plasma fat-soluble vitamin and carotenoid concentrations ... · hydrocarbon carotenoids ·...

1 3

Eur J Nutr (2017) 56:909–923DOI 10.1007/s00394-016-1289-7

REVIEW

Plasma fat‑soluble vitamin and carotenoid concentrations after plant sterol and plant stanol consumption: a meta‑analysis of randomized controlled trials

Sabine Baumgartner1 · Rouyanne T. Ras2 · Elke A. Trautwein2 · Ronald P. Mensink1 · Jogchum Plat1

Received: 29 April 2016 / Accepted: 29 July 2016 / Published online: 3 September 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com

−18.3; −14.3) and −10.1 % (−12.3; −8.0), α-carotene by −14.4 % (−17.5; 11.3) and −7.8 % (−11.3; −4.3), and lyco-pene by −12.3 % (−14.6; −10.1) and −6.3 % (−8.6; −4.0). Lutein concentrations decreased by −7.4 % (−10.1; −4.8), while TC-standardized concentrations were not changed. For zeaxanthin, these values were −12.9 % (−18.9; −6.8) and −7.7 % (−13.8; −1.7) and for β-cryptoxanthin −10.6 % (−14.3; −6.9) and −4.8 % (−8.7; −0.9). Non-standardized α-tocopherol concentrations decreased by −7.1 % (−8.0; −6.2) and γ-tocopherol by −6.9 % (−9.8; −3.9), while TC-standardized tocopherol concentrations were not changed. Non-standardized retinol and vitamin D concentrations were not affected. Results were not affected by baseline concentra-tions, dose, duration and type of plant sterols/stanols, except for significant effects of duration (≤4 vs. >4 weeks) on TC-standardized lutein concentrations (1.0 vs. −5.6 %) and type of plant sterol/stanol on TC-standardized β-carotene concen-trations (−8.9 vs. −14.2 %).Conclusions Plant sterol and stanol intake lowers TC-standardized hydrocarbon carotenoid concentrations, differently affects TC-standardized oxygenated carot-enoid concentrations, but does not affect TC-standardized tocopherol concentrations or absolute retinol and vitamin D concentrations. Observed concentrations remained within normal ranges.

Keywords Plant sterols · Plant stanols · Cholesterol · Hydrocarbon carotenoids · Oxygenated carotenoids · Fat-soluble vitamins

Introduction

Numerous studies have shown that consuming plant sterol- or plant stanol-enriched foods (0.6–3.3 g sterols or stanols/

Abstract Purpose Plant sterols and stanols interfere with intestinal cholesterol absorption, and it has been questioned whether absorption and plasma concentrations of fat-soluble vita-mins and carotenoids are also affected. We conducted a meta-analysis to assess the effects of plant sterol and stanol consumption on plasma fat-soluble vitamin and carotenoid concentrations.Methods Forty-one randomized controlled trials involv-ing 3306 subjects were included. Weighted absolute and relative changes of non-standardized and total cholesterol (TC)-standardized values (expressed as summary estimates and 95 % CIs) were calculated for three fat-soluble vita-mins (α- and γ-tocopherol, retinol and vitamin D) and six carotenoids (β-carotene, α-carotene, lycopene, lutein, zeax-anthin and β-cryptoxanthin) using a random effects model. Heterogeneity was assessed using predefined subject and treatment characteristics.Results Average plant sterol or stanol intake was 2.5 g/d. Rel-ative non-standardized and TC-standardized concentrations of β-carotene decreased by, respectively, −16.3 % (95 % CI

S. Baumgartner and R. T. Ras have contributed equally to this work.

Electronic supplementary material The online version of this article (doi:10.1007/s00394-016-1289-7) contains supplementary material, which is available to authorized users.

* Sabine Baumgartner [email protected]

1 Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands

2 Unilever R&D Vlaardingen, Vlaardingen, The Netherlands

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910 Eur J Nutr (2017) 56:909–923

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day) lowers plasma or serum low-density lipoprotein cho-lesterol (LDL-C) concentrations by 6−12 % [1–3]. Since plant sterols and plant stanols interfere with intestinal cho-lesterol absorption and consequently affect whole-body lipid and lipoprotein metabolism [4], questions have been raised whether plasma fat-soluble vitamin and carotenoid concentrations are also affected by plant sterol and stanol consumption. A reduction in plasma fat-soluble vitamin and carotenoid concentrations may be undesirable, since in prospective cohort studies lower concentrations have been associated with an increased risk of several chronic dis-eases, such as cardiovascular diseases (CVDs), cancer and age-related macular degeneration (AMD) [5–7], although evidence from randomized controlled trials is lacking [8, 9].

Already in 2003, Katan et al. [10] performed a meta-analysis including 18 studies and showed significant reduc-tions in circulating α-tocopherol, α-carotene, β-carotene and lycopene concentrations after plant sterol and stanol ester consumption. Concentrations of the fat-soluble vita-mins retinol and vitamin D were not affected. However, when concentrations were standardized for serum total cholesterol (TC) concentrations, there were no longer decreases in α-tocopherol, α-carotene and lycopene con-centrations, while β-carotene concentrations remained significantly reduced with a mean reduction of 12 %. This implies that at least for some of the vitamins and carote-noids decreases are related to the reduction in the number of circulating lipoproteins, the carriers of the fat-soluble tocopherols and carotenoids. However, it has also been sug-gested that plant sterols and stanols reduce the incorpora-tion of the more lipophilic hydrocarbon carotenoids (i.e., β-carotene, α-carotene and lycopene) into the micelles to a greater extent than those of the less lipophilic oxygenated carotenoids (lutein, zeaxanthin and β-cryptoxanthin) and tocopherols [11]. Finally, plant sterol and plant stanol con-sumption might not affect vitamins that require a specific transporter instead of the lipoprotein-mediated transport route, such as retinol and vitamin D.

Recently, Fardet et al. [12] have summarized the effects of plant sterols and plant stanols on fat-soluble vitamin and carotenoid concentrations. They calculated median relative changes (standardized and non-standardized) in α-tocopherol, γ-tocopherol, α-carotene, β-carotene and β-cryptoxanthin concentrations. However, results seem biased as only studies were included that reported signifi-cant reductions in plasma fat-soluble vitamin and carot-enoid concentrations. In addition, a detailed description of the systematic approach to review the available literature was lacking. Therefore, to provide an up-to-date quanti-tated overview on the effects of plant sterol or plant stanol consumption on plasma fat-soluble vitamin and carot-enoid concentrations, we performed a meta-analysis of randomized controlled trials (RCTs). For this, absolute

and relative changes were estimated for three fat-soluble vitamin (α- and γ-tocopherol, retinol and vitamin D) and six carotenoid (β-carotene, α-carotene, lycopene, lutein, zeaxanthin and β-cryptoxanthin) concentrations after plant sterol or plant stanol consumption. Furthermore, potential sources of heterogeneity between studies were assessed by investigating the impact of predefined subject and treat-ment characteristics on changes in plasma fat-soluble vita-min and carotenoid concentrations.

Methods

Search strategy

Potentially relevant studies were retrieved by a systematic search of five databases (Medline, Embase, the Cochrane Library, Cab abstracts and Food, Science and Technology abstracts) in December 2014. A search strategy was devel-oped including the Medical Subject Heading ‘phytosterols’ and the following search terms: (plant sterol* or phytos-terol* or sitosterol* or campesterol* or stigmasterol* or brassicasterol* or plant stanol* or sitostanol* or camp-estanol*) and (vitamin* or carotene* or carotenoid* or tocotrienol* or tocopherol* or alpha-carotene* or beta-car-otene* or lycopene* or lutein* or zeaxanthin* or retinol* or calciferol*), limited to humans without any restriction on language. Throughout this paper, the term ‘plasma’ is used, irrespective whether plasma or serum concentrations were reported in the different studies.

Selection of studies

Human intervention studies were considered eligible if effects of plant sterol or plant stanol consumption on plasma fat-soluble vitamin or carotenoid concentra-tions were reported. In the first selection round, titles and abstracts were screened and studies were selected if they met the following inclusion criteria: (1) RCT in humans (studies with children were allowed), (2) oral intake of plant sterol- or plant stanol-enriched foods or supplements, (3) measurement of plasma fat-soluble vitamins or carot-enoids, (4) no co-intervention next to the plant sterol or plant stanol intervention, (5) no studies in phytosterolemic patients, (6) duration of at least 2 weeks and (7) no dupli-cates. For the second selection round, full publications were read to assess their eligibility. Studies were excluded when they lacked a control group or were not randomized, when an intentional co-intervention (e.g., extra vitamins) was given that could not be separated from the effects of the plant sterol or plant stanol intervention or when plasma fat-soluble vitamin or carotenoid concentrations were not reported. Studies evaluating the effects of ferulated plant

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sterols (as in shea nut oil) were not included, since they are not commonly used in currently commercially available plant sterol- and stanol-enriched foods and there is no con-sensus on their cholesterol-lowering effects [13, 14]. When inconclusive, the eligibility of studies was discussed among authors until consensus was reached.

Data extraction and transformation

Data were collected using a database that included (1) publi-cation characteristics (reference number, first author and year of publication), (2) study characteristics (parallel or crosso-ver design, sample size and study duration), (3) subject char-acteristics (health status, mean age, mean BMI and gender distribution), (4) treatment characteristics (use of plant ster-ols or plant stanols, dose of plant sterols or plant stanols and food format), (5) measurement characteristics (serum or plasma) and (6) outcome variables [plasma and serum concentrations of α-carotene, β-carotene, α-tocopherol, γ-tocopherol, lutein, zeaxanthin, β-cryptoxanthin, lycopene, vitamin D, retinol, TC, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triacylglycerols (TAG)].

