Nuts and the heart evidence paper 2012 by Heart Foundation

Appendix A. Epidemiological studies investigating the effects of nut consumption on risk of cardiovascular disease and mortality (4 cohorts)1 Author (year) Level of evidence Fraser et al. (1992) 2+

Fraser et al. (1995) 2+ Fraser et al. (1997) 2+ Fraser & Shavlik (1997) 2+

Prineas et al. (1993) 2+ Kushi et al. (1996) 2+

Study design; Subjects’ characteristics The AHS a ; Prospective 6-y follow-up; 10,003 M & 16,740 F; Non-Hispanic white

Endpoints

Frequency of nut consumption < 1 time / week 1 – 4 times / week ≥ 5 times / week < 1 time / week 1 – 4 times / week ≥ 5 times / week < 1 time / week ≥ 5 times / week

Relative risk (95% CI) 1.00 0.76 (0.56 – 1.04) 0.52 (0.36 – 0.76) 1.00 0.78 (0.51 – 1.18) 0.49 (0.28 – 0.85) 1.00 0.45 (0.35 – 0.59)

P value for trend2 <0.01

The AHS a ; Prospective 7-y follow-up; 27,321 M & F The AHS a ; Prospective 11-y follow-up; 585 M & 1,083 F Black subjects The AHS a ; Prospective 12-y follow-up; 603 M & F Aged > 84 years at baseline 11,828 person-years

CHD All-cause mortality

< 1 time / week 1 – 4 times / week ≥ 5 times / week

1.00 0.60 (0.40 – 0.90) 0.56 (0.30 – 1.00)

All-cause mortality

< 1 time / week 1 – 4 times / week ≥ 5 times / week < 1 time / week 1 – 4 times / week ≥ 5 times / week Never 1 – 3 times / month 1 time / week 2 – 4 times / week Never 1 – 2 times / week 3 – 4 times / week > 4 times / week

1.00 0.88 (0.76 – 1.01) 0.82 (0.70 – 0.96) 1.00 0.74 (0.57 – 0.97) 0.61 (0.45 – 0.83) 1.00 0.60 (0.40 – 0.89) 0.75 (0.44 – 1.27) 0.43 (0.19 – 0.93) 1.00 0.98 (0.57 – 1.68) 0.96 (0.56 – 1.64) 0.60 (0.36 – 1.01)

<0.01

The IWHS b; Prospective 5-y follow-up; 41,837 F Aged 55 – 69 years The IWHS b ; Prospective 7-y follow-up; 34,486 F

CHD death

Fatal CHD Non fatal MI

Total CHD

Fatal CHD

<0.01 <0.001

<0.001 0.06

0.016

Author (year) Level of evidence Ellsworth et al. (2001) 2+

Study design; Subjects’ characteristics The IWHS b ; Prospective 12-y follow-up; 34,111 F

Endpoints All cause mortality

CHD death

Blomhoff et al. (2006) 2+

The IWHS b ; Prospective 15-y follow-up; 31,778 F

CHD death

CVD death

Hu et al. (1998) 2++

The NHS c ; Prospective 15-y follow-up; 86,016 F nurses Aged 34 – 59 years

Total CHD

Fatal CHD

Non-fatal MI

Frequency of nut consumption < 1 time / month 1 – 3 times / month 1 time / week ≥ 2 times / week < 1 time / month 1 – 3 times / month 1 time / week ≥ 2 times / week Never < 1 time / week 1 – 4 times / week ≥ 5 times / week Never < 1 time / week 1 – 4 times / week ≥ 5 times / week Never ≤ 1 time / week 2 – 4 times / week ≥ 5 times / week Never ≤ 1 time / week 2 – 4 times / week ≥ 5 times / week Never ≤ 1 time / week 2 – 4 times / week ≥ 5 times / week

Relative risk (95% CI) 1.00 0.93 (0.86 – 1.00) 0.92 (0.83 – 1.03) 0.88 (0.77 – 0.99) 1.00 0.85 (0.71 – 1.03) 0.88 (0.69 – 1.14) 0.81 (0.60 – 1.11) 1.00 1.03 (0.84 – 1.26) 0.82 (0.68 – 0.98) 0.71 (0.55 – 0.91) 1.00 1.00 (0.86 – 1.17) 0.84 (0.73 – 0.96) 0.72 (0.60 – 0.88) 1.00 0.91 (0.81 – 1.03) 0.78 (0.61 – 0.99) 0.66 (0.47 – 0.93) 1.00 0.76 (0.61 – 0.94) 0.60 (0.38 – 0.96) 0.60 (0.33 – 1.10) 1.00 1.00 (0.87 – 1.16) 0.89 (0.66 – 1.18) 0.71 (0.47 – 1.07)

P value for trend2 0.047

0.24

0.02

<0.001

0.005

0.004

0.19

Author (year) Level of evidence Li et al. (2009) 2++

Study design; Subjects’ characteristics The NHS c ; Prospective 22-y follow-up; 6,309 F nurses with type 2 diabetes

Endpoints CVD

TC (mmol/L)

LDL-C (mmol/L)

Apo B (g/L)

Albert et al. (2002) 2+

The PHS d ; Prospective 17-y follow-up; 21,454 M physicians; Aged 40 – 84 years

Sudden death

Total CHD death

Frequency of nut consumption Never ≤1 time / week 2 – 4 times / week ≥ 5 times / week Never ≤ 1 time / week 2 – 4 times / week ≥ 5 times / week Never ≤1 time / week 2 – 4 times / week ≥ 5 times / week Never ≤ 1 time / week 2 – 4 times / week ≥ 5 times / week Never ≤ 1 time / week 2 – 4 times / week ≥ 5 times / week < 1 time / month 1 – 3 times / month 1 time / week ≥ 2 times / week < 1 time / month 1 – 3 times / month 1 time / week ≥ 2 times / week

Relative risk (95% CI) 1.00 0.72 (0.50 – 1.02) 0.80 (0.56 – 1.14) 0.56 (0.36 – 0.89) 1.00 0.63 (0.41 – 0.96) 0.74 (0.49 – 1.13) 0.56 (0.33 – 0.97) 6.11 5.83 5.76 5.65 3.66 3.55 3.43 3.31 1.07 1.04 1.01 1.00 1.00 0.80 (0.52 – 1.23) 0.60 (0.36 – 1.00) 0.53 (0.30 – 0.92) 1.00 0.89 (0.67 – 1.16) 0.90 (0.67 – 1.22) 0.70 (0.50 – 0.98)

P value for trend2 0.44

0.85

0.007

0.008

0.016

0.01

0.06

Author (year) Level of evidence Albert et al. (2002) 2+ Djousse et al. (2008) 2+

Study design; Subjects’ characteristics The PHS d ; Prospective 17-y follow-up; 21,454 M physicians; Aged 40 – 84 years The PHS I d ; Prospective 19.6-y followup; 20,976 M physicians

Endpoints Non-fatal MI

Heart failure

Frequency of nut consumption < 1 time / month 1 – 3 times / month 1 time / week ≥ 2 times / week None < 1 time / week 1 time / week ≥ 2 times / week

Relative risk (95% CI) 1.00 1.22 (1.00 – 1.51) 1.20 (0.96 – 1.50) 1.04 (0.82 – 1.33) 1.00 0.98 (0.83 – 1.15) 1.06 (0.89 – 1.27) 1.01 (0.84 – 1.22)

P value for trend2 0.87

0.64

1 a AHS, Adventist Health Study; b IWHS, Iowa Women’s Health Study; c NHS, Nurses’ Health Study; d PHS, Physicians’ Health Study. Abbreviations used: apo, apolipoprotein; CHD, coronary heart disease; CVD, cardiovascular disease; CI, confidence interval; F, female; LDL-C, low-density lipoprotein cholesterol; M, male; MI, myocardial infarction; TC, total cholesterol. 2 Multivariate model, adjusted for some potential confounding variables such as age, BMI, waist to hip ratio, history of diabetes, hypertension, and hypercholesterolaemia, parental history of MI before 60 years of age, presence of hypertension, presence of diabetes, smoking status, alcohol intake, total energy intake, marital status, level of physical activity, level of educational attainment, sex (cohort consisting of both males and females), dietary supplement use, aspirin use, oral contraceptive use (female cohort), menopause status (female cohort), use of hormone-replacement therapy (female cohort). Several dietary confounding variables such as intakes of polyunsaturated fat, saturated fat, trans-fat, fibre, fish, red meat, dairy, fruits and vegetables were also adjusted for in some of the models.

Appendix B. Dietary intervention trials investigating the effects of nut consumption on blood lipids and lipoproteins (n = 46)1 Author (y) Study design Evidence Almonds (n = 12) Spiller et al. Randomised (1998) Parallel 1+ 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics

Duration

Treatment

TC mmol/l

LDL-C mmol/l

HDL-C mmol/l

TAG mmol/l

Between treatments

45 (12 M, 33 F) Hyperlipidaemic

4 weeks

Jenkins et al. (2002) 1+

27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

4 weeks

Baseline2 (i) Control dairy (113g) Change3 Baseline2 (ii) Olive oil diet (48g) Change3 Baseline2 (iii) Almond diet (100g) Change3 Baseline2 (i) Control muffin (147g) Change3 Baseline2 (ii) Almonds (37g) + Muffins (75g) Change3 Baseline2 (iii) Almonds (73g) Change3 (i) Control low fat diet2 (ii) LFD + Almonds (10% en: 57-113g) Difference4 (iii) Control high fat diet2 (iv) HFD + Almonds (10% en: 57-113g) Difference4

6.48 6.81 +0.33 6.48 6.22 -0.26 6.48 5.75 -0.73a 6.54 6.44 -0.10 6.47 6.25

4.27 4.51 +0.24 4.27 4.07 -0.20 4.40 3.65 -0.75c 4.34 4.22 -0.12 4.30 4.10

1.55 1.68 +0.13 1.55 1.55 0.00 1.55 1.55 0.00 1.43 1.41 -0.02 1.38 1.43

1.58 1.47 -0.11 1.58 1.53 -0.05 1.36 1.24 -0.12 1.69 1.80 +0.11 1.75 1.58

-0.22a 6.60 6.21 -0.39c 4.63 4.63

-0.20a 4.45 4.01 -0.44c 2.53 2.53

+0.05a 1.40 1.45 +0.05a 1.16 1.13

-0.17 1.66 1.64 -0.02 2.00 2.10

0.00 4.52 4.46

0.00 2.58 2.51

-0.03b 1.17 1.13

+0.10 1.68 1.77

Compared with the control and olive oil diets, the almond diet had lower TC and LDL-C (both P < 0.001). There were no between-group differences in HDL-C and TAG. Compared to the control group, halfdose almonds had lower TC (P < 0.05), and full-dose almonds had lower TC (P < 0.01), LDL-C (P < 0.01) and higher HDL-C (P < 0.05). Compared to the control diets, HDL-C was significantly lower for the almond diets.

-0.06

-0.07

-0.04b

+0.09

Lovejoy et al. (2002) Study 2 1++

Randomised Crossover 3-arm Control group

Randomised Crossover; CF 4-arm Control group Double-blind

30 (13 M, 17 F) Type 2 diabetics

4 weeks

Author (y) Evidence Sabate et al. (2003) 1++

Study design Randomised Crossover; CF 3-arm Control group Single-blind

Subjectsâ&#x20AC;&#x2122; characteristics 25 (14 M, 11 F) Healthy

Duration

Treatment

4 weeks

(i) Step I diet2 (ii) Almonds (10% en: 27g) Difference4 (i) Step I diet2 (iii) Almonds (20% en: 54g) Difference4 Baseline2 (i) Complex CHO LCD Change3 Baseline2 (ii) Almond LCD (84g) Change3 Baseline2 (i) Step I diet Change3 Baseline2 (ii) Almonds (25g) Change3 Baseline2 (i) NCEP TLC Control Change3 Baseline2 (ii) TLC + Almonds (60g) Change3 Baseline2 (iii) TLC + Chocolate (41g) Change3 Baseline2 (iv)TLC+Al(60g)+Ch(41g) Change3

Wien et al. (2003) 1+

Randomised Parallel 2-arm Control group

65 (28 M, 37 F) Overweight and obese

24 weeks

Tamizifar et al. (2005) 1+

Randomised Crossover 2-arm Control group

30 (17 M, 13 F) Hyperlipidaemic

4 weeks

Kurlandsky & Stote (2006) 1+

Randomised Parallel 4-arm Control group

47 (0 M, 47 F) Normocholesterolaemic

6 weeks

TC mmol/l 5.41 5.36 -0.05 5.41 5.17

LDL-C mmol/l 3.74 3.70 -0.04 3.74 3.48

HDL-C mmol/l 1.18 1.17 -0.01 1.18 1.20

TAG mmol/l 1.52 1.52 0.00 1.52 1.47

-0.24a 5.59 5.09 -0.50c 5.12 4.47 -0.65c 6.71 6.94 +0.23 6.71 6.53 -0.18 5.30 5.29 -0.01 5.60 5.61 +0.01 5.00 5.08 +0.08 5.00 4.96 -0.04

-0.26a 2.79 2.51 -0.28c 2.56 2.17 -0.39c 4.14 4.64 +0.50 4.14 4.07 -0.07 3.10 3.19 +0.09 3.20 3.22 +0.02 2.70 2.84 +0.14 2.60 2.71 +0.11

+0.02 0.85 0.98 +0.13a 0.85 0.80 -0.05 1.03 1.24 +0.21 1.03 1.11 0.08 1.70 1.65 -0.05 1.70 1.69 -0.01 1.80 1.84 +0.04 1.90 1.87 -0.03

-0.05 2.18 1.59 -0.59c 2.03 1.44 -0.59c 3.33 2.66 -0.67 3.33 2.85 -0.48 1.10 0.98 -0.12a 1.60 1.39 -0.21a 1.10 0.88 -0.22a 1.20 0.97 -0.23a

Between treatments The high almond diet had significantly lower TC and LDL-C when compared with the Step I and low-almond diets (both P < 0.05). There were no significant differences between treatments in blood lipids, except for HDL-C (P < 0.05). Compared to the Step I diet, the almond diet lowered TC (P < 0.01) and LDL-C (P < 0.05). There were no significant differences in blood lipids between all four diet groups.

Author (y) Evidence Wien et al. (2010) 1+

Cohen & Johnston (2011) 1+

Damasceno et al. (2011) 1+

Study design Randomised Parallel 2-arm Control group

Randomised Parallel 2-arm Control group

Randomised Crossover 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 65 (17 M, 48 F) Prediabetes

13 (7 M, 6 F) Type 2 diabetics

18 (9 M, 9 F) Moderate hypercholesterolaemic

Duration

Treatment

16 weeks

Baseline2 (i) Control ADA diet Change3 Baseline2 (ii) ADA + Almonds (20% en: 57g) Change3 Baseline2 (i) Control (2 cheese sticks, 5x / week) Change3 Baseline2 (ii) Almonds (28 g, 5x/week) Change3 Baseline (MD)2 (i) MD + Olive oil (22% en: 35-50g) Change3 Baseline (MD)2 (ii) MD + Almonds (22% en: 50-75g) Change3 Baseline (MD)2 (iii) MD + Walnuts (22%en: 40-65g) Change3

12 weeks

4 weeks

TC mmol/l 5.15 5.31 +0.16 5.23 4.95

LDL-C mmol/l 3.06 3.00 -0.06 3.03 2.69

HDL-C mmol/l 1.53 1.58 +0.05 1.63 1.66

TAG mmol/l 1.40 1.20 -0.20 1.28 1.04

-0.28 4.2 3.9

-0.34 2.2 2.1

+0.03 NR NR

-0.24 1.5 1.5

-0.3 4.0 4.1

-0.1 1.6 1.8

NR NR NR

0.0 2.3 2.1

+0.1 7.035 6.71

+0.2 5.085 4.71

NR 1.635 1.61

-0.2 1.365 1.22

-0.32 7.035 6.58

-0.37a 5.085 4.40

-0.02 1.635 1.61

-0.14 1.365 1.21

-0.45a 7.035 6.48

-0.68a 5.085 4.53

-0.02 1.635 1.61

-0.15 1.365 1.13

-0.55a

-0.02

-0.23

Between treatments There were no significant differences in blood lipids between the groups. There were no significant differences in blood lipids between the groups.

Compared with the olive oil diet, the almond and walnut diets resulted in significantly lower TC (P < 0.05). There were no significant differences in LDL-C between the group.

Author (y) Evidence Li et al. (2011) 1++

Study design

Foster et al. (2012) 1+

Randomised Parallel 2-arm Control group

Randomised Crossover; CF 2-arm Control group

Cashew nut (n = 1) MukuddemRandomised Petersen et al. Parallel; CF (2007) 3-arm 1++ Control group

Subjectsâ&#x20AC;&#x2122; characteristics 20 (9 M, 11 F) Chinese Type 2 diabetics

Duration

Treatment

4 weeks

123 (11 M, 112 F) BMI: 27 to 40 kg/m2

18 months

Baseline2 (i) Control Step II diet Change3 Baseline2 (ii) Almonds (20% en: 56g) Change3 Baseline2 (i) Nut-free LCD Change3 Baseline2 (ii) Almond-enriched LCD (56g) Change3

64 (29 M, 35 F) Metabolic syndrome

8 weeks

Baseline2 (i) Control diet Change3 Baseline2 (ii) Cashew nuts (20%en: 66-115g) Change3 Baseline2 (iii) Walnut(20%:60-100g) Change3

TC mmol/l 5.7 5.5 -0.2 5.7 5.2 -0.5b 5.04 5.19 +0.15 5.05 5.15

LDL-C mmol/l 3.5 3.4 -0.1 3.5 3.0 -0.5a 2.85 2.85 0.00 2.98 2.90

HDL-C mmol/l 1.3 1.2 -0.1 1.3 1.2 -0.1 1.58 1.64 +0.06 1.47 1.59

TAG mmol/l 1.6 1.6 0 1.6 1.5 -0.1 1.12 1.00 -0.12 1.18 1.13

+0.10

-0.08

+0.12

-0.05

4.905 5.39 +0.07 4.495 4.51

3.215 3.36 +0.19 2.645 2.84

0.85 0.91 +0.06a 1.02 1.01

1.86 1.96 +0.11 1.81 1.64

+0.07 4.805 4.72 -0.03

+0.12 2.995 3.19 +0.18

-0.01 0.94 0.91 -0.03

-0.16 1.90 1.86 -0.04

Between treatments Compared with the control diet, the almond diet significantly reduced TC and LDL-C. There were no significant differences in blood lipids between groups at 18 months. Compared to the control diet, both nut intervention diets had no significant effect on blood lipids.

Author (y) Study design Evidence Hazelnuts (n = 1) Tey et al. Randomised (2011) Parallel 1+ 3-arm Control group

Subjects’ characteristics

Duration

Treatment

TC mmol/l

LDL-C mmol/l

HDL-C mmol/l

TAG mmol/l

Between treatments

55 M, 63 F Healthy

12 weeks

Baseline * (i) Control habitual diet Change † Baseline * (ii) Chocolate (50g) Change † Baseline * (iii) Potato crisps (50g) Change † Baseline * (iv) Hazelnut (42g) Change †

4.70 4.79 +0.09 4.79 5.01 +0.22a 4.76 4.81 +0.05 4.94 4.88 -0.06

2.80 2.90 +0.10 2.93 3.07 +0.14 2.90 2.85 -0.05 3.12 3.04 -0.08

1.42** 1.41 -0.01 1.34** 1.39 +0.05 1.39** 1.45 +0.06 1.33 1.36 +0.03

1.03** 1.08 +0.05 1.13** 1.21 +0.08 1.01** 1.11 +0.10 1.06** 1.07 +0.01

At week 12, there was no significant difference in blood lipids between the groups.

Macadamia nuts (n = 2) Curb et al. Randomised (2000) Crossover; CF 1++ 3-arm Control group

30 (15 M, 15 F) Normo- and hyperlipidaemic

30 days

5.31 5.20 -0.11 5.31 4.99 -0.32 5.31 4.95

3.47 3.37 -0.10 3.47 3.21 -0.26 3.47 3.22

1.42 1.43 +0.01 1.42 1.34 -0.08 1.42 1.37

0.91 0.87 -0.04 0.91 0.94 +0.03 0.91 0.79

Griel et al. (2008) 1++

25 (10 M, 15 F) Mildly hypercholesterolaemic

5 weeks

Baseline2 (i) AAD (16% en SFA) Change3 Baseline2 (ii) Step I diet (30% en fat) Change3 Baseline2 (iii) Macadamia (21% en MUFA) Change3 Baseline2 (i) Average American diet Change3 Baseline2 (ii) Macadamias (42.5g) Change3

-0.36 5.66 5.45 -0.21a 5.66 4.94 -0.72a

-0.25 3.68 3.44 -0.24a 3.68 3.14 -0.54a

-0.05 1.24 1.20 -0.04a 1.24 1.11 -0.13a

-0.12 1.51 1.59 +0.08 1.51 1.55 +0.04

Compared to the AAD group, Step I and macadamia nut diets significantly reduced TC, LDL-C, and HDL-C. Step I diet significantly increased TAG whereas macadamia nuts reduced TAG. Compared with the AAD control diet, macadamia nut diet resulted in lower TC, LDL-C and HDL-C (P < 0.05).

Randomised Crossover; CF 2-arm Control group

Author (y) Evidence Peanuts (n = 3) Kris-Etherton et al. (1999) 1++

Study design

Subjectsâ&#x20AC;&#x2122; characteristics

Duration

Treatment

TC mmol/l

LDL-C mmol/l

HDL-C mmol/l

TAG mmol/l

Between treatments

Randomised Crossover; CF 5-arm Control group Double-blind

22 (9 M, 13 F) Normocholesterolaemic

24 days

Claesson et al. (2009) 1+

Randomised Parallel 2-arm Control group

25 (11 M, 14 F) Non-obese (BMI < 27 kg/m2)

2 weeks

Nouran et al. (2010) 1+

Randomised Crossover 2-arm Control group

54 (54 M, 0 F) Hypercholesterolaemic

4 weeks

(i) Average American diet2 (ii) Step II Diet Difference4 (i) Average American diet2 (iii) Olive oil Difference4 (i) Average American diet2 (iv) Peanut oil Difference4 (i) Average American diet2 (v) Peanuts &Peanut butter Difference4 Baseline2 (i) Candy (84 kJ/ kg BW) Change3 Baseline2 (ii) Peanuts (84 kJ/ kg BW) Change3 Baseline2 (i) Habitual diet Change3 Baseline2 (ii) Peanuts (20% en: 77g) Change3

5.41 4.92 -0.49 5.41 4.79 -0.62a 5.41 4.93 -0.48a 5.41 4.82 -0.59a 4.30 4.30 0.00 4.10 3.80 -0.30 6.55 6.46 -0.09 6.60 6.78 +0.18

3.52 3.01 -0.51a 3.52 2.98 -0.54a 3.52 3.13 -0.39a 3.52 3.03 -0.49a 2.60 2.60 0.00 2.30 2.10 -0.20 4.38 4.14 -0.24 4.40 4.58 +0.18

1.29 1.24 -0.05a 1.29 1.28 -0.01 1.29 1.26 -0.03 1.29 1.26 -0.03 1.20 1.20 0.00 1.40 1.30 -0.10 0.93 0.90 -0.03 0.87 0.99 +0.12c

1.33 1.48 +0.15 1.33 1.15 -0.18a 1.33 1.18 -0.15a 1.33 1.16 -0.17a 1.01 1.16 +0.15 0.80 0.73 -0.07 2.59 2.46 -0.13 2.62 2.54 -0.08

Compared with the AAD, all four diets reduced TC (NS only for the STEP II diet) and LDL-C. HDL-C was significantly lower whereas the TAG was higher following the Step II diet compared with the three high-MUFA diets (P < 0.05). There were no significant differences in the changes in blood lipids between the groups (P ď&#x201A;ł 0.1). Compared with the habitual diet, peanut-enriched diet significantly increased HDL-C (P < 0.001).

