The impact of equol-producing status in modifying the effect of soya isoflavones on risk factors for CHD: a systematic review of randomised controlled trials

Rahel L Birru; Vasudha Ahuja; Abhishek Vishnu; Rhobert W Evans; Yoshihiro Miyamoto; Katsuyuki Miura; Takeshi Usui; Akira Sekikawa

doi:10.1017/jns.2016.18

. 2016 Jul 19;5:e30. doi: 10.1017/jns.2016.18

The impact of equol-producing status in modifying the effect of soya isoflavones on risk factors for CHD: a systematic review of randomised controlled trials

Rahel L Birru ¹, Vasudha Ahuja ¹, Abhishek Vishnu ², Rhobert W Evans ¹, Yoshihiro Miyamoto ³, Katsuyuki Miura ⁴, Takeshi Usui ⁵, Akira Sekikawa ^1,^*

PMCID: PMC4976117 PMID: 27547393

Abstract

Recent studies suggest that the ability to produce equol, a metabolite of the soya isoflavone daidzein, is beneficial to coronary health. Equol, generated by bacterial action on isoflavones in the human gut, is biologically more potent than dietary sources of isoflavones. Not all humans are equol producers. We investigated whether equol-producing status is favourably associated with risk factors for CHD following an intervention by dietary soya isoflavones. We systematically reviewed randomised controlled trials (RCT) that evaluated the effect of soya isoflavones on risk factors for CHD and that reported equol-producing status. We searched PubMed, EMBASE, Ovid Medline and the Cochrane Central Register for Controlled Trials published up to April 2015 and hand-searched bibliographies to identify the RCT. Characteristics of participants and outcomes measurements were extracted and qualitatively analysed. From a total of 1671 studies, we identified forty-two articles that satisfied our search criteria. The effects of equol on risk factors for CHD were mainly based on secondary analyses in these studies, thus with inadequate statistical power. Although fourteen out of the forty-two studies found that equol production after a soya isoflavone intervention significantly improved a range of risk factors including cholesterol and other lipids, inflammation and blood pressure variables, these results need further verification by sufficiently powered studies. The other twenty-eight studies primarily reported null results. RCT of equol, which has recently become available as a dietary supplement, on CHD and its risk factors are awaited.

Key words: Equol, Soya isoflavones, CHD, Risk factors

Abbreviations: HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; RCT, randomised controlled trial

CHD is the leading cause of morbidity and mortality in the USA⁽¹⁾ and worldwide⁽²⁾. Nutrition is an important determinant for the risk of developing CHD; poor dietary habits are estimated to account for 20 % of CHD cases in the US adult population⁽¹⁾. Soya foods are a potential nutritional source for modifying biomarkers of CHD⁽³^,⁴⁾. One of the main components of soya that may exert protective cardioprotective effects are isoflavones, bioactive phyto-oestrogens found in soyabeans⁽³⁾. The predominant soya isoflavones are genistein, daidzein and glycitein. Isoflavones may reduce the risk of CHD by: (1) their action via oestrogen receptor β, due to their structural similarity to oestradiol, leading to decreased vasodilation and inflammation⁽⁴^–⁷⁾; (2) their antioxidant activity, which may prevent the oxidative damage to LDL-cholesterol (LDL-C) that contributes to atherogenesis⁽⁸⁾; and (3) modulating the vascular system, reducing atherosclerotic lesions and improving vascular reactivity and vascular stiffness⁽⁹^,¹⁰⁾.

Although there are clear cardiovascular benefits of isoflavones in vitro and in animal studies⁽⁹^,¹¹⁾, the evidence in humans is conflicting⁽¹²^–¹⁴⁾. A growing hypothesis is that the ability of humans to metabolise daidzein to equol, referred to as ‘equol producers’, may contribute to the protective effects of soya⁽¹⁵^,¹⁶⁾. Equol has a greater affinity for oestrogen receptors than its precursor daidzein⁽¹⁷⁾, a longer half-life and bioavailability in plasma than daidzein and genistein⁽³^,¹⁸⁾, and more potent antioxidant activity than any other isoflavone⁽³⁾. Therefore, the potential beneficial effects of soya isoflavones for CHD and its risk factors may be greater among equol producers. While all tested animals, including rodents and monkeys, can produce equol, not all humans have the gut microflora required to convert daidzein to equol, a bioactive metabolite⁽¹⁵^,¹⁹⁾.

