Sense and Nonsense of Dietary Supplements

Scientific evaluation of Cardiovascular health benefits of dietary supplements


Flavonoids and Polyphenols

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One large class of phytonutrients is called polyphenols. There has been a lot of interest in these compounds in recent years. There are over 8000 different phenols and there are many as 14 classes. Some of the common ones are coumarins, flavonoids, phenolic acids, simple phenols, lignans, quinines, and xanthones. Over 2/3 of these polyphenols are in the class called flavonoids or bioflavonoids. Flavonoids are the most important plant pigments responsible for flower and fruit coloration producing yellow or red/blue pigmentation. The flavonoid subgroup anthocyanidins (anthocyanins) for example are the components that give berries (Blue-, choke- cran- and billberries) their specific dark blue color. Other fruits and vegetables with red or orange colors also contain anthocyanins ( 1 ). Proanthocyanidins are the principal substances in red wine that are linked to a reduced risk of coronary heart disease and to lower overall mortality ( 2 ). Proanthocyanidins, refer to a different class of flavonoids, called flavanols, in which occur PCOs (proanthocyanidin oligomers) or the more commonly known dietary supplement ingredient OPCs (oligomeric proanthocyanidins) or in more complex form the well-known tannins.

Several mechanisms of action of flavonoids in general have been described ( 3 ):

  1. Strong antioxidant induction properties. Oxidative stress has been implicated in the development of a number of conditions including cancer, arthritic disorders and cardiovascular disease.
  2. Stabilization of collagen fibers and promotion of collagen biosynthesis
  3. Decreased permeability and fragility of capillaries
  4. Inhibition of blood clotting (platelet aggregation)
  5. Reduction of inflammation by prevention of the release and synthesis of proinflammatory compounds (e.g. histamine, prostaglandins, and leukotrienes)
  6. Lower blood glucose levels 

Antioxidant role of flavonoids compared to Beta-carotin, Vitamin C and Vitamin E

Oxidative stress caused by free radicals is one of the driving forces behind ageing and the development of cardiovascular disease, dementia and cancer (Click here for more details). The importance and protective effect of daily intake of antioxidants is well known and has been scientifically proven. However, antioxidant consumption has been hyped beyond reason by dietary supplement manufacturers and the food industry. As a result, a large number of dietary supplements contain tremendous amounts of the antioxidants like vitamin C, up to doses that cause more harm than good. In addition, a wide range of “extremely powerful” anti-oxidants are currently being marketed, without significant evidence of actually improving the body’s antioxidant function. These are all misleading products that exploit the ignorance of the average consumer.

What most people don’t know is that most of the antioxidant function of the human body is not derived from the consumption of dietary antioxidants. Dietary antioxidants undeniably contribute to the body’s antioxidant function, but the most potent antioxidants are produced by the body itself. The increased antioxidant function of the human body after consumption of fruits and vegetables is mostly due to an induction of the body’s own antioxidant production by the flavonoids in those fruits and vegetables ( 4 ).

Thus manufacturers that tell you that flavonoids or OPCs are strong antioxidants are wrong! These compounds do have antioxidant properties, but blood levels of flavonoids after consumption of flavonoid rich food or dietary supplements are very low (in nanomolar range). This is due to limited uptake in the intestine (low bioavailability). Flavonoids are poorly absorbed (less than 5%), with most of what is absorbed being quickly metabolized into smaller substances. This means that antioxidant effect of flavonoids cannot be attributed to the antioxidant function of the flavonoids in the blood stream.

Recently researchers discovered that the metabolites derived from digestion of flavonoids are actually light toxic substances. Due to their toxicity these substances activate the natural antioxidants and defense of the human body, such as the very strong antioxidant uric acid. These are far more efficient than dietary antioxidants and therefore offer highly valuable protection against oxidative stress ( 5-7 ).

Please note that this does not mean that dietary intake beta-carotene, vitamin C and vitamin E is not important, but if your main goal is to increase antioxidant levels in the body flavonoids are the best option.