Author (y) Evidence Pecans (n = 3) Morgan & Clayshulte (2000) 1+

Study design

Subjectsâ&#x20AC;&#x2122; characteristics

Duration

Treatment

TC mmol/l

LDL-C mmol/l

HDL-C mmol/l

TAG mmol/l

Between treatments

Randomised Parallel 2-arm Control group

19 (4 M, 15 F) Normolipidaemic

8 weeks

Rajaram et al. (2001) 1++

Randomised Crossover; CF 2-arm Control group Single-blind

23 (14 M, 9 F) Normal â&#x20AC;&#x201C; High cholesterol

4 weeks

Eastman & Clayshulte (2005) 1+

Randomised Parallel 2-arm Control group

17 (4 M, 13 F) Hyperlipidaemic

8 weeks

Baseline2 (i) Habitual diet Change3 Baseline2 (ii) Pecans (68g) Change3 Baseline2 (i) Step I diet Change3 Baseline2 (ii) Pecans (20% en: 72g) Change3 Baseline2 (i) Habitual diet Change3 Baseline2 (ii) Pecans (68g) Change3

4.68 5.02 +0.34a 4.37 4.22 -0.15 5.04 4.78 -0.26 5.04 4.47 -0.57 6.70 6.67 -0.03 6.03 6.00 -0.03

2.74 3.03 +0.29 2.61 2.46 -0.15a 3.27 3.05 -0.22 3.27 2.73 -0.54 4.42 4.37 -0.05 3.93 3.96 +0.03

1.40 1.47 +0.07 1.29 1.37 +0.08 1.20 1.14 -0.06 1.20 1.21 +0.01 1.34 1.49 +0.15 1.16 1.09 -0.07

1.19 1.14 -0.05 1.04 0.90 -0.14 1.23 1.29 +0.06 1.23 1.16 -0.07 2.07 1.81 -0.26 2.31 2.50 +0.19

At week 8, TC, LDLC, and HDL-C in the pecan group were significantly lower than in the control group (P < 0.05). Pecan-enriched diet resulted in significantly lower TC, LDL-C, and TAG while higher HDL-C than the Step I diet. At week 8, there were no significant differences in blood lipids between the groups.

44 (24 M, 20 F) Healthy

3 weeks

Baseline2 (i) Habitual diet Change3 Baseline2 (ii) Pistachios (20% en: 6575g) Change3

4.09 4.07 -0.02 4.08 3.61

1.98 1.95 -0.03 1.94 1.89

1.15 1.12 -0.03 1.01 1.28

1.34 1.35 +0.01 1.18 1.07

-0.47a

-0.05

+0.27b

-0.11

TC was lower (P < 0.05) while HDL-C (P < 0.001) was higher on the pistachio diet, compared with the regular diet.

Pistachio nuts (n = 6) Kocyigit et al. Randomised (2006) Parallel 1+ 2-arm Control group

Author (y) Evidence Sheridan et al. (2007) 1+

Study design

Gebauer et al. (2008) 1++

Randomised Crossover; CF 3-arm Control group

Randomised Crossover 2-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 15 (11 M, 4 F) Moderate hypercholesterolaemic

Duration

Treatment

4 weeks

28 (10 M, 18 F) Elevated LDL-C

4 weeks

Baseline2 (i) Regular diet Change3 Baseline2 (ii) Pistachio (15%:57-85g) Change3 Baseline2 (i) Step I diet Change3 Baseline2 (ii) Pistachios (10% en: 3263g) Change3 Baseline2 (iii) Pistachios (20% en: 63-126g) Change3 Baseline2 (ii) LCD + Pretzel (56g) Change3 Baseline2 (i) LCD + Pistachios (53g) Change3 (i) Control diet2 (ii) Pistachio (42g) Difference4 (i) Control diet2 (iii) Pistachio (84g) Difference4

Li et al. (2010) 1+

Randomised Parallel 2-arm Control group

59 (59 M & F) BMI: 27 to 35 kg/m2

12 weeks

Baer et al. (2012) 1++

Randomised Crossover; CF 2-arm Control group

16 (8 M, 8 F) Healthy

18 days

TC mmol/l 6.37 6.37 0.00 6.37 6.14 -0.23 5.40 5.42 +0.02 5.40 5.01

LDL-C mmol/l 4.25 4.22 -0.03 4.25 3.83 -0.42a 3.43 3.42 -0.01 3.43 3.08

HDL-C mmol/l 1.42 1.40 -0.02 1.42 1.48 +0.06 1.48 1.43 -0.05 1.48 1.43

TAG mmol/l 1.59 1.47 -0.12 1.59 1.48 -0.11 1.15 1.40 +0.25a 1.15 1.28

-0.39a 5.40 4.92

-0.35a 3.43 2.98

-0.05a 1.48 1.48

+0.13 1.15 1.20

-0.48a 5.30 4.74 -0.56 5.11 4.96 -0.15 NR NR NS NR NR NS

-0.45a 2.08 1.89 -0.19 2.15 2.07 -0.08 3.40 3.21 -0.19a 3.40 3.20 -0.20a

0.00 1.04 1.02 -0.02 1.13 1.11 -0.02 NR NR NS NR NR NS

+0.05 1.52 1.49 -0.03 1.28 1.00 -0.28 NR NR NS NR NR NS

Between treatments Compared with the regular diet, HDL-C on the pistachio diet significantly increased (P = 0.02). Compared with the Step I diet, TC and LDL-C were lower with the 1PD and 2PD (P < 0.001), and TAG was lower with the 2PD (P < 0.01). The 2PD had higher HDL-C than 1PD (P < 0.05). Compared with the salted pretzel group, pistachio group had significantly lower TAG (P < 0.05). Plasma LDL-C was lower after both pistachios diets albeit there was no additional reduction from 42 to 84g.

Author (y) Evidence Wang et al. (2012) 1+

Study design Randomised Parallel 3-arm Control group

Walnuts (n = 17) Sabate et al. Randomised (1993) Crossover; CF 1++ 2-arm Control group Chisholm et al. Randomised (1998) Crossover 1+ 2-arm Control group Zambon et al. (2000) 1++

Randomised Crossover; CF 2-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 90 (41 M, 49 F) Metabolic syndrome

Duration

Treatment

12 weeks

Baseline2 (i) Control no nuts Change3 Baseline2 (ii) Pistachios (42g) Change3 Baseline2 (iii) Pistachios (70g) Change3

18 (18 M, 0 F) Healthy

4 weeks

(i) Step I diet2 (ii) Step I diet + Walnuts (20% en: 84g) Difference4 Baseline2 (i) Low fat diet Change3

21 (21 M, 0 F) Hyperlipidaemic

4 weeks

Baseline2 (ii)LFD+ Walnut(20% en:78g) Change3

49 (26 M, 23 F) Polygenic hypercholesterolaemic

6 weeks

Baseline2 (i) Mediterranean diet Change3 Baseline2 (ii) Walnuts (18% en: 4156g) Change3

TC mmol/l 5.01 5.15 +0.14 5.29 5.20 -0.09 5.29 5.41 +0.12

LDL-C mmol/l 2.70 2.99 +0.29a 3.08 3.10 +0.02 3.00 3.30 +0.30b

HDL-C mmol/l NR NR NS NR NR NS NR NR NS

TAG mmol/l 2.09 1.88 -0.21 2.47 2.14 -0.33a 2.19 2.05 -0.14

Between treatments There were no significant differences in blood lipids between the groups.

4.71 4.14

2.90 2.43

1.22 1.17

1.29 1.16

-0.57c 6.24 6.11 -0.13 6.24 5.99 -0.25b 7.16 6.81 -0.35c 7.16 6.52

-0.47c 4.30 4.10 -0.20 4.30 3.94 -0.36b 5.05 4.77 -0.28a 5.05 4.48

-0.05b 1.06 1.18 +0.12b 1.06 1.21 +0.15b 1.44 1.37 -0.07 1.44 1.42

-0.13 1.95 1.86 -0.09 1.95 2.00 +0.05 1.54 1.51 -0.03 1.54 1.42

The walnut diet had lower serum TC, LDL-C, and HDL-C than the Step I diet. There were no significant differences in blood lipids between the two treatments.

-0.64c

-0.57c

-0.02

-0.12a

Compared with the MD, the walnut diet produced greater reductions in TC and LDL-C (both P < 0.001).

Author (y) Evidence Iwamoto et al. (2002) 1++

Study design Randomised Crossover; CF 2-arm Control group Randomised Crossover 2-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 40 (20 M, 20 F) Healthy

Duration 4 weeks

Treatment

(i) Japanese, low fat diet2 (ii) Walnuts (12.5% en: 4458g) Difference4 Ros et al. 20 (8 M, 12 F) 4 weeks Baseline2 (2004) Hyper(i) Mediterranean diet 1+ cholesterolaemic Change3 Baseline2 (ii) MD + Walnuts (18% en: 40-65g) Change3 Tapsell et al. Randomised 58 (34 M, 24 F) 6 months Baseline2 (2004) Parallel Type 2 diabetics (i) Low fat diet 1+ 3-arm Change3 Control group Baseline2 (ii) Modified LFD Change3 Baseline2 (iii) Modified LFD + Walnuts (30g) Change3 Zhao et al. Randomised 23 (20 M, 3 F) 6 weeks (i) AAD2 7.7% LA, 0.8% ALA (2004) Crossover; CF Moderate hyper(ii) Walnut diet high in LA: 1++ 3-arm cholesterolaemic 12.6% en LA, 3.6% en ALA Control group Overweight / Difference4 obese class I (i) AAD2 7.7% LA, 0.8% ALA Postmenopausal (iii) Walnuts diet high in F ALA: 10.5% LA, 6.5% ALA Difference4 Mukuddem-Petersen et al. (2007): Please refer to the cashew nut section.

TC mmol/l 4.22 4.03

LDL-C mmol/l 2.05 1.86

HDL-C mmol/l 1.50 1.48

TAG mmol/l 1.50 1.50

-0.19b 6.93 6.72 -0.21 6.93 6.43

-0.20b 4.75 4.64 -0.11 4.75 4.33

-0.02 1.61 1.59 -0.02 1.61 1.57

0.00 1.39 1.32 -0.07 1.39 1.43

-0.50 4.79 4.90 +0.11 4.58 4.83 +0.25 4.11 4.02

-0.42 2.70 2.69 -0.01 2.58 2.73 +0.15 2.17 1.95

-0.04 1.11 1.25 +0.14c 1.11 1.34 +0.23c 1.10 1.30

+0.04 2.18 2.13 -0.05 1.76 1.55 -0.21 1.90 1.70

-0.09 5.59 4.98

-0.22a 3.74 3.28

+0.20c 1.18 1.15

-0.20 1.47 1.20

-0.61a 5.59 4.99

-0.46a 3.74 3.33

-0.03 1.18 1.11

-0.27a 1.47 1.20

-0.60a

-0.39a

-0.07a

-0.27a

Between treatments TC and LDL-C were lower in the walnut diet, compared with the reference diet. Compared with the MD, the walnut diet significantly lower TC (P = 0.017) and LDL-C (P = 0.010). The walnut group had significantly lower TC (P = 0.021) and LDL-C (P = 0.032) than the other two groups.

Compared with an AAD, both LA and ALA diets decreased TC, LDL-C, and TAG (P < 0.05); the ALA diet also decreased HDL-C (P < 0.05).

Author (y) Evidence PerezMartinez et al. (2007) 1++

Study design Randomised Crossover; CF 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 16 (16 M, 0 F) Healthy Medical students

Duration

Treatment

4 weeks

(i) Western diet (38% fat)2 (ii) MD + VOO: <10% en SFA, 24% MUFA, 4% PUFA Difference4 (i) Western diet (38% fat)2 (ii) High CHO & n-3 walnut: <10% en SFA, 2% en ALA Difference4 Baseline2 (i) Average American diet Change3 Baseline2 (i) Walnuts (24% en: 75g) Change3 (i) Control (no nuts or fish)2 (ii) Salmon (113g, 2x/week) Difference4 (i) Control (no nuts or fish)2 (iii) Walnuts (42.5g/10mJ, 6x/week) Difference4 Baseline2 (i) Control (30% en: fat) Change3 Baseline2 (ii) Walnuts (30g) Change3

Spaccarotella et al. (2008) 1+

Randomised Crossover 2-arm Control group

21 (21 M, 0 F) Total PSA â&#x2030;Ľ 2.0 ng/mL At risk for prostate cancer

8 weeks

Rajaram et al. (2009) 1++

Randomised Crossover; CF 3-arm Control group

25 (14 M, 11 F) Mildly to hyperlipidaemic

4 weeks

Tapsell et al. (2009) 1+

Randomised Parallel design 2-arm Control group

50 (50 M & F) Type 2 diabetics Non insulintreated BMI: 25 to 32 kg/m2

12 months

TC mmol/l 3.83 3.60

LDL-C mmol/l 2.24 2.04

HDL-C mmol/l 1.16 1.17

TAG mmol/l 0.91 0.86

-0.23a 3.83 3.55

-0.20a 2.24 2.03

+0.01 1.16 1.11

-0.05 0.91 0.87

-0.28a 5.01 4.99 -0.02 5.01 4.83 -0.18 5.14 5.33

-0.21a 3.11 3.14 +0.03 3.11 3.01 -0.10 3.06 3.20

-0.05 1.36 1.32 -0.04 1.36 1.31 -0.05 1.19 1.23

-0.04 1.31 NR +1.006 1.31 NR +1.006 1.12 1.00

+0.19a 5.14 4.87

+0.14a 3.06 2.77

+0.04a 1.19 1.18

-0.12a 1.12 1.11

-0.27a 4.9 4.6 -0.3 5.0 4.9 -0.1

-0.29a 2.6 2.5 -0.1 2.7 2.4 -0.3

-0.01 1.3 1.4 +0.1 1.4 1.5 +0.1a

-0.01 2.0 1.8 -0.2 2.0 2.1 +0.1

Between treatments Compared with the Western diet, both Mediterranean diet and omega-3 diet significantly reduced TC and LDL-C. There were no significant differences in blood lipids between the groups. When compared with the control and fish diets, the walnut diet decreased TC and LDL- C.

There were no significant differences between the groups in blood lipids at 12 months.

Author (y) Evidence Ma et al. (2010) 1+

Torabian et al. (2010) 1+ Wu et al. (2010) 1+

Study design Randomised Crossover 2-arm Control group

Randomised Crossover 2-arm Control group Randomised Parallel 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 24 (10 M, 14 F) Type 2 diabetics, Non insulintreated

87 (38 M, 49 F) Normal to moderate high plasma TC 283 (158 M, 125 F) Metabolic syndrome

Duration

Treatment

8 weeks

Baseline2 (i) Ad libitum diet(no nuts) Change3 Baseline2 (ii) Ad libitum diet with walnuts (56g) Change3 (i) Control habitual diet2 (ii) Walnuts (12% en: 2865g) Difference4 Baseline2 (i) LC + AHA guidelines Change3 Baseline2 (ii) LC + Flaxseed (30g) Change3 Baseline2 (ii) LC + Walnuts (30g) Change3

6 months

12 weeks

Damasceno et al. (2011): Please refer to the almond section. Din et al. Randomised 30 (30 M, 0 F) 4 weeks (2011) Crossover Healthy 1+ 2-arm Control group

Baseline2 (i) Control (no walnuts) Change3 Baseline2 (ii) Walnuts (15g) Change3

TC mmol/l 4.75 4.87 +0.12 4.75 4.50

LDL-C mmol/l 2.67 2.47 -0.20 2.67 2.47

HDL-C mmol/l 1.45 1.50 +0.05 1.45 1.43

TAG mmol/l 1.40 1.49 +0.09 1.40 1.38

-0.25b 5.54 5.41

-0.20b 3.38 3.29

-0.02 1.51 1.50

-0.02 1.44 1.35

-0.13a 6.10 5.63 -0.47a 6.00 5.44 -0.56a 5.80 5.45 -0.35a

-0.09 4.30 3.93 -0.37a 4.20 3.76 -0.44a 4.10 3.83 -0.27a

-0.01 1.40 1.28 -0.12a 1.40 1.25 -0.15a 1.30 1.21 -0.09a

-0.09a 1.945 1.90 -0.04 1.895 1.82 -0.07 1.995 1.92 -0.07

4.57 4.37 -0.20b 4.57 4.25 -0.32b

2.70 2.46 -0.24b 2.70 2.30 -0.40b

1.32 1.24 -0.08 1.32 1.24 -0.08

1.22 1.45 +0.23 1.22 1.55 +0.33

Between treatments There were no significant differences in blood lipids between the groups. The walnut diet lowered TC and TAG compared to control diet. There were no significant differences in blood lipids between the groups.

There were no significant differences in blood lipids between the groups.

Author (y) Study design Evidence Mixed nuts (n = 3) Chisholm et al. Randomised (2005) Crossover 1+ 2-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics

Duration

Treatment

TC mmol/l

LDL-C mmol/l

HDL-C mmol/l

TAG mmol/l

Between treatments

28 (5 M, 23 F) Moderate hypercholesterolaemic

6 weeks

5.60 5.18

3.77 3.40

1.26 1.20

1.23 1.21

50 (28 M, 22 F) Metabolic syndrome BMI: 24 to 35 kg/m2

12 weeks

-0.42c 5.96 5.44 -0.51c 5.82 5.34 -0.48a 5.38 5.22

-0.37b 4.08 3.67 -0.40b 3.79 3.43 -0.36a 3.45 3.32

-0.06 1.27 1.18 -0.09 1.12 1.10 -0.02 1.17 1.15

-0.02 1.25 1.25 0.00 1.69 1.62 -0.07 1.53 1.51

There were no significant differences in blood lipids between the groups.

CasasAgustench et al. (2011) 1+

Baseline2 (i) LF + Canola oil cereal (82g) Change3 Baseline2 (ii) LF + Mixed nuts7 (30g) Change3 Baseline2 (i) Control (AHA guideline) Change3 Baseline2 (ii) AHA + Mixed nuts8 (30g) Change3 Baseline (Control)2 (i) Control muffins (2-4) Change3 Baseline (Half-dose)2 (ii) Mixed nuts9 (25-50g) + Muffin (1-2) Change3 Baseline (Full-dose)2 (iii) Mixed nuts9 (50-100g) Change3

-0.16 4.2 4.3 +0.1 4.0 4.0

-0.13 2.3 2.3 0 2.2 2.1

-0.02 1.2 1.2 0 1.1 1.2

-0.02 1.6 1.6 0 1.6 1.6

0 4.4 4.2 -0.2

0.1 2.5 2.3 0.2

+0.1 1.2 1.2 0

0 1.8 1.7 -0.1

Jenkins et al. (2011) 1+

Randomised Parallel 2-arm Control group

Randomised Parallel 3-arm Control group

117 (78 M, 39 F) Type 2 diabetics Postmenopausal F

12 weeks

There were no differences in changes between groups in blood lipid profile. Full-dose nut group showed a greater reduction in TC than the control and halfdose nut groups. Half-dose and fulldose nut groups had greater reduction in LDL-C than the control group.

1 SI conversion factors: To convert mmol/L TC, LDL-C, HDL-C to mg/dL, multiply mmol/L by 38.67. To convert mmol/L TAG to mg/dL, multiply mmol/L by 88.57. Abbreviations used: % en, percentage of the total energy in the diet; AAD, average American diet; ADA, American Diabetes Association; AHA, American Heart Association; ALA, alpha linoleic acid; BMI, body masss index; BW, body weight; CF, controlled feeding; CHO, carbohydrate; CVD, cardiovascular disease; F, female; HD, habitual diet; HDL-C, high-density lipoprotein cholesterol; HFD, high fat diet; LA, linoleic acid; LC, lifestyle counselling; LCD, low calorie diet; LDL-C, low-density lipoprotein cholesterol; LF, low fat; LFD, low fat diet; LFMR, low fat monounsaturated rich; M, male; MD, Mediterranean diet; MUFA, monounsaturated fatty acids; NCEP, national cholesterol education program; NR, not reported; NS, non significant; PCOS, polycystic ovary syndrome; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; TAG, triacylglycerol; TC, total cholesterol; TLC, therapeutic lifestyle changes. 2 Comparison made. 3 Change (within group) = Post treatment value â&#x20AC;&#x201C; Pre treatment value (i.e. baseline); a P < 0.05; b P < 0.01; c P < 0.001. 4 Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001. 5 Data was reported as median. Analysis was performed either using non parametric tests or log-transformed values. 6 Change score was reported as geometric mean. Analysis was performed on log-transformed values. 7 Almonds, Brazil nuts, cashew nuts, hazelnuts, macadamia nuts, peanuts, pecan nuts, pistachio nuts, and walnuts. 8 15 g walnuts, 7.5 g almonds, and 7.5 g hazelnuts. 9 Unsalted and mostly raw almonds, pistachios, walnuts, pecans, hazelnuts, peanuts, cashews, and macadamias.

Appendix C. Dietary intervention trials investigating the effects of nut consumption on apolipoprotein A1 and B (n = 19)1 Author (y) Evidence Almonds (n = 4) Jenkins et al. (2002) 1+

Study design

Subjectsâ&#x20AC;&#x2122; characteristics

Duration

Treatment

Apo A g/L

Apo B g/L

Between treatments

Randomised Crossover 3-arm Control group

27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

4 weeks

Baseline2 (i) Control-Muffin (147g) Change3 Baseline2 (ii) Half-dose almond (37g) + Muffins (75g) Change3 Baseline2 (iii) Full-dose almond (73g) Change3 (i) Step I diet2 (ii) Almonds (10% en: 27g) Difference4 (i) Step I diet2 (iii) Almonds (20% en: 54g) Difference4 Baseline (MD)2 (i) MD + Olive oil (22% en: 35-50g) Change3 Baseline (MD)2 (ii) MD + Almonds (22% en: 50-75g) Change3 Baseline (MD)2 (iii) MD + Walnuts (22% en: 40-65g) Change3

1.74 1.73 -0.01 1.71 1.73

1.30 1.27 -0.03 1.27 1.23

Compared to the control group, full-dose almonds had significantly lower apo B concentration (P < 0.01).

+0.02 1.74 1.76 +0.02 1.38 1.39 +0.01 1.38 1.40 +0.02 1.485 1.52

-0.04 1.31 1.21 -0.10c 1.00 0.99 -0.01 1.00 0.94 -0.06a 1.345 1.35

+0.04 1.485 1.44

+0.01 1.345 1.27

-0.04 1.485 1.41

-0.07 1.345 1.29

-0.07

-0.05

Sabate et al. (2003) 1++

Randomised Crossover; CF 3-arm Control group Single-blind

25 (14 M, 11 F) Healthy

4 weeks

Damasceno et al. (2011) 1+

Randomised Crossover 3-arm Control group

18 (9 M, 9 F) Moderate hypercholesterolaemic

4 weeks

When compared with the Step I and low almond diets, high almond diet had significantly lower apo B concentration (P < 0.05). There were no significant differences between the groups in apo A and apo B.

Author (y) Evidence Li et al. (2011) 1++

Study design Randomised Crossover; CF 2-arm Control group

Peanuts (n = 2) Kris-Etherton Randomised et al. (1999) Crossover; CF 1++ 5-arm Control group Double-blind

Claesson et al. (2009) 1+

Randomised Parallel 2-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 20 (9 M, 11 F) Chinese Type 2 diabetics

Duration

Treatment

4 weeks

Baseline2 (i) Control Step II diet Change3 Baseline2 (ii) Almonds (20% en: 56g) Change3

22 (9 M, 13 F) Normocholesterolaemic

24 days

25 (11 M, 14 F) Non-obese (BMI < 27 kg/m2)

2 weeks

(i) Average American diet2 (ii) Step II diet Difference4 (i) Average American diet2 (iii) Olive oil Difference4 (i) Average American diet2 (iv) Peanut oil Difference4 (i) Average American diet2 (v) Peanuts / Peanut butter Difference4 Baseline2 (i) Candy (84 kJ/ kg BW) Change3 Baseline2 (i) Roasted and salted peanuts (84 kJ/ kg BW) Change3

Apo A g/L 1.24 1.21 -0.03 1.24 1.21 -0.03

Apo B g/L 1.38 1.34 -0.04 1.38 1.11 -0.27b

Between treatments

1.54 1.50 -0.04 1.54 1.52 -0.02 1.54 1.49 -0.05 1.54 1.48 -0.06 1.19 1.19 0.00 1.27 1.26

1.01 0.95 -0.06a 1.01 0.92 -0.09a 1.01 0.95 -0.06a 1.01 0.92 -0.09a 0.77 0.81 +0.04 0.69 0.65

Compared with the AAD, all four diets reduced apo B (P < 0.05). There were no significant differences in apo A1 concentrations between the diets.

