Researchers have found a consistent cholesterol-lowering effect for soy protein

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Researchers at the University of Toronto have found a consistent cholesterol-lowering effect for soy protein, with pooled data from dozens of clinical trials that span the last two decades.

The study calls into question the U.S. Food and Drug Administration’s current proposal to revoke the health claim for soy protein and heart disease.

“At no time since the original claim for soy as a reducer of serum cholesterol has its ability been in question,” says David Jenkins, professor of nutritional sciences and of medicine at U of T. “It’s been consistent since 1999. The data have not changed.”

The researchers showed a reduction from soy in both total cholesterol and low-density lipoprotein cholesterol, which can damage the heart.

The effect is steady across all 46 trials that the FDA cited in 2017, when it first proposed to revoke the health claim for soy based on recent trials that showed variable results.

The Journal of the American Heart Association published the findings today.

“Sometimes you see a regression to the mean, where analyses with small studies produce big effects that diminish over time as sample sizes increase and results get more precise,” says John Sievenpiper, a professor of nutritional sciences at U of T and clinician-scientist at St. Michael’s Hospital who co-authored the study.

“We saw that with fish oil, for example. But in this case nothing has changed.”

The researchers performed a cumulative meta-analysis, which let them look at the effect of soy in all the trials combined, but at different points in time with the addition of data from each new trial.

The FDA will likely make a decision on the health claim for soy this summer; options include a full retraction and retention of a qualified health claim.

“These data strongly support the rationale behind the original FDA heart health claim for soy,” says Jenkins, who is also a researcher in the Joannah & Brian Lawson Centre for Child Nutrition at U of T and a clinician-scientist at St. Michael’s Hospital.

“And it’s important to note that while the reduction in cholesterol was less than five percent, if you put that together with other plant-based foods in a portfolio you get a much stronger effect.”

Jenkins and his colleagues in the 1980s pioneered the glycemic index, which shows the effect of various foods on blood sugar levels.

More recently, he helped develop a dietary portfolio that includes nuts, plant-based protein, viscous fibre and plant sterols, which together can lower risk factors for heart disease by up to 30 per cent.

This portfolio of foods has been incorporated into dietary guidelines by Heart UK and the European Atherosclerosis Society, among others. Health Canada released a national food guide that encourages plant-based eating this year, and the FDA maintains health claims for several other plant foods in the dietary portfolio.

“It’s disheartening that the FDA has focused on soy,” says Jenkins.

“We see similar data for other foods in the portfolio.

If you knock out one leg of that stool then the others could be up for grabs, right when concerns about health and the environment are bringing plant-based eating into the mainstream.”

Companies such as Beyond Meat and Impossible Foods have seen huge growth this year with plant-based alternatives to meat. Burger King plans to offer its soy-based burger nation-wide in the U.S. by the end of 2019.

“We’re moving into an age of plant-based protein, and it would be a shame to see that shift undermined,” says Jenkins.

“Plant-based food producers, industry and retailers need all the help they can get, to make their products accessible.”

Professors Jenkins and Sievenpiper have received support from government, non-profit and industry funding sources, some of which include companies and industry groups that produce or promote soy and other plant-based foods. See the Disclosures section at the end of the study for a full list of their funding sources and industry connections.


Cardiovascular disease (CVD) describes a collection of disorders affecting the vasculature of the heart, brain and peripheral tissue and is the leading cause of death globally [1].

Atherosclerosis is the underlying cause of coronary heart disease (CHD), the most common form of CVD, and is thought to be initiated through an inflammatory response by the vascular endothelium following injury [2].

The origin of these endothelial lesions is unclear, but implicated factors include: chronic elevations in blood pressure [3]; prolonged hyperglycemia and the resulting formation of advanced glycation end products [4]; elevated LDL cholesterol (LDL-C), particularly molecules that have undergone oxidized modification [2]; and oxidative stress and inflammation [5].

Consequently, major CVD risk factors include hypertension, the presence of type 2 diabetes, dyslipidemia, obesity (body mass index (BMI) >30), and inflammation [1].

