Cholesterol-lowering effects of soy protein: Historical and clinical perspective
By Mark Messina, PhD, Executive Director, Soy Nutrition Institute
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.