-0.01

-0.04

Almond diet significantly reduced apo B compared with the control diet.

There was a significant difference in the changes in apo B between the groups (P = 0.05). No between-group difference was seen in apo A.

Author (y) Evidence Pecans (n = 1) Rajaram et al. (2001) 1++

Study design

Subjects’ characteristics

Duration

Treatment

Apo A g/L

Apo B g/L

Between treatments

Randomised Crossover; CF 2-arm Control group Single-blind

23 (14 M, 9 F) Normal – high cholesterol

4 weeks

Baseline2 (i) Step I diet Change3 Baseline2 (ii) Pecans (20% en: 72g) Change3

1.36 1.30 -0.06 1.36 1.33 -0.03

0.87 0.85 -0.02 0.87 0.75 -0.12

Apo B was significantly lower and apo A significantly greater when subjects consumed the pecan diet compared with the Step I diet (P  0.001).

15 (11 M, 4 F) Moderate hypercholesterolaemic

4 weeks

28 (10 M, 18 F) Elevated LDL-C

4 weeks

Baseline2 (i) Regular diet Change3 Baseline2 (ii) Pistachio(15% en:57-85g) Change3 Baseline2 (i) Step I diet Change3 Baseline2 (ii) Pistachio(10% en:32-63g) Change3 Baseline2 (iii) Pistachio (20% en: 63126g) Change3

1.35 1.38 +0.03 1.35 1.46 +0.11b 1.36 1.36 0.00 1.36 1.36 0.00 1.36 1.37

1.32 1.24 -0.08 1.32 1.19 -0.13b 0.99 1.01 +0.02 0.99 0.96 -0.03 0.99 0.95

Compared with the regular diet, apo A (P = 0.004) was significantly higher while apo B was significantly lower on the pistachio diet (P = 0.005). Compared with the Step I diet, both pistachio diets significantly reduced apo B (P < 0.01).

+0.01

-0.04a

Baseline2 (i) Low fat diet Change3 Baseline2 (ii)LFD+Walnut(20% en: 78g) Change3

1.30 1.30 0.00 1.30 1.32 +0.02

1.01 0.92 -0.09 1.01 0.87 -0.14a

Pistachio nuts (n = 2) Sheridan et al. Randomised (2007) Crossover 1+ 2-arm Control group Gebauer et al. (2008) 1++

Randomised Crossover; CF 3-arm Control group

Walnuts (n = 9) Chisholm et al. Randomised (1998) Crossover 1+ 2-arm Control group

21 (21 M, 0 F) Hyperlipidaemic

4 weeks

Compared to the low fat diet, apo B was significantly lower at the end of the walnutenriched diet.

Author (y) Evidence Zambon et al. (2000) 1++

Study design

Iwamoto et al. (2002) 1++ Ros et al. (2004) 1+

Zhao et al. (2004) 1++

Subjectsâ&#x20AC;&#x2122; characteristics 49 (26 M, 23 F) Polygenic hypercholesterolaemic

Duration

Treatment

6 weeks

Randomised Crossover; CF 2-arm Control group Randomised Crossover 2-arm Control group

40 (20 M, 20 F) Healthy

4 weeks

20 (8 M, 12 F) Hypercholesterolaemic

4 weeks

Randomised Crossover; CF 3-arm Control group

23 (20 M, 3 F) Moderate hypercholesterolaemic Overweight / obese class I

6 weeks

Baseline2 (i) Mediterranean diet Change3 Baseline2 (ii) Walnut (18% en: 41-56g) Change3 (i) Japanese, low fat diet2 (ii) Walnuts (12.5% en: 4458g) Difference4 Baseline2 (i) Mediterranean diet Change3 Baseline2 (ii) MD + Walnuts (18% en: 40-65g) Change3 (i) AAD (7.7% LA, 0.8% ALA)2 (ii) Walnut diet high in LA: 12.6% LA, 3.6% ALA Difference4 (i) AAD (7.7% LA, 0.8% ALA)2 (iii) Walnut diet high in ALA: 10.5% LA, 6.5% ALA Difference4

Randomised Crossover; CF 2-arm Control group

Apo A g/L 1.70 1.61 -0.09a 1.70 1.62 -0.08a 1.39 1.35

Apo B g/L 1.65 1.52 -0.13c 1.65 1.44 -0.21c 0.73 0.67

+0.03 1.48 1.46 -0.02 1.48 1.44

-0.06a 1.42 1.33 -0.09 1.42 1.27

-0.04 1.51 1.45

-0.15 1.11 1.01

-0.06 1.51 1.43

-0.10a 1.11 1.01

-0.08a

-0.10a

Between treatments Compared with the MD, the walnut diet produced greater reduction in apo B (P < 0.001).

Apo B was significantly lower in the walnut diet, compared to the reference diet. There were no significant differences in apo A and apo B between the Mediterranean and walnut diets.

Compared with an AAD, both LA and ALA diets decreased apo B (P < 0.05); the ALA diet also decreased apo A (P < 0.05).

Author (y) Evidence Perez-Martinez et al. (2007) 1++

Study design Randomised Crossover; CF 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 16 (16 M, 0 F) Healthy Medical students

Duration

Treatment

4 weeks

(i) Western diet (38% en fat)2 (ii) MD + VOO: <10% en SFA, 24% MUFA, 4% en PUFA Difference4 (i) Western diet (38% en fat)2 (ii) High CHO & n-3 walnuts: <10%en SFA, 2% en ALA Difference4 (i) Control (no nuts or fish)2 (ii) Salmon (113g, 2x/week) Difference4 (i) Control (no nuts or fish)2 (iii) Walnut (42.5g, 6x/week) Difference4 Baseline2 (i) LC + AHA guidelines Change3 Baseline2 (ii) LC + Flaxseed (30g) Change3 Baseline2 (ii) LC + Walnuts (30g) Change3

Rajaram et al. (2009) 1++

Randomised Crossover; CF 3-arm Control group

25 (14 M, 11 F) Mildly to hyperlipidaemic

4 weeks

Wu et al. (2010) 1+

Randomised Parallel 3-arm Control group

283 (158 M, 125 F) Metabolic syndrome

12 weeks

Damasceno et al. (2011): Please refer to the almond section. Mixed nuts (n = 2) Chisholm et al. Randomised 28 (5 M, 23 F) (2005) Crossover Moderate hyper1+ 2-arm cholesterolaemic Control group

6 weeks

Baseline2 (ii) LF+ Canola oil cereal(82g) Change3 Baseline2 (i) LF + Mixed nuts6 (30g) Change3

Apo A g/L 1.25 1.20

Apo B g/L 0.70 0.64

-0.05 1.25 1.22

-0.06a 0.70 0.63

-0.03 1.66 1.66 0.00 1.66 1.65 -0.01 1.54 1.45 -0.09a 1.53 1.40 -0.13a 1.47 1.40 -0.07a

-0.07a 1.03 1.07 +0.04a 1.03 0.94 -0.09a 1.15 1.08 -0.07a 1.10 1.01 -0.09a 1.08 1.02 -0.06a

1.25 1.19 -0.06 1.28 1.16 -0.12

1.03 0.99 -0.04 1.08 1.01 -0.07

Between treatments Compared with the Western diet, both Mediterranean diet and omega-3 diet significantly reduced apoB.

When compared with the control and fish diets, the walnut diet decreased apo B (P < 0.001). There were no significant differences in apo A and apo B between the groups.

There were no significant differences in blood apo A and apo B concentrations between the groups.

Author (y) Evidence Jenkins et al. (2011) 1+

Study design Randomised Parallel design 3-arm Control group

Subjects’ characteristics 117 (78 M, 39 F) Type 2 diabetics Postmenopausal F

Duration

Treatment

12 weeks

Baseline (Control)2 (i) Control – Muffins (2-4) Change3 Baseline (Half-dose)2 (ii) Mixed nuts7 (25-50g) + Muffin (1-2) Change3 Baseline (Full-dose)2 (iii) Mixed nuts7 (50-100g) Change3

Apo A g/L 1.5 1.5 0 1.5 1.5

Apo B g/L 0.79 0.80 +0.01 0.76 0.75

0 1.5 1.5 0

-0.01 0.85 0.80 -0.05

Between treatments Compared to the control group, both nut groups had greater reduction in apo B concentration (half-dose: P =0.012; full-dose: P < 0.001).

1 Abbreviations used: % en, percentage of the total energy in the diet; AAD, Average American diet; AHA, American Heart Association; ALA, alpha linoleic acid; apo, apolipoprotein; BMI, body mass index; BW, body weight; CF, controlled feeding; CHO, carbohydrate; F, female; HD, habitual diet; LA, linoleic acid; LC, lifestyle counselling; LCD, low-calorie diet; LDL-C, low-density lipoprotein cholesterol; LF, low fat; LFD, low fat diet; LFMR, low fat monounsaturated rich; M, male; MD, Mediterranean diet; MUFA, monounsaturated fatty acids; NCEP, national cholesterol education program; NE, not evaluated; NR, not reported; PCOS, polycystic ovary syndrome; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids. 2 Comparison made. 3 Change (within group) = Post treatment value – Pre treatment value (i.e. baseline); a P < 0.05; b P < 0.01; c P < 0.001. 4 Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001. 5 Data was reported as median. Analysis was performed using non parametric tests. 6 Almonds, Brazil nuts, cashew nuts, hazelnuts, macadamia nuts, peanuts, pecan nuts, pistachio nuts, and walnuts. 7 Unsalted and mostly raw almonds, pistachios, walnuts, pecans, hazelnuts, peanuts, cashews, and macadamias.

Appendix D. Epidemiological studies investigating the effects of nut consumption on the risk of hypertension, stroke, and atrial fibrillation (2 cohorts)1 Author (year) Level of evidence Djousse et al. (2009) 2+

Study design; Subjects’ characteristics The PHS I a ; Prospective study; 15,966 M physicians; 237,585 person-years of follow-up

Endpoints Hypertension2

Hypertension Subjects with BMI < 25 kg/m2 Hypertension Subjects with BMI ≥ 25 kg/m2 Martinez-Lapiscina et al. (2010) 2+ Djousse et al. (2010) 2+

The SUN b ; Prospective median of 4.3y follow-up; 9,919 Spanish university graduates The PHS I a ; Prospective 21.1-y followup; 21,078 M physicians

Hypertension3

Total stroke4

Frequency of nut consumption None 1 – 3 times / month 1 time / week 2 – 6 times / week ≥ 7 times / week None 1 – 3 times / month 1 time / week 2 – 6 times / week ≥ 7 times / week None 1 – 3 times / month 1 time / week 2 – 6 times / week ≥ 7 times / week None 1 – 3 times / month 1 time / week ≥ 2 times / week

Relative Risk (95% CI) 1.00 0.97 (0.91 – 1.03) 0.98 (0.92 – 1.05) 0.96 (0.89 – 1.03) 0.82 (0.71 – 0.94) 1.00 0.93 (0.86 – 1.01) 0.94 (0.86 – 1.03) 0.87 (0.79 – 0.96) 0.77 (0.64 – 0.93) 1.00 1.02 (0.93 – 1.11) 1.04 (0.94 – 1.15) 1.07 (0.96 – 1.20) 0.90 (0.71 – 1.14) 1.00 0.99 (0.72 – 1.38) 1.17 (0.81 – 1.68) 0.77 (0.46 – 1.30)

P value for trend

None < 1 time / week 1 time / week 2 – 4 times / week 5 – 6 times / week ≥ 7 times / week

1.00 0.91 (0.79 – 1.05) 0.95 (0.81 – 1.11) 0.90 (0.75 – 1.08) 1.11 (0.85 – 1.46) 1.07 (0.79 – 1.46)

0.125

0.014

0.0019

0.39

0.795

Author (year) Djousse et al. (2010) 2+

Study design; Subjects’ characteristics The PHS I a ; Prospective 21.1-y followup; 21,078 M physicians

Endpoints Ischemic stroke

Hemorrhagic stroke

Khawaja et al. (2012) 2+

The PHS I a ; Prospective median 24-y follow-up; 21,054 M physicians

Relative Risk (95% CI) 1.00 0.86 (0.74 – 1.01) 0.94 (0.79 – 1.11) 0.97 (0.80 – 1.18) 1.06 (0.79 – 1.43) 0.93 (0.65 – 1.34) 1.00 1.13 (0.78 – 1.62) 1.05 (0.70 – 1.58) 0.49 (0.27 – 0.89) 1.50 (0.79 – 2.84) 1.84 (0.95 – 3.57) 1.00 1.00 (0.91 – 1.11) 1.09 (0.97 – 1.21) 1.07 (0.95 – 1.21) 0.91 (0.70 – 1.17)

P value for trend 0.305

0.125

0.26

SUN, Seguimiento Universidad de Navarra Cohort. Abbreviations used: BMI, body mass index; CI, confidence interval; M, male. 2 Multivariate model, adjusted for age, BMI, smoking, alcohol consumption, exercise, fruit and vegetable intake, breakfast cereal and type, red meat, fish, dairy, multivitamin use, treatment assignment, and history of diabetes and hypercholesterolemia/treatment for hypercholesterolemia. 3 Multivariate model, adjusted for age, sex, smoking, education, hypercholesterolaemia, family history of hypertension and physical activity, total energy intake, alcohol intake, polyunsaturated fatty acids, monounsaturated fatty acids, protein intake, carbohydrates intake, magnesium intake, sodium intake, potassium intake, calcium intake, fibre intake, BMI baseline and weight change during follow-up. 4 Multivariate model, adjusted for age, aspirin assignment, BMI, smoking, alcohol consumption, regular exercise, fruit and vegetable intake, breakfast cereal, red meat, fish, dairy, and prevalent hypertension, diabetes, atrial fibrillation, coronary heart disease. 5 P value for quadratic trend. 6 Multivariate model, adjusted for age, BMI, aspirin, beta-carotene, physical activity, smoking, cereal servings per week, fruit/vegetable servings per week, alcohol consumption, history of hypertension, history of hypercholesterolemia, and history of diabetes. 1a

PHS, Physicians’ Health Study;

Atrial fibrillation6

Frequency of nut consumption None < 1 time / week 1 time / week 2 – 4 times / week 5 – 6 times / week ≥ 7 times / week None < 1 time / week 1 time / week 2 – 4 times / week 5 – 6 times / week ≥ 7 times / week Rarely / never 1 – 3 times / month 1 time / week 2 – 6 times / week ≥ 7 times / week

Appendix E. Dietary intervention trials investigating the effects of nut consumption on diastolic and systolic blood pressure (n = 20)1 Author (y) Evidence Almonds (n = 6) Jenkins et al. (2002) 1+

Study design

Subjectsâ&#x20AC;&#x2122; characteristics

Duration

Treatment

Systolic mm/Hg

Diastolic mm/Hg

Between treatments

Randomised Crossover 3-arm Control group

27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

4 weeks

Baseline (i) Control muffins (147g) Change3 Baseline2 (ii) Half-dose almond (37g) + Muffins (75g) Change3 Baseline2 (iii) Full-dose almond (73g) Change3 Baseline (CHO LCD)2 (i) Complex CHO LCD Change3 Baseline (Almond LCD)2 (ii) Almond LCD (84g) Change3 Baseline2 (i) Control ADA diet Change3 Baseline2 (ii) ADA + Almonds (20% en: 57g) Change3

119 121 +2 121 121

75 76 +1 75 76

There were no betweengroup differences in blood pressure.

0 120 121 +1 140 138 -2 143 127 -16b 129 127 -2 132 126

+1 75 76 +1 78 72 -6 77 71 -6 75 74 -1 78 75

-6

-3

Wien et al. (2003) 1+

Randomised Parallel 2-arm Control group

65 (28 M, 37 F) Overweight and obese

24 weeks

Wien et al. (2010) 1+

Randomised Parallel design 2-arm Control group

65 (17 M, 48 F) Prediabetes

16 weeks

Systolic blood pressure was significantly lower in the almond group when compared with the complex CHO-enriched formula group (P < 0.02). There were no differences in blood pressure between the groups.

Author (y) Evidence Damasceno et al. (2011) 1+

Study design Randomised Crossover 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 18 (9 M, 9 F) Moderate hypercholesterolaemic

Duration

Treatment

4 weeks

Li et al. (2011) 1++

Randomised Crossover; CF 2-arm

20 (9 M, 11 F) Chinese Type 2 diabetics

4 weeks

Foster et al. (2012) 1+

Randomised Parallel 2-arm Control group

123 (11 M, 112 F) BMI: 27 to 40 kg/m2

18 months

Baseline (MD)2 (i) MD + Olive oil (35-50g) Change3 Baseline (MD)2 (ii) MD + Almonds (50-75g) Change3

Systolic mm/Hg 1404 130 -10 1404 133 -7

Diastolic mm/Hg 854 86 +1 854 83 -2

Baseline (MD)2 (iii) MD + Walnuts (40-65g) Change3

1404 134 -6

854 84 -1

Baseline2 (i) Control Step II diet Change3 Baseline2 (ii) Almonds (20% en: 56g) Change3 Baseline2 (i) Nut-free LCD Change3 Baseline2 (ii) Almond-enriched LCD (56g) Change3

131 126 -5 131 124 -7 122.4 118.8 -3.6 123.8 120.6

73 73 0 73 71 -2 69.6 68.3 -1.3 72.2 72.9

-3.2

+0.7

Between treatments There were no significant differences between the groups in blood pressure.

There were no differences in blood pressure between the treatments.

There were no significant differences in blood pressure between groups at 18 months.

Author (y) Evidence

Study design

Subjectsâ&#x20AC;&#x2122; characteristics

Duration

Treatment

Systolic mm/Hg

Diastolic mm/Hg

Between treatments

64 (29 M, 35 F) Metabolic syndrome

8 weeks

Baseline2 (i) Control diet Change3 Baseline2 (ii) Cashew nuts (20% en: 66-115g) Change3 Baseline2 (iii) Walnuts (20% en: 60100g) Change3

131 133 +2 131 128

79.2 79.6 +0.5 77.0 76.0

There were no differences in the change in blood pressure from baseline to end between the groups.

-2 128 130

-0.6 78.7 79.1

+1.2

Cashew nuts (n = 1)

MukuddemPetersen et al. (2007) 1++

Peanuts (n = 1) Nouran et al. (2010) 1+

Randomised Parallel; CF 3-arm Control group

Randomised Crossover 2-arm Control group

Pistachio nuts (n = 2) Sheridan et al. Randomised (2007) Crossover 1+ 2-arm Control group

54 (54 M, 0 F) Hypercholesterolaemic

4 weeks

Baseline2 (i) Habitual diet Change3 Baseline2 (ii) Peanuts (20% en: 77g) Change3

120.0 118.0 -2.0 120.1 119.9 -0.2

78.2 80.5 +2.3 80.8 80.5 -0.3

There were no significant differences in blood pressure between the groups.

15 (11 M, 4 F) Moderate hypercholesterolaemic

4 weeks

Baseline2 (i) Regular diet Change3 Baseline2 (ii) Pistachios (57-85g) Change3

129 125 -4 129 128 -1

84 81 -3 84 84 0

There were no significant differences in blood pressure between the pistachio diet and regular diet.

Author (y) Evidence Wang et al. (2012) 1+

Walnuts (n = 9) Iwamoto et al. (2002) 1++

Ros et al. (2004) 1+

Study design

Subjectsâ&#x20AC;&#x2122; characteristics 90 (41 M, 49 F) Metabolic syndrome

Duration

Treatment

12 weeks

Baseline2 (i) Control no nuts Change3 Baseline2 (ii) Pistachios (42g) Change3 Baseline2 (iii) Pistachios (70g) Change3

Randomised Crossover; CF 2-arm Control group Single-blind

40 (20 M, 20 F) Healthy

4 weeks

Randomised Crossover 2-arm Control group

20 (8 M, 12 F) Hypercholesterolaemic

4 weeks

Randomised Parallel 3-arm Control group

Mukuddem-Petersen et al. (2007): Please refer to the cashew nut section. Spaccarotella et Randomised 21 (21 M, 0 F) 8 weeks al. (2008) Crossover Total PSA â&#x2030;Ľ 2.0 1+ 2-arm ng/mL Control group At risk for prostate cancer

Systolic mm/Hg 128.5 NR NS 129.1 NR NS 128.7 NR NS

Diastolic mm/Hg 79.3 NR NS 81.1 NR NS 81.7 NR NS

Between treatments

(i) Japanese, LFD2 (Male) (ii) Walnut (12.5%: 44-58g) Difference5 (i) Japanese, LFD2 (Female) (ii) Walnut (12.5%: 44-58g) Difference5 Baseline2 (i) Mediterranean diet Change3 Baseline2 (ii) MD + Walnuts (18% en: 40-65g) Change3

108 111 +3 101 103 +2 131 127 -4 131 127

66 69 +3 63 63 0 80 75 -5 80 77

There were no significant differences in the systolic or diastolic blood pressures between the diets.

-4

-3

Baseline2 (i) Average American diet Change3 Baseline2 (i) Walnuts (24% en: 75g) Change3

NR NR -1.65 NR NR -3.05

NR NR -2.50 NR NR -3.45

There were no significant differences in systolic and diastolic blood pressure between the groups.

There were no significant differences in blood pressure between the Mediterranean diet and walnut-enriched diet.

There were no significant differences in systolic and diastolic blood pressure between the groups.

Author (y) Evidence Ma et al. (2010) 1+

West et al. (2010) 1++

Wu et al. (2010) 1+

Study design Randomised Crossover 2-arm Control group

Randomised Crossover; CF 3-arm Control group

Randomised Parallel 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 24 (10 M, 14 F) Type 2 diabetes, non insulin-treated

20 (20 M & F) Hypercholesterolaemic Elevated LDL-C Overweight / obese class I 283 (158 M, 125 F) Metabolic syndrome

Duration

Treatment

8 weeks

Baseline2 (i) Ad libitum diet (no nuts) Change3 Baseline2 (ii) Ad libitum diet with walnuts (56g) Change3 (i) AAD (7.7%LA, 0.8%ALA)2 (ii) Walnut diet high in LA: 12.6% en LA, 3.6% en ALA Difference5 (i) AAD (7.7%LA, 0.8%ALA)2 (iii)Walnut diet high inALA: 10.5% en LA, 6.5% en ALA Difference5 Baseline2 (i) LC + AHA guidelines Change3 Baseline2 (ii) LC + Flaxseed (30g) Change3 Baseline2 (ii) LC + Walnuts (30g) Change3

6 weeks

12 weeks

Systolic mm/Hg 133.2 128.3 -4.9 133.2 137.2

Diastolic mm/Hg 77.7 75.2 -2.5 77.7 79.3

+4.0 128.76 129.2

+1.6 79.86 77.4

+0.5 128.76 126.6

-2.4c 79.86 77.0

-2.1 133.7 126.7 -7.0a 133.0 124.2 -8.8a 135.0 126.8 -8.2a

-2.8c 85.4 81.0 -4.4a 85.6 80.6 -5.0a 86.5 82.3 -4.2a

Between treatments The control diet had significantly lower systolic (P = 0.01) and diastolic blood pressure (P = 0.02) compared with the walnut diet. Compared with the AAD, the 2 walnut-enriched diets significantly reduced diastolic blood pressure by 2-3 mm Hg (P ď&#x201A;Ł 0.001).

There were no significant differences in blood pressure between the groups.

Damasceno et al. (2011): Please refer to the almond section.