For all outcome variables, mean concentrations and accompanying variance measures were extracted at base-line and at the end of the intervention. In the circulation, tocopherols and carotenoids are transported by lipoprotein particles and therefore often standardized for serum cho-lesterol concentrations. Since vitamin D and retinol are not transported by lipoproteins, they were solely expressed as non-standardized concentrations. To unify the use of all cholesterol-standardized tocopherol and carotenoid concentrations, absolute TC data were extracted and TC-standardized tocopherol and carotenoid concentrations were calculated by dividing the absolute tocopherol/carot-enoid concentrations at baseline and at end of intervention by the respective TC concentrations. Original authors were contacted for non-standardized tocopherol and carotenoid concentrations if only cholesterol-standardized levels were reported [15–19].

Cholesterol data (TC, LDL-C and HDL-C) and TAG data expressed in mg/dL were converted into mmol/L by using their molecular weights (386.7 and 885.7 g/mol, respectively). In case fat-soluble vitamin or carotenoid con-centrations were expressed in ng/mL, ng/dL, μg/mL, μg/dL, μg/L, mg/dL, mg/L, g/mL, these data were also trans-formed based on their molecular weights to derive concen-trations in μmol/L or nmol/L (g/mol for α- and β-carotene: 536.9, α-tocopherol: 430.7, γ-tocopherol: 416.7, lutein and zeaxanthin: 568.9; β-cryptoxanthin: 552.9, lycopene: 536.9, retinol: 286.5 and vitamin D: 400.6). These transfor-mations were done for means and for SEs or SDs.

Placebo-adjusted absolute and relative changes with accompanying SEs were calculated for α-carotene,

β-carotene, α-tocopherol, γ-tocopherol, lutein, zeaxanthin, β-cryptoxanthin, lycopene, vitamin D, retinol, TC, LDL-C, HDL-C and TAG for each study (when data were avail-able). For parallel studies, absolute and relative changes (with accompanying SEs) were calculated based on average concentrations and variance measures at baseline and at end of intervention of treatment and control groups. For crosso-ver studies, absolute and relative changes were calculated based on concentrations at end of intervention of treatment and control periods. In case it was not possible to calculate placebo-adjusted changes and SEs, these data were used as reported in the papers [16, 20–25]. Data expressed as median (minimum, maximum) values were transformed to means ± SDs using the method of Wan et al. [26, 27] and data displayed in graphs were extracted using ScanIt ver-sion 1.0 [23, 28–31]. To derive SE from 95 % CI [13, 14] or from an effect estimate and P value [20], equations were used as described by the Cochrane handbook for system-atic reviews of interventions [32]. The Friedewald equation [33] was used for one study [34] to estimate the TC con-centration based on the reported concentrations of LDL-C, HDL-C and TG. In case only TC-standardized data were available, these data were added in SAS [23].

Statistical analysis

For each outcome parameter, a weighted net effect (expressed as summary estimate and 95 % CI) was calcu-lated using a random effects model and the inverse of the within-study variance (1/SE2) was used as weighing factor [35]. These effects were calculated for baseline concen-trations, end-of-intervention concentrations, absolute and relative changes of non-standardized and TC-standardized values. For interpretation of the data, the various outcome parameters were clustered in hydrocarbon or oxygenated carotenoids, in fat-soluble vitamins or plasma lipids. For-est plots were made for relative changes in representa-tives of the three fat-soluble vitamin/carotenoid categories (β-carotene representing the hydrocarbon carotenoids, lutein the oxygenated carotenoids and α-tocopherol the tocopherols).

Funnel plots were created to visualize the likeliness of heterogeneity (in case many effect sizes fall outside the confidence limits) and publication bias (in case of asym-metry). Heterogeneity was assessed using Cochran’s Q test (P < 0.1 indicates significant heterogeneity) and quantified by I2, which indicates the percentage of variability in effect estimate that is due to heterogeneity rather than sampling error [35, 36]. Publication bias was evaluated by Egger’s weighted regression test where the absence of publication bias is reflected by an intercept close to 0 (P ≥ 0.05) [37].

Subgroup analyses were performed for β-carotene, lutein and α-tocopherol as representatives of the

912 Eur J Nutr (2017) 56:909–923

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hydrocarbon carotenoids, oxygenated carotenoids and tocopherols to evaluate whether TC-standardized absolute and relative changes were influenced by predefined subject characteristics (i.e., baseline concentrations of β-carotene, lutein and α-tocopherol) or treatment characteristic (i.e., use of plant sterols or plant stanols, dose of plant sterols or plant stanols and duration of intervention). Subgroup anal-yses were also performed for effects on TC. Subgroups were defined using the median baseline concentrations and the median duration (4 weeks) as cut-offs. For the dose categories, we used 1.6, 2.0, 3.0 and 9.0 g/d as cut-offs allowing a more or less equal distribution of studies across the four dose categories.

Results were considered to be statistically significant if P < 0.05 based on two-sided testing. All statistical analyses were performed using SAS version 9.4 (SAS institute Inc., Cary, NC, USA). Forest plots were created using STATA version 12.1 (STATA Corporation, College Station, TX, USA). This meta-analysis adheres to the PRISMA state-ment guidelines for reporting in systematic reviews and meta-analyses.

Results

Overview of included studies

The systematic search retrieved 1084 potentially relevant papers, and after two selection rounds, 41 RCTs were included in the meta-analysis. A flowchart of the study selection process is presented in Fig. 1.

Of the 41 included studies (Online Supplemental Mate-rial Tables 1 and 2), 23 were conducted as a parallel study [15–17, 19, 21–26, 28–31, 34, 38–45] and 18 studies had a crossover design [13, 14, 18, 20, 46–59]. In total, 3306 sub-jects participated with an average age of 47.6 years (range 10.5–61.8 years) and an average BMI of 25.1 kg/m2 (range 19.0–28.3 kg/m2). The median study duration was 28 days (range 21–364 days) with an average dose of 2.5 g/d (range 0.45–9.0 g/d), and 80 % of the studies were performed with esterified plant sterols or plant stanols.

Plasma fat‑soluble vitamin/carotenoid outcomes

The weighted effects of plant sterol or plant stanol con-sumption on plasma fat-soluble vitamin and carotenoid concentrations are presented in Table 1. Non-standardized and TC-standardized hydrocarbon carotenoid concen-trations, i.e., lycopene, α-carotene and β-carotene, were significantly (P < 0.0001) lowered after consumption of plant sterol- or plant stanol-enriched foods. β-Carotene concentrations decreased on average by 0.08 µmol/L (−16.3 %; −10.1 % when TC-standardized), α-carotene concentrations by 0.02 µmol/L (−14.4 %; −7.8 % when TC-standardized) and lycopene concentrations by −0.04 µmol/L (−12.3 %; −6.3 % when TC-standardized). For the oxygenated carotenoids, i.e., lutein, zeaxanthin and β-cryptoxanthin, non-standardized concentrations were significantly (P < 0.0001) lowered, while changes in TC-standardized concentrations showed less conclusive results. Lutein concentrations decreased on average by 0.02 µmol/L (−7.4 %), while the TC-standardized concentrations in

Fig. 1 Flowchart study selec-tion process. The literature search retrieves 1084 poten-tially relevant papers, 1009 are excluded after screening titles and abstracts, 75 articles are reviewed in full and 41 randomized controlled trials (RCTs) are included in the meta-analysis

913Eur J Nutr (2017) 56:909–923

1 3

Tabl

e 1

Eff

ects

of

plan

t ste

rol o

r pl

ant s

tano

l con

sum

ptio

n on

pla

sma

caro

teno

id, f

at-s

olub

le v

itam

in, l

ipid

and

lipo

prot

ein

conc

entr

atio

ns

Exp

ress

ed a

s m

eans

(95

% C

I)

HD

L-C

hig

h-de

nsity

lipo

prot

ein

chol

este

rol,

LD

L-C

low

-den

sity

lipo

prot

ein

chol

este

rol,

PS

plan

t ste

rols

or

plan

t sta

nols

, TC

tota

l cho

lest

erol

, TA

G tr

iacy

lgly

cero

l1

P <

0.0

001;

2 P <

0.0

1; 3 P

< 0

.05

a For

par

alle

l st

udie

s, t

he w

eigh

ted

aver

age

base

line

conc

entr

atio

ns w

ere

calc

ulat

ed b

ased

on

the

base

line

conc

entr

atio

ns in

the

activ

e an

d pl

aceb

o gr

oups

and

for

cro

ssov

er s

tudi

es, t

he e

nd-o

f-in

terv

entio

n co

ncen

trat

ions

of

the

plac

ebo

peri

ods

wer

e us

edb F

or p

aral

lel s

tudi

es, t

he w

eigh

ted

aver

age

conc

entr

atio

ns a

fter

PS

inte

rven

tion

wer

e ca

lcul

ated

bas

ed o

n th

e co

ncen

trat

ions

aft

er P

S in

terv

entio

n in

the

activ

e gr

oups

and

for

cro

ssov

er s

tudi

es,

the

end-

of-i

nter

vent

ion

conc

entr

atio

ns o

f th

e ac

tive

peri

ods

wer

e us

ed

n (s

trat

a)U

nit

Bas

elin

e co

ncen

trat

iona

Con

cent

ratio

n af

ter

PS

inte

rven

tionb

Abs

olut

e ch

ange

ve

rsus

pla

cebo

Rel

ativ

e ch

ange

ve

rsus

pla

cebo

Hyd

roca

rbon

car

oten

oids

β-C

arot

ene

53µm

ol/L

0.60

(0.

54; 0

.67)

0.52

(0.

46; 0

.57)

−0.

08 (−

0.09

; −0.

07)1

−16

.3 (−

18.3

; −14

.3)1

54µm

ol/m

mol

TC

0.10

(0.

09; 0

.11)

0.09

(0.

08; 0

.10)

−0.

01 (−

0.01

; −0.

01)1

−10

.1 (−

12.3

; −8.

0)1

α-C

arot

ene

38µm

ol/L

0.19

(0.

15; 0

.24)

0.18

(0.

14; 0

.22)

−0.

02 (−

0.02

; −0.

01)1

−14

.4 (−

17.5

; −11

.3)1

37µm

ol/m

mol

TC

0.03

(0.

03; 0

.04)

0.03

(0.