Dietary modification lowers CVD risk by attenuating associated risk factors, and in particular, legumes are emphasized as part of a cardioprotective diet because increased consumption is associated with improved weight management and glycemic control, reduced blood pressure, and an improved plasma lipid profile [6].

Soybeans (Glycine max) are widely cultivated for their lipid content, and indeed are the top oilseed produced worldwide [7].

In addition, soybeans are recognized as a valuable source of nutrients as they contain high-quality protein (~40%); polyunsaturated fatty acids (18%); carbohydrates (primarily sucrose, stachyose, and raffinose); and dietary fibers [8].

Soy foods have been part of the human diet for millennia, but more recently considerable attention has been given to the associated health benefits of soy, particularly reduction of CVD risk via the lowering of LDL-C. Much of the focus on soy has been directed toward the hypocholesterolemic properties of bioactive peptides in soy protein, which exert their effects primarily through mechanisms involving the LDL-C receptor (LDLR), and bile acid regulation [9,10].

These findings are supported by several meta-analyses [11,12,13,14,15,16,17,18,19,20,21] and have culminated in a soy health claim relating 25 g soy protein with a reduced risk of CHD in the United States [22] and Canada [23], but not Europe [24].

However, other constituents in soy have been shown to confer many health benefits, including reduction of CVD risk, and these are worthy of further examination.

Soybeans are a significant source of phytochemicals such as isoflavones, phytosterols and lecithins, as well as soluble fibers, saponins and polysaccharides, which may act collectively or through independent mechanisms to confer unique health benefits [25,26,27].

For example, soy lecithins and saponins have a role in lipid metabolism; phytosterols and linoleic acid produce hypocholesterolemic effects [25]; and soy fibers have been shown to promote weight loss [28].

Further, the health benefits of soy protein appear to reach beyond its putative LDL-C lowering effect by offering protection against renal dysfunction [29], oxidative stress [30], and by improving markers of endothelial function [31].

Finally, the health benefits of isoflavones, of which soybeans are the single greatest dietary source, have also been extensively examined.

They represent a class of phytoestrogens belonging to the flavonoid family, and there are three primary isoflavones (daidzein, genistein, glycitein) which are characterized by their general di-phenolic structure resembling mammalian estrogen [32].

The structural similarity between soy isoflavones and estradiol suggests that isoflavones may elicit estrogenic effects. Although the affinity for the estrogen receptor by soy isoflavones is 100–1000 times less than mammalian estrogen, isoflavone concentrations can appear in plasma >1000-fold greater than that of endogenous estrogen, thus lending support to the suggestion that isoflavones can exert significant physiological effects [33].

The cholesterol-lowering effect of soy protein has generated much interest in the past and has been extensively studied, but other components in soy appear to confer significant cardiovascular health benefits despite receiving less attention over the years.

This review serves to examine and expand on the health effects of soy and soy constituents beyond cholesterol reduction. Herein, we provide an up-to-date summary of the epidemiological and clinical evidence associating dietary soy, and other soy-derived components, with reduced CVD risk.

This review will examine the cardio-protective effects of dietary soy in the context of major disease outcomes such as hypertension, hyperglycemia, dyslipidemia, inflammation, and obesity.Go to:

Epidemiological Studies

Current epidemiological findings show an inverse association between consuming whole soy foods/products and CVD risk. For example, Shimazu et al. (2007) studied Japanese dietary patterns and found that increased soybean intake (up to 101 g/day) was associated with lower CVD mortality [34].

However, the recent Takayama study, which examined dietary intakes of soy and natto (fermented soy beans) and CVD mortality among Japanese adults, found that there was a significant decrease in mortality from stroke at the highest quartiles of total soy protein and natto intake [35].

Despite this finding, the authors conclude that except for natto, there were no significant associations between CVD related mortality and intakes of total soy protein, total soy isoflavone, and soy protein or soy isoflavones from soy foods [35].

It appears that different soy foods may vary in their biological efficacy and protective effects.

In this regard, it is worthwhile to examine the role of soy isoflavones, given that their estrogenicity may protect against the sharp rise in CVD incidence after menopause, when endogenous estrogen concentrations are depleted [15].