Author (y) Evidence Din et al. (2011) 1+

Study design

Subjectsâ&#x20AC;&#x2122; characteristics 0 (30 M, 0 F) Healthy

Duration

Treatment

4 weeks

Baseline2 (i) Control (no walnuts) Change3 Baseline2 (ii) Walnuts (15g) Change3

Mixed nuts (n = 3) Chisholm et al. Randomised (2005) Crossover 1+ 2-arm Control group

28 (5 M, 23 F) Moderate hypercholesterolaemic

6 weeks

Casas-Agustench et al. (2011) 1+

50 (28 M, 22 F) Metabolic syndrome BMI: 24 to 35 kg/m2

12 weeks

Baseline2 (i) LF + Mixed nuts7 (30g) Change3 Baseline * (ii) LF + Canola oil cereal (82g) Change3 Baseline2 (i) Control (AHA guideline) Change3 Baseline2 (ii) AHA+Mixed nuts8 (30g) Change3

Randomised Crossover 2-arm Control group

Randomised Parallel 2-arm Control group

Systolic mm/Hg 117 117 0 60 62 +2

Diastolic mm/Hg 117 120 +3 60 63 +3

Between treatments

130 131 +1 133 128 -5

81 80 -1 81 80 -1

There were no significant differences in systolic and diastolic blood pressure between the groups.

137 127 -10a 145 139 -6a

82 78 -4a 86 83 -3a

There were no differences in changes between groups in systolic (P = 0.238) and diastolic (P = 0.466) blood pressure.

There were no significant differences in peripheral blood pressure between the groups.

Author (y) Evidence Jenkins et al. (2011) 1+

Study design Randomised Parallel 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 117 (78 M, 39 F) Type 2 diabetics Postmenopausal F

Duration

Treatment

12 weeks

Baseline2 (i) Control muffins (2-4) Change3 Baseline2 (ii) Mixed nuts9 (25-50g) + Muffin (1-2) Change3 Baseline2 (iii) Mixed nuts9 (50-100g) Change3

Systolic mm/Hg 125 124 -1 123 124

Diastolic mm/Hg 71 72 +1 71 72

+1 121 119 -2

+1 70 69 -1

Between treatments Full-dose nut group had greater reduction in systolic (P = 0.005) and diastolic (P = 0.021) blood pressure than the half-dose nut group. Full- dose group also had greater reduction in diastolic blood pressure than controls (P = 0.024).

1 Abbreviations used: % en, percentage of the total energy in the diet; AAD, average American diet; ADA, American Diabetes Association; AHA, American Heart Assoication; ALA, alpha linoleic acid; CF, controlled feeding; CHO, carbohydrate; F, female; LA, linoleic acid; LC, lifestyle counselling; LCD, low calorie diet; LFD, low fat diet; M, Male; MD, Mediterranean diet; NCEP, national cholesterol education program; NR, not reported; NS, non significant. 2 Comparison made. 3 Change (within group) = Post treatment value â&#x20AC;&#x201C; Pre treatment value (i.e. baseline); a P < 0.05; b P < 0.01; c P < 0.001. 4 Data was reported as median. Analysis was performed using non parametric tests. 5 Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001. 6 Blood pressure reported here was an average blood pressure measured both at rest and during acute stress. 7 Almonds, Brazil nuts, cashew nuts, hazelnuts, macadamia nuts, peanuts, pecan nuts, pistachio nuts, and walnuts. 8 15 g walnuts, 7.5 g almonds, and 7.5 g hazelnuts. 9 Unsalted and mostly raw almonds, pistachios, walnuts, pecans, hazelnuts, peanuts, cashews, and macadamias.

Appendix F. Epidemiological studies investigating the effects of nut consumption on novel risk factors for CVD (5 populations)1 Author (year) Level of evidence Jiang et al. (2006) 3

Study design; Subjects’ characteristics The MESA a ; Cross-sectional study; 6,080 M & F; Aged 45 – 84 y

Endpoints C-reactive protein (mg/L)2 Interleukin-6 (pg/mL)2

Fibrinogen (mg/dL)2

Mantzoros et al. (2006) 3

The NHS b ; Cross-sectional study; 987 F; Diabetics

Adiponectin (g/mL)3

Salas-Salvado et al. (2008) 3

PREDIMED c ; Cross-sectional study; 339 M & 433 F; Individuals at high risk of CHD; Aged 55 – 80 y

C-reactive protein (mg/L)4 Interleukin-6 (pg/mL)4

Frequency of nut consumption Never / rare <1 time / week 1 – 4 times / week ≥ 5 times / week Never / rare <1 time / week 1 – 4 times / week ≥ 5 times / week Never / rare <1 time / week 1 – 4 times / week ≥ 5 times / week Quintile of nut intake Q1: 0.0 serving/d Q2: 0.1 serving/d Q3: 0.2 serving/d Q4: 0.3 serving/d Q5: 0.7 serving/d Tertile of nut intake T1: < 3.92 g/d T2: 3.92 - 10.84 g/d T3: >10.84 g/d Tertile of nut intake T1: < 3.92 g/d T2: 3.92 - 10.84 g/d T3: >10.84 g/d

Mean ± SE

P value for trend

1.91 1.94 1.82 1.78 1.23 1.24 1.21 1.17 342 338 338 332

0.06

4.84 ± 1.06 5.08 ± 1.06 5.43 ± 1.06 5.26 ± 1.06 5.44 ± 1.06

0.08

3.30 3.42 3.18

0.75

6.58 6.26 6.49

0.34

0.05

0.03

Author (year) Level of evidence Salas-Salvado et al. (2008) 3

Gopinath et al. (2011) 2+ O’Neil et al. (2011) 3

O’Neil et al. (2012) 3

Study design; Subjects’ characteristics PREDIMED c ; Cross-sectional study; 339 M & 433 F; Individuals at high risk of CHD; Aged 55 – 80 y

Endpoints

The Blue Mountains Eye Study d ; Prospective 15-y follow-up; 2,514 M & F NHANES e ; Cross-sectional study; 6,747 M & 6,545 F

Inflammatory disease mortality5

NHANES e ; Cross-sectional study; 6,747 M & 6,545 F

ICAM-1 (ng/mL)4

VCAM-1 (ng/mL)4

C-reactive protein6

Frequency of nut consumption Tertile of nut intake T1: < 3.92 g/d T2: 3.92 - 10.84 g/d T3: >10.84 g/d Tertile of nut intake T1: < 3.92 g/d T2: 3.92 - 10.84 g/d T3: >10.84 g/d Tertile of nut intake T1 (0.00 – 0.90 g/d) T2 (1.40 – 4.55 g/d) T3 (4.90 – 100.0 g/d) All nuts & nut butters <7 g ≥7 g Tree nuts & nut butters <7 g ≥7 g Out-of-hand nuts <7 g ≥7 g

Mean

P value for trend

287 268 238

0.003

1141 1103 1058

0.08

1.0 0.49 (0.33, 0.72) 0.68 (0.48, 0.98)

0.13

0.43 0.40

>0.05

0.43 0.38

<0.05

0.42 0.36

<0.05

MESA, Multi-Ethnic Study of Atherosclerosis; b NHS, Nurses’ Health Study; c PREDIMED, Prevencion con Dieta Mediterranea; d The Blue Mountains Eye Study; NHANES, National Health and Nutrition Examination Survey. Abbreviations used: ICAM-1, inter-cellular adhesion molecule-1; SE, standard error; VCAM-1, vascular adhesion molecule-1. 2 Tests of significance were based on log-transformed values. Antilogs of adjusted mean levels of log-transformed inflammatory markers were presented. Multivariate models were adjusted for age, gender, race/ethnicity, site, educational attainment, family income, smoking status, pack-years of smoking, alcohol consumption, total physical activity, use of fish oil supplements, hypertension, diabetes, levels of TC and LDL-C, use of statins, angiotensin-converting enzyme inhibitors, β-blockers, thiazolidinediones, aspirin, and estrogens, BMI (a strong determinant of inflammatory markers which could be on the causal pathway between nut and seed consumption and systemic inflammation), dietary intakes of fruits, vegetables, trans-fat, fish, and total energy. 3 Results are reported in median ± SE. Adjusted for age, total energy intake, BMI, waist circumference, activity level, and smoking status. 1a

4 Inflammatory marker values were log-transformed for the statistical analyses of trend. Adjusted for age, gender, BMI, diabetes, smoking, educational level, use of statins, NSAID, and aspirin. 5 Results were reported as hazard ratios (95% CIs). Models were adjusted for age, sex, current smoking, alcohol consumption, poor self-rated health, BMI, presence of diabetes, total fiber, dietary glycemic index, use of corticosteroid drugs, and white blood cell count. 6 Covariates include energy (in kilojoules), sex, race-ethnicity, and age (in years).

Appendix G. Dietary intervention trials investigating the effects of nut consumption on antioxidant activity and biomarkers of antioxidant status (n = 19)1 Author (y) Study design Evidence Almonds (n = 6) Jambazian et Randomised al. (2005) Crossover; CF 1++ 3-arm Control group Single-blind Jia et al. Randomised (2006) Parallel; CF 1++ 3-arm Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

16 (8 M, 8 F) Healthy

4 weeks

(i) Control

(i) Low almond diet (10% en: 27g) (ii) High almond diet (20% en: 54g)

30 (30 M, 0 F) 18-25 years old Habitual smoker (10 – 20 cigarettes/day)

4 weeks

Li et al. (2007) 1++

60 (60 M, 0 F) Habitual smoker (5 – 20 cigarettes/day)

4 weeks

α-tocopherol (mol/L): (i) Control: 26.3, Low: 29.9, Difference: +3.6c (ii) Control: 26.3, High: 31.2, Difference: +4.9c Compared with the control diet, plasma αtocopherol increased on the almond diets. SOD activity (U/mL): (i) Baseline: 70.1, Control: 67.2, Δ: -2.9 (ii) Baseline: 69.6, 3 oz Almond: 68.7, Δ: -0.9 (iii) Baseline: 76.8, 6 oz Almond: 89.4, Δ: +12.6 GPx activity (U/L): (i) Baseline: 908, Control: 915, Δ: +7 (ii) Baseline: 918, 3 oz Almond: 927, Δ: +9 (iii) Baseline: 901, 6 oz Almond: 935, Δ: +34 Compared with the control group, no effects of almonds on SOD and GSH-PX were found. -tocopherol (mol/L): (i) Baseline: 14.43, Control: 14.25, Δ: -0.18 (ii) Baseline: 14.10, Almond: 15.48, Δ: +1.38 SOD activity (kU/L): (i) Baseline: 60.0, Control: 63.5, Δ: +3.5 (ii) Baseline: 56.2, Almond: 75.9, Δ: +19.7 GPx activity (U/L): (i) Baseline: 163.6, Control: 161.7, Δ: -1.9 (ii) Baseline: 161.2, Almond: 187.8, Δ: +26.5 Serum -tocopherol, SOD, and GPx increased significantly after the almond diet compared with no change after the pork diet (P < 0.05).

Randomised Crossover; CF 2-arm Control group

(ii) Control (i) Baseline

(i) Control group

(ii) Baseline

(ii) Almond powder (3 oz: 84g) (iii) Almond powder (6 oz:168g)

(iii) Baseline

(i) Baseline (ii) Baseline

(i) Control (Pork: 120g) (ii) Almond powder (3 oz: 84g)

Author (y) Evidence Jenkins et al. (2008) 1+

Subjects’ characteristics 27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

Duration

65 (17 M, 48 F) Prediabetes

16 weeks

20 (9 M, 11 F) Chinese Type 2 diabetics

4 weeks

Brazil nuts (n = 1) Thomson et Randomised al. (2008) Parallel 1+ 3-arm Control group

59 (30 M, 29 F) Low plasma selenium

12 weeks

Cashew nuts (n = 1) Davis et al. Randomised (2007) Parallel; CF 1++ 3-arm Control group

64 (29 M, 35 F) Metabolic syndrome

Wien et al. (2010) 1+ Li et al. (2011) 1++

Study design Randomised Crossover 3-arm Control group Randomised Parallel 2-arm Control group Randomised Crossover; CF 2-arm Control group

4 weeks

Comparison made (i) Baseline (ii) Baseline (iii) Baseline (i) Baseline (ii) Baseline (i) Baseline (ii) Baseline

Outcome measurements: Results2

(i) Control muffins (147g) (ii) Almonds (37g) + Muffins (75g) (iii) Almonds (73g) (i) Control ADA

α-tocopherol (mol/L): End value NR. This study only reported the baseline serum αtocopherol concentration (44.0 mol/L) and this was not influenced by the half-dose and full-dose almond supplementation (P < 0.05). α-tocopherol (mg/L): Baseline value NR. Plasma α-tocopherol decreased in the control group (-0.27 mg/L) whereas it increased (+1.74 mg/L) in the almond diet (P < 0.01). α-tocopherol (mol/L): (i) Baseline: 27.8, Step II: 25.8, : -2.0 (ii) Baseline: 27.8, Almond: 31.8, : +4.0c Almond diet increased α-tocopherol compared with the control diet (P < 0.001).

(ii) ADA + Almonds (20% en: 57g) (i) Control Step II diet * (ii) Almonds (20% en: 56g)

(i) Baseline

(i) Placebo

(ii) Baseline

(ii) Selenomethionine (iii) Brazil nuts (2 nuts = 8g)

(iii) Baseline

8 weeks

Treatment

(i) Baseline

(i) Control diet

(ii) Baseline

(ii) Cashew nuts (20% en: 66-115g) (iii) Walnuts (20% en: 60-100g)

(iii) Baseline

GPx activity (U/g protein): (i) Baseline: 2.80, Placebo: 2.74, Δ: -0.06 (ii) Baseline: 2.91, Selenomethionine: 3.12, Δ: +0.21a (iii) Baseline: 2.55, Brazil nuts: 2.83, Δ: +0.28c Week-12 plasma GPx activities were significantly higher in Brazil nut and selenomethionine groups than the placebo. ORAC (mg TE/g): (i) Baseline: 1067, Control: 1340, : +273c (ii) Baseline: 1105, Almond: 1315, : +209c (ii) Baseline: 1073, Walnut: 1489, : +417c There was no significant difference in ORAC between groups.

Author (y) Study design Evidence Peanuts (n = 2) Hargrove et Randomised al. (2001) Crossover; CF 1++ 5-arm Control group Double-blind

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

20 (9 M, 11 F) Normocholesterolaemic

24 days

(i) AAD (ii) AAD (iii) AAD (iv) AAD

(i) Step II Diet (ii) Olive oil (iii) Peanut oil (iv) Peanuts & Peanut butter

Nouran et al. (2010) 1+

54 (54 M, 0 F) Hypercholesterolaemic

4 weeks

(i) Baseline

(i) Habitual diet

(ii) Baseline

(ii) Peanuts (20% en: 77g)

LDL α-tocopherol content (i) AAD: 12.5, Step II: 11.6, Difference: -0.9 (ii) AAD: 12.5, Olive oil: 12.3, Difference: -0.2 (iii) AAD: 12.5, Peanut oil: 13.5,Difference:+1.0 (iv) AAD: 12.5, Peanuts: 13.5, Difference: +1.0 There were no significant differences in the amount of α-tocopherol present in LDL between the diets. TAC (U/mL): (i) Baseline: 9.5, Habitual: 8.5, : -1.0a (ii) Baseline: 10.7, Peanuts: 11.0, : +0.3 There were significant differences in TAC between the groups (P = 0.04).

24 (14 M, 10 F) Healthy

4 weeks

(i) Control

(i) Pecan-enriched diet (20% en: 72g)

Randomised Crossover 2-arm Control group

Pecans (n = 1) Haddad et al. Randomised (2006) Crossover; CF 1++ 2-arm Control group Single-blind

FRAP (mmol/L): (i) Control: 0.83, Pecan: 0.84, Difference: +0.01 TEAC (mmol/L): (i) Control: 1.78, Pecan: 1.79, Difference: +0.01 α-tocopherol (mol/L): (i) Control: 24.7, Pecan: 21.4, Difference: -3.3c -tocopherol (mol/L): (i) Control: 3.82, Pecan: 3.84, Difference: +0.02 There was a decrease in serum α-tocopherol on the pecan diet compared with the control diet (P < 0.001). There was no significant difference between the two diets in the antioxidant capacity (FRAP or TEAC assay).

Author (y) Study design Evidence Pistachio nuts (n = 2) Kocyigit et Randomised al. (2006) Parallel 1+ 2-arm Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

44 (24 M, 20 F) Healthy

3 weeks

(i) Baseline

(i) Regular diet

(ii) Baseline

(ii) Pistachio nuts (20% en: 65-75g)

Kay et al. (2010) 1++

28 (10 M, 18 F) Elevated LDL-C

4 weeks

(i) Baseline

(i) Step I diet

(ii) Baseline

(ii) Pistachio (10% en: 32-63g) (iii) Pistachio (20% en: 63-126g)

Antioxidant Potential (mol/L): (i) Baseline: 1.79, Regular diet: 1.84, : +0.48 (ii) Baseline: 1.83, Pistachio: 2.68, : +0.85a The AOP in the pistachio diet was significantly higher than the regular diet. α-tocopherol (nmol/L): (i) Baseline: 31.35, Control: 31.23, : -0.12 (ii) Baseline: 31.35, 1PD: 30.97, : -0.38 (iii) Baseline: 31.35, 2PD: 28.44, : -5.91 -tocopherol (nmol/L): (i) Baseline: 10.06, Control: 9.72, : -0.34 (ii) Baseline: 10.06, 1PD: 10.68, : +0.62 (iii) Baseline: 10.06, 2PD: 11.28, : +1.22 The 2PD had lower α-tocopherol and higher tocopherol than the Step I and 1PD (P ≤ 0.05).

Randomised Crossover; CF 3-arm Control group

Walnuts (n = 6) Zambon et Randomised al. (2000) Crossover; CF 1++ 2-arm Control group Iwamoto et al. (2002) 1++

Randomised Crossover; CF 2-arm Control group Single-blind

(iii) Baseline

49 (26 M, 23 F) Polygenic hypercholesterolaemic

6 weeks

40 (20 M, 20 F) Healthy

4 weeks

(i) Baseline (ii) Baseline

(i) Japanese, low fat diet

(i) Mediterranean diet (ii) Walnuts (18% en: 41-56 g) (i) Walnuts (12.5% en: 44-58g)

α-tocopherol (g/mg of LDL protein): (i) Baseline: 9.2, MD: 7.2, Δ: -2.0 (ii) Baseline: 9.2, Walnuts: 7.5, Δ: -1.7 There was no significant difference in the αtocopherol content of the LDL particles between the two diets. α-tocopherol (mol/L) in females: (i) LF diet: 21.2, Walnuts: 20.0, Difference: -1.2 In women, there was no significant difference in α-tocopherol concentration between the low fat diet and walnut diet groups.

Author (y) Evidence Ros et al. (2004) 1+

Study design

Tapsell et al. (2004) 1+

Randomised Parallel 3-arm Control group

Randomised Crossover 2-arm Control group

Subjects’ characteristics 20 (8 M, 12 F) Hypercholesterolaemic

Duration

58 (34 M, 24 F) Type 2 diabetics

6 months

4 weeks

Comparison made (i) Baseline (ii) Baseline

Mixed nuts (n = 1) LopezRandomised Uriarte et al. Parallel (2010) 2-arm 1+ Control group

50 (28 M, 22 F) Metabolic syndrome BMI: 24 to 35 kg/m2

12 weeks

Outcome measurements: Results2

(i) Mediterranean diet * (ii) MD + Walnuts (18% en: 40-65g)

LDL α-tocopherol (nmol/mg protein): (i) Baseline: 12.8, MD: 12.6, Δ: -0.2 (ii) Baseline: 12.8, Walnuts: 11.2, Δ: -1.6 LDL -tocopherol (nmol/mg protein): (i) Baseline: 0.55, MD: 0.59, Δ: +0.04 (ii) Baseline: 0.55, Walnuts: 0.98, Δ: +0.43 Compared with the MD, LDL α-tocopherol was significantly lower while the LDL -tocopherol was significantly higher on the walnut diet. TAS (mmol/L): (i) Baseline: 1.08, LFD: 1.14, Δ: +0.06c (ii) Baseline: 1.08, Modified LFD: 1.13,Δ:+0.05c (iii) Baseline: 1.14, Walnuts: 1.21, Δ: +0.07c There were no significant differences in TAS between groups.

(i) Baseline

(i) Low fat diet

(ii) Baseline

(ii) Modified low fat diet (iii) Modified LFD + Walnuts (30g)

(iii) Baseline Davis et al. (2007): Please refer to the cashew nut section. Spaccarotella Randomised 21 (21 M, 0 F) 8 weeks et al. (2008) Crossover Total PSA ≥ 2.0 1+ 2-arm ng/mL Control group At risk for prostate cancer

Treatment

(i) Baseline (ii) Baseline

(i) Average American diet (ii) Walnuts (24% en: 75g)

α-tocopherol (mol/L): (i) Baseline: 29.3, AAD: 28.59, Δ: -0.71 (ii) Baseline: 29.3, Walnuts: 26.65, Δ: -2.65 -tocopherol (mol/L): (i) Baseline: 4.14, AAD: +0.26, Δ: 4.40 (ii) Baseline: 4.14, Walnuts: +0.83, Δ: 4.97 There were no significant between-group differences in α-tocopherol and -tocopherol.

(i) Control (AHA guideline) (ii) AHA + Mixed nuts3 (30g)

ORAC (mol TE/mL): (i) Baseline: 26.00, Control: 25.71, : -0.29 (ii) Baseline: 25.46, Mixed nuts: 26.30, :+0.84 There were no significant differences in plasma ORAC between groups (P = 0.530).

1 Abbreviations used: % en, percentage of the total energy in the diet; AAD, average American diet; ADA, American Diabetes Association; BW, body weight; CF, controlled feeding; F, female; FRAP, ferric-reducing ability of plasma; GPx, gluthathione peroxidase; LFD, low fat diet; M, male; MD, Mediterranean diet; NR, not reported; NS, non significant; ORAC, oxygen radical absorbance capacity; PD, pistachio diet; SOD, superoxide dismutase; TAC, total antioxidant capacity; TAP, total antioxidant performance; TAS, total antioxidant status; TEAC, trolox equivalent antioxidant capacity. 2 Î&#x201D;: Change (within group) = Post treatment value â&#x20AC;&#x201C; Pre treatment value (i.e. baseline); Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001 3 15 g walnuts, 7.5 g almonds, and 7.5 g hazelnuts.

Appendix H. Dietary intervention trials investigating the effects of nut consumption on biomarkers of oxidative stress (n = 16)1 Author (y) Study design Evidence Almonds (n = 5) Jenkins et al. Randomised (2002) Crossover 1+ 3-arm Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

4 weeks

(i) Control muffin (147g) (ii) Control muffin (147g)

(i) Almonds (37g) + Muffins (75g) (ii) Almonds (73g)

Jia et al. (2006) 1++

30 (30 M, 0 F) 18-25 years old Habitual smoker (10 – 20 cigarettes/day)

4 weeks

(i) Baseline

(i) Control group

(ii) Baseline

(ii) Almond powder (3 oz: 84g) (iii) Almond powder (6 oz:168g)

LDL conjugated dienes (mol/L): (i) Baseline: 64, Control: 60, : -4 (ii) Baseline: 65, Half-dose: 53, : -12c (iii) Baseline: 62, Full-dose: 51, : -11c Compared to the control, LDL conjugated dienes was significantly lower in half-dose (P < 0.05) and full-dose almonds (P < 0.05). % tail DNA (i) Baseline: 24.5, Control: 24.5, Δ: 0.0 (ii) Baseline: 24.8, 3 oz Almond: 20.6, Δ: -4.2 (iii) Baseline: 24.9, 6 oz Almond: 17.1, Δ: -7.8 Urinary 8-OH-dG (ng/mg creatinine) (i) Baseline: 8.17, Control: 7.69, Δ: -0.48 (ii) Baseline: 10.26, 3 oz Almond: 2.63, Δ: -7.63 (iii) Baseline: 8.68, 6 oz Almond: 1.95, Δ: -6.73 Plasma MDA (nmol/mL): (i) Baseline: 7.26, Control: 7.46, Δ: +0.20 (ii) Baseline: 6.85, 3 oz Almond: 3.68, Δ: -3.17 (iii) Baseline: 8.01, 6 oz Almond: 3.29, Δ: -4.72 As compared with the control group, percentage tail DNA was significantly lower after the consumption of 6 oz of almonds, urinary 8-OH-dG and plasma MDA were significantly lower in both almond groups.