02; 0

.04)

0.00

(0.

00; 0

.00)

1−

7.8

(−11

.3; −

4.3)

1

Lyco

pene

42µm

ol/L

0.57

(0.

49; 0

.65)

0.54

(0.

45; 0

.63)

−0.

04 (−

0.04

; −0.

03)1

−12

.3 (−

14.6

; −10

.1)1

41µm

ol/m

mol

TC

0.10

(0.

08; 0

.11)

0.10

(0.

08; 0

.11)

0.00

(−

0.01

; 0.0

0)1

−6.

3 (−

8.6;

−4.

0)1

Oxy

gena

ted

caro

teno

ids

Lut

ein

23µm

ol/L

0.38

(0.

31; 0

.45)

0.34

(0.

29; 0

.40)

−0.

02 (−

0.03

; −0.

01)1

−7.

4 (−

10.1

; −4.

8)1

22µm

ol/m

mol

TC

0.06

(0.

05; 0

.07)

0.06

(0.

05; 0

.07)

0.00

(0.

00; 0

.00)

−1.

5 (−

4.6;

1.6

)

Zea

xant

hin

13nm

ol/L

63.9

0 (5

2.22

; 75.

57)

55.3

9 (4

5.13

; 65.

65)

−7.

81 (−

11.0

9; −

4.53

)1−

12.9

(−

18.9

; −6.

8)1

12nm

ol/m

mol

TC

10.7

2 (8

.34;

13.

09)

9.78

(7.

74; 1

1.81

)−

0.70

(−

1.20

; −0.

21)2

−7.

7 (−

13.8

; −1.

7)3

β-C

rypt

oxan

thin

17µm

ol/L

0.28

(0.

22; 0

.35)

0.26

(0.

20; 0

.32)

−0.

03 (−

0.04

; −0.

02)1

−10

.6 (−

14.3

; −6.

9)1

16µm

ol/m

mol

TC

0.05

(0.

04; 0

.06)

0.05

(0.

04; 0

.06)

0.00

(0.

00; 0

.00)

3−

4.8

(−8.

7; −

0.95

)

Fat-

solu

ble

vita

min

s

α-T

ocop

hero

l55

µmol

/L35

.76

(33.

63; 3

7.89

)33

.16

(31.

27; 3

5.06

)−

2.43

(−

2.81

; −2.

05)1

−7.

1 (−

8.0;

−6.

2)1

54µm

ol/m

mol

TC

5.91

(5.

63; 6

.18)

5.92

(5.

63; 6

.20)

−0.

01 (−

0.06

; 0.0

3)−

0.3

(−1.

1; 0

.5)

γ-T

ocop

hero

l22

µmol

/L3.

00 (

2.55

; 3.4

6)2.

91 (

2.39

; 3.4

3)−

0.17

(−

0.24

; −0.

11)1

−6.

9 (−

9.8;

−3.

9)1

21µm

ol/m

mol

TC

0.51

(0.

42; 0

.60)

0.53

(0.

43; 0

.64)

0.00

(−

0.01

; 0.0

1)0.

2 (−

3.2;

3.6

)

Ret

inol

46µm

ol/L

2.65

(2.

14; 3

.16)

2.50

(2.

08; 2

.91)

−0.

02 (−

0.04

; 0.0

0)−

0.8

(−1.

8; 0

.2)

Vita

min

D28

nmol

/L57

.56

(51.

47; 6

3.65

)57

.95

(51.

10; 6

4.80

)−

0.45

(−

0.91

; 1.8

1)1.

4 (−

1.7;

4.4

)

Lip

id a

nd li

popr

otei

ns

TC

63m

mol

/L5.

96 (

5.80

; 6.1

2)5.

54 (

5.39

; 5.6

9)−

0.39

(−

0.42

; −0.

36)1

−6.

5 (−

7.1;

−6.

0)1

LD

L-C

64m

mol

/L3.

87 (

3.72

; 4.0

1)3.

50 (

3.36

; 3.6

4)−

0.35

(−

0.38

; −0.

32)1

−9.

0 (−

9.8;

−8.

2)1

HD

L-C

62m

mol

/L1.

44 (

1.40

; 1.4

8)1.

43 (

1.38

; 1.4

8)0.

00 (−

0.00

; 0.0

1)0.

2 (−

0.4;

0.7

)

TAG

60m

mol

/L1.

37 (

1.30

; 1.4

3)1.

30 (

1.23

; 1.3

7)−

0.06

(−

0.08

; −0.

04)1

−4.

6 (−

6.0;

−3.

2)1

914 Eur J Nutr (2017) 56:909–923

1 3

lutein were not significantly changed (−1.5 %) after plant sterol or plant stanol consumption. Non-standardized zeax-anthin concentrations decreased on average by 7.81 nmol/L (−12.9 %; −7.7 % when TC-standardized (P < 0.05)) and β-cryptoxanthin decreased by −0.03 µmol/L [−10.6 %; −4.8 % when TC-standardized (P < 0.05)]. Non-standard-ized tocopherol concentrations significantly (P < 0.0001) decreased after plant sterol or plant stanol consumption (α-tocopherol on average by 2.43 µmol/L (−7.1 %) and γ-tocopherol by 0.17 µmol/L (−6.9 %). However, when standardized for TC concentrations, α- and γ-tocopherol concentrations were no longer changed after plant sterol or plant stanol consumption (−0.3 and 0.2 %, respectively; P > 0.05). Concentrations of retinol and vitamin D were not changed after plant sterol or plant stanol consumption (−0.8 and 1.4 %, respectively; P > 0.05).

TC concentrations were significantly (P < 0.0001) decreased on average by 0.39 mmol/L (−6.5 %) and LDL-C concentrations by 0.35 mmol/L (−9.0 %). HDL-C concentrations did not change after plant sterol or plant stanol consumption (0.2 %), while TAG concentrations were significantly (P < 0.0001) decreased by 0.06 mmol/L (−4.6 %) (Table 1).

Figures 2, 3 and 4 show forest plots of the relative non-standardized and TC-standardized changes for β-carotene, lutein and α-tocopherol. Funnel plots for the relative non-standardized and TC-standardized changes in β-carotene,

lutein and α-tocopherol are shown in Online Supplemen-tal Material Figs. 1–3. Visual inspection and calculation of I2 statistics (P < 0.05) indicated substantial heterogeneity in the relative non-standardized changes of α-tocopherol. Heterogeneity was also present for relative non-standard-ized changes of zeaxanthin and lycopene and for the rela-tive TC-standardized changes of α-carotene and zeaxanthin (data not shown). Publication bias seemed only present for α-carotene (Egger test: P (intercept) < 0.05; studies report-ing small decreases in plasma changes seemed lacking, data not shown).

Covariate analyses

Table 2 provides an overview of the covariate analyses for the TC-standardized changes in β-carotene, lutein, α-tocopherol (β-carotene representing the hydrocar-bon carotenoids, lutein the oxygenated carotenoids and α-tocopherol the tocopherols) and for TC concentrations. Overall, baseline concentrations did not have a signifi-cant impact on the observed changes after plant sterol or plant stanol consumption. Only some trends were observed implying larger absolute reductions in β-carotene and larger absolute and relative reductions in α-tocopherol with higher baseline values. Furthermore, the plant sterol or plant stanol dose did not significantly affect TC-stand-ardized absolute or relative changes in β-carotene, lutein

NOTE: Weights are from random effects analysis

Overall (I-squared = 0.0%, p = 0.592)

Deveraj et al., 2006

Carr et al., 2009

Mensink et al., 2010 stratum 3

Noakes et al., 2005 stratum 2

Christiansen et al., 2001 stratum 2

Ntanios et al., 2002

Christiansen et al., 2001 stratum 1Plat et al., 2001 stratum 2

Hallikainen et al., 2000b stratum 1

Judd et al., 2002

Korpela et al., 2006

Hallikainen et al., 2000a stratum 1



Plat et al., 2000 stratum 2

Seki et al., 2003a

ID

Gylling et al., 2010

Study




Clifton et al., 2004b stratum 2

Hallikainen et al., 1999 stratum 2

Davidson et al., 2001 stratum 2

Seki et al., 2003b


Rudkowska et al., 2008b stratum 1

Hansel et al., 2007


Plat et al., 2000 stratum 1Maki et al., 2001 stratum 1


Colgan et al., 2004

Mensink et al., 2002

Heggen et al., 2010 stratum 2

Hernandez-Mijares et al., 2010

Amundsen et al., 2002


Homma et al., 2003 stratum 1


Hendriks et al., 2003



Gylling et al., 1999a


Thomsen et al., 2004 stratum 1


Kriengsinyos et al., 2011



Maki et al., 2001 stratum 2


-16.29 (-18.30, -14.28)

-17.07 (-38.63, 4.48)

15.07 (-16.44, 46.57)

-22.59 (-44.24, -0.94)

-15.27 (-27.96, -2.58)

-17.10 (-35.92, 1.73)

-20.80 (-33.33, -8.28)

-18.31 (-36.14, -0.48)-18.44 (-36.67, -0.21)

-11.51 (-29.40, 6.38)

-14.29 (-19.06, -9.51)

-12.22 (-26.28, 1.83)

-4.69 (-31.84, 22.47)

-6.74 (-21.05, 7.58)

-11.55 (-33.11, 10.00)

-21.88 (-32.20, -11.55)

-4.91 (-29.88, 20.05)

b-Carotene (95% CI)

-50.67 (-77.70, -23.63)

-14.06 (-37.69, 9.56)

-6.25 (-32.21, 19.71)

-14.06 (-37.90, 9.77)

-18.18 (-30.42, -5.94)

-33.21 (-53.00, -13.42)

9.50 (-23.86, 42.85)

-3.46 (-14.19, 7.27)

-16.55 (-32.30, -0.79)

10.53 (-27.20, 48.26)

-13.72 (-24.75, -2.68)

5.26 (-32.78, 43.30)

-18.75 (-29.35, -8.15)-18.93 (-40.75, 2.90)

