketed. The FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market. Generally, manufacturers do not need to register their products with the FDA.
Within the heterogeneous group of nutraceuticals, vitamins are mostly considered dietary supplements and only a few may actually play a role in the prevention and therapy of cardiovascular disease. Their benefit seems due to their antioxidant effect and a correction of endothelial dysfunction, which is thought to hinder the progression of atherosclerosis, which is thought to be the pathogenetic foundation of angina, heart attack, sudden death, and stroke. Certain vitamins are also involved in the metabolism of some CV risk factors. Vitamin E, A and C are the most important vitamins with an antioxidant effect.

a) Vitamin E and C
However, despite epidemiological prospective studies that have suggested that a lower plasma level of vitamins E and C increases cardiovascular risk (4), large scale prospective clinical outcome studies did not show a significant reduction of cardiovascular events (5). High levels of vitamin E supplementation has actually been associated with increased mortality (6). Likewise, some studies on CVD risk factors indicate that vitamin C may moderately decrease total serum cholesterol levels, increase HDL levels, and exert a hypotensive effect, however some epidemiological studies have been inconclusive in this regard (7).
A possible explanation to the limited effect of vitamin E and C may be due to the mode, time of administration, and presence of additional endothelium-independent adverse effects due to therapeutic interventions such as a possible blunting of ischemic myocardial “preconditioning” (8).

b) Vitamin D
Evidence seems stronger when it comes to Vitamin D. A lower plasma level of vitamin D is associated with a higher incidence of cardiovascular events (9) and is all the more evident in hypertensives. Moreover, vitamin D deficiency appears to be associated with endothelial disfunction and lipid peroxidation (10).

c) Homocysteine
Homocysteine is a non proteinogenic, sulphur-containing aminoacid. Several vitamins, including vitamin B12, folate, and B2 are involved in its metabolism. Deficiency of one or several of these B-vitamins can result in increased homocysteine concentration in the blood and hyperomocysteinemia seems to play a rule in cardiovascular disease. In fact some recent meta-analyses of observational studies have shown that moderately elevated homocysteine plasma levels are associated with an increased risk of ischemic heart disease and stroke (11) and that elevated homocysteine levels and lower levels of vitamin B6 were independently associated with the risk of coronary and cerebrovascular events (12). A meta-analysis of randomised, double blind, placebo controlled trials have highlighted that high dose of folic acid improve flow-mediated dilation (13). However, elevated long-term reductions in blood homocysteine levels in 12,064 post-myocardial infarction patients receiving folic acid and vitamin B(12) supplementation during 6.7 years did not have beneficial effects on vascular outcomes (14).

d) Niacin
It is well known that B 3 vitamin (niacin) reduces plasma cholesterol levels and rises HDL cholesterol plasma levels (15). Niacin also improves endothelium dependent vasodilatation (16).

e) Vitamin deficiency
Vitamins are usually well represented in a common mutable natural Western diet and nowadays some diseases such as Beri Beri (due to a deficiency of tiamin) are only a bad memory. But some food preservation processes or some unbalanced diet due to psychological or environmental conditions could still give rise to vitamin deficiency. There also could be a shortage of vitamins in some cardiovascular disease such as heart failure or in some infectious disease which would more likely occur due to water-soluble vitamins such as vitamin A, D, E, and K.

f) Omega 3 fatty acids
Omega 3 fatty acids (a family of unsaturated fatty acids) have beneficial effects in cardiovascular disease. In fact they have hypotriglyceridemic effects, improve endothelial function, have antiarrhithmic effects, and reduce platelet aggregation and blood pressure (17). In GISSI-Prevenzione study, a supplement of 850 mg/day of EPA/DHA 1:2 gave a 17% relative decrease in cardiovascular mortality (18). However, low-dose supplementation with Omega 3 fatty acids in 4837 patients during the same time frame frame (3.5 years) did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving antihypertensive, antithrombotic, and lipid-modifying therapy. (19).

