Next year will mark the 50th anniversary of the first clinical study demonstrating the hypocholesterolemic effect of soy protein. Although it was published in the American Journal of Clinical Nutrition, this study by Hodges et al.1 did little to draw attention to soy protein. The finding was actually serendipitous since the focus of that research was on the impact of carbohydrate on cholesterol levels. A decade later, a team of Italian investigators led by Cesare Sirtori published the first in a series of papers showing that in hypercholesterolemic patients soy protein markedly lowered LDL-cholesterol.2
Interest in the effects of soy protein on cholesterol levels grew gradually as the data accumulated. An important intervention study published in the American Journal of Clinical Nutrition in 1993 from the University of Illinois found that soy protein lowered cholesterol even in people whose cholesterol was only mildly elevated.3 But it was the 1995 meta-analysis of 34 clinical studies published in the New England Journal of Medicine (NEJM) by Anderson et al.4 that brought soy to the attention of the medical and scientific communities. Soy protein was estimated to lower LDL-cholesterol by 12.9%, which exceeded the cholesterol-lowering effects of all other individual dietary approaches and came close to matching the efficacy of the available pharmaceuticals. (Statins had not yet entered the mainstream although they were being rigorously investigated.)5
Four years after the NEJM publication, the US Food and Drug Administration (FDA) performed its own analysis and approved a health claim for soyfoods and coronary heart disease based on the cholesterol-lowering effects of soy protein.6 One year later, the American Heart Association (AHA) gave soy its blessing.7 Given the FDA and AHA positions, it seemed that the data were about as solid as could be. But that was not the case.
In 2001, the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) didn’t endorse the cholesterol-lowering effects of soy protein citing the inconsistent data and lack of clear mechanism for cholesterol reduction.8 In 2005, the Agency for Healthcare Research and Quality also raised questions about the hypocholesterolemic effects of soy protein.9 But it was clearly the conclusion by the AHA in 2006 that soy protein no longer warranted a health claim (although they did emphasize the coronary benefits of soyfoods resulting from their high polyunsaturated fat and fiber content) that brought the controversy to the forefront.10
A year later the FDA formalized the controversy by announcing its intention to take a second look at the data in support of the health claim. This reevaluation was not undertaken because of inconsistencies in the data, but rather, was due to considerable volume of research that had been published since the claim was first approved. In 2014, however, the FDA seemed to backtrack a bit on why the reevaluation was undertaken by acknowledging that the data were inconsistent.
It’s important to recognize that in 2006 the AHA errored in its estimate of the cholesterol-lowering effects of soy protein, which they pegged at about 3%.10 In fact, the AHA didn’t actually perform a meta-analysis of the results of the 22 studies upon which they based their conclusion. When Jenkins et al.11 performed this meta-analysis they found that soy protein lowered LDL-C 4.3%, an effect similar to that of soluble fiber, which has an existing health claim.12
The results by Jenkins et al.11 are consistent with meta-analyses published over the past decade or so which show LDL-C reductions in response to soy protein of about four to six percent.11,13-21 Obviously, the potency of soy protein is less than initially reported by Anderson et al., 4 something that was actually fairly evident soon after the health claim was approved.22 Despite the lower estimate, Health Canada approved a health claim for soy protein in 2014 on the basis of its finding that soy protein lowered LDL-C by about 4%.16
It’s not clear why the cholesterol-lowering effect of soy protein is so much lower than initially reported. It’s also not clear why the evidence, despite the findings of the meta-analyses, is inconsistent. Is it because the initial cholesterol level of study participants is lower in studies published since the initial health claim was approved (and subjects with significantly elevated cholesterol would have been treated by the now approved statin drugs)? Is it because habitual (background) diets have changed over time? Have the intervention products changed in some way, or is soy protein being provided to study participants in forms that differ from the early studies? Or is it simply a case of regression to the mean?
On June 30, 2016, the FDA announced that after evaluating the health claim-related evidence it intends to publish a proposed rule in the Federal Register and solicit public comments and scientific information concerning the proposal by June 30, 2017. The implications of this announcement aren’t clear. Is the claim going to be approved as is, modified, or rescinded? Will some soy protein products qualify for the claim and others not? Only time will tell.