-18.64 (-36.46, -0.82)

-19.49 (-30.18, -8.81)

-27.50 (-50.78, -4.22)

-17.98 (-27.28, -8.68)

-24.10 (-58.16, 9.97)

-17.46 (-25.96, -8.96)

-32.51 (-57.20, -7.81)

7.86 (-39.85, 55.58)

-21.09 (-32.95, -9.22)

-20.63 (-31.69, -9.57)

0.84 (-24.90, 26.58)

-12.73 (-27.38, 1.93)

-24.20 (-37.55, -10.86)

-12.54 (-35.32, 10.24)

-13.11 (-27.04, 0.81)

-15.73 (-25.48, -5.98)

-30.77 (-46.25, -15.29)

0.79 (-33.02, 34.60)

-25.66 (-51.96, 0.64)

-29.36 (-53.51, -5.22)

-13.11 (-26.90, 0.67)

100.00

0.87

0.41

0.86

2.50

1.14

2.57

1.271.21

1.26

17.65

2.04

0.55

1.96

0.87

3.78

0.65

Weight

0.55

%

0.72

0.60

0.71

2.69

1.03

0.36

3.50

1.62

0.28

3.31

0.28

3.590.85

1.27

3.53

0.74

4.66

0.35

5.58

0.66

0.18

2.86

3.29

0.61

1.88

2.26

0.78

2.08

4.23

1.68

0.35

0.58

0.69

2.12

-16.29 (-18.30, -14.28)

-17.07 (-38.63, 4.48)

15.07 (-16.44, 46.57)

-22.59 (-44.24, -0.94)

-15.27 (-27.96, -2.58)

-17.10 (-35.92, 1.73)

-20.80 (-33.33, -8.28)

-18.31 (-36.14, -0.48)-18.44 (-36.67, -0.21)

-11.51 (-29.40, 6.38)

-14.29 (-19.06, -9.51)

-12.22 (-26.28, 1.83)

-4.69 (-31.84, 22.47)

-6.74 (-21.05, 7.58)

-11.55 (-33.11, 10.00)

-21.88 (-32.20, -11.55)

-4.91 (-29.88, 20.05)

b-Carotene (95% CI)

-50.67 (-77.70, -23.63)

-14.06 (-37.69, 9.56)

-6.25 (-32.21, 19.71)

-14.06 (-37.90, 9.77)

-18.18 (-30.42, -5.94)

-33.21 (-53.00, -13.42)

9.50 (-23.86, 42.85)

-3.46 (-14.19, 7.27)

-16.55 (-32.30, -0.79)

10.53 (-27.20, 48.26)

-13.72 (-24.75, -2.68)

5.26 (-32.78, 43.30)

-18.75 (-29.35, -8.15)-18.93 (-40.75, 2.90)

-18.64 (-36.46, -0.82)

-19.49 (-30.18, -8.81)

-27.50 (-50.78, -4.22)

-17.98 (-27.28, -8.68)

-24.10 (-58.16, 9.97)

-17.46 (-25.96, -8.96)

-32.51 (-57.20, -7.81)

7.86 (-39.85, 55.58)

-21.09 (-32.95, -9.22)

-20.63 (-31.69, -9.57)

0.84 (-24.90, 26.58)

-12.73 (-27.38, 1.93)

-24.20 (-37.55, -10.86)

-12.54 (-35.32, 10.24)

-13.11 (-27.04, 0.81)

-15.73 (-25.48, -5.98)

-30.77 (-46.25, -15.29)

0.79 (-33.02, 34.60)

-25.66 (-51.96, 0.64)

-29.36 (-53.51, -5.22)

-13.11 (-26.90, 0.67)

100.00

0.87

0.41

0.86

2.50

1.14

2.57

1.271.21

1.26

17.65

2.04

0.55

1.96

0.87

3.78

0.65

Weight

0.55

%

0.72

0.60

0.71

2.69

1.03

0.36

3.50

1.62

0.28

3.31

0.28

3.590.85

1.27

3.53

0.74

4.66

0.35

5.58

0.66

0.18

2.86

3.29

0.61

1.88

2.26

0.78

2.08

4.23

1.68

0.35

0.58

0.69

2.12

0-77.7 0 77.7





Nguyen et al., 1999b stratum 2



ID


Seki et al., 2003b

Ntanios et al., 2002












Seki et al., 2003a





Hansel et al., 2007







Colgan et al., 2004







Carr et al., 2009













Judd et al., 2002


Study


-10.12 (-12.24, -7.99)

13.35 (-37.40, 64.10)

-16.38 (-27.43, -5.33)

-27.00 (-126.62, 72.62)

-20.40 (-44.53, 3.73)

-7.12 (-29.12, 14.88)

b-Carotene (95% CI)

-7.70 (-23.20, 7.79)

6.07 (-4.53, 16.67)

-15.92 (-29.22, -2.62)

-25.18 (-54.25, 3.89)

-13.23 (-35.78, 9.32)

-16.59 (-27.53, -5.65)

-16.47 (-51.65, 18.70)

-25.20 (-110.41, 60.01)

-12.49 (-31.11, 6.13)

1.39 (-14.17, 16.96)

-5.05 (-19.51, 9.42)

-13.80 (-26.76, -0.84)

-21.31 (-47.98, 5.36)

-2.21 (-21.99, 17.56)

-1.75 (-28.39, 24.89)

16.79 (-17.70, 51.28)

-9.82 (-20.25, 0.62)

-24.06 (-40.22, -7.91)

-3.87 (-30.30, 22.55)

-9.19 (-20.54, 2.17)

-19.80 (-100.91, 61.31)

-8.26 (-22.97, 6.44)

-10.59 (-29.64, 8.45)

13.82 (-25.03, 52.67)

-9.74 (-26.78, 7.30)

-12.27 (-31.36, 6.82)

-17.04 (-28.05, -6.02)

0.71 (-27.18, 28.60)

-43.76 (-72.10, -15.43)

-13.40 (-31.24, 4.43)

-10.30 (-23.73, 3.13)

-14.35 (-36.00, 7.30)

-2.70 (-29.69, 24.28)

19.09 (-14.11, 52.29)

-6.63 (-30.13, 16.87)

-10.13 (-19.38, -0.88)

3.96 (-21.86, 29.79)

-15.04 (-36.78, 6.70)

-18.27 (-32.66, -3.88)

9.83 (-29.86, 49.52)

-10.83 (-24.17, 2.50)

-2.13 (-30.01, 25.75)

-23.15 (-47.67, 1.38)

-6.17 (-21.06, 8.72)

-12.22 (-22.17, -2.27)

-13.22 (-24.54, -1.90)

-7.41 (-12.57, -2.25)

-28.68 (-51.10, -6.27)

5.09 (-30.46, 40.64)

100.00

0.17

3.69

0.05

0.77

0.93

Weight

1.88

4.01

2.55

0.53

0.89

3.77

0.36

0.06

1.30

1.86

2.15

2.68

0.63

1.15

0.64

0.38

4.14

1.73

0.65

3.50

0.07

2.08

1.24

0.30

1.55

1.24

3.71

0.58

0.56

1.42

2.50

0.96

0.62

0.41

0.82

5.26

0.68

0.95

2.18

0.29

2.53

0.58

0.75

2.03

4.55

3.52

16.92

0.90

%

0.36

-10.12 (-12.24, -7.99)

13.35 (-37.40, 64.10)

-16.38 (-27.43, -5.33)

-27.00 (-126.62, 72.62)

-20.40 (-44.53, 3.73)

-7.12 (-29.12, 14.88)

b-Carotene (95% CI)

-7.70 (-23.20, 7.79)

6.07 (-4.53, 16.67)

-15.92 (-29.22, -2.62)

-25.18 (-54.25, 3.89)

-13.23 (-35.78, 9.32)

-16.59 (-27.53, -5.65)

-16.47 (-51.65, 18.70)

-25.20 (-110.41, 60.01)

-12.49 (-31.11, 6.13)

1.39 (-14.17, 16.96)

-5.05 (-19.51, 9.42)

-13.80 (-26.76, -0.84)

-21.31 (-47.98, 5.36)

-2.21 (-21.99, 17.56)

-1.75 (-28.39, 24.89)

16.79 (-17.70, 51.28)

-9.82 (-20.25, 0.62)

-24.06 (-40.22, -7.91)

-3.87 (-30.30, 22.55)

-9.19 (-20.54, 2.17)

-19.80 (-100.91, 61.31)

-8.26 (-22.97, 6.44)

-10.59 (-29.64, 8.45)

13.82 (-25.03, 52.67)

-9.74 (-26.78, 7.30)

-12.27 (-31.36, 6.82)

-17.04 (-28.05, -6.02)

0.71 (-27.18, 28.60)

-43.76 (-72.10, -15.43)

-13.40 (-31.24, 4.43)

-10.30 (-23.73, 3.13)

-14.35 (-36.00, 7.30)

-2.70 (-29.69, 24.28)

19.09 (-14.11, 52.29)

-6.63 (-30.13, 16.87)

-10.13 (-19.38, -0.88)

3.96 (-21.86, 29.79)

-15.04 (-36.78, 6.70)

-18.27 (-32.66, -3.88)

9.83 (-29.86, 49.52)

-10.83 (-24.17, 2.50)

-2.13 (-30.01, 25.75)

-23.15 (-47.67, 1.38)

-6.17 (-21.06, 8.72)

-12.22 (-22.17, -2.27)

-13.22 (-24.54, -1.90)

-7.41 (-12.57, -2.25)

-28.68 (-51.10, -6.27)

5.09 (-30.46, 40.64)