g) The Mediterranean diet
But, in our opinion recommendation to get plenty of these vitamins and omega 3 fatty acid is to follow a good diet such as the Mediterranean diet. It is based on fruit, vegetables, fish, olive oil, and a daily glass of red wine. On the 19th of November 2010 the Mediterranean diet was awarded UNESCO recognition and was inscribed on the representative list of the intangible cultural heritage, as a means to promoting healthy lifestyle.

h) Functional food 
A functional food is defined as a food cooked or prepared using "scientific intelligence" with or without knowledge of how or why it is being used. It provides the body with the required amounts of vitamins, fats, proteins, carbohydrates etc. needed for its healthy survival. Functional foods are designed to allow consumers to eat enriched foods close to their natural state, rather than by taking dietary supplements manufactured in liquid or capsule form. They have been either enriched or fortified by a process called nutrification. Functional foods definitively are and must be foods and not drugs (20).

II - Nutraceuticals and cardiovascular disease

It is when a functional food aids in the prevention and/or treatment of disease(s) and/or disorder(s) other than anemia, that it is called a nutraceutical. Natraceuticals were first defined by Dr. DeFelice as "a food, or part of a food, that provides medical or health benefits, including the prevention and/or treatment of a disease." Today, Health Canada also issue that nutraceuticals not only supplement the diet but should also aid in the prevention and/or treatment of a disease and/or a disorder. Since most functional foods act in some way or other as antianemic, other than regarding anemia, it is considered that there is a clear distinction between the terms, functional food and nutraceutical. Thus, a functional food for one consumer can act as a nutraceutical for another consumer. Examples of nutraceuticals include fortified dairy products (e.g. milk) and citrus fruits (e.g. orange juice).
As highlighted above, certain nutraceuticals affect chronic disease and are claimed to have a favourable impact on cardiovascular diseases such as heart attack/ischemia, stroke, coronary artery disease, corpulmonale, hypertension, deep vein thrombosis and/or atherosclerosis. Nutraceuticals can have an effect on cardiovascular disease in several ways. First of all they tend to reduce circulating levels of LDL-cholesterol. This is achieved by modulating cholesterol production in the liver (i.e. monacolin, policosanol, red yeast, rice etc.), binding cholesterol within the intestines and/or increasing LDL-c receptor uptake in the liver (i.e. berberina, phitosterols etc.). In a 2003 research review from the UK's Peninsula Medical School, 11 nutraceuticals were found among 25 clinical studies to reduce cholesterol. The second strategy is to reduce the possibility of oxidation by neutralising radicals with antioxidants (i.e. resveratrol, bioflavonoids, ubiquinone, phenols, flavones etc.). The third strategy is to reduce artery plaque through fibrinolytic activity and to reduce blood pressure (i.e. dietary peptides derived from milk protein mediated by ACE inhibition). Nutraceuticals are reported to follow all three strategies.
According to a recent review, most cardiologists overlook the use of dietary supplements, nutraceuticals and over-the-counter (OTC) drugs by heart patients because they consider them innocuous; lump them with dietary measures and lifestyle interventions; or consider them to be ‘natural’ and, therefore, safe and effective. In other words clinical providers “largely ignore” the use of nutraceuticals and OTC drugs in their patients. The study concluded that “clinicians should use a structured approach for identifying patient use of nutraceuticals and OTC drugs” (21).

III - Marketing and regulation

Where herbals, dietary supplements and functional foods are sold in many different venues outside pharmacies (e.g. in supermarkets, herbalist shops etc.), nutraceuticals are essentially sold in pharmacies and parapharmacies in drug form with a claim to having drug properties. Furthermore one bigger, attractive and sometimes dangerous increasing market is via the Internet. Here, some companies looking to create a wide profit margin may create unregulated products with low-quality or ineffective ingredients.
The medicalisation of today's society and the alleged favourable outcomes with low side effects of such productsi have also lead to the increase in the consumption of these products. Moreover the high cost of prescribing pharmaceuticals and the reluctance of some insurance companies and health national systems to cover the costs of drugs, help nutraceuticals to solidify their presence in the global market of therapies and therapeutic agents. According to CORDIS - the information service of the European Commission for research and development of science – nutraceuticals in 2008 had a European turnover of approximately 1.4 billion Euros in 2008 with an 11% growth compared to the preceding year. Many pharmaceutical and biotechnology companies, detecting good business opportunities, have invested heavily in the nutraceutical sector to create a market that aims to cover 5% of the value of food sales worldwide.

