Table 3.
RCTs of polyphenols (isoflavones and procyanidins) in CVD risk.
| Group (Class) | Author/Date | Jadad Score | Design (Follow up) | (n) Population | Intervention | Outcomes | Significant Results |
|---|---|---|---|---|---|---|---|
| Flavonoids (Isoflavones) | McVeigh et al. (2006) [56] | 3 | 1B, X (57 days, 4 weeks washout) | (35) Healthy males | Milk protein isolate (MPI), low-isoflavone soy protein isolate (low-iso SPI; 1.64 ± 0.19 mg aglycone isoflavones/day), and high-isoflavone SPI (high-iso SPI; 61.7 ± 7.4 mg aglycone isoflavones/day) | Lipids profile | ↓ TC/HDLc, LDLc/HDLc, and Apo B/Apo A-I with both SPI treatments than with MPI treatment |
| Flavonoids (Isoflavones) | Sanders et al. (2002) [57] | 3 | X (17 days, 25 days washout) | (22) Healthy subjects | 56 vs. 2 mg isoflavones/day | Lipids profile, fibrinogen, and active TGF-β, factor VII coagulant and PAI-1 | ↑ HDL and Apo A1 in high-isoflavone |
| Flavonoids (Isoflavones) | Thorp et al. (2008) [58] * | 5 | 2B, PCB, X (6 weeks) | (91) Hypercholesterolemia | 24 g SP+70–80 mg ISOs (diet S) vs. 12 g SP + 12 g dairy protein (DP) + 70–80 mg ISOs (diet SD) vs. 24 g DP without ISOs (diet D) | HDLc, LDLc, TC | No significant effect |
| Flavonoids (Isoflavones) | Atkinson et al. (2004) [59] | 5 | 2B, PCB (12 months) | (205) Female | 43.5 mg red clover-derived isoflavones/day vs. PCB | Lipids profile, BP, fibrinogen and PAI-1 | No significant effect |
| Flavonoids (Isoflavones) | Marini et al. (2010) [60] | 5 | 2B, PCB (24 months) | (138) Females with low bone mass | 54 mg/day genistein aglycone vs. PCB | Lipids profile, CHO metabolism, HOMA, fibrinogen, osteoprotegerin and homocysteine | ↓ fasting glucose and insulin, HOMA, fibrinogen and homocysteine |
| Flavonoids (Isoflavones) | Hodis et al. (2011) [61] | 5 | 2B, PCB (2 years) | (350) Postmenopausal women | 25 g/day soy protein (91 mg/day aglycone isoflavone equivalents) vs. PCB | Atherosclerosis progression | No significant effect |
| Flavonoids (Isoflavones) | Atteritano et al. (2007) [62] | 5 | 2B, PCB (24 months) | (191) Postmenopausal women | 54 mg/day genistein vs. PCB | Lipids profile, CHO metabolism, HOMA, fibrinogen, sVCAM-1, sICAM-1, 8-iso-PGF2α, and osteoprotegerin | ↓ Fasting glucose and insulin as well as HOMA, fibrinogen, 8-iso-PGF2α, sICAM-1, and sVCAM-1. ↑ Serum osteoprotegerin |
| Flavonoids (Isoflavones) | Garrido et al. (2006) [63] | 3 | PCB (12 weeks) | (29) Postmenopausal women | 100 mg/day isoflavones vs. PCB | Lipids profile, CHO metabolism and platelet thromboxane A2 receptor density. BP, BMI, subcutaneous fat | ↓ Thromboxane A2 after the experimental treatment. |
| Flavonoids (Isoflavones) | Hall et al. (2005) [64] | 4 | 2B, PCB, X (8 weeks, 8 weeks washout) | (117) Postmenopausal women | Isoflavone-enriched (genistein-to-daidzein ratio of 2:1; 50 mg/day) vs. PCB cereal | Inflammatory and vascular homeostasis biomarkers | ↓ CRP |
| Flavonoids (Isoflavones) | Rios et al. (2008) [65] | 3 | 2B, PCB (6 months) | (47) Postmenopausal women | 40 mg/day isoflavone vs. casein PCB | Lipids profile | No significant effect |
| Flavonoids (Isoflavones) | Villa et al. (2009) [66] | 3 | PCB (24 weeks) | (50) Postmenopausal women | 54 mg/day genistein vs. PCB | Anthropometric measures, lipid profile, CHO metabolism and C-peptide evaluation, IR and EF | HOMA and fasting glucose levels significantly improved |