100.00

0.17

3.69

0.05

0.77

0.93

Weight

1.88

4.01

2.55

0.53

0.89

3.77

0.36

0.06

1.30

1.86

2.15

2.68

0.63

1.15

0.64

0.38

4.14

1.73

0.65

3.50

0.07

2.08

1.24

0.30

1.55

1.24

3.71

0.58

0.56

1.42

2.50

0.96

0.62

0.41

0.82

5.26

0.68

0.95

2.18

0.29

2.53

0.58

0.75

2.03

4.55

3.52

16.92

0.90

%

0.36

0-127 0 127

Fig. 2 Forest plot relative change (expressed as summary estimates and 95 % CIs) in non-standardized (left panel) and TC-standardized (right panel) plasma β-carotene concentrations. The solid squares represent the weight of individual study arms, and the pooled effect

estimate is represented as a diamond. Heterogeneity is assessed using Cochran’s Q test (P < 0.1 indicates significant heterogeneity) and quantified by I2, where >50 % indicates substantial heterogeneity

915Eur J Nutr (2017) 56:909–923

1 3

and α-tocopherol. Only study duration (≤4 vs. >4 weeks) resulted in larger TC-standardized absolute and relative reductions in lutein (0.000 vs. −0.002 µmol/mmol TC and 1.0 vs. −5.6 %, respectively), whereas only a trend for such effect was observed for β-carotene. Consump-tion of plant stanols seemed to have a stronger effect on

lowering relative TC-standardized β-carotene concentra-tions than plant sterols (−14.2 vs. −8.9 %, respectively), while changes in α-tocopherol concentrations showed a trend toward larger reductions after plant stanol vs. sterol consumption. Changes in TC concentrations were also larger after consumption of plant stanols vs. plant sterols





ID




Colgan et al., 2004












Study






-7.48 (-10.34, -4.63)

6.25 (-19.12, 31.62)

-5.00 (-13.62, 3.62)

Lutein (95% CI)

-7.21 (-21.40, 6.99)

-2.46 (-16.77, 11.85)

-0.85 (-20.96, 19.25)

-9.32 (-18.54, -0.10)

-5.13 (-13.43, 3.17)

-12.33 (-27.77, 3.12)

-8.58 (-22.59, 5.43)

5.00 (-5.19, 15.19)

-18.69 (-38.22, 0.84)

-7.35 (-28.95, 14.24)

-4.55 (-13.85, 4.76)

-6.82 (-16.22, 2.59)

-8.97 (-20.12, 2.18)

-12.16 (-20.85, -3.47)

-1.94 (-12.75, 8.88)

-14.01 (-38.05, 10.03)

-15.67 (-24.49, -6.85)

-13.24 (-34.38, 7.91)

-35.69 (-54.31, -17.06)

-4.45 (-13.65, 4.74)

100.00

1.21

7.62

Weight

3.48

3.43

1.87

6.93

8.03

3.01

3.56

5.98

1.97

1.63

6.84

6.73

5.19

7.54

5.45

%

1.34

7.38

1.70

2.15

6.96

-7.48 (-10.34, -4.63)

6.25 (-19.12, 31.62)

-5.00 (-13.62, 3.62)

Lutein (95% CI)

-7.21 (-21.40, 6.99)

-2.46 (-16.77, 11.85)

-0.85 (-20.96, 19.25)

-9.32 (-18.54, -0.10)

-5.13 (-13.43, 3.17)

-12.33 (-27.77, 3.12)

-8.58 (-22.59, 5.43)

5.00 (-5.19, 15.19)

-18.69 (-38.22, 0.84)

-7.35 (-28.95, 14.24)

-4.55 (-13.85, 4.76)

-6.82 (-16.22, 2.59)

-8.97 (-20.12, 2.18)

-12.16 (-20.85, -3.47)

-1.94 (-12.75, 8.88)

-14.01 (-38.05, 10.03)

-15.67 (-24.49, -6.85)

-13.24 (-34.38, 7.91)

-35.69 (-54.31, -17.06)

-4.45 (-13.65, 4.74)

100.00

1.21

7.62

Weight

3.48

3.43

1.87

6.93

8.03

3.01

3.56

5.98

1.97

1.63

6.84

6.73

5.19

7.54

5.45

%

1.34

7.38

1.70

2.15

6.96

0-54.3 0 54.3









ID




Study


Colgan et al., 2004












-1.52 (-4.76, 1.72)

9.26 (-16.36, 34.89)

-10.65 (-32.42, 11.12)

2.59 (-6.72, 11.90)

-4.91 (-16.12, 6.31)

-32.01 (-50.78, -13.23)

-1.21 (-17.86, 15.44)

Lutein (95% CI)

0.25 (-14.50, 15.00)

-11.17 (-19.88, -2.47)

1.55 (-8.70, 11.80)

0.95 (-8.89, 10.79)

-6.56 (-16.06, 2.94)

-13.29 (-33.13, 6.55)

-2.20 (-16.73, 12.33)

2.12 (-18.07, 22.32)

-4.05 (-13.54, 5.45)

1.15 (-8.58, 10.88)

6.61 (-5.15, 18.37)

-6.59 (-31.37, 18.18)

10.86 (0.11, 21.62)

3.30 (-5.74, 12.33)

-3.33 (-25.86, 19.20)

2.65 (-12.10, 17.40)

100.00

1.46

1.95

7.02

5.57

2.52

3.09

Weight

3.74

7.57

6.25

%

6.58

6.86

2.30

3.83

2.23

6.86

6.67

5.22

1.55

5.88

7.27

1.84

3.74

-1.52 (-4.76, 1.72)

9.26 (-16.36, 34.89)

-10.65 (-32.42, 11.12)

2.59 (-6.72, 11.90)

-4.91 (-16.12, 6.31)

-32.01 (-50.78, -13.23)

-1.21 (-17.86, 15.44)

Lutein (95% CI)

0.25 (-14.50, 15.00)

-11.17 (-19.88, -2.47)

1.55 (-8.70, 11.80)

0.95 (-8.89, 10.79)

-6.56 (-16.06, 2.94)

-13.29 (-33.13, 6.55)

-2.20 (-16.73, 12.33)

2.12 (-18.07, 22.32)

-4.05 (-13.54, 5.45)

1.15 (-8.58, 10.88)

6.61 (-5.15, 18.37)

-6.59 (-31.37, 18.18)

10.86 (0.11, 21.62)

3.30 (-5.74, 12.33)

-3.33 (-25.86, 19.20)

2.65 (-12.10, 17.40)

100.00

1.46

1.95

7.02

5.57

2.52

3.09

Weight

3.74

7.57

6.25

%

6.58

6.86

2.30

3.83

2.23

6.86

6.67

5.22

1.55

5.88

7.27

1.84

3.74

0-50.8 0 50.8

Fig. 3 Forest plot relative change (expressed as summary estimates and 95 % CIs) in non-standardized (left panel) and TC-standardized (right panel) plasma lutein concentrations. The solid squares repre-sent the weight of individual study arms, and the pooled effect esti-

mate is represented as a diamond. Heterogeneity is assessed using Cochran’s Q test (P < 0.1 indicates significant heterogeneity) and quantified by I2, where >50 % indicates substantial heterogeneity




Carr et al., 2009




Judd et al., 2002





Deveraj et al., 2006Noakes et al., 2005 stratum 1

Study



Raeini-Sarjaz et al., 2002 stratum 2

Davidson et al., 2001 stratum 2Davidson et al., 2001 stratum 3

Matsuoka et al., 2004a

ID





Maki et al., 2001 stratum 2Plat et al., 2000 stratum 1



Seki et al., 2003a

Hendriks et al., 1999 stratum 2









Colgan et al., 2004


















-7.11 (-8.06, -6.16)

-9.14 (-20.14, 1.85)

3.28 (-16.46, 23.03)

-5.43 (-15.87, 5.02)

-6.77 (-10.13, -3.41)

-12.84 (-17.32, -8.36)

-7.75 (-12.63, -2.86)

-15.53 (-24.05, -7.02)

-4.02 (-8.60, 0.56)

-13.10 (-21.59, -4.60)

-6.89 (-11.09, -2.69)

-2.82 (-16.27, 10.62)-2.81 (-7.17, 1.55)

-12.54 (-20.21, -4.88)

-7.97 (-12.09, -3.85)

-7.62 (-23.20, 7.95)

1.80 (-13.04, 16.63)2.97 (-12.41, 18.35)

-2.19 (-10.17, 5.80)

a-Tocopherol (95% CI)

-9.51 (-14.28, -4.75)

-7.26 (-11.81, -2.71)

-11.27 (-19.63, -2.91)

-6.18 (-12.14, -0.21)

-7.41 (-16.32, 1.50)-7.46 (-11.33, -3.58)

-6.79 (-13.31, -0.27)

-4.86 (-13.48, 3.76)

-9.09 (-25.53, 7.35)

-8.19 (-11.71, -4.66)

-10.65 (-14.64, -6.66)

-2.90 (-8.15, 2.36)

-4.27 (-7.82, -0.72)

-5.79 (-10.06, -1.51)

3.49 (-8.92, 15.91)

-8.88 (-12.87, -4.89)

4.57 (-7.70, 16.83)

-6.44 (-10.92, -1.96)

-5.75 (-10.15, -1.36)

-13.67 (-18.92, -8.42)

-2.19 (-6.99, 2.60)

0.00 (-10.52, 10.52)

-4.75 (-7.67, -1.83)

-10.03 (-14.96, -5.10)

0.28 (-16.47, 17.03)

-5.93 (-11.71, -0.16)

-12.04 (-19.95, -4.12)

-9.55 (-18.83, -0.26)

-6.89 (-11.64, -2.15)

-4.43 (-8.31, -0.54)

-9.07 (-29.50, 11.35)

-3.76 (-8.79, 1.26)

-14.54 (-20.65, -8.44)

-12.54 (-20.15, -4.94)

-15.61 (-35.67, 4.45)

-8.90 (-12.45, -5.34)

100.00

0.67

0.22

0.73

3.73

2.73

2.45

1.05

2.66

1.05

2.95

0.462.82

%

1.25

3.01

0.35

0.380.36

1.17

Weight

2.53

2.68

1.08

1.85

0.973.23

1.62

1.03

0.32

3.56

3.13

2.22

3.54

2.89

0.54

3.12

0.55

2.73

2.80

2.22

2.51

0.73

4.22

2.42

0.31

1.94

1.19

0.90

2.54

3.22

0.21

2.36

1.79

1.27

0.22

3.53

-7.11 (-8.06, -6.16)

