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DLM: Plant Stanols and Sterols (2010)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
  • To assess compliance and changes in lipid levels during a maintenance phase of unregulated intake of plant sterol ester spread in children and their parents
  • Secondary aim was to measure serum concentrations of fat-soluble vitamins, carotenoids and non-cholesterol sterols during the same maintenance phase.
Inclusion Criteria:
  • Child participant in preceding controlled crossover study examining the intake of a sterol ester-enriched spread (PSE):
    • Aged seven to 13 years
    • Healthy except diagnosed with "definite" or "possible" familial hypercholesterolemia
    • No clinical symptoms of hypercholesterolemia
    • No cholesterol-lowering medications
    • Can use multivitamin and fish oil supplements
  • Parent of child participant in above-mentioned study:
    • Could have history of coronary heart disease
    • Could use lipid-lowering medications (stable dose)
    • Known history of familial hypercholesterolemia
    • Written informed consent.
Exclusion Criteria:
  • Child participant:
    • No familial hypercholesterolemia
    • Use of cholesterol-lowering medications
  • Parent: Unstable dose of lipid-lowering medications.
Description of Study Protocol:

Recruitment 

  • Initial study: Outpatient lipid clinic
  • Open-label follow-up study: Child and parent of child invited to continue participation at the conclusion of the initial study.

Design

Non-randomized open-label follow-up study.

 Intervention

  • Initial study:
    • Crossover design with two treatments (PSE and controlled spread) each lasting eight weeks:
      • Two- to three-week run-in period prior to each dietary treatment
      • Four-week washout period between dietary treatments in addition to run in period
      • Randomized order of spread vs control
    • Recommended intake of 20g per day of spread
  • Open label (present study):
    • Six-month follow-up study
    • Began at the conclusion of the initial study
    • Free consumption of PSE spread with recommendation to consume 20g per day
  • Composition of PSE spread:
    • Sterols:
      • 8.79% free plant sterols, with 20g supplying 1.76g plant sterols
      • Cholesterol: 0.29%
      • Brassicasterol: 1.08%
      • Campesterol: 24.34%
      • Stigmasterol: 20.25%
      • β-sitosterol: 46.96%
      • Other sterols: 7.07%
    • 35% total fat: 23.8% saturated fat, 27.7% MUFA, 47.8% PUFA
    • Retinol: 900mcg per 100g
    • Vitamin D3: 7.5mcg per 100g
    • α-tocopherol: 53mcg per 100g
    • β-carotene: 0.5mcg per 100g.

 Statistical Analysis

  • Descriptive data and results: Means and standard deviations
  • Two-sided, paired Students T-test compared differences between baseline and six-month end-point
  • Regression analyses examined the interaction between cod liver oil intake and lipid changes
  • Significance level: P<0.05.
Data Collection Summary:

Timing of Measurements

  • Baseline and six months in both child and parent:
    • Serum lipids and lipoproteins
    • Non-cholesterol sterols
    • Carotenoids
    • Fat-soluble vitamins
    • Liver enzymes and bilirubin.

Dependent Variables

  • Compliance
  • Lipids:
    • Total cholesterol (TC)
    • LDL cholesterol
    • HDL cholesterol
    • Triglycerides (TG)
    • Apolipoprotein A-I
    • Apolipoprotein B
  • Carotenoids (standardized for plasma lipid concentrations as lipoproteins are carriers of carotenoids and fat-soluble vitamins):
    • Lutein
    • Retinol
    • Lycopene
    • α-carotene
    • β-carotene
  • Fat-soluble vitamins (standardized for plasma lipid concentrations): α-tocopherol
  • Phytosterol (adjusted for total cholesterol):
    • Lathosterol
    • Campesterol
    • Sitosterol.

Independent Variables

Intake of PSE spread.

Description of Actual Data Sample:

Initial N

  • Children: Unsure whether N=37 or N=38
  • Parents: N=22.

Attrition (final N)

  • Children: N=37 (18 males, 19 females)
  • Parents: N=20 (10 males, 10 females)
    • Change in hypercholesterolemic medication: N=1
    • Gastrointestinal symptoms unrelated to study spread: N=1.

Age

  • Children: 9.6±1.5 years
  • Parents: 42.9±5.2 years (range 32 to 51 years).

Other Relevant Demographics

  • Children:
    • Total cholesterol: 6.94±1.33mmol per L
    • LDL-cholesterol: 5.31±1.49mmol per L
    • HDL-cholesterol: 1.36±0.32mmol per L
    • Triglycerides: 0.60±0.21mmol per L
  • Parents:
    • Total cholesterol: 5.81±1.18mmol per L 
    • LDL-cholesterol: 4.10±1.22mmol per L
    • HDL-cholesterol: 1.23±0.27mmol per L
    • Triglycerides: 1.09±0.47mmol per L
  • Apo E Genotypes:
    • Children:
      • Apo E2-3: N=1
      • Apo E3-3: N=19
      • Apo E3-4: N=16
      • Apo E2-4: N=1
    • Parents:
      • Apo E3-3: N=10
      • Apo E3-4: N=8
      • Apo E2-4: N=1
  • 21 or initial 22 parents recruited for the study used lipid-lowering medications (statins).

Anthropometrics

  • Children:
    • Height: 1.46±0.14 meters
    • Weight: 40.6±14.0kg
  • Parents:
    • Height: 1.74±0.08 meters
    • Weight: 77.0±14.9kg.

Location

Oslo, Norway.