| Flavonoids (Isoflavones) | Liu et al. (2012) [67] | 4 | 2B, PCB (6 months) | (180) Postmenopausal women | 15 g/day soy protein and 100 mg/day isoflavone (Soy group), vs. 15 g/day milk protein and 100 mg/day isoflavone (Iso group) vs. 15 g/day milk protein (PCB) | Lipids profile, inflammatory markers and composite cardiovascular | No significant effect |
| Flavonoids (Isoflavones) | Yang et al. (2012) [68] | 3 | Open-labelled, prospective (24 week) | (130) Healthy Taiwanese postmenopausal women | 35 mg/day vs. 70 mg/day soy extractª | Lipids profile | ↓ TC, LDLc in patients with TC >200 mg/dL |
| Flavonoids (Isoflavones) | Liu et al. (2013) [67] | 5 | 2B, PCB (6 months) | (270) Pre-hypertensive women | 40 g/day soy flour (whole soy group), 40 g/day low-fat milk powder + 63 mg/day daidzein (daidzein group), vs. 40 g/day low-fat milk powder (PCB) | Anthropometric indicators and body composition | No significant effect |
| Flavonoids (Isoflavones) | Aubertin-Leheudre et al. (2008) [69] | 3 | 2B, PCB (6 months) | (50) Obese postmenopausal women | 70 mg/day isoflavones vs. PCB | Body composition (DXA), and Lipid profile and CHO metabolism | No significant effect |
| Flavonoids (Isoflavones) | Choquette et al. (2011) [70] | 4 | 2B, PCB (6 months) | (100) Overweight to obese postmenopausal women | PCB or isoflavones (70 mg/day) or exercise + PCB or exercise + isoflavones (70 mg/day). Exercise consisted of three weekly sessions of resistance training and aerobics | Body composition, lipids profile, CHO metabolism and HOMA. | No significant effect |
| Flavonoids (Isoflavones) | Aubertin-Leheudre M et al. (2007) [71] | 3 | 2B, PCB (12 months) | (56) Obese postmenopausal women | 70 mg/day isoflavonesb (+weight loss exercise program from the 6 months) vs. PCB | Anthropometry, lipids profile, CHO metabolism, CRP | ↓ body weight, BMI, total and abdominal FM (kg and %), ↑ FFM/FM ratio with exercise program |
| Flavonoids (Isoflavones) | Hodgson et al. (1999) [72] | 3 | 2B, PCB, PA (8 weeks) | (59) High-normal BP | 55 mg/day isoflavonoid vs. PCB | 8-iso-PGF2α | No significant effect |
| Flavonoids (Isoflavones) | Sagara et al. (2004) [73] | 3 | PCB, 2B, PA (5 weeks) | (61) Men with relatively higher BP or TC | Diets containing at least 20 g/day soy protein + 80 mg/day isoflavones vs. PCB diets | BP and Lipid profile | ↓ BP, TC and non-HDLc and ↑ HDLc. |
| Flavonoids (Isoflavones) | Clerici et al. (2007) [74] | 4 | Ctrl, PA (8 weeks) | (62) Hypercholesterolemia | 80 g serving/d (33 mg/day isoflavones + negligible soy protein + led to a serum isoflavone concentration of 222 +/- 21 nmol/L) vs. Ctrl group | Lipids profile, hsCRP, urinary 8-iso-PGF2α, and EF | ↓ LDLc, TC |
| Flavonoids (Isoflavones) | Meyer et al. (2004) [75] | 3 | PCB, X (5 weeks, without washout) | (23) Mildly hypercholesterolemic and/or hypertensive | Soy-based milk (30 g/day soy protein + 80 mg/day isoflavones) + yoghurt (treatment) vs. equivalent dairy products (Ctrl) | BP, arterial compliance, lipid profile, fatty acids | No significant effect |