-9.14 (-20.14, 1.85)

3.28 (-16.46, 23.03)

-5.43 (-15.87, 5.02)

-6.77 (-10.13, -3.41)

-12.84 (-17.32, -8.36)

-7.75 (-12.63, -2.86)

-15.53 (-24.05, -7.02)

-4.02 (-8.60, 0.56)

-13.10 (-21.59, -4.60)

-6.89 (-11.09, -2.69)

-2.82 (-16.27, 10.62)-2.81 (-7.17, 1.55)

-12.54 (-20.21, -4.88)

-7.97 (-12.09, -3.85)

-7.62 (-23.20, 7.95)

1.80 (-13.04, 16.63)2.97 (-12.41, 18.35)

-2.19 (-10.17, 5.80)


-9.51 (-14.28, -4.75)

-7.26 (-11.81, -2.71)

-11.27 (-19.63, -2.91)

-6.18 (-12.14, -0.21)

-7.41 (-16.32, 1.50)-7.46 (-11.33, -3.58)

-6.79 (-13.31, -0.27)

-4.86 (-13.48, 3.76)

-9.09 (-25.53, 7.35)

-8.19 (-11.71, -4.66)

-10.65 (-14.64, -6.66)

-2.90 (-8.15, 2.36)

-4.27 (-7.82, -0.72)

-5.79 (-10.06, -1.51)

3.49 (-8.92, 15.91)

-8.88 (-12.87, -4.89)

4.57 (-7.70, 16.83)

-6.44 (-10.92, -1.96)

-5.75 (-10.15, -1.36)

-13.67 (-18.92, -8.42)

-2.19 (-6.99, 2.60)

0.00 (-10.52, 10.52)

-4.75 (-7.67, -1.83)

-10.03 (-14.96, -5.10)

0.28 (-16.47, 17.03)

-5.93 (-11.71, -0.16)

-12.04 (-19.95, -4.12)

-9.55 (-18.83, -0.26)

-6.89 (-11.64, -2.15)

-4.43 (-8.31, -0.54)

-9.07 (-29.50, 11.35)

-3.76 (-8.79, 1.26)

-14.54 (-20.65, -8.44)

-12.54 (-20.15, -4.94)

-15.61 (-35.67, 4.45)

-8.90 (-12.45, -5.34)

100.00

0.67

0.22

0.73

3.73

2.73

2.45

1.05

2.66

1.05

2.95

0.462.82

%

1.25

3.01

0.35

0.380.36

1.17

Weight

2.53

2.68

1.08

1.85

0.973.23

1.62

1.03

0.32

3.56

3.13

2.22

3.54

2.89

0.54

3.12

0.55

2.73

2.80

2.22

2.51

0.73

4.22

2.42

0.31

1.94

1.19

0.90

2.54

3.22

0.21

2.36

1.79

1.27

0.22

3.53

0-35.7 0 35.7







Colgan et al., 2004



Seki et al., 2003a







ID





Judd et al., 2002















Seki et al., 2003b






Matsuoka et al., 2004a

Hallikainen et al., 2000a stratum 2Hendriks et al., 1999 stratum 3





Carr et al., 2009








Study

-0.32 (-1.11, 0.48)

0.61 (-8.24, 9.46)

7.52 (-4.76, 19.80)

9.48 (-3.66, 22.61)

3.51 (-8.32, 15.35)

-2.88 (-7.41, 1.65)

8.22 (-7.50, 23.95)

5.73 (0.00, 11.45)

3.43 (-7.82, 14.69)

1.07 (-3.89, 6.03)

2.54 (-2.26, 7.34)

6.70 (-1.57, 14.98)

-4.25 (-12.47, 3.97)

-4.43 (-13.05, 4.18)

-0.93 (-5.99, 4.14)


0.64 (-4.88, 6.15)

-4.40 (-9.27, 0.47)

-0.01 (-3.71, 3.70)

4.34 (-0.63, 9.32)

1.35 (-5.10, 7.80)

-7.78 (-15.66, 0.11)

-0.04 (-12.13, 12.06)

0.71 (-3.84, 5.25)

-2.92 (-9.49, 3.64)

-6.63 (-12.18, -1.09)

-4.87 (-20.91, 11.17)

2.89 (-1.73, 7.50)

0.50 (-6.53, 7.53)

0.68 (-2.95, 4.31)

8.08 (-7.15, 23.31)

-0.46 (-4.83, 3.90)

2.08 (-2.07, 6.23)

0.57 (-2.51, 3.65)

1.78 (-3.53, 7.09)

-0.15 (-16.27, 15.97)

-2.11 (-5.87, 1.64)

0.33 (-13.16, 13.82)

-5.39 (-14.28, 3.49)

-1.83 (-6.26, 2.61)

1.70 (-2.85, 6.26)

-0.53 (-9.54, 8.48)

-2.80 (-7.92, 2.33)-2.27 (-6.08, 1.54)

0.22 (-5.66, 6.11)

-3.64 (-12.61, 5.33)

-6.98 (-14.97, 1.01)

-11.74 (-31.76, 8.28)

7.80 (-12.98, 28.58)

-1.32 (-6.40, 3.75)

0.82 (-3.75, 5.40)

-1.72 (-22.34, 18.90)

1.80 (-8.68, 12.28)

-4.38 (-8.65, -0.11)

4.63 (-12.84, 22.10)

-0.95 (-5.09, 3.20)

100.00

0.80

0.42

0.37

0.45

3.01

0.26

1.90

0.50

2.52

2.69

0.92

0.93

0.85

2.42

Weight

2.05

2.61

4.45

2.50

1.50

1.01

0.43

2.99

1.45

2.02

0.25

2.90

1.27

4.63

0.27

3.24

3.57

6.34

2.20

0.24

4.34

0.35

0.80

3.13

2.98

0.77

2.374.21

1.80

0.78

0.98

0.16

0.15

2.41

2.95

0.15

0.57

3.38

0.21

3.58

%

-0.32 (-1.11, 0.48)

0.61 (-8.24, 9.46)

7.52 (-4.76, 19.80)

9.48 (-3.66, 22.61)

3.51 (-8.32, 15.35)

-2.88 (-7.41, 1.65)

8.22 (-7.50, 23.95)

5.73 (0.00, 11.45)

3.43 (-7.82, 14.69)

1.07 (-3.89, 6.03)

2.54 (-2.26, 7.34)

6.70 (-1.57, 14.98)

-4.25 (-12.47, 3.97)

-4.43 (-13.05, 4.18)

-0.93 (-5.99, 4.14)


0.64 (-4.88, 6.15)

-4.40 (-9.27, 0.47)

-0.01 (-3.71, 3.70)

4.34 (-0.63, 9.32)

1.35 (-5.10, 7.80)

-7.78 (-15.66, 0.11)

-0.04 (-12.13, 12.06)

0.71 (-3.84, 5.25)

-2.92 (-9.49, 3.64)

-6.63 (-12.18, -1.09)

-4.87 (-20.91, 11.17)

2.89 (-1.73, 7.50)

0.50 (-6.53, 7.53)

0.68 (-2.95, 4.31)

8.08 (-7.15, 23.31)

-0.46 (-4.83, 3.90)

2.08 (-2.07, 6.23)

0.57 (-2.51, 3.65)

1.78 (-3.53, 7.09)

-0.15 (-16.27, 15.97)

-2.11 (-5.87, 1.64)

0.33 (-13.16, 13.82)

-5.39 (-14.28, 3.49)

-1.83 (-6.26, 2.61)

1.70 (-2.85, 6.26)

-0.53 (-9.54, 8.48)

-2.80 (-7.92, 2.33)-2.27 (-6.08, 1.54)

0.22 (-5.66, 6.11)

-3.64 (-12.61, 5.33)

-6.98 (-14.97, 1.01)

-11.74 (-31.76, 8.28)

7.80 (-12.98, 28.58)

-1.32 (-6.40, 3.75)

0.82 (-3.75, 5.40)

-1.72 (-22.34, 18.90)

1.80 (-8.68, 12.28)

-4.38 (-8.65, -0.11)

4.63 (-12.84, 22.10)

-0.95 (-5.09, 3.20)

100.00

0.80

0.42

0.37

0.45

3.01

0.26

1.90

0.50

2.52

2.69

0.92

0.93

0.85

2.42

Weight

2.05

2.61

4.45

2.50

1.50

1.01

0.43

2.99

1.45

2.02

0.25

2.90

1.27

4.63

0.27

3.24

3.57

6.34

2.20

0.24

4.34

0.35

0.80

3.13

2.98

0.77

2.374.21

1.80

0.78

0.98

0.16

0.15

2.41

2.95

0.15

0.57

3.38

0.21

3.58

%

0-31.8 0 31.8

Fig. 4 Forest plot relative change (expressed as summary estimates and 95 % CIs) in non-standardized (left panel) and TC-standardized (right panel) plasma α-tocopherol concentrations. The solid squares represent the weight of individual study arms, and the pooled effect

estimate is represented as a diamond. Heterogeneity is assessed using Cochran’s Q test (P < 0.1 indicates significant heterogeneity) and quantified by I2, where >50 % indicates substantial heterogeneity

916 Eur J Nutr (2017) 56:909–923

1 3

Tabl

e 2

Cov

aria

te a

naly

ses

of a

bsol

ute

and

rela

tive

TC

-sta

ndar

dize

d ch

ange

s in

β-c

arot

ene,

lut

ein,

α-t

ocop

hero

l an

d to

tal

chol

este

rol

conc

entr

atio

ns a

fter

pla

nt s

tero

l or

pla

nt s

tano

l co

nsum

p-tio

n

Cov

aria

teSu

bgro

up d

efini

tion

nC

hang

e vs

. pla

cebo

95 %

CI

P v

alue

bet

wee

n su

bgro

ups1

Cha

nge

vs. p

lace

bo95

% C

IP

val

ue b

etw

een

subg

roup

s

Abs

olut

e ch

ange

in β

-car

oten

e (µ

mol

/mm

olT

C)

Rel

ativ

e ch

ange

in β

-car

oten

e (%

)

Bas

elin

e<

0.09

µm

ol/m

moL

TC

27−

0.00

7(−

0.00

9; −

0.00

5)0.