Randomised Parallel; CF 3-arm Control group

(iii) Baseline

Author (y) Evidence Li et al. (2007) 1++

Study design

Jenkins et al. (2008) 1+

Damasceno et al. (2011) 1+

Duration

Randomised Crossover; CF 2-arm Control group

Subjects’ characteristics 60 (60 M, 0 F) Habitual smoker (5 – 20 cigarettes/day)

Randomised Crossover 3-arm Control group

27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

4 weeks

Randomised Crossover 3-arm Control group

18 (9 M, 9 F) Moderate hypercholesterolaemic

4 weeks

Comparison made (i) Baseline (ii) Baseline

(i) Baseline

Treatment

Outcome measurements: Results2

(i) Control (Pork: 120g) (ii) Almond powder (3 oz: 84g)

% tail DNA (i) Baseline: 15.3, Control: 14.3, Δ: -1.0 (ii) Baseline: 15.1, Almond: 9.8, Δ: -5.2 Urinary 8-OH-dG (mol/mol creatinine) (i) Baseline: 17.0, Control: 17.2, Δ: +0.2 (ii) Baseline: 18.2, Almond: 13.2, Δ: -5.0 Urinary MDA (mol/mol creatinine): (i) Baseline: 2.1, Control: 2.1, Δ: 0.1 (ii) Baseline: 1.9, Almond: 1.5, Δ: -0.4 Compared to the control, the almond group significantly reduced DNA strand breaks, urinary 8-OH-dG, and urinary MDA (P < 0.05). Serum MDA (mol/L): (i) Baseline: 1.6, Control: 1.7, Δ: +0.1 (ii) Baseline: 1.4, Half-dose: 1.6, Δ: +0.2 (iii) Baseline: 1.6, Full-dose: 1.3, Δ: -0.3 Creatinine adjusted urinary isoprostane output (nmol/mmol): Control: 1.1, half-dose: 0.7 a, full-dose: 0.8 a Compared to the control, MDA was lower in the full-dose almond and urinary isoprostane output was lower in both almonds. All P <0.05. Lag time CD production (min)3: (i) Baseline: 47, Olive oil: 50, Δ: +3 (ii) Baseline: 47, Almonds: 47, Δ: 0 (iii) Baseline: 47, Walnuts: 45, Δ: -2 Oxidised LDL (U/L)3: (i) Baseline: 80, Olive oil: 76, Δ: -4 (ii) Baseline: 80, Almonds: 78, Δ: -2 (iii) Baseline: 80, Walnuts: 84, Δ: +4

(iii) Baseline

(i) Control muffins (147g)* (ii) Almonds (37g) + Muffins (75g) (iii) Almonds (73g)

(i) Baseline (MD) (ii) Baseline (MD) (iii) Baseline (MD)

(i) MD + Olive oil (22% en: 35-50g) (ii) MD + Almonds (22% en: 50-75g) (iii) MD + Walnuts (22% en: 40-65g)

(ii) Baseline

Author (y) Evidence Damasceno et al. (2011) 1+

Study design Randomised Crossover 3-arm Control group

Peanuts (n = 2) Hargrove et Randomised al. (2001) Crossover; CF 1++ 5-arm Control group Double-blind

Subjects’ characteristics 18 (9 M, 9 F) Moderate hypercholesterolaemic

Duration

20 (9 M, 11 F) Normocholesterolaemic

24 days

4 weeks

Comparison made (i) Baseline (MD) (ii) Baseline (MD) (iii) Baseline (MD)

Treatment

Outcome measurements: Results2

(i) MD + Olive oil (22% en: 35-50g) (ii) MD + Almonds (22% en: 50-75g) (iii) MD + Walnuts (22% en: 40-65g)

MDA (nmol/L)3: (i) Baseline: 109, Olive oil: 107, Δ: -2 (ii) Baseline: 109, Almonds: 95, Δ: -14 (iii) Baseline: 109, Walnuts: 92, Δ: -17 There were no significant differences in any of the oxidation analytes between the groups.

(i) AAD (ii) AAD (iii) AAD (iv) AAD

(i) Step II Diet (ii) Olive oil (iii) Peanut oil (iv) Peanuts & Peanut butter

Lag time (min): (i) AAD: 57, Step II: 66, Difference: +9 (ii) AAD: 57, Olive oil: 66, Difference: +9 (iii) AAD: 57, Peanut oil: 63, Difference: +6 (iv) AAD: 57, Peanuts: 66, Difference: +9 Rate of oxidation: (i) AAD: 28, Step II: 26, Difference: -2 (ii) AAD: 28, Olive oil: 24, Difference: -4a (iii) AAD: 28, Peanut oil: 28, Difference: 0 (iv) AAD: 28, Peanuts: 29, Difference: +1 Amount of dienes (nmol/mg LDL protein): (i) AAD: 510, Step II: 496, Difference: -14 (ii) AAD: 510, Olive oil: 502, Difference: -8 (iii) AAD: 510, Peanut oil: 518, Difference: +8 (iv) AAD: 510, Peanuts: 512, Difference: +2 There was a tendency that the Step II, olive oil, and peanuts & peanut butter diets result in longer lag time than the AAD (P  0.1). The olive oil had a lower rate of LDL-oxidation than AAD, peanut oil, peanuts & peanut butter diets (P<0.05). No between-group differences in the amount of total CD produced.

Author (y) Evidence Nouran et al. (2010) 1+

Study design Randomised Crossover 2-arm Control group

Pecans (n = 1) Haddad et al. Randomised (2006) Crossover; CF 1++ 2-arm Control group Single-blind Pistachio nuts (n = 2) Kocyigit et Randomised al. (2006) Parallel 1+ 2-arm Control group Kay et al. (2010) 1++

Randomised Crossover; CF 3-arm Control group

Subjects’ characteristics 54 (54 M, 0 F) Hypercholesterolaemic

Duration

24 (14 M, 10 F) Healthy

44 (24 M, 20 F) Healthy

28 (10 M, 18 F) Elevated LDL-C

Comparison made (i) Baseline

Treatment

Outcome measurements: Results2

(i) Habitual diet

(ii) Baseline

(ii) Peanuts (20% en: 77g)

Oxidised LDL (mU/L): (i) Baseline: 11.9, Habitual: 12.8, : +0.9 (ii) Baseline: 12.2, Peanuts: 12.0, : -0.2 There were no significant differences in oxidised LDL between the groups.

4 weeks

(i) Control Step I diet

(i) Pecans (20% en: 72g)

Plasma MDA (mmol/L): Control: 0.58, Pecan: 0.54, Difference: -0.05a Compared with the control diet, plasma MDA reduced on the pecan diet (P < 0.014).

3 weeks

(i) Baseline

(i) Regular diet

(ii) Baseline

(ii) Pistachio nuts (20% en: 65-75g)

(i) Baseline

(i) Step I diet

(ii) Baseline

(ii) Pistachios (10% en: 32-63g) (iii) Pistachios (20% en: 63-126g)

Plasma MDA (nmol/mL): (i) Baseline: 2.19, Regular diet: 2.12, : -0.07 (ii) Baseline: 2.11, Pistachio: 1.68, : -0.43a The MDA in the pistachio diet group was significantly lower than in the regular diet group (P < 0.05). Oxidised LDL (U/L): (i) Baseline: 48.57, Control: 51.29, : +2.72 (ii) Baseline: 48.57, 1PD: 46.57, : -2.00 (iii) Baseline: 48.57, 2PD: 43.43, : -5.14a Lipid hydroperoxide (mol/L): (i) Baseline: 0.60, Control: 0.50, : -0.10 (ii) Baseline: 0.60, 1PD: 0.54, : -0.06 (iii) Baseline: 0.60, 2PD: 0.65, : +0.05 Compared with the Step I diet, both the 1PD and 2PD periods resulted in lower Ox-LDL concentrations (P ≤ 0.05).

4 weeks

(iii) Baseline

Author (y) Study design Evidence Walnuts (n = 5) Zambon et Randomised al. (2000) Crossover; CF 1++ 2-arm Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

49 (26 M, 23 F) Polygenic hypercholesterolaemic

6 weeks

(i) Baseline

(i) Mediterranean diet (ii) MD + Walnuts (18% en: 41-56 g)

Iwamoto et al. (2002) 1++

40 (20 M, 20 F) Healthy

4 weeks

(i) Japanese, low fat diet

(i) LFD + Walnuts (12.5% en: 44-58g)

Lag time of CD production (min): (i) Baseline: 41.9, MD: 42.0, Δ: +0.1 (ii) Baseline: 41.9, Walnuts: 40.6, Δ: -1.3 There was no significant difference in the lag time of CD production between the two diets. Lag time (min) in females: (i) LF diet: 39.4, Walnuts: 37.0, Difference: -2.4 In women, there was no significant difference in the lag time between the groups.

20 (8 M, 12 F) Hypercholesterolaemic

4 weeks

(i) Baseline

(i) Mediterranean diet * (ii) MD + Walnuts (18% en: 40-65g)

Ros et al. (2004) 1+

Spaccarotella et al. (2008) 1+

Randomised Crossover; CF 2-arm Control group Single-blind Randomised Crossover 2-arm Control group

Randomised Crossover 2-arm Control group

(ii) Baseline

21 (21 M, 0 F) 8 weeks Total PSA ≥ 2.0 ng/mL At risk for prostate cancer Damasceno et al. (2011): Please refer to the almond section.

(ii) Baseline

(i) Baseline (ii) Baseline

(i) Average American diet (ii) Walnuts (24% en: 75g)

Oxidised LDL (U/L): (i) Baseline: NR, MD: 48.5, Δ: NR (ii) Baseline: NR, Walnuts: 45.9, Δ: NR Lag time of LDL CD production (min): (i) Baseline: 50.6, MD: 44.9, Δ: -5.7 (ii) Baseline: 50.6, Walnuts: 40.1, Δ: -10.5 MDA (nmol/L): (i) Baseline: 110, MD: 123, Δ: +13 (ii) Baseline: 110, Walnuts: 106, Δ: -4 There were no significant between-group differences in any of the oxidation analytes. Oxidised LDL (mmol/L): (i) Baseline: 2.61, AAD: 2.46, Δ: -0.15 (ii) Baseline: 2.61, Walnuts: 2.45, Δ: -0.16 There was no significant between-group difference in oxidised LDL.

Author (y) Study design Evidence Mixed nuts (n = 2) LopezRandomised Uriarte et al. Parallel (2010) 2-arm 1+ Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

50 (28 M, 22 F) Metabolic syndrome BMI: 24 to 35 kg/m2

12 weeks

(i) Baseline

(i) Control (AHA guideline) (ii) AHA + Mixed nuts4 (30g)

Jenkins et al. (2011) 1+

117 (78 M, 39 F) Type 2 diabetics Postmenopausal F

12 weeks

Oxidised LDL (U/L): (i) Baseline: 67.64, Control: 65.77, : -1.87 (ii) Baseline: 70.67, Mixed nuts: 63.08, : -7.59 Lag phase (min) (i) Baseline: 14.50, Control: 17.20, : +2.70 (ii) Baseline: 15.76, Mixed nuts: 16.47,: +0.71 V-max (nmol/min/mL): (i) Baseline: 26.5, Control: 25.9, : -0.6 (ii) Baseline: 23.8, Mixed nuts: 23.4, : -0.4 C-max (nmol/mL): (i) Baseline: 1193, Control: 1165, : +28 (ii) Baseline: 1088, Mixed nuts: 1017, : -71 Urine 8-oxo-dG (nmol/mmol creatinine): (i) Baseline: 11.96, Control: 8.03, : -3.93c (ii) Baseline: 11.90, Mixed nuts: 5.55, : -6.35c There were no significant differences in oxidised LDL, lag phase, Vmax, and Cmax between the groups. The DNA damage was significantly lower in the nut group, when compared with the control group (P < 0.001). Oxidised LDL & Oxidised proteins: (i) Baseline: NR, Control: NR, : NS (ii) Baseline: NR, Half nuts: NR, : NS (iii) Baseline: NR, Full nuts: NR, : NS

Randomised Parallel design

(ii) Baseline

(i) Baseline (ii) Baseline (iii) Baseline

(i) Control – Muffins (2-4) (ii) Mixed nuts5 (25-50g) + Muffin (1-2) (iii) Mixed nuts5 (50-100g)

There were no differences in the measures of oxidative damage between groups.

1 Abbreviations used: % en, percentage of the total energy in the diet; 8-OH-dG, 8-hydroxy-deoxyguanosinel; 8-oxo-dG, 8-oxo-7,8-dihydro-20-deoxyguanosine; AAD, average American diet; AOP, antioxidant potential; CD, conjugated dienes; CF, controlled feeding; F, female; GPx, glutathione peroxidase; LDL, low-density lipoprotein; M, male; MD, Mediterranean diet; MDA, malondialdehyde; NR, not reported; NS, non significant; OD-max, maximal amount of lipid peroxide products; Ox-LDL, oxidised-LDL; PD, pistachio diet; SOD, superoxide dismutase; t-lag, lag time; T-max, time needed to gain the maximal rate of lipid peroxide products accumulation during the lipid oxidation course; TOS, total oxidant status; V-max, maximal rate of oxidation. 2 Î&#x201D;: Change (within group) = Post treatment value â&#x20AC;&#x201C; Pre treatment value (i.e. baseline); Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001. 3 Data was reported as median. Analysis was performed using non parametric tests. 4 15 g walnuts, 7.5 g almonds, and 7.5 g hazelnuts. 5 Unsalted and mostly raw almonds, pistachios, walnuts, pecans, hazelnuts, peanuts, cashews, and macadamias.

Appendix I. Dietary intervention trials investigating the effects of nut consumption on biomarkers of inflammation (n = 11)1 Author (y) Study design Evidence Almonds (n = 4) Jenkins et al. Randomised (2002) Crossover 1+ 3-arm Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

4 weeks

(i) Baseline

(i) Control – Muffin (147g)* (ii) Almonds (37g) + Muffins (75 g) (iii) Almonds (73g)

CRP (mg/L): (i) Baseline: 3.21, Control: 2.37, Δ: -0.84 (ii) Baseline: 1.81, Half-dose: 1.77, Δ: -0.04 (iii) Baseline: 1.62, Full-dose: 2.27, Δ: +0.65 No significant difference in CRP was seen between the groups. Hs-CRP (mg/L): (i) Baseline: 4.5, Control: 4.73, : -1.3 (ii) Baseline: 6.9, Almonds: 5.96; : -1.8 (iii) Baseline: 4.8, Chocolate: 4.25, : +1.1 (iv) Baseline: 7.0, Al. + Choc.: 4.25, : -1.2

(ii) Baseline (iii) Baseline

Kurlandsky & Stote (2006) 1+

Randomised Parallel 4-arm Control group

47 (0 M, 47 F) Normocholesterolaemic

6 weeks

(i) Baseline (ii) Baseline (iii) Baseline (iv) Baseline

Rajaram et al. (2010) 1++

Randomised Crossover; CF 3-arm Control group Single-blind

25 (14 M, 11 F) Healthy

4 weeks

(i) Baseline (ii) Baseline (iii) Baseline

(i) NCEP TLC Control (ii) TLC + Almonds (60g) (iii) TLC + Chocolate (41g) (iv) TLC + Almonds (60g) + Choc. (41g) (i) Step I diet (ii) Low almond diet (10% en: 27g) (iii) High almond diet (20% en: 54g)

There were no significant differences in HsCRP concentration between the groups. CRP (mg/L)3: (i) Baseline: 1.53, Step I: 1.54, : +0.01 (ii) Baseline: 1.53, LA: 1.40, : -0.13 (ii) Baseline: 1.53, HA: 1.47, : -0.06 IL-6 (ng/L)3: (i) Baseline: 1.18, Step I: 1.39, : +0.21 (ii) Baseline: 1.18, LA: 1.25, : +0.07 (iii) Baseline: 1.18, HA: 1.35, : +0.17 Fibrinogen (g/L)3: (i) Baseline: 3.0, Step I: 2.9, : -0.1 (ii) Baseline: 3.0, LA: 3.0, : 0.0 (iii) Baseline: 3.0, HA: 2.9, : 0.1

Author (y) Evidence Rajaram et al. (2010) 1++ Damasceno et al. (2011) 1+

Study design Randomised Crossover; CF 3-arm Control group Randomised Crossover 3-arm Control group

Cashew nuts (n = 1) Mukuddem- Randomised Petersen et Parallel; CF al. (2007) 3-arm 1++ Control group

Subjects’ characteristics 25 (14 M, 11 F) Healthy

Duration

Comparison made (i) Baseline (ii) Baseline (iii) Baseline

Treatment

Outcome measurements: Results2

(i) Step I diet (ii) Low almond (iii) High almond

4 weeks

(i) Baseline (MD) (ii) Baseline (MD)* (iii) Baseline (MD)*

(i) MD + Olive oil (22% en: 35-50g) (ii) MD + Almonds (22% en: 50-75g) (iii) MD + Walnuts (22% en: 40-65g)

Compared to the control group, both almond diets had significantly lower CRP. There were no significant between-group differences in IL-6 and fibrinogen. CRP (mg/L): (i) Baseline: 2.1, Olive oil: 1.7, Δ: -0.4 (ii) Baseline: 2.1, Almonds: 1.7, Δ: -0.4 (iii) Baseline: 2.1, Walnuts: 1.9, Δ: -0.2 There were no significant differences in CRP between groups.

18 (9 M, 9 F) Moderate hypercholesterolaemic

64 (29 M, 35 F) Metabolic syndrome

8 weeks

(i) Baseline

(i) Control diet

(ii) Baseline

(ii) Cashews (20% en: 66-115g) (iii) Walnuts (20% en: 60-100g)

4 weeks

(iii) Baseline Walnuts (n = 6) Ros et al. Randomised (2004) Crossover 1+ 2-arm Control group Zhao et al. (2004) 1++

Randomised Crossover; CF 3-arm Control group

20 (8 M, 12 F) Hypercholesterolaemic

4 weeks

(i) Baseline (ii) Baseline

23 (20 M, 3 F) 6 weeks (i) AAD Moderate hyper7.7% en LA, cholesterolaemic 0.8% en ALA Overweight / (ii) AAD obese class I 7.7% en LA, Postmenopausal 0.8% en ALA F Mukuddem-Petersen et al. (2007): Please refer to the cashew nuts section.

(i) Mediterranean diet (ii) MD + Walnuts (18% en: 40-65g) (i) Walnut diet high in LA: 12.6% en LA, 3.6% en ALA (ii) Walnut diet high in ALA: 10.5% en LA, 6.5% en ALA

Hs-CRP (mg/L)4: (i) Baseline: 3.05, Control: 3.65, : +0.60 (ii) Baseline: 4.30, Cashews: 4.20; : -0.10 (iii) Baseline: 2.40, Walnuts: 3.00, : +0.60a There were no significant differences in the change in Hs-CRP between the groups. CRP (mg/dL): (i) Baseline: 1.6, MD: 1.6, Δ: 0.0 (ii) Baseline: 1.6, Walnuts: 1.5, Δ: -0.1 No differences in the changes in CRP between the walnut and control groups. CRP (mg/L): (i) AAD: 1.51, LA: 0.83, Difference: -0.68 (ii) AAD: 1.51, ALA: 0.37, Difference: -1.14b Compared with the AAD, the ALA diet reduced CRP by 75% (P < 0.01) and the LA reduced CRP by 45% (P = 0.08). No differences in CRP between ALA diet and LA diet were seen.

Author (y) Evidence PerezMartinez et al. (2007) 1++

Study design

Zhao et al. (2007) 1++

Randomised Crossover; CF 3-arm Control group

Subjects’ characteristics 16 (16 M, 0 F) Healthy Medical students

Duration

23 (20 M, 3 F) Moderate hypercholesterolaemic Overweight / obese class I

6 weeks

4 weeks

Comparison made (i) Western diet: 38% en fat (ii) Western diet: 38% en fat

Treatment

Outcome measurements: Results2

(ii) MD + VOO: < 10% en SFA, 24% MUFA, 4% PUFA (ii) High CHO & n-3 walnuts: <10% en SFA, 2% en ALA

(i) AAD: 7.7% en LA, 0.8% en ALA (ii) AAD: 7.7% en LA, 0.8% en ALA

(i) Walnut diet high in LA: 12.6% LA, 3.6% ALA (ii) Walnut diet high in ALA: 10.5% LA, 6.5% ALA

IL-6: (i) Western: NR, MD: NR, Difference: NR (ii) Western: NR, n-3: NR, Difference: NR TNF-: (i) Western: NR, MD: NR, Difference: NR (ii) Western: NR, n-3: NR, Difference: NR MCP-1: (i) Western: NR, MD: NR, Difference: NR (ii) Western: NR, n-3: NR, Difference: NR There were no significant between-treatment differences in plasma IL-6 (P = 0.463), TNF- (P = 0.181), and MCP-1 (P = 0.513). Serum IL-6 (ng/L)4: (i) AAD: 239.9, LA: 169.6, Difference: -70.3 (ii) AAD: 239.9, ALA: 107.9, Difference: -132.0 Serum IL-1 (ng/L)4: (i) AAD: 29.8, LA: 42.5, Difference: +12.7 (ii) AAD: 29.8, ALA: 20.0, Difference: -9.8 Serum TNF-α (ng/L)4: (i) AAD: 18.2, LA: 13.3, Difference: -4.9 (ii) AAD: 18.2, ALA: 10.3, Difference: -7.9 After consumption of the ALA diet, serum TNF-α concentration was lower (P < 0.08) and the production of IL-6, IL-1, and TNF-α by PBMCs were significantly reduced (P < 0.05) than after the LA diet and the AAD.

Damasceno et al. (2011): Please refer to the almond section.

Author (y) Study design Evidence Mixed nuts (n = 2) CasasRandomised Agustench et Parallel al. (2011) 2-arm 1+ Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

50 (28 M, 22 F) Metabolic syndrome BMI: 24 to 35 kg/m2

12 weeks

(i) Baseline

(i) Control (AHA guideline) (ii) AHA + Mixed nuts5 (30g)

CRP (mg/L)4: (i) Baseline: 1.98, Control: 2.28, : +0.30 (ii) Baseline: 1.08, Mixed nuts: 1.18, : +0.10 IL-6 (ng/L)4: (i) Baseline: 3.14, Control: 3.34, : +0.20 (ii) Baseline: 2.39, Mixed nuts: 1.59, : -0.80a IL-18 (pg/mL): (i) Baseline: 105.1, Control: 88.4, : -16.7a (ii) Baseline: 113.9, Mixed nuts: 91.9, : -22a Adiponectin (ng/L): (i) Baseline: 6.2, Control: 6.7, : +0.5 (ii) Baseline: 6.1, Mixed nuts: 6.6, : +0.5 MCP-1 (pg/mL): (i) Baseline: 234, Control: 203, : -31a (ii) Baseline: 241, Mixed nuts: 221, : -20a Leukocyte count (cells/nL): (i) Baseline: 6.8, Control: 6.6, : -0.2 (ii) Baseline: 7.3, Mixed nuts: 6.4, : -0.9a There were no significant between-group differences in CRP, IL-18, adiponectin, MCP-1, and leukocyte count. The mixed nut diet decreased IL-6 (P = 0.035) as compared with the control diet, but adjustment for changes in body weight attenuated statistical significance (P = 0.078).

(ii) Baseline

Author (y) Evidence Jenkins et al. (2011) 1+

Study design Randomised Parallel 3-arm Control group

Subjects’ characteristics 117 (78 M, 39 F) Type 2 diabetics Postmenopausal F

Duration 12 weeks

Comparison made (i) Baseline (ii) Baseline (iii) Baseline

Treatment

Outcome measurements: Results2

(i) Control muffins (2-4) (ii) Mixed nuts6 (25-50g) + Muffin (1-2) (iii) Mixed nuts6 (50-100g)

CRP (mg/L): (i) Baseline: 1.9, Control: 2.0, Change: +0.1 (ii) Baseline: 1.8, Half-dose: 1.5, Change: -0.3 (iii) Baseline: 1.6, Full-dose: 2.2, Change: +0.6 Compared to the control group, CRP concentration was significantly lower in the half-dose nut group (P = 0.042).