| Flavonoids (Isoflavones) | Jenkins et al. (2002) [76] | 3 | 1B (1 month, 2 weeks washout) | (41) Postmenopausal women with hypercholesterolemia | A low-fat dairy food Ctrl diet, high- (50 g soy protein and 73 mg isoflavones/day), low- (52 g soy protein and 10 mg isoflavones/day) isoflavone soy food diets | BP, lipids profile, oxidized LDL, calculated CAD risk | Soy diets ↓ TC estimated CAD risk, TC/HDLc, LDLc/HDLc, ApoB/A-I. Blood lipid and BP changes, the calculated CAD risk ↓ with the soy diets |
| Flavonoids (Isoflavones) | Blum et al. (2003) [77] | 4 | 2B, PCB, X (6 weeks, 1 month washout) | (24) Postmenopausal women with hypercholesterolemia | 25 g/day soy protein vs. PCB | Vascular inflammation biomarkers | No significant effect |
| Flavonoids (Isoflavones) | Teede et al. (2006) [78] | 3 | Ctrl, X (3 months) | (41) Hypertensive postmenopausal | Soy cereal (40 g/day soy protein + 118 mg/day isoflavones) vs. gluten PCB cereal | BP, arterial function | ↑ 24 hour HR, area under curve of 24 h SBP |
| Flavonoids (Isoflavones) | Cicero et al. (2013) [79] | 4 | Ctrl, 1B prospective study with PA (12 weeks) | (40) Mildly dyslipidemic postmenopausal women | 60 mg/day soy isoflavones + 500 mg/day berberine vs. PCB (1 tablet/d) | BP, HOMA, lipids profile, metalloproteinase | Isoflavones-berberine experienced a significant improvement in plasma lipid and metalloproteinase serum levels. |
| Flavonoids (Isoflavones) | Curtis et al. (2013) [80] | 5 | 2B, PCB, PA (1 year) | (180) Postmenopausal women with T2D | 27 g/day flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] + 100 mg isoflavones [aglycone equivalents)] /d) vs. PCB. | Intima-media thickness of the common carotid artery, pulse wave velocity, augmentation index, BP, and vascular biomarkers | Only pulse pressure variability improved |
| Flavonoids (Isoflavones) | Curtis et al. (2013) [80] | 5 | PA, PCB (1 year) | (93) Postmenopausal women with T2D | 27 g/day flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] + 100 mg isoflavones [aglycone equivalents)] /d) vs. PCB. | HOMA and QUICKI, lipid profile, BP | Estimated 10-year total coronary heart disease risk (derived from UK Prospective Diabetes Study algorithm) was attenuated after flavonoid intervention |
| Flavonoids (Isoflavones) | Chan et al. (2008) [81] | 5 | 2B, PCB (12 weeks) | (102) Prior ischemic stroke | 80 mg/day isoflavone supplement vs. PCB | EF, nitro-glycerine-mediated dilatation, BP, HR, CHO metabolism, haemoglobin A1c, and oxidative stress biomarkers | ↓ serum hsCRP and improved brachial EF in patients with clinically manifest atherosclerosis |
| Flavonoids (Isoflavones) | Webb et al. (2008) [82] | 4 | 2B, PA (5 days) | (71) Subjects with CAD | Isoflavone-intact soy protein (75 mg/day of isoflavones) vs. isoflavone-free PCB | Stimulated coronary blood flow, Basal and stimulated coronary artery luminal diameters | No significant effect |
| Flavonoids (Isoflavones) | Fanti et al. (2006) [83] | 3 | 2B, Crtl, prospective, pilot study (8 weeks) | (32) ESRD patients with systemic inflammation | Nutritional supplements (soy groups) containing 26–54 mg isoflavones aglycones vs. isoflavone-free milk-based supplements (Ctrl group) | Inflammatory biomarkers | Inverse correlation between blood isoflavones levels and CRP, positive correlation between blood isoflavones levels and IGF-1 |
| Flavonoids (Procyanidins) | Ras et al. (2013) [84] | 5 | 2B, PCB, PA (8 weeks) | (70) Healthy subjects | 300 mg/day Grape Seed Extract vs. PCB | BP | No significant effect |