Equol is a promising candidate for hindering the initiation and progression of atherosclerosis due to its ability to induce vasorelaxation and its anti-inflammatory and antioxidant activity⁽²⁰⁾. Specifically, it induces vasorelaxation through enhancing the production of endothelium nitric oxide synthase-derived NO⁽²¹⁾. It can also inhibit NO derived by inducible nitric oxide synthase, expressed by immune cells during host defence, which is linked to atherosclerosis development⁽²²⁾. Furthermore, equol prevents lipid and lipoprotein peroxidation, a crucial process in the pathogenesis of atherosclerosis⁽²³^,²⁴⁾.

The purpose of the present review is to examine if there is a difference in the cardioprotective effect of soya isoflavones in humans based on the hosts’ ability to produce equol. No previous reviews have thoroughly examined the impact of equol-producing status on risk factors for CHD. We conducted a comprehensive search of the scientific literature to identify randomised controlled trials (RCT) that evaluated the effects of soya isoflavones on risk factors for CHD and selected studies that included analyses based on equol producer status.

Methods

Literature search

The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines⁽²⁵⁾. We initially searched PubMed (1950 to April 2015), EMBASE through Embase.com (1966 to April 2015), Ovid Medline (1946 to April 2015) and the Cochrane Library (Cochrane Central Register of Controlled Trials, 1999 to April 2015) for papers in any language using one or more textual or medical subject heading (MESH) terms for isoflavones (isoflavones, isoflavonoids, genistein, daidzein, equol), risk factors for CHD (cardiovascular disease, coronary heart disease, myocardial infarction, lipids, low-density lipoprotein-cholesterol, triglyceride, lipoproteins, hypercholesterolemia, lipid metabolism, blood pressure, glucose, vital signs, arterial stiffness, vascular stiffness, intima-media thickness, inflammation, endothelial function, endothelium, adipocytes) and RCT (randomised control study, clinical trial, placebo, intervention studies, pilot projects, sampling studies, twin studies, prospective studies, double blind study, single blind study, epidemiologic research design). We reviewed the reference lists of the collected articles to identify additional potentially relevant papers not identified by the original keyword search.

Study selection

Studies were selected for the systematic review if they met the following criteria: (1) RCT; (2) full-text was published in English; (3) analysed adult subjects who ingested soya with isoflavones or isolated isoflavones as an intervention; (4) analysed traditional risk factors for CHD (including lipids, inflammatory, blood pressure, glycaemic and body composition variables) as outcome measurements; (5) determined the equol producer status of the participants; and (6) stratified the outcome measurements by equol producer status. The exclusion criteria included reviews or commentaries.

Data synthesis and quality assessment

Searching, data extraction and the quality assessment were completed by two authors independently according to the inclusion criteria. Discrepancies were resolved by consensus. For each RCT, extracted data included sample size, baseline characteristics of the participants (sex, mean age, health status, demographics, equol producer status), study design, treatment regimen (dose, duration, isoflavone content, and type of soya intervention), and the assessment of the risk factor(s) for CHD.

The quality of the RCT methodology was graded using a fourteen-point evaluation tool for controlled clinical trials developed by the National Heart, Lung, and Blood Institute⁽²⁶⁾. Questions were answered with a ‘yes’, ‘no’, ‘not reported’, ‘cannot determine’ or ‘not applicable’. The evaluation was based on the primary outcome measurements of the RCT. The RCT were given an overall rating of ‘good’, ‘fair’ or ‘poor’ at the discretion of the reviewers based on the guidelines provided by this tool.

Results

Search results

A total of 1671 papers were collected and, of these, 829 were excluded because they were not RCT, did not measure the traditional risk factors for CHD, or were not published in English (Fig. 1). Of the remaining 247 papers screened, forty-two met the selection criteria for this review. An outline of our search strategy using PubMed is provided in Supplementary Table S1.

Fig. 1. — Study flow diagram of screened, excluded and analysed publications.

