Functional Foods to Increase the Efficacy of Diet in Lowering Serum Cholesterol

Canadian Journal of Cardiology 27 (2011) 397– 400

Editorial

Functional Foods to Increase the Efficacy of Diet in Lowering Serum Cholesterol David J. A. Jenkins, MD,a,b,c Korbua Srichaikul, MSc,a,b Arash Mirrahimi, BSc,a,b Laura Chiavaroli, MSc,a,b and Cyril W. C. Kendall, PhDa,b a

Clinical Nutrition & Risk Factor Modification Center, St. Michael’s Hospital, University of Toronto, Ontario, Canada b c

Department of Nutritional Sciences, University of Toronto, Ontario, Canada

Department of Medicine, Faculty of Medicine, University of Toronto, Ontario, Canada

It is an unwritten assumption that palatable diets are ineffective and that effective diets are unpalatable. The ineffective nature of currently recommended diets for the control of hypercholesterolemia has resulted in our reliance on statin drugs. These medications save lives, have notably few side effects, and are easy to take. However, although the use of statins may lower low-density lipoprotein cholesterol (LDL-C) by as much as 60%, even the newer studies have not shown statin use to reduce congestive heart disease (CHD) mortality by ⬎50%. Half the problem therefore remains—a problem that, it has been proposed, could be reduced by 80% through diet and lifestyle changes.1,2 Consequently, there has been renewed encouragement to provide dietary advice to promote heart health.3 At the same time, an analysis in the World Health Organization Bulletin has drawn attention to the fact that highand middle-income countries are not providing adequate control for raised serum lipids,4 even though in Britain statins are now available as over-the-counter drugs. Nevertheless, even the fundamentals of diet are surrounded by controversy. The time honoured principle that dietary cholesterol influences serum cholesterol, allowed in the equations of Keys and Hegsted, is now challenged, despite recent indications that in diabetes, increased cholesterol intake is associated with increased CHD risk.5,6 Part of the reason may be the excellent CHD health record of lacto-ovo vegetarians such as those in the Studies of Seventh-Day Adventists and Other Vegetarians.7 At the same time, the deleterious consequences, from the standpoint of CHD risk, of increased consumption of saturated fatty acids (SFA) has been challenged, because it has been demonstrated that the studies since 1980 have failed to implicate SFA in CHD risk.8 The reason may be the increased prevalence of overweight and obesity in the population for Received for publication March 2, 2011. Accepted March 3, 2011. See article by Huang et al. (pages 488-505) in this issue. Corresponding author: Dr David J. A. Jenkins, Clinical Nutrition and Risk Factor Modification Centre, 61 Queen Street East, Toronto, Ontario M5C 2T2, Canada. Tel.: ⫹1-416-867-7475; fax: ⫹1-416-867-7495. E-mail: [email protected] See page 399 for disclosure information.

whom the refined high glycemic index carbohydrates are the problem due to preexisting carbohydrate intolerance. This dietary change therefore obscures the adverse effect of SFA, as has been pointed out.8 The fundamentals of the ideal diet for CHD risk reduction have therefore now been challenged. Furthermore, it has been recognized that whatever dietary advice is given, by and large, it has failed to achieve therapeutic targets. Therefore, to increase the effectiveness and therefore relevance of diet, emphasis has extended to the use of functional foods, which are the topic of the current review by Huang et al.9 It is now nearly a decade since The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) advised the use of viscous fibres and plant sterols to increase the lipid-lowering potential of diet and at the same time eliminated the “Step 1” diet and focused only on what had previously been the “Step 2” diet, with SFA ⬍7% and dietary cholesterol ⬍200 mg/d.10 In the present issue of the Canadian Journal of Cardiology, Huang et al. provide a detailed analysis of the evidence regarding the effects of a wide range of dietary modifications in preventing heart disease.9 This is a timely and useful review of ways to enhancing the lipid-lowering potential of diet. The detailed analysis performed by Huang et al. adds to the list of evidencebased dietary recommendations by endorsing the lipid-lowering benefits not only of viscous fibres (in oats, barley, and psyllium) and plant sterols but also of soy protein, nuts, red wine, and green tea and the supplements (red yeast rice, omega-3 fatty acids, and polycosanols). The review further supports the use of diets, including the Mediterranean, portfolio, and low-fat diets, containing elements of these items. In general, the effects are in the 2%-20% LDL-C reduction range reported for individual components with 3%-7% reductions being more likely in terms of general application. Nevertheless, relatively small differences can have the potential for clinically significant lipid reductions if bundled together in the same diet to allow for their additive effects (dietary portfolio).11,12 We have a few comments or updates because the time-frame of the studies selected does not include 2010. We believe the