| Flavonoids (Procyanidins) | Yubero et al. (2013) [85] | 3 | 2B, PCB, X (56 days) | (60) Healthy subjects | 700 mg/day the Grape Extract (Eminol®) vs. PCB | CVD risk and oxidative stress markers | ↓TC, LDLc and ↑ TAC and vitamin E. |
| Flavonoids (Procyanidins) | Asher et al. (2012) [86] | 5 | 2B, PCB, four-period X (3.5 days, 4 days washout) | (21) Pre-hypertensive or mildly hypertensive adults | Hawthorn Extract (1000, 1500, and 2500 mg/day) vs. PCB | EF and nitric oxide release | No significant effect |
| Flavonoids (Procyanidins) | Liu et al. (2004) [87] | 3 | PCB, 2B, PA (12 weeks) | (58) HT subjects | 100 mg/day Pycnogenol vs. PCB | Endothelin | ↓ Calcium antagonist nifedipine. ↓ endothelin-1 concentration and ↑ of 6-keto prostaglandin F1a. |
| Flavonoids (Procyanidins) | Enseleit et al. (2012) [88] | 5 | 2B, PCB, X (8 weeks, 2 weeks washout) | (23) Patients with stable CAD | 200 mg/day Pycnogenol vs. PCB | EF, oxidation and inflammatory markers, platelet adhesion and 24 h BP | EF improvement. ↓ 8-iso-PGF2α |
| Flavonoids (Procyanidins) | Mellen et al. (2010) [89] | 3 | 2B, PCB, X (4 weeks, 4 weeks washout) | (50) Patients with CAD | 1300 mg/day muscadine grape seed vs. PCB | EF, oxidation and inflammatory markers, antioxidant status | No significant effect |
| Flavonoids (Procyanidins) | Tauchert et al. (2002) [90] | 3 | 2B, PCB (16 weeks) | (209) Chronic stable heart failure patients | 1800 mg/day crataegus extract WS 1442 or 900 mg/day crataegus extract WS 1442 vs. PCB | Typical heart failure symptoms | Typical heart failure symptoms as rated by the patients were ↓ to a greater extent |
ªSoy extract contains: contains 17.5 mg soy isoflavones consisting of 5.25 mg glycitin, 8.75 mg daidzein, and 3.5 mg genistein; b 44 mg of daidzein, 16 mg of glycitein, and 10 mg of genistein; c Soy groups in three formats: Protein powder (54mg isoflavones), Cereal-like product (26mg isoflavones), energy bar (26 mg isoflavones).
8-iso-PGF2α, 8-iso-prostaglandin F2α; 1B, one-blind, 2B, double-blinded; ACN, anthocyanins; Apo, apolipoprotein; BMI, body mass index; BP, blood pressure; CAD, chronic artery disease; CAT, catalase; CHF, chronic heart failure; CHO, carbohydrate; CRP, C-reactive protein; hsCRP, high sensitivity c-reactive protein; Ctrl, control, CVD, cardiovascular disease; DXA, Dual-energy X-ray absorptiometry; EF, endothelial function; EGCG, epigallocatechin gallate; ESRD, European and North American end-stage renal disease; FM, fat mass; FFM, fat-free mass; HDLc, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; HR, heart rate; HT, hypertension; sICAM, soluble intercellular adhesion molecule; IGF-1, insulin-like growth factor-1; IR, insulin resistance; IL, interleukin; LDLc, low-density lipoprotein cholesterol; MDA, malonaldehyde; MPFF, micronized purified flavonoid fraction; MPI, milk protein isolate; NTG, nitro-glycerine-mediated dilation; PA, parallel design, PAI-1, plasminogen activator inhibitor-1; PCB, placebo, PBMCs, peripheral blood mononuclear cells; PS, plant sterols; PWV, pulse wave velocity; QUICKI, quantitative insulin sensitivity check index; SBP, systolic blood pressure; SOD, superoxide dismutase; TC, total cholesterol; TGF, transforming growth factor; T2D, type 2 diabetes; VCAM, soluble vascular cellular adhesion molecule; vWf, von Willebrand factor; X, crossover design. *Included after proofreading.