Study characteristics

Study characteristics are summarised in Tables 1 and 2, and Supplementary Table S2. Thirty studies included only female participants⁽¹⁴^,²⁷^–⁵⁵⁾, eleven studies included both males and females⁽⁵⁶^–⁶⁶⁾, and one study had only male participants⁽⁶⁷⁾. Of the forty-one studies involving women, thirty-four included postmenopausal women only⁽¹⁴^,²⁷^,²⁸^,³⁰^–⁵⁵^,⁶⁰^,⁶³^,⁶⁵^,⁶⁶⁾. The age of the participants ranged from 27 to 73 years. Participants were hypercholesterolaemic in seven studies⁽⁵⁶^,⁵⁷^,⁵⁹^,⁶²^,⁶⁴^–⁶⁶⁾, hyperlipidaemic in two studies⁽⁵⁸^,⁶⁶⁾, prehypertensive or hypertensive in five studies⁽³⁹^–⁴¹^,⁵⁵^,⁵⁹⁾, had type 2 diabetes in two studies⁽³⁰^,⁶¹⁾, had the metabolic syndrome in two studies⁽²⁷^,⁶³⁾, and considered healthy in twenty-three studies⁽¹⁴^,²⁹^,³¹^,³⁴^–³⁸^,⁴²^–⁵⁴^,⁶⁰^,⁶⁷⁾. Diet interventions in nineteen studies used soya protein isolate with isoflavone flour, or powder, or tablets⁽³¹^–³³^,³⁷^–⁴²^,⁴⁸^–⁵¹^,⁵⁷^,⁵⁸^,⁶¹^,⁶²^,⁶⁵^,⁶⁷⁾, fifteen used soya- and isoflavone-enriched milk or foods⁽¹⁴^,²⁷^,³⁰^–³⁶^,⁴⁶^,⁴⁷^,⁵⁵^–⁵⁷^,⁵⁹^,⁶³^–⁶⁶⁾, and nine used isolated isoflavone tablets or capsules⁽²⁸^,²⁹^,⁴²^–⁴⁵^,⁵²^–⁵⁴⁾, with Gardner et al.⁽⁵⁷⁾ using interventions that covered two categories. Isoflavone doses ranged from approximately 40 to 120 mg/d, with one dose particularly high at 900 mg/d⁽⁴⁴⁾. Twenty-three studies examined cholesterol markers⁽²⁷^,²⁸^,³¹^,³²^,³⁵^,³⁸^,³⁹^,⁴²^,⁴³^,⁴⁸^,⁵²^,⁵⁶^–⁶⁷⁾, twenty-one examined other lipid variables⁽²⁷^,²⁸^,³¹^,³²^,³⁵^,³⁸^,³⁹^,⁴²^,⁴³^,⁴⁷^,⁴⁸^,⁵²^,⁵⁶^,⁵⁸^,⁵⁹^,⁶¹^,⁶²^,⁶⁴^–⁶⁷⁾, eighteen examined blood pressure and vascular variables⁽¹⁴^,²⁷^,³⁰^,³⁴^–³⁷^,³⁹^,⁴⁰^,⁴³^,⁴⁸^,⁴⁹^,⁵¹^,⁵⁵^,⁵⁶^,⁵⁹^,⁶³^,⁶⁶⁾, seventeen examined inflammatory markers⁽²⁷^,³³^,³⁴^,⁴²^,⁴⁴^–⁴⁶^,⁴⁸^,⁵⁰^,⁵³^,⁵⁴^,⁵⁶^,⁶²^,⁶³^,⁶⁵^–⁶⁷⁾, ten examined glucose and insulin variables⁽²⁷^,²⁹^,³⁵^,³⁹^,⁴³^,⁵⁰^,⁵⁷^,⁶²^,⁶³^,⁶⁵⁾ and five examined body composition variables⁽²⁷^,⁴¹^,⁴³^,⁶⁵^,⁶⁶⁾. There were numerous methods and standards used to distinguish equol producers from non-equol producers, including sampling from urine or serum, different threshold levels for differentiation, and various analytical techniques.

Table 1.

Demographic and clinical characteristics of the participants in the randomised controlled trials (RCT) employing soya interventions and examining the effect of equol producer (EP) status on risk factors for CHD