059

−9.

8(−

12.6

; −7.

0)0.

747

>0.

09 µ

mol

/mm

oLT

C27

−0.

011

(−0.

015;

−0.

007)

−10

.5(−

13.7

; −7.

3)

Dos

e0.

45 ≤

dos

e ≤

1.6

16−

0.00

8(−

0.01

2; −

0.00

5)0.

985

−8.

5(−

12.3

; −4.

7)0.

587

1.6

< d

ose ≤

2.0

14−

0.00

8(−

0.01

3; −

0.00

4)−

9.9

(−14

.4; −

5.5)

2.0

< d

ose ≤

3.0

16−

0.00

7(−

0.01

0; −

0.00

5)−

11.2

(−15

.1; −

7.3)

3.0

< d

ose ≤

9.0

8−

0.00

8(−

0.01

4; −

0.00

3)−

13.8

(−21

.2; −

6.4)

Dur

atio

n≤

4 w

eeks

28−

0.00

7(−

0.00

9; −

0.00

5)0.

093

−8.

7(−

11.2

; −6.

1)0.

050

>4

wee

ks26

−0.

010

(−0.

014;

−0.

007)

−13

.2(−

17.0

; −9.

5)

Ster

ol v

s. s

tano

lSt

erol

31−

0.00

7(−

0.00

9; −

0.00

5)0.

206

−8.

9(−

11.3

; −6.

5)0.

039

Stan

ol23

−0.

010

(−0.

014;

−0.

006)

−14

.2(−

18.6

; −9.

8)

Abs

olut

e ch

ange

in lu

tein

(µm

ol/m

mol

TC

)R

elat

ive

chan

ge in

lute

in (

%)

Bas

elin

e<

0.06

µm

ol/m

moL

TC

110.

001

(−0.

003;

0.0

01)

0.65

6−

2.7

(−6.

8; 1

.5)

0.41

6

>0.

06 µ

mol

/mm

oLT

C11

0.00

0(−

0.00

3; 0

.003

)−

0.1

(−4.

6; 4

.3)

Dos

e0.

45 ≤

dos

e ≤

1.6

100.

000

(−0.

002;

0.0

01)

0.13

4−

1.1

(−4.

9; 2

.7)

0.17

1

1.6

< d

ose ≤

2.0

40.

002

(−0.

002;

0.0

06)

3.0

(−4.

5; 1

0.6)

2.0

< d

ose ≤

3.0

30.

001

(−0.

004;

0.0

05)

1.6

(−8.

2; 1

1.4)

3.0

< d

ose ≤

9.0

5−

0.00

5(−

0.01

0; −

0.00

1)−

7.8

(−14

.6; −

0.9)

Dur

atio

n≤

4 w

eeks

110.

000

(−0.

001;

0.0

02)

0.04

81.

0(−

2.6;

4.5

)0.

028

>4

wee

ks11

−0.

002

(−0.

004;

0.0

00)

−5.

6(−

10.2

; −0.

9)

Ster

ol v

ersu

s st

anol

Ster

ol19

−0.

001

(−0.

002;

0.0

01)

0.95

4−

1.6

(−4.

9; 1

.6)

0.78

5

Stan

ol3

0.00

0(−

0.00

9; 0

.009

)−

0.2

(−9.

8; 9

.4)

Abs

olut

e ch

ange

in α

-toc

ophe

rol (

µmol

/mm

olT

C)

Rel

ativ

e ch

ange

in α

-toc

ophe

rol (

%)

Bas

elin

e<

5.6

4 µm

ol/m

moL

TC

270.

014

(−0.

039;

0.0

67)

0.07

20.

3(−

0.7;

1.3

)0.

074

> 5

.64

µmol

/mm

oLT

C27

−0.

077

(−0.

161;

0.0

07)

−1.

2(−

2.4;

0.1

)

Dos

e0.

45 ≤

dos

e ≤

1.6

170.

008

(−0.

064;

0.0

80)

0.31

8−

0.1

(−1.

3; 1

.2)

0.35

4

1.6

< d

ose ≤

2.0

14−

0.02

1(−

0.10

5; 0

.063

)−

0.5

(−1.

9; 1

.0)

2.0

< d

ose ≤

3.0

140.

031

(−0.

067;

0.1

29)

0.5

(−1.

3; 2

.2)

3.0

< d

ose ≤

9.0

9−

0.10

6(−

0.22

5; 0

.012

)−

2.0

(−4.

2; 0

.2)

Dur

atio

n≤

4 w

eeks

32−

0.01

1(−

0.06

4; 0

.042

)0.

952

−0.

3(−

1.2;

0.6

)0.

947

>4

wee

ks22

−0.

014

(−0.

102;

0.0

74)

−0.

3(−

1.9;

1.4

)

Ster

ol v

s. s

tano

lSt

erol

330.

017

(−0.

037;

0.0

71)

0.06

20.

2(−

0.8;

1.1

)0.

070

Stan

ol21

−0.

076

(−0.

157;

0.0

05)

−1.

4(−

2.7;

0.0

)

917Eur J Nutr (2017) 56:909–923

1 3

(−8.0 vs. −6.1 %, respectively), which is probably related to a higher dose in the plant stanol compared to the plant sterol studies (3.2 vs. 2.1 g/d). In addition, changes in TC concentrations after plant sterol or plant stanol consump-tion were significantly affected by baseline concentrations (only absolute TC changes) and by the dose of plant sterol or plant stanol intake.

Discussion

Although there is general consensus about the serum cho-lesterol-lowering efficacy of consuming foods enriched with plant sterols and stanols, there is an ongoing discus-sion around the potential effects of these ingredients on plasma fat-soluble vitamin and carotenoid concentrations. Therefore, we here present the first extensive systematic review and meta-analysis to estimate the effects of plant sterol and plant stanol consumption on plasma fat-soluble vitamin and carotenoid concentrations. We observed a decrease in non-standardized (hydrocarbon and oxygen-ated) carotenoids and in tocopherol concentrations, but not in vitamin D and retinol concentrations. TC-standardized concentrations remained significantly decreased for all individual hydrocarbon carotenoids, while the oxygen-ated carotenoid concentrations were differently affected and TC-standardized tocopherol concentrations were not changed after plant sterol and plant stanol consumption.

In an earlier less extensive review from 2003 by Katan et al. [10] including eighteen studies, a reduction in TC-standardized β-carotene was found, while TC-standard-ized concentrations of α-carotene, lycopene, α-tocopherol and absolute concentrations of vitamin D and retinol were not affected by plant sterol and plant stanol consumption. Our data based on 41 studies available in December 2014 are partly in agreement with these earlier findings, since we observed a significant decrease in all TC-standardized hydrocarbon carotenoid concentrations, while Katan et al. only reported a significant decrease in TC-standardized β-carotene but not in TC-standardized α-carotene and lyco-pene concentrations.

Regarding the interpretation of changes in absolute fat-soluble vitamin and carotenoid concentrations, it needs to be emphasized that these components are transported by lipoproteins (except retinol and vitamin D) [60, 61]. There-fore, a reduction in non-standardized concentrations might be the result of reduced carrier capacity, as evidenced by lower serum cholesterol concentrations after plant sterol or plant stanol intake. For this reason, fat-soluble vitamin and carotenoid concentrations are generally standardized for various plasma lipid fractions. We chose to standardize for TC (reflecting cholesterol in all lipoproteins), since fat-soluble vitamins and carotenoids are not selectively carried Ta

ble

2 c

ontin

ued

Abs

olut

e ch

ange

in T

C (

mm

ol/L

)R

elat

ive

chan

ge in

TC

(%

)

Bas

elin

e<

6.1

mm

oL/L

30−

0.33

7(−

0.38

2; −

0.29

1)0.

002

−6.

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in one lipoprotein fraction. After standardization for TC, α- and γ-tocopherol concentrations were not changed, while changes in oxygenated carotenoids became less significant (zeaxanthin and β-cryptoxanthin) or were no longer present (lutein). Reductions in TC-standardized concentrations for all hydrocarbon carotenoids (β-carotene, α-carotene and lycopene) remained significant although relative changes were smaller compared with the non-standardized changes. This suggests that reductions in non-standardized tocoph-erol concentrations can primarily be explained by a reduc-tion in the number of lipoprotein particles, while changes in non-standardized carotenoid concentrations can only partly be explained by a decrease in carrier capacity. For the lipophilic hydrocarbon carotenoids, other factors should be considered to explain the observed reductions. Analog to cholesterol, plant sterol and plant stanols, fat-soluble vita-mins and carotenoids are lipophilic compounds that require solubilization into mixed micelles for intestinal absorp-tion [60, 61]. Plant sterols and plant stanols interfere with micellar sterol composition and probably also interact with incorporation of fat-soluble vitamins and carotenoids in the micelles. This seems particularly evident for the more lipo-philic hydrocarbon carotenoids for which the largest reduc-tions in serum concentrations were found after plant sterol or plant stanol intake. Indeed, Plat and Mensink [19] have shown that changes in hydrocarbon (but not in oxygenated) carotenoid concentrations were significantly related to reductions in markers of cholesterol absorption after plant stanol consumption.