Although plausible mechanistic evidence supports the cardio-protective effects of soy isoflavones, there is discrepancy in the literature regarding the health effects of isoflavones extracts that are consumed in isolation of other soybean components, and this has created disagreements about their health benefits.

Observational studies among East Asian populations consistently find that chronic disease incidence is lowered with the intake of isoflavone-containing whole soy and traditional soy-based foods [36].

In contrast, studies performed with Western populations frequently utilize various combinations of isolates to evaluate the health effects of soy, and have failed to consistently demonstrate health benefits [36].

Furthermore, there is emerging evidence on the diverging biological effects among individuals capable of metabolizing the soy isoflavone daidzein to the more bioactive metabolite equol, which suggests a complex interplay between gut microbiota composition and host benefit, perhaps accounting for some of the conflicting results in the literature [37].

For example, in exploring the effect of soy on CVD risk factors, it was found that blood pressure, plasma triglycerides (TG) and C-reactive protein (CRP) concentrations were significantly lowered among equol- and O-desmethylangolensin (ODMA)-producing pre-hypertensive, postmenopausal Chinese women, compared to non-producers [38].

In addition, racial differences in the ability to convert daidzein into equol have been reported.

For example, 30%–40% of Western populations are estimated to be equol producers while greater proportions have been observed in Japanese, Chinese, and Korean populations, which are purportedly linked to differences in genetics, gut microbiome composition, and perhaps diet [39].

Interestingly, background diet did not influence isoflavone bioavailability in Chinese Asian adults who were acclimatized to a French Western dietary pattern [40].

Other health benefits observed among soybean consumers include lower BMI and mortality due to CHD [41], while lower circulating inflammatory markers are observed among female soy consumers [42].

Soy consumption has also been associated with the lowering of blood pressure.

In the US, a pooled analysis of three longitudinal cohort studies (Nurses’ Health Study, Nurses’ Health Study II and Health Professionals Follow-up Study) found that consuming ≥4 servings/week of broccoli, carrots, and tofu/soybeans was associated with a lower risk of hypertension compared to consuming <1 serving/month [43].

However, the Tehran Lipid and Glucose Study, which involved 1546 normotensive adults, did not find an association between incident hypertension and dietary phytochemical intake, which provided an indirect estimate of soybean consumption [44].

Soy intake may also lower CVD risk by mitigating risk factors for type 2 diabetes (T2D), although this protective effect appears to be limited to populations living in East Asia.

In the Saku Study, which stratified participants by sex and BMI, Japanese men with a higher BMI (>23.6 kg/m2) who consumed soybean products ≥4 servings/week experienced lower fasting and postprandial blood glucose concentrations, and lower T2D incidence compared to those consuming <1 serving/week [45].

Additionally, higher intake of soy products, daidzein and/or genistein was associated with lower T2D risk among overweight Japanese women [46] and adult Chinese Singaporeans [47].

By contrast, intake of soy foods (tofu/soy milk) among US adults does not appear to lower T2D risk, although an inverse relationship between soy isoflavone intake and T2D risk was identified in one study [48].

Similarly, a multi-ethnic cohort study conducted in Hawaii did not find an association between soy food intake and diabetes risk among Caucasian, Japanese American, and Native Hawaiian adults [49].

More recently, a meta-analysis was unable to establish a relationship between soy intake and risk of stroke or CHD, although the authors reason that this may be attributed to the limited pool of case-control and cohort studies currently available [50].

Taken together, population-based studies suggest soy intake mitigates CVD risk factors, but it is unclear whether Western populations gain similar health benefits observed among populations living in East Asia.

The results of observational studies conducted in Western populations often lack rigor and are controversial, quite possibly because the active components of soy-based interventions are not adequately characterized. Additionally, it is possible that there are coexisting dietary and environmental factors in East Asian cultures that confound the outcome of these studies.


More information:Journal of the American Heart Association (2019). www.ahajournals.org/doi/10.1161/JAHA.119.012458

Journal information: Journal of the American Heart Association
Provided by University of Toronto

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