a) US regulation
The FDA considers a medical food “to be formulated, consumed or administered internally under the supervision of a physician, and one which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, on the basis of recognised scientific principles, are established by medical evaluation.”
In January 2007 the Nutraceutical Research & Education Act (NREA), proposed by the Foundation for Innovation in Medicine (supported by Dr DeFelice), aimed to establish a new mechanism in the nutraceutical area that is essential for the creation of a responsible, industry-funded, primarily clinical research-based industry. It is also crucial to create appropriate channels for the review, approval and regulation of new products and claims (22).

b) EU regulation
The harmonisation of EU food and food derived products has been in progress for forty years. In 1985, a White Paper from the European Commission recommended new legislation. In 2000, the European Commission published five horizontal framework directives which identified requirements of public health and safety, consumer information and general food control measurements. The five directives regard: 1) Food labelling and presentation 2) Food additives 3) Materials and articles in contact with food 4) Official control of food stuffs 5) Food for particular nutritional uses (PARNUTS). Since, more than 90% of the White Paper proposals have been implemented. The ILSI Europe Report Series has published the “Application of the margin of exposure approach to compounds in food which are both genotoxic and carcinogenetic”. The European Food Safety Authority (EFSA) controls the safety assessment of botanicals and “botanical preparations” intended for use as ingredients in food supplements (23). The rules of the general food law regulation are applicable to all foods. In other words, there are a lot of regulations and, there is not, as such, a regulatory framework for ‘functional foods’ or ‘nutraceuticals’ in EU food law.
This is why doctors and members of the medical community are asking for the term "nutraceutical" to be clearly defined in order to distinguish the wide varieties of products out there.
However, with all of the aforementioned positive points, nutraceuticals still need support of an extensive scientific study to prove "their effects with reduced side effects." Issues of study quality and bias, true efficacy and toxicity continue to cause uncertainty. The accumulated knowledge regarding nutraceuticals needs to be validated and this need represents a great challenge for many professionals such as nutritionists, physicians, food technologists and food chemists. Only after this process is completed can public health authorities consider prevention and treatment with nutraceuticals as a powerful, natural, and inexpensive tool for the prevention of disease and in maintaining health.
Where herbals, dietary supplements and functional foods are sold in many different venues outside pharmacies (e.g. in supermarkets, herbalist shops etc.), nutraceuticals are essentially sold in pharmacies and parapharmacies in drug form with a claim to having drug properties. Furthermore one bigger, attractive and sometimes dangerous increasing market is via the Internet. Here, some companies looking to create a wide profit margin may create unregulated products with low-quality or ineffective ingredients.The medicalisation of today's society and the alleged favourable outcomes with low side effects of such productsi have also lead to the increase in the consumption of these products. Moreover the high cost of prescribing pharmaceuticals and the reluctance of some insurance companies and health national systems to cover the costs of drugs, help nutraceuticals to solidify their presence in the global market of therapies and therapeutic agents. According to CORDIS - the information service of the European Commission for research and development of science – nutraceuticals in 2008 had a European turnover of approximately 1.4 billion Euros in 2008 with an 11% growth compared to the preceding year. Many pharmaceutical and biotechnology companies, detecting good business opportunities, have invested heavily in the nutraceutical sector to create a market that aims to cover 5% of the value of food sales worldwide.