First author, year	Country	Sex (no. M/no. F)	Mean age (years)	No. of EP (no. EP/no. NEP)	Guidelines for determining EP status	Subjects’ characteristics	Study design	Quality rating^*
Acharjee et al. (2015)⁽²⁷⁾^†	USA	60 F	MetS: 54·1 (sd 6·5), without MetS: 54·6 (sd 5·8)	35 EP/25 NEP	Urinary equol concentration >1000 nmol/l	Postmenopausal, with and without MetS	CO	Fair
Badeau et al. (2007)⁽²⁸⁾^‡	Finland	30 F	54	15 EP/15 NEP	Equol concentration > five times baseline	Postmenopausal breast cancer survivors	CO, DB	Fair
Campbell et al. (2004)⁽²⁹⁾	UK	23 F	Premenopausal: 34, postmenopausal: 57	7 EP/9 NEP in premenopausal group, 1 EP/6 NEP in postmenopausal group	Urinary equol concentrations >1 mg/ml	Healthy	CO, DB	Fair
Clerici et al. (2007)⁽⁵⁶⁾	Italy	25 M/37 F	Control: 52·0 (sem 2·4), intervention: 58·1 (sem 2·2)	20 EP/9 NEP (of intervention group)	Plasma equol concentrations >83 nmol/l are EP, <40 nnmol/l are NEP, 24 h urinary log₁₀ S-equol:daidzein ratio > −1·75 after daidzein challenge	Hypercholesterolaemic, adhering to Italian Heart Association Step II diet	CO, P, B	Fair
Curtis et al. (2013)⁽³⁰⁾	UK	118 F	Control: 63·0 (sem 0·8), intervention: 62·1 (sem 0·7)	17 EP/30 NEP (of intervention group)	Not reported	Postmenopausal, type 2 diabetic, using statins	DB	Poor
Gallagher et al. (2004)⁽³¹⁾	USA	65 F	55	36 EP/29 NEP	Serum equol >10 ng/ml	Postmenopausal	DB	Poor
Gardner et al. (2007)⁽⁵⁷⁾	USA	6 M/22 F	52 (sd 9)	9 EP/19 NEP	Plasma equol >50 nM	Hypercholesterolaemic	CO, SB	Poor
Greany et al. (2004)⁽³²⁾^§	USA	37 F	57·5 (sem 2·2)	8 EP/29 NEP	Plasma equol concentrations >15 nmol/l and urinary excretion >1500 nmol/24 h	Postmenopausal, history of breast cancer not treated with chemotherapy or no family history of breast cancer, no history of reproductive cancer	CO	Poor
Greany et al. (2008)⁽³³⁾^§	USA	34 F	57·7 (sd 6·0)	6 EP/28 NEP	Plasma equol concentration >15 nmol/l and urinary equol excretion >1500 nmol/d	Postmenopausal, with and without a history of breast cancer	CO	Poor
Hall et al. (2005)⁽³⁴⁾^‖	UK, Germany, Denmark, Italy	117 F	57·7 (sd 5·4)	33 EP/84 NEP	24 h urinary equol concentration during the isoflavone intervention >936 nmol/l	Postmenopausal	CO, DB	Fair
Hall et al. (2006)⁽³⁵⁾^‖	UK, Germany, Denmark, Italy	117 F	57·7 (sd 5·4)	33 EP/84 NEP	24 h urinary equol concentration during the isoflavone intervention >936 nmol/l	Postmenopausal	CO, DB	Fair
Hallund et al. (2006)⁽³⁶⁾^‖	Denmark, UK, Germany, Italy	28 F	57 (sd 5)	6 EP/22 NEP	24 h urinary equol concentration during the isoflavone intervention >936 nmol/l	Postmenopausal	CO, DB	Fair
Hodis et al. (2011)⁽¹⁴⁾	USA	350 F	60·9	39 consistent EP/35 intermittent EP/76 NEP	Consistent EP: plasma equol >20 nmol/l at all visits, intermittent EP: plasma equol >20 nmol/l at some visits, NEP: plasma equol never >20 nmol/l	Postmenopausal	DB	Good
Kreijkamp-Kaspers et al. (2005)⁽³⁷⁾^¶	Netherlands	175 F	Control: 66·8 (sd 4·7), intervention: 66·6	26 EP/62 NEP (of intervention group)	Plasma equol concentration >83 nmol/l	Postmenopausal	DB	Fair