Abbreviations used: % en, percentage of the total energy in the diet; AAD, average American diet; AHA, American Heart Association; ALA, alpha-linoleic acid; CF, controlled feeding; CRP, C-reactive protein; F, female; Hs-CRP, high sensitivity C-reactive protein; IL, interleukin; LA, linoleic acid; M, male; MCP-1, monocyte chemotactic protein-1; MUFA, monounsaturated fatty acids; NCEP, national cholesterol education program; NR, not reported; PBMC, peripheral blood mononuclear cell; PCOS, polycystic ovary syndrome, PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; TLC, therapeutic lifestyle changes; TNF-α, tumor necrosis factor-alpha; VOO, virgin olive oil. 2 Δ: Change (within group) = Post treatment value – Pre treatment value (i.e. baseline); Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001. 3 Data was reported as arithmetic mean. Log transformed values were used for statistical analysis. 4 Data was reported as median. Analysis was performed either using non parametric tests or log-transformed values. 5 15 g walnuts, 7.5 g almonds, and 7.5 g walnuts. 6 Unsalted and mostly raw almonds, pistachios, walnuts, pecans, hazelnuts, peanuts, cashews, and macadamias. 1

Appendix J. Dietary intervention trials investigating the effects of nut consumption on biomarkers of endothelial function (n = 9)1 Author (y) Study design Evidence Almonds (n = 3) Kurlandsky Randomised & Stote Parallel (2006) 4-arm 1+ Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

47 (0 M, 47 F) Normocholesterolaemic

6 weeks

(i) Baseline

(i) NCEP TLC Control (ii) TLC + Almonds (60g) (iii) TLC + Chocolate (41g) (iv) TLC + Almonds (60g) + Chocolate (41g)

ICAM (ng/mL): (i) Baseline: 188.6, Control: 192.3, : +3.7 (ii) Baseline: 198.4, Almonds: 195.8; : -2.6 (iii) Baseline: 178.8, Chocolate: 159.6,:-19.2a (iv) Baseline: 167.6, Al.+Choc.: 165.16,:-2.44 VCAM (ng/mL): (i) Baseline: 530.4, Control: 462.3, : -68.1 (ii) Baseline: 504.9, Almonds: 452.7; : -52.2 (iii) Baseline: 437.8, Chocolate: 394.4,: -43.4 (iv) Baseline: 466.0, Al. + Choc.: 421.8, :-44.2 There were no significant differences in ICAM and VCAM between the groups. E-selectin (g/L): (i) Baseline: 55.9, Step I: 54.3, : -1.6 (ii) Baseline: 55.9, Low almond: 53.5, : -2.4 (iii) Baseline: 55.9, High almond: 50.1, : -5.8 High almond diet had significantly lower low E-selectin than the other groups. ICAM-1 (ng/ml)4: (i) Baseline: 291, Olive oil: 272, Δ: -19 (ii) Baseline: 291, Almonds: 260, Δ: -31 (iii) Baseline: 291, Walnuts: 238, Δ: -53 VCAM-1 (ng/ml)4: (i) Baseline: 670, Olive oil: 730, Δ: +60 (ii) Baseline: 670, Almonds: 760, Δ: +90 (iii) Baseline: 670, Walnuts: 824, Δ: +154

(ii) Baseline (iii) Baseline (iv) Baseline

Rajaram et al. (2010) 1++

Damasceno et al. (2011) 1+

Randomised Crossover; CF 3-arm Control group Single-blind

25 (14 M, 11 F) Healthy

Randomised Crossover 3-arm Control group

18 (9 M, 9 F) Moderate hypercholesterolaemic

4 weeks

(i) Baseline

(i) Step I diet *

(ii) Baseline

(ii) Low almond (10% en: 27g) (iii) High almond (20% en: 54g) (i) MD + Olive oil (22% en: 35-50g) (ii) MD + Almonds (22% en: 50-75g) (iii) MD + Walnuts (22% en: 40-65g)

(iii) Baseline 4 weeks

(i) Baseline (MD) (ii) Baseline (MD) (iii) Baseline (MD)

There were no between-group difference in ICAM and VCAM.

Author (y) Study design Evidence Walnuts (n = 6) Ros et al. Randomised (2004) Crossover 1+ 2-arm Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

20 (8 M, 12 F) Hypercholesterolaemic

4 weeks

(i) Baseline

(i) Mediterranean diet (ii) MD + Walnuts (18% en: 40-65g)

Zhao et al. (2004) 1++

23 (20 M, 3 F) Moderate hypercholesterolaemic Overweight / obese class I Postmenopausal F

6 weeks

ICAM-1 (mol/L): (i) Baseline: 355, MD: 370, Δ: +25 (ii) Baseline: 355, Walnuts: 343, Δ: -12 VCAM-1 (mol/L): (i) Baseline: 474, MD: 465, Δ: -9 (ii) Baseline: 474, Walnuts: 378, Δ: -96 EDV (%) (i) Baseline: 3.4, MD: 3.6, Δ: +0.2 (ii) Baseline: 3.4, Walnuts: 5.9, Δ: +2.5 EIDV (%) (i) Baseline: 14.4, MD: 12.5, Δ: -1.9 (ii) Baseline: 14.4, Walnuts: 12.2, Δ: -2.2 Compared with the MD, the walnut diet significantly improved EDV (P = 0.043) and lower VCAM-1 by 19% (P = 0.045). No changes in ICAM-1 (walnut vs. control). ICAM-1 (mol/L): (i) AAD: NR, LA: NR, Difference: b (ii) AAD: NR, ALA: NR, Difference: b VCAM-1 (mol/L): (i) AAD: NR, LA: NR, Difference: NS (ii) AAD: NR, ALA: NR, Difference: b E-selectin (mol/L): (i) AAD: NR, LA: NR, Difference: b (ii) AAD: NR, ALA: NR, Difference: b Compared with the AAD, both LA and ALA diets significantly decreased ICAM-1 and Eselectin. The ALA diet resulted in greater decreases in VCAM-1 than the other diets.

Randomised Crossover; CF 3-arm Control group

(ii) Baseline

(i) AAD: 7.7% en LA, 0.8% en ALA (ii) AAD: 7.7% en LA, 0.8% en ALA

(i) Walnut diet high in LA: 12.6% LA, 3.6% ALA (ii) Walnut diet high in ALA: 10.5% LA, 6.5% ALA

Author (y) Evidence PerezMartinez et al. (2007) 1++

Study design

Ma et al. (2010) 1+

Randomised Crossover 2-arm Control group

24 (10 M, 14 F) Type 2 diabetes, non insulintreated

Randomised Crossover; CF 3-arm Control group

20 (20 M & F) Hypercholesterolaemic Elevated LDL-C Overweight / obese class I

West et al. (2010) 1++

Randomised Crossover; CF 3-arm Control group

Subjects’ characteristics 16 (16 M, 0 F) Healthy Medical students

Duration 4 weeks

Comparison made (i) Western diet: 38% en fat (ii) Western diet: 38% en fat

8 weeks

(i) Baseline (ii) Baseline

6 weeks

(i) AAD: 8%en LA, 1%en ALA (ii) AAD: 8%en LA, 1%en ALA

Treatment

Outcome measurements: Results2

(ii) MD + VOO: < 10% en SFA, 24% en MUFA, 4% en PUFA (ii) High CHO & n3 walnuts: <10% en SFA, 2% en ALA

ICAM-1: (i) Western: NR, MD: NR, Difference: NR (ii) Western: NR, n-3: NR, Difference: NR VCAM-1: (i) Western: 663, MD: 495, Difference: -168a (ii) Western: 663, n-3: 486, Difference: -177a There was no between-treatment difference in plasma ICAM-1 (P = 0.596). Compared with the Western diet, MD and n-3 diet significantly decreased VCAM-1 (P < 0.05) with no differences between MD and n-3 diet. Flow-mediated dilatation (%): (i) Baseline: 8.6, Control: 9.8, : +1.2a (ii) Baseline: 8.6, Walnuts: 10.8, : +2.2a Compared with the control diet, the walnut diet significantly improved FMD (P = 0.04). Flow-mediated dilation (n =12): (i) AAD: 6.1, LA: 6.7, Difference: +0.6 (ii) AAD: 6.1, ALA: 8.2, Difference: +2.1a Endothelin-1 (pg/mL) (n = 20): (i) AAD: 2.0, LA: 1.7, Difference: -0.3 (ii) AAD: 2.0, ALA: 1.0, Difference: -0.1 Compared with the AAD, the ALA diet increased FMD (P = 0.02).

(i) Ad libitum diet (no nuts) with ~SFA content (ii) Walnut diet (56g) (i) LA (12.6% en LA, 3.6% en ALA) (ii) ALA (10.5% en LA, 6.5% en ALA)

Damasceno et al. (2011): Please refer to the almond section.

Author (y) Study design Evidence Mixed nuts (n = 1) LopezRandomised Uriarte et Parallel al. (2010) 2-arm 1+ Control group

Subjects’ characteristics

Duration

Comparison made

Treatment

Outcome measurements: Results2

50 (28 M, 22 F) Metabolic syndrome BMI: 24 to 35 kg/m2

12 weeks

(i) Baseline

(i) Control (AHA guideline) (ii) AHA + Mixed nuts4 (30g)

ICAM (g/L): (i) Baseline: 566.9, Control: 555.6, : -11.4 (ii) Baseline: 609.1, Mixed nut: 517.1, :-92.0a VCAM (g/L): (i) Baseline: 1179, Control: 1236, : +56.8 (ii) Baseline: 1082, Mixed nuts: 1039, : -42.9 ENDOPAT index: (i) Baseline: 1.92, Control: 1.79, : -0.13 (ii) Baseline: 1.82, Mixed nuts: 1.71, : -0.11 There were no significant between-group differences in ICAM, VCAM, and ENDOPAT.

(ii) Baseline

Abbreviations used: % en, percentage of the total energy in the diet; AAD, average American diet; AHA, American Heart Association; ALA, alpha-linoleic acid; CF, controlled feeding; ET-1, endothelin-1; EDV, endothelium-dependent vasodilation; EIDV, endothelium-independent vasodilation; F, female; LA, linoleic acid; LF, low fat; M, male; MD, Mediterranean diet; MUFA, monounsaturated fatty acids; NCEP, national cholesterol education program; NR, not reported; NS, non significant; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; sICAM-1, soluble inter-cellular adhesion molecule-1; sVCAM-1, soluble vascular adhesion molecule-1; TLC, therapeutic lifestyle changes; VOO, virgin olive oil. 2 Δ: Change (within group) = Post treatment value – Pre treatment value (i.e. baseline); Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001. 3 Data was reported as median. Analysis was performed using non parametric tests. 4 15 g walnuts, 7.5 g almonds, and 7.5 g hazelnuts. 1

Appendix K. Epidemiological studies: Effects of nut consumption on type 2 diabetes (4 cohorts)1 Author (year) Level of evidence Jiang et al. (2002) 2++

Study design; Subjects’ characteristics The NHS a ; Prospective 16-y followup; 83,818 F nurses; Aged 34 – 59 years

Endpoints Type 2 diabetes2

Type 2 diabetes2

Parker et al. (2003) 2+

The IWHS b ; Prospective 12-y followup; 35,988 F Postmenopausal; Aged 55 – 69 years

Type 2 diabetes3

Villegas et al. (2008) 2++

The SWHS c ; Prospective 4.6-y followup; 64,227 F; Aged 40 – 70 years

Type 2 diabetes4

Frequency of nut consumption Nut consumption Never / almost never < Once / week 1 – 4 times / week ≥ 5 times / week Peanut butter Never / almost never < Once / week 1 – 4 times / week ≥ 5 times / week Nut consumption < Once / month < 1 time / week 1 – 4 times / week ≥ 5 times / week Peanut butter < Once / month < 1 time / week 1 – 4 times / week ≥ 5 times / week Peanut intake (Median) Q1: 0.1 g/d Q2: 0.4 g/d Q3: 0.7 g/d Q4: 1.4 g/d Q5: 3.1 g/d

Relative Risk (95% CI)

P for trend

1.00 0.91 (0.84 – 0.99) 0.81 (0.74 – 0.90) 0.71 (0.57 – 0.87)

< 0.001

1.00 0.98 (0.90 – 1.07) 0.91 (0.84 – 1.00) 0.81 (0.69 – 0.94)

0.002

1.00 0.98 (0.87 – 1.10) 1.06 (0.93 – 1.22) 1.51 (1.13 – 2.04)

0.004

1.00 0.96 (0.84 – 1.09) 0.99 (0.88 – 1.12) 0.97 (0.80 – 1.18)

0.86

1.00 0.80 (0.69 – 0.94) 0.95 (0.82 – 1.11) 0.79 (0.68 – 0.92) 0.80 (0.68 – 0.93)

< 0.001

Author (year) Level of evidence Kochar et al. (2010)

Study design; Subjects’ characteristics The PHS d ; Prospective 19.2-y followup; 20,224 M physicians

Endpoints Type 2 diabetes5

Frequency of nut consumption Rarely / never < 1 time / week 1 time / week 2 – 4 times / week 5 – 6 times / week > 7 times / week

Relative Risk (95% CI) 1.00 1.06 (0.93 – 1.20) 1.10 (0.95 – 1.26) 0.97 (0.82 – 1.14) 0.99 (0.76 – 1.30) 0.87 (0.61 – 1.24)

P for trend 0.99

NHS, Nurses’ Health Study; b IWHS, Iowa Women’s Health Study; c SWHS, Shanghai Women’s Health Study; d PHS, Physicians’ Health Study. Abbreviations used: CI, confidence interval; F, female; M, male. 2 Adjusted for age, BMI, family history of diabetes in a first-degree relative, exercise, cigarette smoking, alcohol consumption, total energy intake, glycemic load, multivitamin use, intakes of polyunsaturated fat, saturated fat, trans-fat, cereal fibre, magnesium, vegetables, fruits, whole grain, and fish. 3 Adjusted for age, BMI, waist/hip ratio, physical activity, current smoking status, pack-years of smoking, alcohol consumption, total daily energy intake, educational attainment, current estrogen use, fiber, polyunsaturated fat, saturated fat, monounsaturated fat, trans fatty acids, servings per day of total fruit, total vegetables, whole grains, fish and seafood, and daily intake of magnesium. 4 Adjusted for age, energy intake, BMI, waist-to-hip ratio, smoking, alcohol consumption, vegetable intake, fibre, physical activity, income level, education level, occupation, and hypertension. 5 Adjusted for age, smoking, randomization arm, alcohol consumption, breakfast cereal consumption, dairy consumption, red meat consumption, physical activity, BMI, history of hypertension. 1a

Appendix L. Dietary intervention trials: Effects of nut consumption on markers of glycaemic control (n = 19)1 Author (y) Study design Evidence Almonds (n = 8) Lovejoy et Randomised al. (2002) Crossover; CF Study 2 4-arm 1++ Control group Double-blind

Subjects’ characteristics

Duration

Comparison Made

Treatment

Outcome measurements: Results2

30 (13 M, 17 F) Type 2 diabetics

4 weeks

(i) Low fat control diet

(i) Low fat diet + Almonds (10% en: 57-113g) (ii) High fat diet + Almonds (10% en: 57-113g)

Sabate et al. (2003) 1++

25 (14 M, 11 F) Healthy

Glucose (mmol/L): (i) LFC: 8.00, LFA: 8.63, Difference: +0.63 (ii) HFC: 8.73, HFA: 8.14, Difference: +0.59 Insulin (pmol/L): (i) LFC: 93.6, LFA: 89.4, Difference: -4.2 (ii) HFC: 88.8, HFA: 88.2, Difference: -0.6 Hemoglobin A1c (%): (i) LFC: 6.8, LFA: 7.1, Difference: +0.3 (ii) HFC: 7.2, HFA: 7.0, Difference: -0.2 No differences in glucose, insulin and HbA1c between groups. Glucose (mmol/L): (i) Step I: 4.70, LA: 4.72, Difference: +0.02 (ii) Step I: 4.70, HA: 4.71, Difference: +0.01 No between-group differences in blood glucose. Glucose (mmol/L): (i) Baseline: 8.44, CHO: 7.05, Δ: -1.39c (ii) Baseline: 8.44, Almond: 7.10, Δ: -1.33c Insulin (U/ml): (i) Baseline: 47, CHO: 32, Δ: -15c (ii) Baseline: 46, Almond: 21, Δ: -25c HOMA-IR: (i) Baseline: 17, CHO: 11, Δ: -6c (ii) Baseline: 20, Almond: 7, Δ: -13c There were no significant difference between the groups in blood glucose, insulin, and HOMA-IR.

Wien et al. (2003) 1+

Randomised Crossover; CF 3-arm Control group Single-blind Randomised Parallel 2-arm Control group

(ii) High fat control diet

4 weeks

(i) Step I diet (ii) Step I diet

65 (28 M, 37 F) Overweight and obese

24 weeks

(i) Baseline (ii) Baseline

(i) Low almond (10% en: 27g) (ii) High almond (20% en: 54g) (i) Complex CHO LCD (ii) Almond LCD (84g)

Author (y) Evidence Jenkins et al. (2008) 1+

Study design Randomised Crossover 3-arm Control group

Subjects’ characteristics 27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

Duration 4 weeks

Comparison Made (i) Baseline (ii) Baseline (iii) Baseline

Wien et al. (2010) 1+

Randomised Parallel 2-arm Control group

65 (17 M, 48 F) Prediabetes

16 weeks

(i) Baseline (ii) Baseline

Treatment

Outcome measurements: Results2

(i) Control muffin (147g) (ii) Half-dose almonds (37g) + Muffins (75g) (iii) Full-dose almonds (73g)

Insulin (pmol/L): (i) Baseline: 41.2, Control: 38.4, Δ: -2.8 (ii) Baseline: 40.0, Half-dose: 39.2, Δ: -0.8 (iii) Baseline: 40.4, Full-dose: 37.6, Δ: -2.8 Glucose (mmol/L): (i) Baseline: 4.86, Control: 4.77, Δ: -0.09 (ii) Baseline: 4.87, Half-dose: 4.88, Δ: +0.01 (iii) Baseline: 4.84, Full-dose: 4.91, Δ: +0.07 HOMA-IR: (i) Baseline: 1.53, Control: 1.39, Δ: -0.14 (ii) Baseline: 1.48, Half-dose: 1.46, Δ: -0.02 (iii) Baseline: 1.49, Full-dose: 1.39, Δ: -0.10 There were no significant differences in insulin, glucose, and HOMA-IR between the groups. Glucose (mmol/L): (i) Baseline: 5.77, Control: 5.55, Δ: -0.22 (ii) Baseline: 5.61, Almond: 5.55, Δ: -0.06 Insulin (U/ml): (i) Baseline: 9.00, Control: 9.10, Δ: +0.10 (ii) Baseline: 11.4, Almond: 5.85, Δ: -5.55 HOMA-IR: (i) Baseline: 2.40, Control: 2.21, Δ: -0.19 (ii) Baseline: 2.90, Almond: 1.44, Δ: -1.46 HbA1c: (i) Baseline: 6.1, Control: 5.8, Δ: -0.3 (ii) Baseline: 5.8, Almond: 5.9, Δ: +0.1 Compared to the control diet, the almond diet had significantly lower insulin and HOMA-IR.

(i) Control ADA diet (ii) ADA diet + Almonds (20% en: 57g)

Author (y) Evidence Cohen & Johnston (2011) 1+

Study design

Subjects’ characteristics 13 (7 M, 6 F) Type 2 diabetics

Duration

Damasceno et al. (2011) 1+

Randomised Crossover 3-arm Control group

18 (9 M, 9 F) Moderate hypercholesterolemia

4 weeks

Li et al. (2011) 1++

Randomised Crossover; CF 2-arm Control group

20 (9 M, 11 F) Chinese Type 2 diabetics

4 weeks

Randomised Parallel 2-arm Control group

12 weeks

Comparison Made (i) Baseline (ii) Baseline

(i) Baseline (MD) (ii) Baseline (MD) (iii) Baseline (MD) (i) Baseline (ii) Baseline

Treatment

Outcome measurements: Results2

(i) Control (2 cheese sticks, 5x / week) (ii) Almonds (28g, 5x / week)

Glucose (mmol/L): (i) Baseline: 7.0, Control: 7.1, : +0.1 (ii) Baseline: 7.5, Almonds: 7.1, : -0.4 Insulin (IU/mL): (i) Baseline: 14.7, Control: 20.3, : +5.6 (ii) Baseline: 18.8, Almonds: 20.2, : +1.4 HbA1c (%): (i) Baseline: 6.6, Control: 6.6, : 0.0 (ii) Baseline: 7.1, Almonds: 6.8, : -0.3 There was a significant between-group difference in the change in HbA1c (P = 0.045). Glucose (mmol/L): (i) Baseline: 4.83, Olive oil: 5.00, Δ: +0.17 (ii) Baseline: 4.83, Almonds: 4.56, Δ: -0.27 (iii) Baseline: 4.83, Walnuts: 4.89, Δ: +0.06 There were no between-group differences in blood glucose. Glucose (mmol/L): (i) Baseline: 8.7, Step II: 8.6, Δ: -0.1 (ii) Baseline: 8.7, Almond: 8.3, Δ: -0.4a Insulin (U/mL): (i) Baseline: 15.3, Step II: 13.8, Δ: -1.5 (ii) Baseline: 15.3, Almond: 12.7, Δ: -2.6a HOMA-IR: (i) Baseline: 5.7, Step II: 5.2, Δ: -0.5 (ii) Baseline: 5.7, Almond: 4.6, Δ: -1.1b Almond diet significantly reduced glucose, insulin, and HOMA-IR compared with the control diet.

(i) MD + Olive oil (22% en: 35-50g) (ii) MD + Almonds (22% en: 50-75g) (iii) MD + Walnuts (22% en: 40-65g) (i) Control Step II diet (ii) Almonds (20% en: 56g)

Author (y) Study design Evidence Cashew nuts (n = 1) Mukuddem- Randomised Petersen et Parallel; CF al. (2007) 3-arm 1++ Control group

Subjects’ characteristics

Duration

Comparison Made

Treatment

Outcome measurements: Results2

64 (29 M, 35 F) Metabolic syndrome

8 weeks

(i) Baseline

(i) Control diet

(ii) Baseline

(ii) Cashew nuts (20% en: 66-115g) (iii) Walnuts (20% en: 60-100g)

Glucose (mmol/L): (i) Baseline: 4.55Υ, Control: 4.55, Δ: -0.75 (ii) Baseline: 4.70Υ, Cashews: 5.30, Δ: +0.70a (iii) Baseline: 4.50Υ, Walnuts: 4.70, Δ: +0.40 There was a significant difference in the change in plasma glucose between the cashew nut and the control groups (P =0.04).

(iii) Baseline Peanuts (n = 1) Claesson et Randomised al. (2009) Parallel 1+ 2-arm Control group

Pistachio nuts (n = 2) Li et al. Randomised (2010) Parallel 1+ 2-arm Control group

25 (11 M, 14 F) Non-obese (BMI < 27 kg/m2)

2 weeks

59 (59 M & F) BMI: 27 to 35 kg/m2

12 weeks

(i) Baseline (ii) Baseline

(i) Candy (84 kJ/ kg BW) (ii) Roasted & salted peanuts (84 kJ/ kg BW)

Glucose (mmol/L): (i) Baseline: 4.7, Candy: 4.6, Δ: -0.1 (ii) Baseline: 4.7, Peanuts: 4.6, Δ: -0.1 Insulin (pmol/L): (i) Baseline: 27, Candy: 39, Δ: +12a (ii) Baseline: 24, Peanuts: 27, Δ: +3 There were no significant differences in blood glucose and insulin between the groups.