IV - Nutritional Genomics

A new powerful and troubled market is emerging from the study of nutritional genomics - which is the application of highly advanced functional genomic technologies to nutrition. It means new or modified food for human and animal nutrition, but also the definition of gene polymorphisms that predispose individuals to disease and modify nutritional requirements (24). Furthermore another interesting opportunity comes from the effect of certain nutraceuticals on stem cell growth and proliferation (25).

Conclusion:

In conclusion, we need doctors to pay more attention to nutraceuticals, as well as improved taxonomy, further regulation and the introduction of registers and national surveys to acquire knowledge of today's consumption and indications. More controlled studies will give the scientific evidence essential for the administration of nutraceuticals both in prevention and as therapy for cardiovascular disease. The study and regulation of nutritional genomics might lead to the use of nutraceuticals as an alternative to stem cell transplantation, and would enable the targeting of optimal nutritional advice and the development of food-derived treatments by new nutraceuticals for best treatment, in particular, for uses in groups with cardiovascular risk and individuals with cardiovascular disease.

References


1) Zeisel SH. Regulation of "Nutraceuticals." Science. 1999;285:185-186
2) Arber, Agnes 1986. Herbals, Their Origin and Evolution, a Chapter in the History of Botany 1470–1670. Cambridge: Cambridge University Press. ISBN 0521338794. (first published in 1912)
3) FDA/CFSAN resources page. Food and Drug Administration Website.
Dietary Supplement Health and Education Act of 1994. 
4) Stampfer MJ, Hennekens CH, Manson JE, et al.
Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444–1449
5) Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of
antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis. JAMA 2007;297:842–857
6) Miller ER, 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: High-dosage
vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37–46
7) Lynch SM, Gaziano JM, Frei B.
Ascorbic acid and atherosclerotic cardiovascular disease. Subcell Biochem. 1996;25:331-67
8) Tritto I, Ambrosio G. Role of
oxidants in the signalling pathway of preconditioning. Antioxid Redox Signal 2001;3:3–10
9) Wang TJ, Pencina MJ, Booth SL, et al.
Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503–511
10) Sugden JA, Davies JI, Witham MD, et al.
Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med 2008;25:320–325.
11) The Homocysteine Studies Collaboration.
Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis. JAMA 2002;288:2015–2022.

12) Vanuzzo D, Pilotto L, Lombardi R, et al. Both vitamin B6 and total homocysteine plasma levels predict long-term atherothrombotic events in healthy subjects. Eur Heart J 2007;28:484–491
13) de Bree A, van Mierlo LA, Draijer R.
Folic acid improves vascular reactivity in humans: A meta-analysis of randomized controlled trials. Am J Clin Nutr 2007;86:610–617
14) Armitage JM, Bowman L, Clarke RJ et al.
Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial.

JAMA. 2010 Jun 23;303(24):2486-94.
15) Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem1955;54:558–559
16) Sorrentino SA, Besler C, Rohrer L, et al.
Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation 2010;121:110–122
17) De Caterina R, Zampolli A.
Omega-3 fatty acids, atherogenesis, and endothelial activation. J Cardiovasc Med (Hagerstown) 2007;8(Suppl 1):S11–S14
18) Dietary supplementation with
n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447–455.
19) Kromhout D, Giltay EJ, Geleijnse JM; Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction, N Engl J Med. 2010 Nov 18;363(21):2015-26. Epub 2010 Aug 28.
20) Roberfroid MB. A European consensus of scientific concepts of
functional foods.
Nutrition 2000 Jul-Aug;16(7-8):689-91.
21) Patricia Uber, Kelly Summers, and Mandeep R. Mehra - Clinicians and
Nutraceutical Use in Cardiology Patients: Ignorance and Neglect - Ann Intern Med July 6, 2010 153:65-66
22) The
Foundation for Innovative Medicine
23)
The European Food Safety Authority
24) Bickford et al. – Nutraceuticals sinergistically promote proliferation of human stem cells –Stem cells Dev 2006;15:118-23  
25) David M Much et al. –
Nutrigenomics and nutrigenetics: the emerging faces of nutrition – The Faseb Journal review 

VolumeNumber:

Vol9 N°11

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.