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benefits of long-chain omega-3 fish fatty acids may have been overrated because evidence of an advantage in cardiovascular and all-cause mortality is lacking in individuals who are already well treated with conventional pharmacologic agents.13-15 Similarly, the benefits for polycosanols require broader confirmation as the key studies in this area come from the same group of Cuban investigations and studies outside Cuba have not confirmed the effect.16 It is also worth noting that with the exception of red clover isoflavones17,18 and high isoflavone soy germ incorporated into pasta,19 the majority of the work on soy supports a soy protein rather than isoflavone effect on serum cholesterol. Furthermore, soy provides a food rather than a supplement and may have the added advantages of a potential displacement value in eliminating some foods (eg, milk, hamburgers, hotdogs, etc) that would otherwise have contributed SFA and cholesterol to the diet.20 On the other hand, there is growing evidence for the potential value of nuts both in lowering LDL-C and in raising high-density lipoprotein cholesterol,21-25 and the US Food and Drug Administration (FDA) allows a heart health claim for nuts at a dosage of 42 g/d.26 Red yeast rice contains a naturally produced lovastatin, and it has been claimed to achieve cholesterol reduction without increasing muscle pain even in those who are susceptible to muscle discomfort on conventional statins.27,28 Last, is it red wine or all alcoholic beverages that, in moderation, have cardiovascular advantages? Is this the result of reducing platelet adhesiveness29 or of improving endothelial function30 at intake levels that do not raise blood pressure, as seen in general with alcoholic beverages? Red wine certainly is a source of resveratrol,31 the powerful antioxidant, but a clear advantage over other alcoholic beverages remains to be determined. In making practical use of the comprehensive data provided by Huang and et al., a number of questions arise: Should individuals interested in heart health try to adopt all of the beneficial components suggested or only some? If only some, how should they choose which components to use? Are there any health risks, and should this review trigger additions to current dietary recommendations for the general public and specifically for those with cardiovascular disease? Our personal approach is to focus on a defined portfolio of 4 classes of functional foods (the dietary portfolio [Table 1]) consisting of viscous fibres (eg, oat bran, barley, psyllium products), plant sterols (eg, in fortified margarines), soy protein (eg, soy milk, simulated meats, tofu, etc), and nuts (as described in detail elsewhere).32,33 Overall, a conservative estimate of 22.5% reduction in LDL-C can be achieved with these 4 components of the dietary portfolio. If, in addition, attention is paid to hygienic dietary practices, then a further 20% reduction in LDL-C could be achieved (Table 2). The combined effect of a healthy diet and

Table 1. Dietary portfolio effects on serum low-density lipoprotein cholesterol (LDL-C) Functional foods Viscous fibre Soy protein Plant sterols Nuts Total

Dietary change, g/d

Approximate LDL-C reduction, %

5-10 25 1-2 42 Full portfolio

5 4-6 5-10 5 22.5%

Table 2. Healthy dietary effects on serum low-density lipoprotein cholesterol (LDL-C) Healthy diet effect

Dietary change

Approximate LDL-C reduction, %

Body weight Dietary cholesterol Saturated fat Total

Lose 10 lb (5 kg) ⬍200 mg/d ⬍7% of calories Hygienic diet

5 5 10 20

functional foods could potentially provide an impressive LDL-C reduction if all these factors were additive.32,33 In this respect, the closer to a plant-based diet, the more of these components will be captured and the more effective will be the LDL-C reduction. Such diets are by definition very low in trans-fatty acids and SFA and very low in dietary cholesterol.5 Although results differ by study, we ascribe ⬃5% of LDL-C reductions to manageable amounts of these 4 components: 50-75 g oat bran diet or 2-3 teaspoons of psyllium; 1-2 g plant sterol as 15-30 g fortified margarine (2 g plant sterol is reported to give as much as 10%-15% LDL-C reduction); 25 g soy protein in soy milk, meat analogues, and tofu; and a handful of mixed nuts (42 g, raw or dry roasted). These foods, especially soy foods, may also have a valuable displacement value, resulting in the elimination from the diet of foods containing high levels of SFA and cholesterol, thereby providing a greater LDL-C reduction benefit.20 Other components discussed in the review can then be added to the basic 4. Unfortunately, the red yeast rice, which may be potentially effective, is difficult to find, even in health food stores. The use of combinations of these components has special appeal because they are more likely to be additive in their effects due to the combination of different mechanisms of action. The viscous fibre increases bile acid losses, the plant sterols reduce cholesterol absorption, soy protein tends to inhibit apolipoprotein B and cholesterol synthesis, and nuts may work through a combination of these mechanisms. Palatability of products, including variety, remains an issue and detailed dietary advice is required to achieve reasonable levels of compliance. The challenge of compliance also presents an opportunity for the food industry to become involved in product development, a challenge that is being taken up and will make cholesterol-lowering diets more effective in the future. Side effects are few. The volume of fibre foods (bulk) may be a problem but may also be an advantage in limiting total caloric intake in the overweight. In some, flatulence may limit the appeal of these foods. Soy products have attracted concern over the ability of the isoflavones they contain to promote the growth of MCF-7 cells (human breast cancer cells) in athymic ovariectomized nude mice with implanted estrogen pellets. By contrast, human data, including the recent Shanghai breast cancer study,34,35 suggest mild protection from breast cancer and cancer recurrence in soy consumers. Hyperabsorbers of plant sterols who are homozygous for a defect in the ATP G5/8 sterol transporter may experience premature cardiovascular disease. Such cases are, however, very rare and usually diagnosed early in life. The use of plant sterol– enriched margarines by the more common heterozygotes has not been associated with major increases in serum plant sterols. Nuts are associated with allergic responses. These are particularly