(i) LCD + salted pretzels (56g) (ii) LCD + pistachios (53g)

Glucose (mmol/L): (i) Baseline: 5.37, Pretzels: 4.93, : -0.44 (ii) Baseline: 4.87, Pistachios: 4.65, : -0.22 Insulin (IU/ml): (i) Baseline: 14.8, Pretzels: 16.2, : +1.4 (ii) Baseline: 11.4, Pistachios: 8.7, : -2.7 There were no significant differences in blood glucose and insulin between the groups.

Author (y) Evidence Wang et al. (2012) 1+

Study design Randomised Parallel 3-arm Control group

Walnuts (n = 6) Tapsell et Randomised al. (2004) Parallel 1+ 3-arm Control group

Subjects’ characteristics 90 (41 M, 49 F) Metabolic syndrome

Duration 12 weeks

Comparison Made (i) Baseline

Treatment

Outcome measurements: Results2

(i) Control no nuts

(ii) Baseline

(ii) Pistachios (42g) (iii) Pistachios (70g)

Glucose (mmol/L): (i) Baseline: 5.27, Control: 5.57, Δ: +0.30a (ii) Baseline: 5.30, Pistachio: 5.41, Δ: +0.11 (iii) Baseline: 5.18, Pistachio: 5.20, Δ: +0.02 Insulin (U/L): (i) Baseline: 16.74, Control: 18.66 Δ: +1.92 (ii) Baseline: 14.13, Pistachio: 14.41, Δ: +0.28 (iii) Baseline: 17.08, Pistachio: 14.68, Δ: -2.40 There were no significant differences in blood glucose and insulin between the groups.

(iii) Baseline

58 (34 M, 24 F) Type 2 diabetics

6 months

(i) Baseline

(i) Low fat diet

(ii) Baseline

(ii) Modified LFD

(iii) Baseline

(iii) Modified LFD + Walnuts (30g)

Mukuddem-Petersen et al. (2007): Please refer to the cashew nut section. Tapsell et Randomised 50 (50 M & F) 12 (i) Baseline al. (2009) Parallel T2DM, non insulinmonths 1+ 2-arm treated (ii) Baseline Control group BMI: 25 to 32 kg/m2

(i) Control (30% en: fat) (i) Walnuts (30g)

HbA1c (%): (i) Baseline: 6.56, LFD: 6.75, Δ: +0.19 (ii) Baseline: 6.82, Mod. LFD: 6.97, Δ: +0.15 (iii) Baseline: 6.94, Walnuts: 6.89, Δ: -0.05 There were no significant differences in HbA1c between groups. Glucose (mmol/L): (i) Baseline: 8.4, Control: 7.6, Δ: -0.8 (ii) Baseline: 8.8, Walnuts: 8.9, Δ: +0.1 Insulin (U/l): (i) Baseline: 16.8, Control: 12.3, Δ: -4.5 (ii) Baseline: 20.1, Walnuts: 15.9, Δ: -4.2 HbA1c (%): (i) Baseline: 7.0, Control: 6.7, Δ: -0.3a (ii) Baseline: 7.3, Walnuts: 7.1, Δ: -0.2a

Author (y) Evidence Tapsell et al. (2009) 1+

Study design

Ma et al. (2010) 1+

Wu et al. (2010) 1+

Subjects’ characteristics 50 (50 M & F) T2DM, non insulintreated BMI: 25 to 32 kg/m2

Duration

Randomised Crossover 2-arm Control group

24 (10 M, 14 F) Type 2 diabetes, Non insulin-treated

8 weeks

Randomised Parallel 3-arm Control group

283 (158 M, 125 F) Metabolic syndrome

Randomised Parallel 2-arm Control group

12 months

Comparison Made (i) Baseline (ii) Baseline

(i) Baseline

(ii) Baseline

12 weeks

(i) Baseline (ii) Baseline (iii) Baseline

Treatment

Outcome measurements: Results2

(i) Control (30% en: fat) (i) Walnuts (30g)

No significant between-group differences were seen in blood glucose and HbA1c. There was a significant interaction between the treatments and time for the insulin values (P = 0.046). A greater reduction in fasting insulin was observed in walnut group, an effect mainly seen in the first 3 months. Glucose (mmol/L): (i) Baseline: 7.20, Control: 7.36, : +0.16 (ii) Baseline: 7.20, Walnuts: 7.75, : +0.55a Insulin (mIU/ml): (i) Baseline: 15.6, Control: 12.2, : -3.4 (ii) Baseline: 15.6, Walnuts: 19.2, : +3.6 Plasma A1C (%): (i) Baseline: 6.7, Control: 6.7, : 0.0 (ii) Baseline: 6.7, Walnuts: 6.7, : 0.0 Compared with the control diet, the walnutenriched diet increased insulin (P = 0.02). Glucose (mmol/L): (i) Baseline: 6.3, AHA: 5.86, : -0.44a (ii) Baseline: 6.3, Flaxseed: 5.73, : -0.57a (iii) Baseline: 6.1, Walnuts: 5.70, : -0.40a Insulin (pmol/L): (i) Baseline: 52.4, AHA: 56.54, : +4.14 (ii) Baseline: 47.1, Flaxseed: 46.62, : -0.48 (iii) Baseline: 47.5, Walnuts: 51.16, : +3.66 HbA1c (%): (i) Baseline: 5.7, AHA: 5.76, : +0.06 (ii) Baseline: 5.7, Flaxseed: 5.69, : -0.01 (iii) Baseline: 5.7, Walnuts: 5.75, : +0.05

(i) Control (ad libitum diet no nuts) with similar SFA content (ii) Walnutenriched diet (56g)

(i) LC + AHA guidelines (ii) LC + Flaxseed (30g) (iii) LC + Walnuts (30g)

Author (y) Evidence Wu et al. (2010) 1+

Study design Randomised Parallel 3-arm Control group

Subjects’ characteristics 283 (158 M, 125 F) Metabolic syndrome

Duration 12 weeks

Comparison Made (i) Baseline (ii) Baseline (iii) Baseline

Damasceno et al. (2011): Please refer to the almond section. Mixed nuts (n = 3) Chisholm et Randomised 28 (5 M, 23 F) 6 weeks al. (2005) Crossover Moderate hyper1+ 2-arm cholesterolaemic Control group

(i) Baseline (ii) Baseline

Treatment

Outcome measurements: Results2

(i) LC + AHA guidelines (ii) LC + Flaxseed (30g) (iii) LC + Walnuts (30g)

MetS counts (n): (i) Baseline: NR, AHA: NR, : -0.58a (ii) Baseline: NR, Flaxseed: NR, : -0.81a (iii) Baseline: NR, Walnuts: NR, : -0.93a There were no between-group differences in blood glucose, insulin, and HbA1c. However, the severity of MetS, presented as the mean count of Mets components, was lower in the walnuts group than the AHA group (P = 0.045).

(i) LF + Canola oil cereal (82g) (ii) LF + Mixed nuts3 (30g)

Glucose (mmol/L): (i) Baseline: 4.5, Canola oil: 4.4, Δ: -0.1 (ii) Baseline: 4.7, Mixed nuts: 4.7, Δ: 0.0 Insulin (IU/mL): (i) Baseline: 9.2, Canola oil: 9.0, Δ: -0.2 (ii) Baseline: 10.0, Mixed nuts: 8.7, Δ: -1.3 There were no significant differences in blood glucose and insulin between the groups.

Author (y) Evidence CasasAgustench et al. (2011) 1+

Study design

Jenkins et al. (2011) 1+

Randomised Parallel 3-arm Control group

Randomised Parallel 2-arm Control group

Subjects’ characteristics 50 (28 M, 22 F) Metabolic syndrome BMI: 24 to 35 kg/m2

Duration

117 (78 M, 39 F) Type 2 diabetics Postmenopausal F

12 weeks

Comparison Made (i) Baseline (ii) Baseline

(i) Baseline (ii) Baseline (iii) Baseline

Treatment

Outcome measurements: Results2

(i) Control (AHA guideline) (ii) AHA + Mixed nuts4 (30g)

Glucose (mmol/L): (i) Baseline: 5.82, Control: 5.78, : -0.04 (ii) Baseline: 5.82, Mixed nuts: 5.76, : -0.06 Insulin (U/mL): (i) Baseline: 6.01, Control: 6.54, : +0.53 (ii) Baseline: 8.01, Mixed nuts: 5.94, : -2.07a HOMA IR: (i) Baseline: 1.56, Control: 1.70, : +0.14 (ii) Baseline: 2.10, Mixed nuts: 1.52, : -0.58a The mixed nut diet decreased fasting insulin concentrations (P = 0.013) and HOMA-IR (P = 0.013) when compared with the control diet. Glucose (mmol/L): (i) Baseline: 7.1, Control: 7.2, Δ: +0.1 (ii) Baseline: 7.4, Half-dose: 7.4, Δ: 0 (iii) Baseline: 7.3, Full-dose: 7.2, Δ: -0.1 HbA1c (%): (i) Baseline: 7.1, Control: 7.1, Δ: 0 (ii) Baseline: 7.1, Half-dose: 7.0, Δ: -0.1 (iii) Baseline: 7.1, Full-dose: 6.9, Δ: -0.2c Full-dose nut group had significantly lower HbA1c than the control (P = 0.001) and halfdose nut (P = 0.004) groups.

(i) Control muffins (2-4) (ii) Mixed nuts5 (25-50g) + Muffin (1-2) (iii) Mixed nuts5 (50-100g)

Abbreviations used: % en, percentage of the total energy in the diet; ADA, American Diabetes Association; AHA, American Heart Association; CF, controlled feeding; CHO, carbohydrate; CVD, cardiovascular disease; F, female; HbA1c, haemoglobin A1c; HOMA-IR, homeostasis model analysis of insulin resistance; LC, lifestyle counselling; LCD, low calorie diet; LF, low fat; LFD, low fat diet; M, male; MD, Mediterranean diet; SFA, saturated fatty acids. 2 Δ: Change (within group) = Post treatment value – Pre treatment value (i.e. baseline); Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001. 3 Almonds, Brazil nuts, cashew nuts, hazelnuts, macadamia nuts, peanuts, pecan nuts, pistachio nuts, and walnuts. 4 15 g walnuts, 7.5 g almonds, 7.5 g hazelnuts. 5 Unsalted and mostly raw almonds, pistachios, walnuts, pecans, hazelnuts, peanuts, cashews, and macadamias. 1

Appendix M. Cross-sectional studies examining the association between baseline nut consumption and BMI (7 populations)1 Author (year) Level of evidence Fraser et al. (1992) 3

Study design; Subjects’ characteristics The AHS a ; 10,003 M, 16,740 F

Endpoints

Frequency of nut consumption < 1 time / week 1 – 4 times / week ≥ 5 times / week

Mean ± SD

Results

NR NR NR

BMI (kg/m2)

Never ≤ 1 time / week 2 – 4 times / week ≥ 5 times / week

24.8 24.3 23.8 23.4

The IWHS c ; 34,111 F

BMI (kg/m2)

Albert et al. (2002) 3

The PHS d ; 21,454 M physicians

BMI (kg/m2)

Jiang et al. (2002) 3

The NHS b ; 83,818 F nurses

BMI (kg/m2)

< 1 time / month 1 – 3 times / month 1 time / week 2 – 4 times / week ≥ 5 times / week Rarely / Never 1 – 3 times / month 1 time / week ≥ 2 times / week Never < 1 time / week 1 – 4 times / week ≥ 5 times / week

27.1 26.9 26.7 26.4 26.2 24.9 24.9 25.0 24.7 24.7 24.3 24.0 23.4

There was a statistically significant inverse relationship between frequent nut consumption and the Quetelet index of obesity. Women who rarely consumed nuts had a BMI of 24.8 kg/m2 compared to 23.4 kg/m2 for women consuming nuts more than 5 times per week. There was an inverse association between frequent nut consumption and BMI.

Hu et al. (1998) 3

The NHS b ; 86,016 F nurses

Ellsworth et al. (2001) 3

Jiang et al. (2006) 3

The MESA e ; 6,080 M & F

BMI (kg/m2)

Never / rare <1 time / week 1 – 4 times / week ≥ 5 times / week

28.6 ± 5.7 28.4 ± 5.4 28.0 ± 5.4 27.9 ± 5.1

Obesity

There was no association between frequent nut consumption and BMI. Women who rarely consumed nuts had a BMI of 24.7 kg/m2 compared to 23.4 kg/m2 for women consuming nuts more than 5 times per week. Participants who consumed nuts and seeds more frequently were leaner than those who rarely or never ate nuts and seeds.

Author (year)

Study design; Subjects’ characteristics The PHS I d ; 15,966 M physicians

Endpoints

Li et al. (2009) 3

The NHS b ; 6,309 F nurses with type 2 diabetes

BMI (kg/m2)

Kochar et al. (2010) 3

The PHS I d ; 20,224 M physicians

BMI (kg/m2)

Martinez-Lapiscina et al. (2010) 3

The SUN f ; 9,919 Spanish university graduates

BMI (kg/m2)

Khawaja et al. (2012) 3

The PHS I d ; 21,054 M physicians

BMI (kg/m2)

Casas-Agustench et al. (2011) 3

The PREDIMED g ; 375 M & 472 F

BMI (kg/m2)

Djousse et al. (2009) 3

BMI (kg/m2)

Waist circumference (cm)

Frequency of nut consumption None 1 – 3 times / month 1 time / week 2 – 6 times / week ≥ 7 times / week Almost never < 1 time / week 1 – 4 times / week ≥ 5 times / week None ≤ 1 time / week 1 time / week 2 – 4 times / week 5 – 6 times / week ≥ 7 times / week None 1 – 3 times / month 1 time / week ≥ 2 times / week Rarely / Never 1 – 3 times / month 1 time / week 2 – 6 times / week ≥ 7 times / week Nut intake (per serving of 30 g/d)* Nut intake (per serving of 30 g/d)*

Mean ± SD

Results

24.5 ± 2.8 24.5 ± 2.6 24.6 ± 2.6 24.4 ± 2.5 24.0 ± 2.4 29.6 30.1 29.9 28.4 24.7 ± 2.8 24.8 ± 2.7 24.8 ± 2.8 24.7 ± 2.6 24.6 ± 2.7 24.0 ± 2.4 23.0 ± 3.3 23.2 ± 3.2 23.2 ± 3.1 23.2 ± 3.2 24.8 ± 2.9 24.8 ± 2.8 24.9 ± 2.8 24.7 ± 2.6 24.1 ± 2.5 Male: -0.690 Female: -0.930 Male: -2.070 Female: -2.220

There was an inverse association between frequent nut consumption and BMI (P for trend = 0.015). Women who rarely consumed nuts had a higher BMI than women consuming nuts > 5 times per week. There was an inverse association between frequent nut consumption and BMI.

There was no association between frequent nut consumption and BMI. There was an inverse association between frequent nut consumption and BMI. Male: P = 0.033 Female: P = 0.020 Male: P = 0.018 Female: P = 0.035

1 a AHS, Adventist Health Study; b IWHS, Iowa Women’s Health Study; c NHS, Nurses’ Health Study; d PHS, Physicians’ Health Study; e MESA, Multi-Ethnic Study of Atherosclerosis; f SUN, Seguimiento Universidad de Navarra; g PREDIMED, Prevencion con Dieta Mediterranea 1 Abbreviations used: BMI, body mass index; F, female; M, male; NR, not reported, SD; standard deviation. * Stepwise linear regression model, adjusted for gender, age, education level, total energy intake, and energy expenditure in physical activity. Non-standardised regression coefficients are reported.

Appendix N. Epidemiological studies investigating the effects of nut consumption on weight gain and obesity (3 cohorts)1 Author (year) Bes-Rastrollo et al. (2007) 2+

Bes-Rastrollo et al. (2009) 2++ Martinez-Gonzalez et al. (2011) 2++

Study design; Subjects’ characteristics The SUN a ; 3,699 M & 5,166 F Prospective median 28-month follow-up The SUN a ; 6,300 M & F; Not overweight or obese at baseline Prospective median 28-month follow-up The NHS II b ; 51,188 F nurses; Aged 20 – 45 y Prospective 8-year follow up The SUN a ; 11,895 M & F Prospective median 6-year followup

Endpoints Weight gain2 (≥5 kg of body weight during follow-up) Overweight or obesity2 (BMI ≥ 25 kg/m2) Obesity3 (BMI ≥ 30 kg/m2) Weight gain4 (≥3 kg of body weight per year during follow-up)

Frequency of nut consumption Never / almost never 1 – 3 times / month 1 time / week ≥ 2 times / week Never / almost never 1 – 3 times / month 1 time / week ≥ 2 times / week

Relative Risk (95% CI) 1.00 0.95 (0.79 – 1.13) 0.97 (0.78 – 1.19) 0.73 (0.55 – 0.96) 1.00 0.87 (0.66 – 1.15) 0.97 (0.70 – 1.35) 0.73 (0.48 – 1.11)

P value for trend

Never / almost never 1 – 3 times / month 1 time / week ≥ 2 times / week Never / almost never 1 – 3 times / month 1 time / week ≥ 2 times / week

1.00 1.00 (0.91 – 1.09) 0.88 (0.80 – 0.97) 0.81 (0.61 – 1.08) 1.00 1.02 (0.72 – 1.44) 1.16 (0.77 – 1.74) 0.61 (0.34 – 1.10)

0.008

0.026

0.214

0.093

SUN, Seguimiento Universidad de Navarra; b NHS, Nurses’ Health Study. Abbreviations used: CI, confidence interval; F, female; M, male. Adjusted for age, sex, baseline BMI, leisure time physical activity, smoking status, snacking, television viewing, total energy intake, and total fiber intake. 3 Adjusted for age, baseline alcohol intake, physical activity, smoking, postmenopausal hormone use, oral contraceptive use, baseline BMI, glycemic load, and intakes of total fibre, trans fat, fruit, vegetables, red meat, processed meat, refined grain, whole grain, snacks, sugar-sweetened beverages, diet beverages, low-fat dairy products, and high fat daity products at baseline, changes in the adherence of prudent and Western dietary patterns. 4 Adjusted for age, baseline BMI, leisure time physical activity, weight gain during the 5 years previous to entering the cohort, prevalence of hypertension, hyperlipidemia, and diabetes. 1a 2

Appendix O. Dietary intervention trials investigating the effects of nut consumption on body weight (n = 43)1 Author (y) Study design Subjectsâ&#x20AC;&#x2122; Duration Comparison made Evidence characteristics Body weight Nut interventions with body weight as one of the outcomes (n = 37) Sabate et al. Randomised 18 (18 M, 0 F) 4 weeks Baseline: (1993) Crossover; CF Healthy 73.0 kg 1++ 2-arm Control group Chisholm et al. (1998) 1+ Spiller et al. (1998) 1+

Kris-Etherton et al. (1999) 1++ Curb et al. (2000) 1++ Morgan and Clayshulte (2000) 1+

Randomised Crossover 2-arm Control group Randomised Parallel 3-arm Control group

21 (21 M, 0 F) Hyperlipidaemic

4 weeks

(i) Low fat diet: 87.3 kg

45 (12 M, 33 F) Hyperlipidaemic

4 weeks

Randomised Crossover; CF 5-arm Control group Double-blind Randomised Crossover; CF 3-arm Control group Randomised Parallel 2-arm Control group

22 (9 M, 13 F) Normocholesterolaemic

24 days

30 (15 M, 15 F) Normo- and hyper-lipidaemic

30 days

(i) Baseline: 64 kg (i) Baseline: 69 kg (i) Baseline: 65 kg (i) Baseline: NR (ii) Baseline: NR (iii) Baseline: NR (iv) Baseline: NR (v) Baseline: NR (i) Baseline: NR (ii) Baseline: NR (iii) Baseline: NR

19 (4 M, 15 F) Normolipidaemic

8 weeks

(i) Baseline: 66 kg (ii) Baseline: 64 kg

Treatment Body weight

Change in Body weight2

Between treatments

After two treatments: 71.6 kg (i) Step I diet (ii) Step I + Walnuts (20% en: 84g) (ii) Walnuts (20% en: 78g): 87.3 kg

ď&#x201A;Ż 1.4 kg at the end of study EI adjusted

There were no differences in weight lost between the treatments (P = 0.97).

(i) No change

(i) Control dairy diet (113g): 63 kg (ii) Olive oil diet (48g): 67 kg (iii) Almonds (100g): 65 kg (i) AAD: NR (ii) Step II diet: NR (iii) Olive oil: NR (iv) Peanut oil: NR (v) Peanuts / PB: NR (i) AAD: NR (ii) Step I diet: NR (iii) Macadamia nuts: NR (i) Habitual diet: 66 kg (i) Pecans (68g): 64 kg

(i) No change (ii) No change (iii) No change

There were no between-group differences in body weight. There were no significant changes in body weight between groups at week 4.

(i) to (v): No change EI adjusted

Between-group analysis was not reported.

(i) to (iii): No change EI adjusted

Between-group analysis was not reported.

(i) No change

Between-group analysis was not reported.

(ii) No change

Author (y) Evidence Zambon et al. (2000) 1++

Subjects’ characteristics 49 (26 M, 23 F) Polygenic hypercholesterolaemic

Duration

23 (14 M, 9 F) Normal – high cholesterol

4 weeks

40 (20 M, 20 F) Healthy

Randomised Crossover 3-arm Control group

Sabate et al. (2003) 1++

Ros et al. (2004) 1+

Rajaram et al. (2001) 1++ Iwamoto et al. (2002) 1++ Jenkins et al. (2002) 1+

Study design

Comparison made Body weight (i) Baseline: 70.6 kg (ii) Baseline: 70.6 kg (i) Step I diet: NR

Treatment Body weight (i) Mediterranean diet: 70.1 kg (ii) Walnuts (18% en: 41-56g): 69.9 kg (i) Pecans (20% en: 72g): NR

Change in Body weight2 (i) No change

4 weeks

Baseline: Male: 66.1 kg Female: 52.0 kg

Male: 1.3 kg Female:0.1kg EI adjusted

27 (15 M, 12 F) Hyperlipidaemic Postmenopausal F

4 weeks

Randomised Crossover; CF 3-arm Control group Double-blind

25 (14 M, 11 F) Healthy

4 weeks

Randomised Crossover 2-arm Control group

20 (8 M, 12 F) Hypercholesterolaemic

4 weeks

(i) Baseline: 71.0 kg (ii) Baseline: 71.1 kg (iii) Baseline: 71.2 kg (i) Baseline: 71.0 kg (ii) Baseline: 71.0 kg (iii) Baseline: 71.0 kg (i) Baseline: 70.6 kg (ii) Baseline: 70.6 kg

After two treatments: NR (i) Japanese LFD (ii) Walnuts (12.5% en: 44-58g) (i) Control muffin: 71.2 kg (ii) Half-dose almond(37g):70.9kg (ii) Full-dose almond(73g):71.0kg (i) Step I diet: 71.0 kg (ii) Almonds (10% en: 27g): 71.2 kg (iii) Almonds (20% en: 54g): 70.7 kg (i) Mediterranean diet: 70.2 kg (ii) MD + Walnut (18% en: 40-65g): 70.4 kg

Randomised Crossover; CF 2-arm Control group Randomised Crossover; CF 2-arm Control group Single-blind Randomised Crossover; CF 2-arm Control group

6 weeks

4 weeks

(ii) No change (i)  0.43 kg EI adjusted

(i) No change (ii) No change (iii) No change (i) No change EI adjusted (ii) No change EI adjusted (iii) No change EI adjusted (i) No change (ii) No change

Between treatments Between-group analysis was not reported. Compared with the Step I diet, body weight was significantly lower during pecan period. There were no differences in weight lost between the treatments (P ≥ 0.102). There was a significant difference in body weight change between the control and half-dose almonds. There were no significant differences in the change of body weight between the diets. There were no significant differences in body weight between the groups.