Obviously, the soyfood industry is hoping the existing claim is reaffirmed. But from a clinical perspective the eventual FDA decision won’t change things very much. As Jenkins et al.23 have shown, to markedly lower blood cholesterol through dietary means requires a comprehensive approach that includes nuts, phytosterols, fiber, reduced saturated fat intake, and soy protein. All of these products are part of the solution. Jenkins et al.23 included soyfoods because they are low in saturated fat and high in polyunsaturated fat, provide high-quality protein, and soy protein directly lowers blood cholesterol. Regardless of the FDA decision, soyfoods are still a very beneficial component of heart-healthful diets.
- Hodges RE, Krehl WA, Stone DB, Lopez A. Dietary carbohydrates and low cholesterol diets: effects on serum lipids on man. Am J Clin Nutr 1967;20:198-208.
- Sirtori CR, Agradi E, Conti F, Mantero O, Gatti E. Soybean-protein diet in the treatment of type-II hyperlipoproteinaemia. Lancet 1977;1:275-7.
- Potter SM, Bakhit RM, Essex-Sorlie DL, et al. Depression of plasma cholesterol in men by consumption of baked products containing soy protein. Am J Clin Nutr 1993;58:501-6.
- Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995;333:276-82.
- Kjekshus J, Pedersen TR. Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1995;76:64C-8C.
- Food labeling: health claims; soy protein and coronary heart disease. Food and Drug Administration, HHS. Final rule. Fed Regist 1999;64:57700-33.
- Erdman JW, Jr. Soy protein and cardiovascular disease: A statement for healthcare professionals from the nutrition committee of the AHA. Circulation 2000;102:2555-9.
- 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.
- Balk E, Chung M, Chew P, et al. Effects of soy on health outcomes. Evid Rep Technol Assess (Summ) 2005:1-8.
- Sacks FM, Lichtenstein A, Van Horn L, Harris W, Kris-Etherton P, Winston M. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 2006;113:1034-44.
- 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.
- Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 1999;69:30-42.
- Zhan S, Ho SC. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am J Clin Nutr 2005;81:397-408.
- Harland JI, Haffner TA. Systematic review, meta-analysis and regression of randomised controlled trials reporting an association between an intake of circa 25 g soya protein per day and blood cholesterol. Atherosclerosis 2008;200:13-27.
- Anderson JW, Bush HM. Soy protein effects on serum lipoproteins: A quality assessment and meta-analysis of randomized, controlled studies. J Am Coll Nutr 2011;30:79-91.
- Benkhedda KB, B, Sinclair SE, Marles RJ, Xiao CW, Underhill L. Food Risk Analysis Communication. Issued By Health Canada’s Food Directorate. Health Canada’s Proposal to Accept a Health Claim about Soy Products and Cholesterol Lowering. Int Food Risk Anal J 2014;4:22 | doi: 10.5772/59411.
- Tokede OA, Onabanjo TA, Yansane A, Gaziano JM, Djousse L. Soya products and serum lipids: a meta-analysis of randomised controlled trials. Br J Nutr 2015;114:831-43.
- Yang B, Chen Y, Xu T, et al. Systematic review and meta-analysis of soy products consumption in patients with type 2 diabetes mellitus. Asia Pac J Clin Nutr 2011;20:593-602.
- Hooper L, Kroon PA, Rimm EB, et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008;88:38-50.
- Reynolds K, Chin A, Lees KA, Nguyen A, Bujnowski D, He J. A meta-analysis of the effect of soy protein supplementation on serum lipids. Am J Cardiol 2006;98:633-40.
- Weggemans RM, Trautwein EA. Relation between soy-associated isoflavones and LDL and HDL cholesterol concentrations in humans: a meta-analysis. Eur J Clin Nutr 2003;57:940-6.
- Messina M. Potential public health implications of the hypocholesterolemic effects of soy protein. Nutr 2003;19:280-1.
- Jenkins DJ, Kendall CW, Faulkner D, et al. A dietary portfolio approach to cholesterol reduction: combined effects of plant sterols, vegetable proteins, and viscous fibers in hypercholesterolemia. Metabolism 2002;51:1596-604.