Kreijkamp-Kaspers et al. (2004)⁽³⁸⁾^¶	Netherlands	175 F	Control: 66·7 (sd 4·8), intervention: 66·5 (sd 4·7)	26 EP/62 NEP (of intervention group)	Plasma equol concentration >83 nmol/l	Postmenopausal	DB	Fair
Liu et al. (2014)⁽³⁹⁾^**	China	287 F	Control: 58·5 (sd 4·7), whole soya: 57·6 (sd 5·3), daidzein: 57·7 (sd 5·0)	287 EP/0 NEP	24 h urinary log₁₀ S-equol:daidzein ratio > −1·75 after daidzein challenge	Postmenopausal, prehypertensive	DB	Good
Liu et al. (2015)⁽⁴⁰⁾^**	China	265 F	Control: 58·5 (sd 4·7), whole soya: 57·6 (sd 5·3), daidzein: 57·7 (sd 5·0)	265 EP/0 NEP	24 h urinary log₁₀ S-equol:daidzein ratio > −1·75 after daidzein challenge	Postmenopausal, prehypertensive or untreated hypertensive	P, DB	Good
Liu et al. (2013)⁽⁴¹⁾^**	China	253 F	Control: 58·5 (sd 4·7), whole soya: 57·6 (sd 5·3), daidzein: 57·7 (sd 5·0)	253 EP/0 NEP	24 h urinary log₁₀ S-equol:daidzein ratio > −1·75 after daidzein challenge	Postmenopausal, prehypertensive	DB	Good
Ma et al. (2005)⁽⁵⁸⁾	USA	70 M/89 F	56 (sd 8·46)	21 EP/59 NEP (of intervention group)	Serum equol concentration >20 ng/ml	Hyperlipidaemic	DB	Fair
Mangano et al. (2013)⁽⁴²⁾	USA	97 F	Control: 72·9 (sd 6·1), soya protein: 74·0 (sd 6·2), isoflavone: 72·3 (sd 5·7), soya protein and isoflavone: 73·0 (sd 5·7)	25 EP/26 NEP	12-month serum concentration of S-equol 20 nmol/l (5 µg/l)	Postmenopausal	DB	Poor
McVeigh et al. (2006)⁽⁶⁷⁾	Canada	35 M	27·9 (sd 5·7)	12 EP/23 NEP	Urinary equol >1000 nmol/24 h	Healthy	CO, B	Poor
Meyer et al. (2004)⁽⁵⁹⁾	Australia	13 M/10 F	54·0 (sem 1·8)	8 EP/15 NEP	Equol detected in the plasma or urine	Postmenopausal, hypercholesterolaemic and/or hypertensive	CO	Poor
Nestel et al. (2004⁽⁶⁰⁾	Australia	46 M/34 F	Males: 58 (sd 7), Females: 58 (sd 6)	15 EP/65 NEP	Excretion of equol >1000 nmol/24 h	Postmenopausal	CO, P, DB	Fair
Nikander et al. (2004)⁽⁴³⁾^‡	Finland	56 F	54 (sd 6)	8 EP/40 NEP	EP: equol concentration >83 nmol/l, NEP: equol concentration <40 nmol/l	Postmenopausal	CO, DB	Fair
Pipe et al. (2009)⁽⁶¹⁾	Canada	16 M/13 F	60·1 (sd 9·64)	6 EP/23 NEP	Urinary equol > 1000 nmol/24 h	Postmenopausal, diet-controlled type 2 diabetic	CO, DB	Poor
Pop et al. (2008)⁽⁴⁴⁾	USA	30 F	Placebo: 53·50 (se 1·06), intervention: 56·78 (se 1·25)	6 EP/23 NEP/1 intermediate EP	EP: plasma equol concentrations >20 µg/l; intermediate EP: (≥10 to ≤20 µg/l; NEP: plasma equol concentration <10 µg/l	Postmenopausal	DB	Poor
Pusparini & Hidayat (2015)⁽⁴⁵⁾	Indonesia	182 F	Control EP: 54·3 (sd 3·42), control NEP: 52·2 (sd 3·24), intervention EP: 53·3 (sd 34·6), intervention NEP: 53·7 (sd 3·65)	110 EP/72 NEP	Baseline blood equol concentration >5 ng/ml	Postmenopausal	DB	Fair
Qin et al. (2014)⁽⁶²⁾	China	91 M/86 F	Control: 52·9 (sd 6·0), low daidzein: 54·5 (sd 6·6), high daidzein: 53·4 (sd 6·4)	106 EP/71 NEP	Urinary equol concentration >1000 nmol/l, log₁₀-transformed urinary S-equol:daidzein ratio > −1·75 after daidzein intervention	Hypercholesterolaemic	DB	Fair
Reimann et al. (2006)⁽⁴⁶⁾^‖	Denmark, UK, Germany	89 F	59 (sd 5)	29 EP/59 NEP	Urinary equol concentration >936 nmol/l urine	Postmenopausal	CO, DB	Poor