Author (y) Evidence Tapsell et al. (2004) 1+

Chisholm et al. (2005) 1+ Eastman & Clayshulte (2005) 1+ Tamizafar et al. (2005) 1+ Kocyigit et al. (2006) 1+ Kurlandsky & Stote (2006) 1+

Study design Randomised Parallel 3-arm Control group

Subjectsâ&#x20AC;&#x2122; characteristics 58 (34 M, 24 F) Type 2 diabetics

Duration 6 months

Comparison made Body weight (i) Baseline: 81.87 kg (ii) Baseline: 84.55 kg (iii) Baseline: 87.61 kg (i) Baseline: 74.2 kg (ii) Baseline: 74.1 kg (i) Baseline: BMI: 27 kg/m2

Treatment Body weight (i) Low fat diet: 82.27 kg (ii) Modified low fat diet: 84.36 kg (iii) Modified LFD + Walnut(30g):86.33kg (i) LF + Canola oil cereal (82g): 73.3 kg (ii) LF + Mixed nuts3 (30g): 73.4 kg (i) Pecan diet (68g): BMI: 27 kg/m2

Change in Body weight2 (i) No change (ii) No change (iii) No change

Randomised Crossover 2-arm Control group Randomised Parallel 2-arm Control group Randomised Crossover 2-arm Control group Randomised Parallel 2-arm Control group

28 (5 M, 23 F) Moderate hypercholesterolaemic

6 weeks

17 (4 M, 13 F) Hyperlipidaemic

8 weeks

30 (17 M, 13 F) Hyperlipidaemic

4 weeks

(i) Baseline: 62.8 kg

(i) Almonds (25g): 63.0 kg

(i) No change

44 (24 M, 20 F) Healthy

3 weeks

(i) Baseline: BMI: 24.6 kg/m2 (i) Baseline: BMI: 24.2 kg/m2

(i) No change

Randomised Parallel 4-arm Control group

47 (0 M, 47 F) Normocholesterolaemic

6 weeks

(i) Habitual diet: BMI: 24.5 kg/m2 (ii) Pistachio (20% en: 65-75g): BMI: 24.3 kg/m2 (i) NCEP TLC Control: NR (ii) TLC + Almonds (60g): NR (iii) TLC + Chocolate (41g): NR (iv) TLC + Al. (60g) + Chocolate (41g): NR

(i) Baseline: BMI: 26.1 kg/m2 (ii) Baseline: BMI: 25.3 kg/m2 (iii) Baseline: BMI: 23.9 kg/m2 (iv) Baseline: BMI: 27.2 kg/m2

(i) No change (ii) No change (i) No change

(ii) No change (i) No change (ii) No change

Between treatments There were no significant differences in body weight between the groups. There were no significant differences in body weight between the groups. There were no differences in BMI between the treatments. Between-group analysis was not reported. There were no significant differences in the change of BMI between the groups. Between-group analysis was not reported.

(iii) No change (iv) No change

Author (y) Evidence MukuddemPetersen et al. (2007) 1++

Study design

Subjects’ characteristics 64 (29 M, 35 F) Metabolic syndrome

Duration

Sheridan et al. (2007) 1+

Randomised Crossover 2-arm Control group

15 (11 M, 4 F) Moderate hypercholesterolaemic

4 weeks

Gebauer et al. (2008) 1++

Randomised Crossover; CF 3-arm Control group

28 (10 M, 18 F) Hypercholesterolaemic

4 weeks

Griel et al. (2008) 1++

Randomised Crossover; CF 2-arm Control group Randomised Crossover 2-arm Control group

25 (10 M, 15 F) Mildly hypercholesterolaemic

5 weeks

21 (21 M, 0 F) Total PSA ≥ 2.0 ng/mL At risk for prostate cancer 25 (11 M, 14 F) Non-obese (BMI < 27 kg/m2)

8 weeks

Spaccarotella et al. (2008) 1+ Claesson et al. (2009) 1+

Randomised Parallel; CF 3-arm Control group

Randomised Parallel 2-arm Control group

8 weeks

2 weeks

Comparison made Body weight (i) Baseline: 106 kg (ii) Baseline: 99.2 kg (iii) Baseline: 106 kg (i) Baseline: 79.4 kg (ii) Baseline: 79.4 kg

Change in Body weight2 (i) No change EI adjusted (ii) No change EI adjusted (iii) No change EI adjusted (i) No change

(i) Baseline diet: 76.8kg (ii) Baseline diet: 76.8 kg (iii) Baseline diet: 76.8 kg (i) Baseline: BMI: 26.3 kg/m2

Treatment Body weight (i) Control diet: 105 kg (ii) Unsalted cashews (66-115g): 99.1 kg (iii) Walnuts (60100g): 106 kg (i) Regular diet: 79.8 kg (i) Pistachio nuts (15% en: 57-85g): 79.8 kg (i) Step I diet: 75.6 kg (ii) Pistachios (10% en: 32-63g): 75.3 kg (iii) Pistachios (20% en: 63-126g): 75.5 kg (i) Macadamia nuts (42.5g): BMI: NR

(i) No change EI adjusted (ii) No change EI adjusted (iii) No change EI adjusted (i) No change EI adjusted

There were no significant differences in body weight between the groups.

(i) Baseline: 84.8 kg (ii) Baseline: 84.8 kg

(i) Average American diet: 83.4 kg (ii) Walnuts (24% en: 75g): 84.3 kg

(i)  1.36 kg c

Between-group analysis was not reported.

(i) Baseline: 67.3 kg (ii) Baseline: 68.7 kg

(i) Candy (84 kJ/kg BW): 68.1 kg (ii) Peanuts (84 kJ/kg BW): 69.0 kg

(i)  0.80 kg a

(ii) No change

Between treatments There were no significant differences in body weight between the groups. Between-group analysis was not reported.

Between-group analysis was not reported.

There were no significant differences in the changes of body weight between the groups.

Author (y) Evidence Rajaram et al. (2009) 1++

Study design

Tapsell et al. (2009) 1+

Randomised Parallel 2-arm Control group

Nouran et al. (2010) 1+

Randomised Crossover 2-arm Control group Randomised Crossover; CF 3-arm Control group

West et al. (2010) 1++

Randomised Crossover; CF 3-arm Control group

Wien et al. (2010) 1+

Randomised Parallel 2-arm Control group

Wu et al. (2010) 1+

Randomised Parallel 3-arm Control group

Subjects’ characteristics 25 (14 M, 11 F) Mildly to hyperlipidaemic

Duration

50 (50 M & F) Type 2 diabetics Non insulintreated BMI:25-32 kg/m2 54 (54 M, 0 F) Hypercholesterolaemic

12 months

20 (20 M & F) Hypercholesterolaemic Elevated LDL-C Overweight / obese class I 65 (17 M, 48 F) Prediabetes

6 weeks

283 (158 M, 125 F) Metabolic syndrome

4 weeks

16 weeks

12 weeks

Comparison made Body weight (i) Control (no nuts or fish): 71.7 kg (ii) Control (no nuts or fish): 71.7 kg (i) Baseline: 93.9 kg (ii) Baseline: 94.3 kg

Treatment Body weight (i) Salmon (113g, 2x/week): 71.7 kg (ii) Walnuts (42.5g/ 10mJ, 6x/week): 71.9 kg (i) Control (30% en: fat): 92.3 kg (ii) Walnuts (30g): 92.0 kg

Change in Body weight2 (i) No change EI adjusted (ii) No change EI adjusted

(i) Baseline: 78.1 kg (ii) Baseline: 78.0 kg (i) AAD (7.7%en LA, 0.8%en ALA): 89.7 kg (ii) AAD (7.7%en LA, 0.8%en ALA): 89.7 kg (i) Baseline: 80.5 kg (ii) Baseline: 82.9 kg

(i) Habitual diet: 78.0 kg (ii) Peanuts (20% en: 77g): 78.1 kg (i) LA (12.6% en LA, 3.6% en ALA): 90.0 kg (ii) ALA (10.5% en LA, 6.5% en ALA): 89.8 kg (i) Control ADA diet: 79.6 kg (ii) ADA + Almonds (20% en: 57g): 80.4 kg (i) LC + AHA guidelines: 69.8 kg (ii) LC + Flaxseed (30g): 68.5 kg (iii) LC + Walnuts (30g): 71.3 kg

(i) No change

(i) Baseline: 70.6 kg (ii) Baseline: 69.7 kg (iii) Baseline: 72.2 kg

(i)  1.6 kg a (ii)  2.3 kg a

(ii) No change (i) No change (ii) No change (i) 0.9 kg (ii)  2.5 kg (i) 0.82 kg a (ii)  1.18 kg a

Between treatments There were no significant betweengroup differences in body weight at the end of the treatments. There were no significant differences in weight lost between the groups. There were no significant differences in body weight change between the groups. There were no significant differences in body weight between the groups. There were no significant differences in body weight change between the groups. There were no significant betweengroup differences in body weight change.

(iii) 0.92 kg a

Author (y) Evidence CasasAgustench et al. (2011) 1+ Cohen & Johnston (2011) 1+ Damasceno et al. (2011) 1+

Jenkins et al. (2011) 1+

Study design Randomised Parallel 2-arm Control group Randomised Parallel 2-arm Control group Randomised Crossover 3-arm Control group

Subjects’ characteristics 50 (28 M, 22 F) Metabolic syndrome BMI:24-35 kg/m2 13 (7 M, 6 F) Type 2 diabetics

Duration

18 (9 M, 9 F) Moderate hypercholesterolaemic

4 weeks

12 weeks

Randomised Parallel 3-arm Control group

117 (78 M, 39 F) Type 2 diabetics Postmenopausal F

12 weeks

Li et al. (2011) 1++

Randomised Crossover; CF 2-arm Control group

20 (9 M, 11 F) Chinese Type 2 diabetics

4 weeks

Baer et al. (2012) 1++

Randomised Crossover; CF 2-arm Control group

16 (8 M, 8 F) Healthy

18 days

Comparison made Body weight (i) Baseline: 79.9 kg (ii) Baseline: 86.4 kg (i) Baseline: 105.1 kg (ii) Baseline: 96.1 kg (i) Baseline (MD): 70.7 kg (ii) Baseline (MD): 70.7 kg (iii) Baseline (MD): 70.7 kg (i) Baseline: 82.9 kg (ii) Baseline: 86.2 kg (iii) Baseline: 80.0 kg (i) Baseline: BMI: 26.0 kg/m2 (ii) Baseline: BMI: 26.0 kg/m2 (i) Baseline: NR (ii) Baseline: NR (iii) Baseline: NR

Treatment Body weight (i) Control (AHA guideline): 78.4 kg (ii) AHA + Mixed nuts4 (30g): 84.2 kg (i) Control (2 cheese, 5x/week): 104.9 kg (ii) Almonds (28g, 5x / week): 93.1 kg (i) MD + Olive oil (35-50g): 68.7 kg (ii) MD + Almonds (50-75g): 68.9 kg (iii) MD + Walnuts (40-65g): 68.7 kg (i) Control muffins (2-4): 82.9 kg (ii) Mixed nuts5 (2550g): 86.5 kg (iii) Mixed nuts5 (50100g): 79.7 kg (i) Control Step II diet: BMI: 25.7 kg/m2 (ii) Almonds (20% en: 56g): BMI: 25.8 kg/m2 (i) Control diet: NR (ii) Pistachio (42g): NR (iii) Pistachio (84g): NR

Change in Body weight2 (i) 1.5 kg a (ii) 2.2 kg a (i) No change (ii)  3.0 kg (i) No change (ii) No change (iii) No change (i) No change (ii) No change (iii) No change

Between treatments There were no significant differences in body weight change between the groups. There were no significant differences in body weight change between the groups. There were no between-group differences in body weight. There were no significant differences in body weight change between the groups.

(i) No change EI adjusted (ii) No change EI adjusted

There were no significant differences in body weight change between the groups.

(i) No change EI adjusted (ii) No change EI adjusted (iii) No change EI adjusted

Between-group analysis was not reported.

Author (y) Evidence Wang et al. (2012) 1+

Study design Randomised Parallel 3-arm Control group

Subjects’ characteristics 90 (41 M, 49 F) Metabolic syndrome

Duration 12 weeks

Nut supplement in the context of weight loss diets (n = 6) McManus et Randomised 101 (10 M, 91 F) 18 months al. (2001) Parallel BMI: 26.5 to 46 1+ 2-arm kg/m2 Control group Wien et al. (2003) 1+

Randomised Parallel 2-arm Control group

65 (28 M, 37 F) BMI ≥ 25 kg/m2

Pelkman et al. (2004) 1++

Randomised Parallel; CF 2-arm Control group

52 (16 M, 36 F) Overweight and obese

24 weeks

10 weeks; 6 weeks of weight loss 4 weeks of weight maintenance

Comparison made Body weight (i) Baseline: BMI: 28.03 kg/m2 (ii) Baseline: BMI: 28.12 kg/m2 (iii) Baseline: BMI: 28.01 kg/m2

Treatment Body weight (i) Control no nuts: NR (ii) Pistachio (42g): NR (iii) Pistachio (70g): NR

Change in Body weight2 (i) No change

(i) Baseline: 89 kg (ii) Baseline: 93 kg

(i) Low fat diet (20% en fat): 91.9 kg (ii) Moderate fat (35% en fat – Source: Nuts, peanut butter, olive oil): 88.9 kg (i) LCD + Complex CHO: 98.9 kg (ii) LCD + Almonds (84 g/d): 91.5 kg

(i)  2.9 kg

(i) Step II + Low fat diet (18% en fat): NR (ii) Step II + Moderate fat diet (33% en fat – Source: Peanuts, PB &peanut oil): NR

(i)  6.5 kg at week-6 (ii)  7.2 kg at week-6

(i) Baseline: 111.0 kg (ii) Baseline: 111.0 kg (i) Baseline: BMI: 29.9 kg/m2 (ii) Baseline: BMI: 29.8 kg/m2

(ii) No change (iii) No change

(ii)  4.1 kg b

(i)  12.1 kg c (ii)  19.5 kg c

Between treatments There were no significant differences in body weight change between the groups.

The nut-enriched diet had a significant greater reduction in body weight compared to the low fat diet (P ≤ 0.001). The almond-enriched diet resulted in a greater reduction in body weight than the complex CHO diet (P < 0.001). There were no significant differences in body weight between the groups at the end of the weightloss period.

Author (y) Evidence Jenkins et al. (2009) 1++

Study design

Subjects’ characteristics 47 M & F BMI > 27 kg/m2 Hyperlipidaemic Postmenopausal F

Duration

Li et al. (2010) 1+

Randomised Parallel 2-arm Control group

59 (59 M & F) BMI: 27 to 35 kg/m2

12 weeks

Foster et al. (2012) 1+

Randomised Parallel 2-arm Control group

123 (11 M, 112 F) BMI: 27 to 40 kg/m2

18 months

Randomised Parallel; CF 2-arm Control group

4 weeks

Comparison made Body weight (i) Baseline: 86.6 kg (ii) Baseline: 82.4 kg

Change in Body weight2 (i)  4.2 kg

(i) Baseline: 85.5 kg (ii) Baseline: 86.0 kg

Treatment Body weight (i) High-CHO, lactoovo vegetarian diet: 82.3 kg (ii) Low-CHO, high vegetable protein plant based diet (43% en fat – Source: 44% nuts): 78.5 kg (i) LCD + Salted pretzel (56g): 82.8 kg (ii) LCD + Pistachios (53g): 82.3 kg

(i) Baseline: 91.5 kg (ii) Baseline: 94.0

(i) Nut-free LCD 85.6 kg (ii) Almond-enriched LCD (56g): 90.3 kg

(i) 5.9 kg

(ii)  3.9 kg

(i)  2.7 kg b (ii)  3.7 kg b

(ii)  3.7 kg

Between treatments There were no significant differences in body weight between the groups at the end of the study.

There was a tendency for the pistachio group to lose more weight than the pretzel group (P = 0.09). There were no significant differences in body weight between the groups at 18-months (P =0.12).

1 Abbreviations used: % en, percentage of the total energy in the diet; AAD, average American diet; ADA, American Diabetes Association; AHA, American Heart Association; Al, almond; ALA, alpha linoleic acid; BMI, body masss index; BW, body weight; CF, controlled feeding; Ch, chocolate; CHO, carbohydrate; CVD, cardiovascular disease; F, female; HD, habitual diet; HDL-C, high-density lipoprotein cholesterol; HFD, high fat diet; LA, linoleic acid; LC, lifestyle counselling; LCD, low calorie diet; LDL-C, low-density lipoprotein cholesterol; LF, low fat; LFD, low fat diet; LFMR, low fat monounsaturated rich; M, male; MD, Mediterranean diet; MUFA, monounsaturated fatty acids; NCEP, national cholesterol education program; NR, not reported; NS, non significant; PB, peanut butter; PCOS, polycystic ovary syndrome; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; TAG, triacylglycerol; TC, total cholesterol; TLC, therapeutic lifestyle changes. 2 Δ: Change (within group) = Post treatment value – Pre treatment value (i.e. baseline); Difference between dietary treatments; a P < 0.05; b P < 0.01; c P < 0.001. 3 Almonds, Brazil nuts, cashew nuts, hazelnuts, macadamia nuts, peanuts, pecan nuts, pistachio nuts, and walnuts. 4 15 g walnuts, 7.5 g almonds, and 7.5 g hazelnuts. 5 Unsalted and mostly raw almonds, pistachios, walnuts, pecans, hazelnuts, peanuts, cashews, and macadamias.

Appendix P. Dietary intervention trials investigating the effects of nut consumption on body weight as a primary outcome (n = 5)1 Author (y) Evidence

Study design

Subjects

Duration

Comparison made

Treatment

Nut interventions with body weight as primary outcome (Assumption: 32,186 kJ = 1 kg body weight) Alper & Mattes Crossover 8 M, 7 F 8 weeks (i) Baseline (Free (i) Normal diet + (2002) Sequential Normo3 weeks feeding): NR Peanuts (89g): NR 1design lipidaemic 8 weeks (ii) Baseline (ii) Prescribed diet + 3-arm (Addition): NR Peanuts (89g): NR (iii) Baseline (iii) Replace 50% en (Substitution): NR fat with peanuts (89g): NR Fraser et al. Crossover 43 M, 38 F 24 weeks (i) Habitual diet: (ii) Almonds (15% en: (2002) Sequential Healthy M: 83.18 kg 42-70g): 1design F: 69.13 kg M: 83.83 kg 2-arm F: 69.24 kg Control group No dietary advice Sabate et al. (2005) 1+

Randomised Crossover 2-arm Control group No dietary advice

39 M, 51 F

6 months

(i) Control diet: 75.6 kg

(ii) Walnuts (12% en: 28-56g): 76.0 kg

% change2 Observed vs. Predicted

Between treatments

(i)  27.8% a; 1.0 vs. 3.6 kg (ii)  42.9% a; 0.6 vs. 1.4 kg (iii) 0%; No change vs. 3.6 kg

Between-group analysis was not reported.

M -  0.65 b F - No change All -  6.3%; 0.4 vs. 6.4 kg

Compared to the control period, males gained 0.65 kg during the almond period (P < 0.01) while no change in body weight was found in females (P = 0.79). Body weight during the walnut supplementation was 0.4 kg higher than the control period (P < 0.01).

 7.5% b; 0.4 vs. 5.3 kg;

Author (y) Evidence

Study design

Subjects

Duration

Comparison made

Treatment

Hollis & Mattes (2007) 1+

Randomised Crossover 2-arm Control group No dietary advice Randomised Parallel Control group 4-arm No dietary advice

20 F Healthy

10 weeks

(i) Baseline: 69.4 kg (ii) Baseline: 70.4 kg

55 M, 63 F Healthy

12 weeks

(i) Baseline: 72.0 kg (ii) Baseline: 69.2 kg (iii) Baseline: 69.5 kg (iv) Baseline: 67.3 kg

Tey et al. (2011) 1+

1 2

Between treatments

(i) Habitual diet: 69.5 kg (ii) Almonds (60g): 70.3 kg

% change2 Observed vs. Predicted (i) 0%; No change (ii) 0%; No change vs. 3.1 kg

(i) Hazelnut (42g): 72.8 kg (ii) Chocolate (50g): 69.8 kg (iii) Potato crisps (50g): 70.1 kg (iv) Control (usual diet): 67.6 kg

(i) 0%; No change (ii) 0%; No change (iii) 0%; No change (iv) 0%; No change

There were no statistically significant in the changes of body weight from baseline to 12 weeks between the groups.

Between-group analysis was not reported.

Abbreviations used: % en: percentage of the total energy in the diet; F, female; M, male; NR, not reported; vs. versus. % change in body weight: a P < 0.05, b P < 0.01.

Appendix Q. Dietary intervention trials investigating the effects of nut consumption on acceptance (n = 4)1 Author (y) Evidence Alper & Mattes (2002) 1McKiernan et al. (2010) 1-

Study design

Subjects

Crossover Sequential design

8 M, 7 F

Randomised Parallel

47 M, 71 F

Tey et al. (2011) 1-

Randomised Crossover

20 M, 28 F

Measurement; Timepoint Pleasantness on a 9-point scale; Measured at pre& post-exposure Palatability on a 100 mm VAS; Measured at preand postexposure

Treatments; Number of exposure

Results2

(i) Normal diet + Peanuts (89g); No. = 56 (ii) Prescribed diet + Peanuts (89g); No. = 21 (iii) Replace 50% en fat with peanuts (89g); No. = 56

Pre- vs. PostNo change: Average 7x vs. Values not reportedx

(i) Desire to consume on a 150 mm VAS; Measured daily during the exposure period (ii) Overall liking on a 150 mm VAS; Measured daily during the exposure period and at pre- & post-exposure

(i) Ground hazelnuts (30g); No. = 28 (ii) Sliced hazelnuts (30g); No. = 28 (iii) Whole hazelnuts (30g); No. = 28

(i) Raw unsalted peanuts (56g); No. = 28 (ii) Roasted unsalted peanuts (56g); No.= 28 (iii) Roasted salted peanuts (56g); No. = 28 (iv) Honey roasted peanuts (56g); No. = 28 (v) Peanut butter (56g); No. = 28

(i) Ground hazelnuts (30g); No. = 28 (ii) Sliced hazelnuts (30g); No. = 28 (iii) Whole hazelnuts (30g); No. = 28

Pre- vs. Post(i) No change: 34a vs. Values not reported (ii) No change: 60a vs. Values not reported (iii) No change: 73a vs. Values not reported (iv) No change: 75a vs. Values not reported (v) No change: 78a vs. Values not reported No change: Average 70x vs. 65x 28-day exposure period (i) Stable: 92.1a (ii) Stable: 107.7b (iii) Stable: 116.2b

28-day exposure period (i) Stable: 100.8a (ii) Stable: 109.9b (iii) Stable: 117.7b Pre- vs. Post(i) No change: 92.8a, x vs. 87.4a, x (ii) No change: 109.1b, x vs. 107.3b, x (iii) No change: 113.7b, x vs. 110.2b, x

Author (y) Evidence Tey et al. (2012) 1+

Study design

Subjects

Randomised Parallel Control group 4-arm

55 M, 63 F

Measurement; Timepoint (i) Desire to consume on a 100 mm VAS; Measured daily during the exposure period (ii) Overall liking on a 100 mm VAS; Measured daily during the exposure period and at pre- and post-exposure

Treatments; Number of exposure

Results2

(i) Hazelnuts (42g); Exp. = 84 (ii) Chocolate (50g); Exp. = 84 (iii) Potato crisps (50g); Exp. = 84

84-day exposure period (i) Stable: 60.9a (ii) Stable: 64.9a (iii) Stable: 62.7a

(i) Hazelnuts (42g); Exp. = 84 (ii) Chocolate (50g); Exp. = 84 (iii) Potato crisps (50g); Exp. = 84

84-day exposure period (i) Stable: 57.9a (ii) Decrease over time: -9.9a (P = 0.002) (iii) Decrease over time: -8.6a (P = 0.031) Pre- vs. Post(i) No change: 61.1a, x vs. 53.8a, x (ii) Decrease: 76.2a, x vs. 53.6a, y (P < 0.001) (iii) No change: 67.0a, x vs. 58.0a, y

Abbreviations used: F, female; M, male; No., number; VAS, visual analogue scale. Between-group comparisons, determined using ANOVA or regression models (P < 0.05). determined using paired t tests or regression models (P < 0.05). 1

2 Results: a, b, c

x, y

Within-group changes from pre- to post-exposure,