Subgroup analyses showed a stronger reduction in rela-tive TC-standardized β-carotene concentrations and a trend toward larger reductions in TC-standardized α-tocopherol concentrations after plant stanol consumption as compared with plant sterol consumption. Changes in TC concentra-tions were also larger after consumption of plant stanols compared with plant sterols. Plant stanol studies inves-tigated overall higher doses (3.2 vs. 2.1 g/d with plant sterols), which probably explains the larger TC-lowering efficacy. Indeed, subgroup analyses indicated that TC con-centrations decreased dose dependently. Even though a dose–response effect was lacking for relative TC-standard-ized β-carotene concentrations, largest decreases were seen in the highest dose category (3.0 < dose ≤ 9.0 g/d). As plant stanol studies investigated overall higher doses, the differ-ence between plant sterol and stanol studies on relative TC-standardized β-carotene concentrations might be explained by a difference in average dose. Nevertheless, this is still an unexpected finding and a side-by-side comparison would be needed to evaluate a difference between plant sterols and plant stanols on serum β-carotene concentrations in more detail. Baseline concentrations as well as the dura-tion of the interventions did not have a major impact on plasma fat-soluble vitamin and carotenoid concentrations

after plant sterol or plant stanol consumption. In addition, as already mentioned, a clear dose–response effect was lacking for fat-soluble vitamin and carotenoid concentra-tions, while TC concentrations decreased dose depend-ently after plant sterol or plant stanol consumption. Such a dose-dependent cholesterol lowering has been shown by Mensink et al. [16], where a linear dose–response relation-ship was reported for plant stanol intake and cholesterol decrease up to 9 g/d. A dose–response relationship for the reduction in LDL-C at least up to intakes of 3 g/d of plant sterols and stanols was also found in the meta-analysis of Ras et al. [3].

Whether the observed reductions in plasma tocopherols and especially carotenoid concentrations are clinically rel-evant is not known. In fact, ranges of plasma fat-soluble vitamin and carotenoid concentrations that are defined as normal are very wide [62, 63]. The Food and Nutri-tion Board of the Health and Medicine Division reported, based on data of more than 20.000 subjects who partici-pated in the NHANES 1988–1994 [64], an average plasma β-carotene concentration of 0.35 μmol/L, and 95 % of the subjects had values between 0.10 and 0.86 μmol/L. We observed that β-carotene was reduced from 0.60 μmol/L (95 % CI 0.54; 0.67) to 0.52 μmol/L (95 % CI 0.46; 0.57) after plant sterol and plant stanol consumption; thus, β-carotene concentrations remained within normal ranges. In addition, they reported [64] average concentrations of α-carotene 0.09 (0.02–0.23) μmol/L, β-cryptoxanthin 0.17 (0.06–0.36) μmol/L and lycopene 0.44 (0.18–0.76) μmol/L. Lutein and zeaxanthin were reported together with an average concentration of 0.37 (0.17–0.68) μmol/L. Our observed carotenoid concentrations remained within these reported ranges after plant sterol and plant stanol con-sumption. Ford et al. [65] reported a mean α-tocopherol concentration of 27.4 (95 % CI 26.7; 28.1) μmol/L and a mean γ-tocopherol concentration of 4.8 (95 % CI 4.5; 5.1) μmol/L in >4000 subjects who participated in NHANES 1999–2000. We observed overall higher α-tocopherol con-centrations and lower γ-tocopherol concentrations, which can be explained by a higher intake of γ-tocopherol in the US diet compared to a higher α-tocopherol intake in the European diet. Nevertheless, our observed total tocopherol concentration (α- and γ-tocopherol) after plant sterol and stanol intake remained within ranges as presented for 450 healthy subjects [63] with a median value of 28.6 (18.4–46.0) μmol/L and >20.000 subjects who participated in NHANES 1988–1994 with a mean concentration of 25.3 (14.6–43.6) μmol/L [64].

For CVD, the overall notion is that a healthy diet with high intakes of fruit and vegetables may lower the risk to develop CVD. Whether this effect is related to antioxi-dants is not known, also because clinical trials do not sup-port a causal role for antioxidant supplementation in the

919Eur J Nutr (2017) 56:909–923

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prevention of chronic diseases such as CVD [8, 9]. In con-trast, some prospective cohort studies have reported inverse associations between absolute carotenoid concentrations and the risk to develop CVD or cancers [5, 7, 66], although such relationships have not been observed in all studies [67, 68]. In addition, associations do not imply causality, com-plicating the interpretation of decreased plasma carotenoid concentrations after plant sterol or stanol consumption. Except for a possible role as antioxidant, it is well estab-lished that carotenoids (particularly β-carotene) are a pre-cursor for the synthesis of vitamin A [69]. However, serum vitamin A (retinol) concentrations were not changed after plant sterol or plant stanol intake. A more consistent asso-ciation is present for dietary lutein and zeaxanthin intake, where higher plasma concentrations are associated with a reduced risk to develop advanced AMD [6]. Although data are limited, active modulation of plasma lutein concentra-tions by supplementation may also affect AMD and CVD risk [70, 71].

The reported changes in fat-soluble vitamins and carot-enoids should also be placed in context of other (dietary) interventions where intestinal absorption of nutrients or carrier capacity in plasma is potentially affected. The addi-tion of dietary fibers such as oat and barley β-glucans to the diet reduces serum cholesterol concentrations [72, 73] but have also been reported to affect fat-soluble vitamin and carotenoid concentrations in humans [74, 75]. Moreover, Kerckhoffs [76] showed a reduction of 7.2 % (P < 0.05) in lipid-standardized hydrocarbon carotenoid concentrations after consumption of 5 g/d of oat β-glucan for 2 weeks in 25 healthy subjects. In six healthy women, adding wheat bran to an antioxidant mixture reduced the postprandial response of lycopene and lutein concentrations, while pectin, guar and alginate (water-soluble fibers) reduced β-carotene, lycopene and lutein concentrations [77]. The postprandial response of α-tocopherol was not changed after consumption of these dietary fibers, which probably relates to the lower lipophi-licity of α-tocopherol [77]. Besides cholesterol-lowering foods, pharmacological intervention aimed to reduce serum cholesterol concentrations might also have an effect on fat-soluble vitamin and carotenoid concentrations. HMG-CoA reductases inhibitors (statins) are the most frequently pre-scribed cholesterol-lowering drugs worldwide, and reduc-tions up to 50 % can be achieved with statin therapy [78]. However, despite their effects on serum cholesterol concen-trations, concentrations of fat-soluble vitamin and carotenoid are not reduced. If anything, lipoprotein particles become enriched in vitamin/carotenoids after statin therapy [76, 79, 80]. Another cholesterol-lowering drug is ezetimibe, which reduces intestinal uptake of cholesterol by acting on the intestinal cholesterol transporter NPC1L1 [81]. Ezetimbe is a relatively new approach to lower cholesterol concentrations and human data describing whether ezetimibe therapy has an

effect on fat-soluble vitamin and carotenoid concentrations is lacking. There are, however, some indications from in vitro studies that ezetimibe affects the intestinal transport of carot-enoids and that this effect decreases with increasing polarity of the carotenoids [82]. Other compounds that interfere with cholesterol absorption (i.e., neomycin), fat absorption (ole-stra) and bile acid reabsorption (cholestyramine) have also been shown to reduce tocopherol and carotenoid concentra-tions. Reported effects were at least as large or larger than observed for plant sterols or stanols [83–85].

The question is whether the observed changes in plasma fat-soluble vitamins and carotenoids during consumption of plant sterol or stanol ester-enriched foods can be corrected for? It has been indeed reported that reductions in plasma carotenoid concentrations can be prevented by adopting a healthy diet with at least five servings per day of vegetables and/or fruit as recommend by many guidelines for a healthy diet [48, 86]. For instance, the recently released AHA/ACC lifestyle management guidelines for healthy living empha-size the consumption of vegetables, fruits and whole grains for adults who wish to lower their LDL-C concentrations [87]. Other guidelines like the one of the ESC/EAS also mention the consumption of plant sterol- and plant stanol-enriched foods in order to further enhance the cholesterol-lowering effect of a healthy diet [88]. Finally, consump-tion of a cholesterol-lowering dietary portfolio, which was rich in plant sterols, viscous fibers, soy proteins and nuts for 6 months, reduced LDL-C concentrations (−13.1 %, CI −16.7 to −9.5 %) without affecting TC-standardized tocopherol and carotenoid concentrations [89]. Again, this demonstrates that it is possible to counteract a decrease in TC-standardized carotenoid concentrations after con-sumption of plant sterol and plant stanol-enriched foods by changing to a recommended dietary pattern.

The current meta-analysis included study evidence based on a variety of experimental study designs regarding aspects such as duration of intervention, food products used and different population groups, which could have contrib-uted to the observed heterogeneity between the studies. However, heterogeneity was only present in a few meas-ured parameters with relative small I2 statistics, suggesting little variability between the included studies. In addition, we here report comparable changes in serum cholesterol and lipoprotein concentrations as found in previously pub-lished meta-analyses [1–3], implying that the included studies in this meta-analyses are representative of all avail-able studies in the literature that have been performed with plant sterols and plant stanols.

In summary, this meta-analysis including data of 41 RCTs showed that consumption of plant sterols and plant stanols reduces TC-standardized hydrocarbon carot-enoid concentrations (β-carotene, α-carotene and lyco-pene), differently affects TC-standardized oxygenated

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carotenoid concentrations (reduction in zeaxanthin and β-cryptoxanthin but not in lutein) and does not affect TC-standardized tocopherol concentrations or absolute reti-nol and vitamin D concentrations. Observed levels in this meta-analysis remained within ranges that are considered to be normal and there are no strong indications that the observed decreases have negative health implications.

Acknowledgments RTR and EAT are employed by Unilever R&D. Unilever markets food products with added plant sterols. This research was supported by a restricted grant from Unilever R&D for the realization of this systematic review and meta-analysis.

Authors’ contributions The authors’ responsibilities were as fol-lows: SB, RTR, EAT, RPM and JP designed the research; SB and RTR conducted the research, analyzed the data and performed the sta-tistical analysis; SB, RTR, EAT, RPM and JP wrote the manuscript and JP had primary responsibility for the final content of the manu-script. All authors approved the final manuscript.

Compliance with ethical standards

Conflict of interest SB, RPM and JP have no conflicts of interest to declare.

Open Access This article is distributed under the terms of the Crea-tive Commons Attribution 4.0 International License (http://crea-tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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