Jenkins et al. Efficacy of Diet in Lowering Serum Cholesterol

well documented for peanuts (which is a legume and not a “true nut” or “tree nut”). Care should be taken to document any potential food allergies before giving dietary advice to increase nut consumption. In terms of dietary advice, NCEP ATP III guidelines clearly endorse the use of plant sterols and viscous fibres to enhance the effectiveness of diet in lowering LDL-C; the FDA allows heart health claims for viscous fibres, plant sterols, soy, and nuts; and other jurisdictions have in general not yet formulated explicit advice on the use of functional food or food components to lower serum cholesterol. The review by Huang et al. provides a basis for such specific dietary advice. Perhaps as important should be the stimulus provided by the review to official government agencies in all jurisdictions to facilitate the appropriate use of these cholesterol-lowering foods and food components along with exercise and smoking cessation as part of the strategy to promote cardiovascular health. Why is Canada almost a decade behind the United States in allowing health claims for plant sterols and viscous fibres, which have just been recognized by Health Canada in the past year, while soy and nuts, recognized by the FDA, are still not permitted to carry a heart health claim in Canada? Reviews such as the present one9 will hopefully provide an important stimulus to the formulation of evidence-based heart health claims. There are therefore multiple issues that relate to the use of functional foods and the important message, delivered by the authors of the current review appearing in this issue of the CJC,9 of means by which the advantages of diet may be captured to lower LDL-C and hence reduce CHD risk.

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ada, Loblaws, Unilever, Barilla, the Almond Board of California and the International Tree Nut Council. Korbua Srichaikul and Arash Mirrahimi have no conflicts of interest to disclose.

References 1. Stampfer MJ, Hu FB, Manson JE, et al. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 2000; 343:16-22. 2. Willett WC. Balancing life-style and genomics research for disease prevention. Science 2002;296:695-8. 3. Raine KD. Addressing poor nutrition to promote heart health: moving upstream. Can J Cardiol 2010;26(suppl C):21C-4C. 4. Roth GA, Fihn SD, Mokdad AH, et al. High total serum cholesterol, medication coverage and therapeutic control: an analysis of national health examination survey data from eight countries. Bull WHO 2011; 89:92-101. 5. Spence JD, Jenkins DJ, Davignon J. Dietary cholesterol and egg yolks: not for patients at risk of vascular disease. Can J Cardiol 2010;26:e336-9. 6. Willet WC, Stampfer MJ. Rebuild the food pyramid. Sci Am 2003;1: 64-71. 7. Fraser GE. Diet, Life Expectancy, and Chronic Disease: Studies of Seventh-Day Adventists and Other Vegetarians. New York: Oxford University Press, 2003. 8. Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. Am J Clin Nutr 2010;91:535-46. 9. Huang J, Frohlich J, Ignasewski AP. The impact of dietary changes and dietary supplements on lipid profile. Can J Cardiol 2011;27:488-505.

Disclosures David J. A. Jenkins has served on the scientific advisory board for or received research support, consultant fees, or honouraria from Griffin Hospital in New Haven for the development of the NuVal System, Abbott Laboratories, Kellogg’s, Quakers, Barilla, Solae, Unilever, Hain Celestial, Loblaws Inc., The Coca Cola Sugar Advisory Board, Sanitarium Company, Herbalife International, Pacific Health Laboratories Inc., Metagenics/MetaProteomics, Bayer Consumer Care, Oldways Preservation Trust, The Almond Board of California, The California Strawberry Commission, Orafti, the Canola and Flax Councils of Canada, Pulse Canada, and the Saskatchewan Pulse Growers. Dr Jenkins also holds additional grant support from the CIHR, Canadian Foundation for Innovation (CFI), Ontario Research Fund (ORF), and Advanced Foods and material Network (AFMNet). Laura Chiavaroli holds a casual Clinical Research Coordinator position at Glycemic Index Laboratories, Toronto, Canada. Cyril Kendall has received honouraria or travel funding from the Canola Council of Canada, Pulse Canada, the Saskatchewan Pulse Growers, the Almond Board of California, the International Tree Nut Council Nutrition Research & Education Foundation, Loblaws, Barilla, and Unilever; has been on the speakers’ panel for the Almond Board of California and the International Tree Nut Council; and has received research grants from the Canola Council of Canada, Pulse Canada, the Saskatchewan Pulse Growers, Agriculture and Agri-Food Can-

10. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. 11. Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA 2003;290:502-10. 12. Jenkins DJ, Chiavaroli L, Wong JM, et al. Adding monounsaturated fatty acids to a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia. CMAJ 2010;182:1961-7. 13. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369: 1090-8. 14. 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;363:2015-26. 15. Rauch B, Schiele R, Schneider S, et al. OMEGA, a randomized, placebocontrolled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 2010;122:2152-9. 16. Varady KA, Wang Y, Jones PJ. Role of policosanols in the prevention and treatment of cardiovascular disease. Nutr Rev 2003;61:376-83. 17. Clifton-Bligh PB, Baber RJ, Fulcher GR, et al. The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause 2001;8:259-65.

400 18. Howes JB, Sullivan D, Lai N, et al. The effects of dietary supplementation with isoflavones from red clover on the lipoprotein profiles of post menopausal women with mild to moderate hypercholesterolaemia. Atherosclerosis 2000;152:143-7. 19. Clerici C, Setchell KD, Battezzati PM, et al. Pasta naturally enriched with isoflavone aglycons from soy germ reduces serum lipids and improves markers of cardiovascular risk. J Nutr 2007;137:2270-8. 20. Jenkins DJ, Mirrahimi A, Srichaikul K, et al. Soy protein reduces serum cholesterol by both intrinsic and food displacement mechanisms. J Nutr 2010;140:2302S-11S. 21. Jenkins DJ, Hu FB, Tapsell LC, et al. Possible benefit of nuts in type 2 diabetes. J Nutr 2008;138:1752S-6S. 22. Jenkins DJ, Kendall CW, Josse AR, et al. Almonds decrease postprandial glycemia, insulinemia, and oxidative damage in healthy individuals. J Nutr 2006;136:2987-92. 23. Jenkins DJ, Kendall CW, Marchie A, et al. Dose response of almonds on coronary heart disease risk factors: blood lipids, oxidized low-density lipoproteins, lipoprotein(a), homocysteine, and pulmonary nitric oxide: a randomized, controlled, crossover trial. Circulation 2002;106:1327-32. 24. Kendall CW, Esfahani A, Truan J, et al. Health benefits of nuts in prevention and management of diabetes. Asia Pac J Clin Nutr 2010;19: 110-6. 25. Spiller GA, Jenkins DA, Bosello O, et al. Nuts and plasma lipids: an almond-based diet lowers LDL-C while preserving HDL-C. J Am Coll Nutr 1998;17:285-90. 26. US Food and Drug Administration (FDA). Qualified health claims: Letter of enforcement discretion: Nuts and coronary heart disease (docket No. 02P-0505). Available at: http://www.fda.gov/Food/LabelingNutrition/

Canadian Journal of Cardiology Volume 27 2011 LabelClaims/QualifiedHealthClaims/ucm072926.htm. Accessed January 31, 2011. 27. Becker DJ, Gordon RY, Halbert SC, et al. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med 2009; 150:830-9, W147-W9. 28. Heber D, Yip I, Ashley JM, et al. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr 1999; 69:231-6. 29. Bertelli AA, Giovannini L, Giannessi D, et al. Antiplatelet activity of synthetic and natural resveratrol in red wine. Int J Tiss React 1995;17:1-3. 30. Karatzi K, Papamichael C, Aznaouridis K, et al. Constituents of red wine other than alcohol improve endothelial function in patients with coronary artery disease. Coron Artery Dis 2004;15:485-90. 31. Pace-Asciak CR, Hahn S, Diamandis EP, et al. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta 1995;235:207-19. 32. Jenkins DJ, Kendall CW, McKeown-Eyssen G, et al. Effect of a lowglycemic index or a high-cereal fiber diet on type 2 diabetes: a randomized trial. JAMA 2008;300:2742-53. 33. Jenkins DJ, Kendall CW, Faulkner DA, et al. Assessment of the longerterm effects of a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia. Am J Clin Nutr 2006;83:582-91. 34. Trock BJ, Hilakivi-Clarke L, Clarke R. Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 2006;98:459-71. 35. Kang X, Zhang Q, Wang S, et al. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ 2010;182:1857-62.