 

Summary of Results:

 Compliance with PSE Spread (Means±SD)

  • Children:
    • Initial study:
      • 18.2±1.5g per day
      • 1.6±0.13g per day plant sterols
    • Open label study:
      • 13.7±4.5g per day
      • 1.21±0.4g per day plant sterols
  • Parents
    • 16.5±6.1g per day
    • 1.45±0.54g per day plant sterols.

Serum Lipids/Lipoproteins (means±SD)

  • Children:
    Variable Control PSE Spread (Initial) P-value % Change Open Label P-value % Change
    Total cholesterol (mmol per L) 7.49±1.72 6.87±1.47 <0.001 -8.3 6.81±1.60 <0.001 -9.1
    LDL-cholesterol (mmol per L) 5.88±1.81 5.24±1.57 <0.001 -10.9 5.21±1.64 <0.001 -11.4

    HDL-cholesterol (mmol per L)

    		 1.25±0.31 1.28±0.33     1.19±0.29 0.041 -4.8
    Apo B (g per L) 1.48±0.40 1.31±0.36 <0.001 -11.5 1.38±0.41 0.001 -6.8

    • Changes in lipids at the end of the PSE spread (initial study) and the open label periods were compared to lipids at the end of the control period (initial study)
    • There were no significant differences in serum levels for triglycerides and Apo A-I between the control period and PSE spread (initial study) and open label periods.
  • Parents:
      Variable Baseline 26 weeks P-value % Change
      Total cholesterol (mmol per L) 5.81±1.18 5.28±0.92 0.002 -9.1
      LDL-cholesterol (mmol per L) 4.10±1.22 3.65±0.83 0.012 -11.0
      HDL-cholesterol (mmol per L) 1.23±0.27 1.10±0.28 <0.001 -10.6
      Apo B (g per L) 1.25±0.36 1.16±0.33 0.049 -7.2
    • There were no significant differences for triglycerides and Apo A-I between the baseline and six-month levels.

Carotenoids and Fat-Soluble Vitamins (means±SD)

  • Children:
      Variable Control PSE (initial) P-value % Change Open label P-value % Change
      Retinol/(TC+TG) (μmol per mmol) 0.187±0.202 0.202±0.060 0.002 8.0 0.209±0.066 <0.001 11.8
       α-Tocopherol/(TC+TG) (μmol per mmol) 4.34±0.71 4.55±0.76 0.019 4.8 4.39±0.66    
       α-Carotene/(TC+TG) (μmol per mmol) 0.0115±0.0083 0.0095±0.0062 0.008 -17.4 0.0124±0.008    
       β-Carotene/(TC+TG) (μmol per mmol) 0.0810±0.0416 0.0722±0.0385 0.018 -10.9 0.0893±0.0589    
    • Serum levels for the PSE Spread and Open Label periods are compared to the control period
    • No significant changes were observed for lutein or lycopene.
  • Parents:
      Variable Baseline 26 Weeks P-value % Change
      Lutein/(TC+TG) (μmol per mmol) 0.055±0.024 0.051±0.024 0.037 -7.3
      Retinol/(TC+TG) (μmol per mmol) 0.297±0.118 0.336±0.091 0.027 13.1

      α-Tocopherol/(TC+TG) (μmol per mmol)

      		 4.57±1.17 4.95±1.8 0.036 8.3

      Lycopene/(TC+TG) (μmol per mmol)

      		 0.123±0.054 0.105±0.039 0.044 -14.6
    • No significant changes were observed for α- or β-carotenes.

Non-cholesterol Sterols (means±SD)

  • Children (N=29):
    • Serum levels for the PSE Spread and Open Label periods are compared to the control period. 
      Variable Control PSE Spread (Initial) P-value % Change Open Label P-value % Change
      Lathosterol/TC (μmol per mmol) 0.29±0.11 0.38±0.14 <0.001 31.0 1.04±0.46 <0.001 258.6
      Campesterol/TC (μmol per mmol) 1.81±0.52 3.55±1.21 <0.001 96.1 3.48±1.58 <0.001 92.3
      Sitosterol/TC (μmol per mmol) 1.60±0.46 2.37±0.80 <0.001 48.1 2.83±1.32 <0.001 76.9
  • Parents (N=15):
    Variable Baseline 26 Week P-value % Change
    Campesterol/TC (μmol per mmol) 2.12±1.38 4.07±2.25 <0.001 92.0
    Sitosterol/TC (μmol per mmol) 2.33±.54 3.24±1.96 <0.001 39.1

 

Other Findings

  • Liver function tests were within the normal range for children and parents
  • No side effects were associated with the consumption of the PSE spread.
Author Conclusion:
  • After achieving significantly reduced cholesterol concentrations with the use of a plant sterol ester spread (PSE) in an initial study, children with familial hypercholesterolemia were able to maintain those lower cholesterol levels during a six-month follow-up period despite a 25% lower intake of the spread
  • Parents with familial hypercholesterolemia and using statins daily achieved significant decreases in lipids
  • To offset the potential decreases in serum carotenoids associated with the use of the PSE spread, increased amounts of fruits and vegetables should be included in the diet.
Funding Source:
Industry:
PSE Spead-Unilever Best Foods, UK; Unilever Research & Development, The Netherlands
Food Company:
Reviewer Comments:
  • Serum lathosterol directly correlated with cholesterol synthesis
  • No dietary assessment during the open label period
  • One of the authors was affiliated with the sponsor, Unilever Research & Development.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? N/A
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? N/A
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) No
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? N/A
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? No
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes