Soy Protein and Risk for Coronary Heart Disease

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(This text was distributed at the American Dietetic Association 80th Annual Meeting and Exhibition, held October 27-30, 1997, in Boston, Massachusetts, by James W. Anderson, M.D. Professor of Medicine and Clinical Nutrition University of Kentucky, Lexington, KY. Phone 606-281-4954; fax 606-233-3832, e-mail: jwandersmd@aol.com) (Collateral information about Estimated Values for Isoflavone Content of Selected Soyfoods was also distributed by Dr. Anderson as part of his presentation.) Coronary heart disease (CHD) is the major cause of death in most developed countries and is rapidly increasing in prevalence in developing countries. In the US, death rates from cardiovascular disease exceed 1 million annually and the total cost is estimated to exceed $120 billion, the largest disease-related cost to health. While many risk factors, such as cigarette smoking and hypertension, contribute to risk for CHD, lipid abnormalities are the major factors. Low-density lipoproteins (LDL) have a central role in the atherosclerotic process. LDL penetrate the walls of blood vessels where they are oxidized by free radicals and accumulate as a gruel-like material that blocks the blood vessel lumen; this material also can leak into the blood vessel to cause a thrombosis. High-density lipoprotein (HDL) cholesterol has a protective effect and act to prevent LDL oxidation and remove cholesterol that accumulates in the blood vessel wall {10}. Soy protein exerts several anti-atherogenic effects. First, it decreases LDL-cholesterol levels significantly {1}. Second, it tends to increase HDL-cholesterol levels {1}; this is rather unique since most dietary interventions such as oat bran intake or decreased saturated fat intake significantly decrease HDL-cholesterol levels. Third, soy isoflavones, plant chemicals unique to soybeans, have antioxidant properties which protect LDL from oxidation {7,14}. Fourth, soy isoflavones have favorable effects on blood vessel function.{15} Meta-analysis methods. Our recent meta-analysis {1} of soy protein studies clearly indicates the potency of soy protein in decreasing LDL-cholesterol levels. In this study we analyzed the results of 38 studies using over 730 research volunteers. The first step in this review was to exhaustively search the literature to identify all of the clinical studies examining soy protein effects on serum lipid levels. Next we had to establish rigorous criteria for inclusion of the study in the analysis. All acceptable studies had to be conducted as controlled clinical studies which were published in peer-reviewed journals. Then we had to determine what were important dependent outcome variables (such as serum cholesterol) and what were important independent variables (such as type or amount of soy protein) which might affect the lipid responses. After these dependent and independent variables were identified, we extracted and tabulated these data from the research reports. Once these data were tabulated, they were entered into the meta-analysis program for analysis. Meta-analysis results. Thirty-eight studies including 730 research volunteers were analyzed. Thirty-four studies included only adults while four studies included only children. As a soy protein source, 20 used isolated soy protein, 15 used textured soy protein, and three used a combination of isolated and textured soy protein. Soy protein intake averaged 47 grams per day (range 17-124 grams/day) and 15 studies (40%) used <31 grams of soy protein daily. In 14 of the studies the test diets resembled a typical Western diet while in 21 studies the diets were low in fat (<30% of energy) and low in cholesterol (<200 mg/day). In 19 studies the soy protein and control diets were considered to be comparable with respect to total fat intake, saturated fat intake, cholesterol intake, and weight maintenance. Soy protein intake was associated with a 9.3% reduction in serum cholesterol, a 12.9% reduction in serum LDL-cholesterol, and a 10.5% reduction in serum triglycerides. All of these decreases were statistically significant. Serum HDL-cholesterol levels increased by 2.4%, a non-significant increase. These findings had a strong consistency because 34 of 38 studies reported that soy protein intake decreased serum cholesterol levels.{1} Serum lipid changes were highly correlated with initial levels (P < 0.001). For serum cholesterol, the baseline value accounted for 77% of the variance observed. This indicates that the initial serum cholesterol level is the strongest and most important determinant of the serum cholesterol response to soy protein. We calculated the expected reduction in serum LDL-cholesterol for research volunteers with initial serum cholesterol levels at these levels: normal; mild hypercholesterolemia; moderate hypercholesterolemia; and severe hypercholesterolemia. Those volunteers with normal initial levels had LDL-cholesterol decreases of 7.7% while those with severe hypercholesterolemia had LDL-cholesterol decreases of 24%. This indicates that individuals with more severe hypercholesterolemia are likely to show a greater response to soy protein use. Most other independent variables or characteristics did not have a significant effect on the serum lipid response to soy protein. Adults and children showed similar responses. The type of diet or matching of diet variables did not have a significant effect. The type of soy protein (isolated versus textured soy protein) did not have a significant effect. Using a special statistical manipulation, we observed that the amount of soy protein had a significant effect. This analysis indicates that the intake of 25 grams of soy protein per day would reduce serum cholesterol by 8.9 mg/dl, 50 grams would reduce it 17.4 mg/dl, and 75 grams of soy protein would reduce serum cholesterol by 26.3 mg/dl. Our study, however, indicated that intake of 17-25 grams of soy protein per day could have a meaningful effect on serum cholesterol levels. Meta-analysis discussion. This analysis documents that daily intake of soy protein significantly decreases serum cholesterol concentrations in adults and children. The average reduction in serum cholesterol levels was 9.3%. Since every one percent reduction in serum cholesterol decreases estimated risk of heart attack by two to three percent {2}, this serum cholesterol reduction has the potential to reduce risk for CHD by 18-28%. This study did not address mechanisms; available information is reviewed {1}. Recent research, however, suggests that the soy isoflavones may have an important role in the hypocholesterolemic effects of soy protein {4}. The monkey studies are discussed below. Monkey studies. Anthony, Clarkson and colleagues{4} have conducted three studies with monkeys. In these studies using either cynomolgus or rhesus monkeys, soy protein rich in soy isoflavones favorably affected serum lipid concentrations while soy protein from which the soy isoflavones had been extracted had a minimal impact. These primate studies suggest that soy isoflavones may account for 60-70% of the effects of soy protein. Practical implications. Emerging research indicates that soy protein intake has a significant favorable effect on serum lipid levels and may reduce risk for atherosclerotic cardiovascular disease.{1,3,8,11,15,16}. The role of soy protein as a protective factor versus breast and prostate cancer is under intense investigation.{10,15} Substituting soy protein for animal protein appears to have protective effects for the kidney, especially for individuals with diabetes.{2} The role of soy protein in reducing menopausal symptoms is also under investigation.{10} Finally isoflavone analogues appear to reduce risk for and have therapeutic value for persons at risk for osteoporosis.{3,10}. Based on this scientific evidence we {3} recently proposed these guidelines for soy protein intake. General prevention. For persons in good general health a suggestions is to have 7 servings of soy protein per week. (1) This would provide an average of approximately 8 to 10 grams of soy protein daily with 16-20 mg of soy isoflavones daily. This could be obtained from 8 oz. of soy beverage daily, or two soy muffins daily, or two servings of tofu four times weekly, or four soy burgers weekly, or 1 tablespoon (14 g.) of isolated soy protein stirred into beverage daily. Tailored protection. For persons with diabetes or risk factors for coronary heart disease or persons with strong family histories of heart disease, osteoporosis or diabetes we suggest a goal of 14 servings of soy protein per week. (1) This would provide an average of approximately 16 to 20 grams of soy protein/d with 32 to 40 mg of soy isoflavones/d. Disease reversal. For persons with coronary heart disease or osteoporosis, we recommended a goal of 21 servings of soy protein per week. (1) This would provide an average of approximately 24 to 30 grams of soy protein daily with 48 to 60 mg of soy isoflavones daily. Isolated soy protein with standardized amounts of isoflavones (1 mg genistein and 2 mg of total isoflavones per gram of protein) are useful for these individuals since they can incorporate most of their daily "quota" of soy protein and isoflavones in a singe milkshake. Sources of soy protein. Textured soy protein or textured vegetable protein (TVP) is an excellent source of soy protein and isoflavones. Soy beverages have variable amounts of soy protein but optimal products provide about 8 grams of soy protein per serving. Soy flour can be used in baking a variety of breads, muffins and cookies. Tofu is an excellent source of soy protein but is more difficult to incorporate into a typical American diet than other soy protein sources. Soy protein concentrates available in some soy burgers and other products have lower concentrations of soy isoflavones because of the alcohol extraction process; the effects of soy protein concentrate products which are low in soy isoflavones on serum lipid concentrations are not well defined. Isolated soy protein products provide about 2 mg of isoflavones per g of protein and may be the most reliable source of isoflavones from food products. Conclusions. Soy protein and its isoflavones provide many health benefits. Careful studies indicate that regular intake of soy protein is associated with favorable changes in serum lipoprotein concentrations. Our meta-analysis {1} noted that soy protein intake was accompanied be a significant 9.3% reduction in serum cholesterol concentrations, a significant 12.9% reduction in LDL-cholesterol levels, a significant 10% reduction in serum triglycerides and a 2.4% increase in serum HDL-cholesterol values. Emerging research indicates that soy protein intake may reduce risk for atherosclerotic cardiovascular disease by favorable alterations in serum lipoprotein concentrations, by the antioxidant action and favorable effects on the health of vascular endothelium mediated by soy isoflavones. (1) These recommendations outlined in our book written for the general public {3} are provisional and are based on the best scientific available at the time of writing (Aug. 1997). Recommendations for use of soy protein for person with breast cancer or prostate cancer or family histories of breast cancer are controversial and are not included here. Bibliography 1. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of effects of soy protein intake on serum lipids in humans. N Engl J Med 1995; 333:276-282. 2. Anderson JW, Blake JE, Turner J, Smith BM. Soy protein effects on renal function and proteinuria for individuals with non-insulin-dependent diabetes mellitus. Am J Clin Nutr 1997; In press. 3. Anderson JW, Breecher MM. Dr. Anderson's Antioxidant, Antiaging Health Program. (Chapter 7. The Joys of Soy). New York: Carroll & Graf. 1996. 4. Anthony MS, Clarkson TB, Hughes CL, Morgan TM, Burke GL. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J Nutr 1996;126:43-50. 5. Dwyer J. Overview: Dietary approaches for reducing cardiovascular disease risks. J Nutr 1995; 125:656S-665S. 6. Dwyer JT, Goldin RB, Saul N, Gaultieri L, Barakat S, Adkercreutz H. Tofu and soy drinks contain phytoestrogens. J Am Diet Assoc 1994; 94:739-743. 7. Hutchins AM, Lampe JW, Martini MC, Campbell DR, Slavin JL. Vegetables, fruits, and legumes: Effect on urinary isoflavonoid phytoestrogen and lignan excretion. J Am Diet Assoc 1995; 95:769-774. 8. Kanazawa T, Osanai T, Zhang XS, Uemura T, Yin XZ, Onedera K, et al. Protective effects of soy protein on the peroxidizability of lipoproteins in cerebral vascular diseases. J Nutr 1995; 125:639S-646S. 9. Lovati MR, Manzoni C, Canavesi A, Sirtori M, Vaccarino V, Marchi M, et al. Soybean protein diet increases low density lipoprotein receptor activity in mononuclear cells from hypercholesterolemic patients. J Clin Invest 1987; 80:1498-1502. 10. Messina M. Modern applications for an ancient bean: soybeans and the prevention and treatment of chronic disease. J Nutr 1995; 125:567S-569S. 11. Raines EW, Ross R. Biology of atherosclerotic plaque formation: possible role of growth factors in lesion development and the potential impact of soy. J Nutr 1995; 125:624S-630S. 12. Rose DP. Dietary fiber, phytoestrogens, and breast cancer. Nutrition 1992; 8:47-51. 13. Sirtori C, Lovati M, Manzoni C, Monetti M, Pazzuccone F, Gatti E. Soy and cholesterol reduction:clinical experience. J Nutr 1995; 125:598S-605S. 14. Wang H, Murphy PA. Isoflavone content in commercial soybean foods. J Agric Food Chem 1994; 42:1666-1673. 15. Wei H, Bowen R, Cai Q, Barnes S, Wang Y. Antioxidant and antipromotional effects of the soybean isoflavone genistein. Proc Soc Exper Biol Med 1995; 208:124-130. 16. Wilcox JN, Blumenthal BF. Thrombotic mechanisms in atherosclerosis: potential impact of soy proteins. J Nutr 1995; 125:631S-638S.