Reverri et al. (2015)⁽⁶³⁾	USA	5 M/12 F	56 (sd 5)	8 EP/9 NEP	Equol/daidzein ≥0·018 with a daidzein threshold of ≥2 nmol/mg creatinine	Postmenopausal, MetS	CO	Poor
Sen et al. (2012)⁽⁴⁷⁾	USA	82 F	39·2 (sd 6·1)	43 EP/39 NEP	Urinary daidzein excretion ≥2 nmol/mg creatinine, urinary equol:daidzein ≥0·018; participants who meet both criteria at least once during the study considered EP	Premenopausal	CO	Poor
Steinberg et al. (2003)⁽⁴⁸⁾	USA	28 F	54·9 (sem 1·0)	10 EP/18 NEP	Not reported	Postmenopausal	CO, DB	Poor
Thorp et al. (2008)⁽⁶⁴⁾	Australia	33 M/58 F	52·7 (sd 1·0)	30 EP/61 NEP	Urinary log₁₀ S-equol:daidzein value > −1·75 after soya or daidzein intervention	Hypercholesterolaemic	CO, DB	Poor
Törmälä et al. (2008)⁽⁴⁹⁾^††	Finland	36 F	57·7 (sem 0·8)	16 EP/20 NEP	>4-fold rise in serum equol concentration	Postmenopausal, using tibolone	CO	Fair
Törmälä et al. (2008)⁽⁵⁰⁾^††	Finland	36 F	57·7 (sem 0·8)	16 EP/20 NEP	>4-fold rise in serum equol concentration	Postmenopausal, using tibolone	CO	Fair
Törmälä et al. (2007)⁽⁵¹⁾^††	Finland	33 F	57·7 (sem 0·8)	14 EP/19 NEP	>4-fold rise in serum equol concentration	Postmenopausal, using tibolone	CO, DB	Fair
Törmälä et al. (2006)⁽⁵²⁾^‡	Finland	30 F	56 (sd 6)	15 EP/15 NEP	Equol concentration > five times baseline after soya isoflavone challenge	Postmenopausal, history of breast cancer	CO, DB	Fair
van der Velpen et al. (2014)⁽⁵³⁾	Netherlands	Low genistein group (LG): 24 F; high genistein group (HG): 31 F	LG: 63·2 (sd 5·5); HG: 63·0 (sd 5·5)	LG: 7 EP/17 NEP; HG: 8 EP/23 NEP	Log₁₀-transformed urinary S-equol:daidzein ratio > 1·75	Postmenopausal	CO, DB	Good
van der Velpen et al. (2013)⁽⁵⁴⁾	Netherlands	30 F	61·1 (sd 5·8)	30 EP/0 NEP	Log₁₀-transformed urinary S-equol:daidzein ratio > −1·75 post-isoflavone or daidzein challenge	Postmenopausal	CO, DB	Good
Welty et al. (2007)⁽⁵⁵⁾^†	USA	60 F	Normotensive: 53·5 (sd 5·3), hypertensive: 58·3 (sd 6·5)	35 EP/25 NEP	Urinary equol concentration greater than 1000 nmol/l	Postmenopausal; hypertensive, prehypertensive, or normotensive	CO	Fair
West et al. (2005)⁽⁶⁵⁾	USA	14 M/18 F	Males: 57·36 (se 1·43), females using HRT: 57·17 (se 2·18), females not using HRT: 59·08 (se 1·54)	11 EP/21 NEP	High concentrations of equol in urine	Postmenopausal, hypercholesterolaemic, adhering to National Cholesterol Education Program Step I diet	CO, DB	Fair
Wong et al. (2012)⁽⁶⁶⁾	Canada	42 M/43 F	59·9 (sd 8·9)	30 EP/55 NEP	Urinary equol >1000 nmol/24 h and log₁₀-transformed urinary equol:daidzein ratio > −1·75	Postmenopausal, hypercholesterolaemic, hyperlipidaemic	Studies 1 and 2: CO; study 3: P	Poor

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M, male; F, female; NEP, non-equol producer; MetS, metabolic syndrome; CO, crossover; DB, double-blind; P, parallel; B, blinded; SB, single-blinded; HRT, hormone replacement therapy.

The quality of the RCT were evaluated based on the main outcomes reported. RCT were given a score of ‘good’, ‘fair’ or ‘poor’ after appraising the degree to which flaws in the study designs could affect the validity of the results.

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