Dietary sources

The amounts of flavonoids and polyphenols in plant-based foods of the human diet —in particular vegetables, fruits, tea, and wine— are generally much greater than the amounts of antioxidants in these foods, such as vitamins C and E and carotenoids. Fruits and fruit juices are among the best sources of polyphenols and flavonoids in the human diet because of the high content in most fruits and the relatively large serving sizes (100–200 g). Apples provide approximately 22% of the total fruit phenols consumed per capita in the United States. A serving of apple provides about 400 mg of total phenols (expressed as gallic acid equivalents). Pears and grapes can provide as much as 300 mg total phenols per serving, and a serving of cranberries, cherries, or blueberries contains 200–400 mg. Total phenols in fruits, fruit juices or extracts, and vegetables is strongly correlated with the total antioxidant capacity of these foods. In fruits containing significant amounts of vitamin C, the antioxidant capacity often reflects both the polyphenol and the vitamin C content. Vegetables such as spinach, broccoli, and onions also provide significant amounts of polyphenols in the human diet. Other plant-derived foods and beverages further contribute to the total daily intake of polyphenols in humans. For example, tea, coffee, chocolate, wine, and beer have high antioxidant inducing capacity, which is almost exclusively due to the presence of polyphenols. In black tea, the levels of polyphenols vary depending on the amount of leaves, brewing time, and brewing temperature and usually are between 150 and 250 mg per 200-ml serving. Because of its wide consumption, coffee has been recently claimed to be the main source of polyphenols in the U.S. diet (J. Vinson, unpublished), providing 150–180 mg per 200-ml serving. In a Norwegian study of 2672 adults, coffee contributed 64% of the total daily intake of dietary antioxidants. Red wine contains 200–500 mg total phenols per 200-ml serving depending on type and varietal. The total phenol content in white wine is considerably lower, about 40–60 mg per 200-ml serving. Total phenol content in beer ranges from 50 to 100 mg in 200 ml. Dark chocolate contains about 340 mg of total phenols per 40-g serving. Considering these amounts of total phenols per serving, a well-balanced diet with the recommended nine daily servings of fruits and vegetables and moderate amounts of tea, coffee, wine, beer, or chocolate can provide well over 1000 mg of total phenols per day ( 5 ).

Cardiovascular risk

Flavonoids have emerged as potential candidates to protect against cardiovascular disease. Many recent human studies suggest that the consumption of flavonoid rich food (Strawberries, Blueberries, Red Wine) decreases the risk of cardiovascular disease mortality. Anthocyanins are a well studied subclass of flavonoids. Relatively low-dose anthocyanin interventions (mostly in the form of pomegranate juice) with patients clinically diagnosed with vascular diseases have been associated with significant reductions in heart ischemia ( 8 ), intima-media thickness (thickness of the arterial wall), blood pressure, LDL oxidation ( 9 ), lipid levels ( 10 ), and inflammatory status ( 11 ). This last study was a double-blind, placebo-controlled, parallel trial in forty-four patients who survived myocardial infraction and have received statin therapy for at least 6 months. Chokeberry flavonoid extract (Aronia melanocarpa E, containg 25% anthocyans, 50% polymeric procyanidines and 9% phenolic acids) supplementation for a period of 6 weeks significantly reduced serum 8-isoprostans by 38% and oxLDL levels by 29%, as well as the inflammatory markers hsCRP by 23% and MCP-1 levels by 29%. In addition, significant increase in the blood levels of the protective substance adiponectin and reductions in systolic and diastolic blood pressure by a mean average of 11 and 7.2 mmHg, respectively were found. A recent study by Karlsen et al. ( 12 ) showed significant improvement of risk biomarkers after supplementation with anthocyanins. Several pro-inflammatory cytokines and chemokines (compounds in the blood that indicate increased inflammation) were reduced in the blood of healthy men and women after supplementation with anthocyanins ( 13, 14 ). In view of the fact that flavonoids reduce the severity of inflammation, regardless of statins, they are a highly interesting supplementation alongside statin treatment.

A large number of cohort studies assessed the association between flavonoid intake and cardiovascular disease incidence anddeaths caused by cardiovascular disease (mortality). A recent review of existing studies revealed that associations are present between flavonoid intake and cardiovascular disease risk and mortality, but that results are not consistent ( 15 ). A meta-analysis of 6 cohort studies revealed that coronary heart disease risk decreased significantly with increased flavonoid intake. A large 16-year follow-up study in 34,489 post-menopausal women without cardiovascular disease showed that the intake of 0.2mg/day of the flavonoid classes, flavones and anthocyanins was associated with a decreased risk of cardiovascular disease ( 16 ). In another very recent study, this protective effect was substantiated ( 17 ). In 1999, a total of 38,180 men and 60,289 women, with a mean age of 70 and 69 y respectively, were included in the Cancer Prevention Study II Nutrition Cohort. During 7 years of follow-up, 1589 cardiovascular disease related deaths in men and 1182 cardiovascular disease related deaths in women occurred.  In this study men and women with total flavonoid intakes in the top (compared with the bottom) quintile had a 18% lower risk of fatal cardiovascular disease. Five flavonoid classes-anthocyanidins, flavan-3-ols, flavones, flavonols, and proanthocyanidins-were individually associated with lower risk of fatal cardiovascular disease ( 18 ). Several other large cohort studies showed that daily moderate red wine consumption resulted in reduced CVD risk ( 19-21 ). These effects are often attributed to the antioxidant inducing
properties of flavonoids.


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Flavonoids and its subcalsses have a proven effect on the body’s antioxidant production, thereby strongly increasing the antioxidant capacity of the body. This results in a wide range of health benefits that are mostly related to reduced inflammation and improved antioaxidant function. However, not all health benefits are adequately proven, though the reduction of cardiovascular disease risk and mortality of cardiovascular disease in individuals with high flavonoid consumption is. Therefore consumption of additional flavonoids on top of a healthy diet is recommended to reduce cardiovascular disease risk, while potentially inducing a wide range of other health benefits. It should be noted however, that not all flavonoids have similar effects and efficacy. Therefore one should be weary of supplements containing one single flavonoid substance.

Accepted EFSA Claims

  • No health claims have been authorized by the European Food Safety Authorisation
Names: Flavonoids, Polyphenols, Flavones, Flavonols, Flavanoids, Flavan-3-ols (or catechins), Flavanones, Anthocyanidins, Proanthocyanidins, Procyanidins,  
Diseases: Cardiovascular disease, Cancer, Hypercholesterolemia, Angina pectoris, Ischemic heart disease, Peripheral artery disease, High blood pressure

Reference List   

  1. Markham ØMAaKR, Ed., Flavonoids: Chemistry, Biochemistry and Applications ,  (CRC Press 2005), pp. 471 -551.
  2. Corder R et al. , Oenology: red wine procyanidins and vascular health. Nature 444 , 566 (Nov 30, 2006).
  3. Havsteen B, Flavonoids, a class of natural products of high pharmacological potency. Biochemical pharmacology 32 , 1141-8 (Apr 1, 1983).
  4. Hertog MG et al. , Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands. Nutrition and cancer 20 , 21-9 (1993).
  5. Lotito SB, B Frei, Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free radical biology & medicine 41 , 1727-46 (Dec 15, 2006).
  6. Wallace TC, Anthocyanins in cardiovascular disease. Advances in nutrition 2 , 1-7 (Jan, 2011).
  7. Godycki-Cwirko M et al. , Uric acid but not apple polyphenols is responsible for the rise of plasma antioxidant activity after apple juice consumption in healthy subjects. Journal of the American College of Nutrition 29 , 397-406 (Aug, 2010).
  8. Sumner MD et al. , Effects of pomegranate juice consumption on myocardial perfusion in patients with coronary heart disease. The American journal of cardiology 96 , 810-4 (Sep 15, 2005).
  9. Aviram M et al. , Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clinical nutrition 23 , 423-33 (Jun, 2004).
  10. Gorinstein S et al. , Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. Journal of agricultural and food chemistry 54 , 1887-92 (Mar 8, 2006).
  11. Naruszewicz M et al. , Combination therapy of statin with flavonoids rich extract from chokeberry fruits enhanced reduction in cardiovascular risk markers in patients after myocardial infraction (MI). Atherosclerosis 194 , e179-84 (Oct, 2007).
  12. Karlsen A et al. , Anthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adults. The Journal of nutrition 137 , 1951-4 (Aug, 2007).
  13. Kelley DS et al. , Consumption of Bing sweet cherries lowers circulating concentrations of inflammation markers in healthy men and women. The Journal of nutrition 136 , 981-6 (Apr, 2006).
  14. Scarabelli TM et al. , Targeting STAT1 by myricetin and delphinidin provides efficient protection of the heart from ischemia/reperfusion-induced injury. FEBS letters 583 , 531-41 (Feb 4, 2009).
  15. Peterson JJ et al. , Associations between flavonoids and cardiovascular disease incidence or mortality in European and US populations. Nutrition reviews 70 , 491-508 (Sep, 2012).
  16. Mink PJ et al. , Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. The American journal of clinical nutrition 85 , 895-909 (Mar, 2007).
  17. Kay CD et al. , Relative impact of flavonoid composition, dose and structure on vascular function: A systematic review of randomised controlled trials of flavonoid-rich food products. Molecular nutrition & food research 56 , 1605-16 (Nov, 2012).
  18. McCullough ML et al. , Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. The American journal of clinical nutrition 95 , 454-64 (Feb, 2012).
  19. Di Castelnuovo A et al. , Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation 105 , 2836-44 (Jun 18, 2002).
  20. van Velden DP et al. , Red wines good, white wines bad? Redox report : communications in free radical research 7 , 315-6 (2002).
  21. Renaud S, M de Lorgeril, Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339 , 1523-6 (Jun 20, 1992).


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