PDM: Metabolic Syndrome (2013)


Tierney AC, McMonagle J, Shaw DI, Gulseth HL, Helal O, Saris WH, Paniagua JA, Golabek-Leszczynska I, Defoort C, Williams CM, Karlstrom B, Vessby B, Dembinska-Kiec A, Lopez-Miranda J, Blaak EE, Drevon CA, Gibney MJ, Lovegrove JA, Roche HM. Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic syndrome--LIPGENE: A European randomized dietary intervention study. Int J Obes (Lond). 2011; 35(6): 800-809.

PubMed ID: 20938439
Study Design:
Randomized Controlled Trial
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Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To determine the relative efficacy of reducing dietary SFA, by isoenergetic alteration of the quality and quantity of dietary fat, on risk factors associated with metabolic syndrome (MetS).

Inclusion Criteria:
  • Age: 35 to 70 years
  • BMI: 20 to 40kg/m2
  • TC: 8.0mmol per L or less
  • Regular consumers of alcohol who did not drink excessively, as defined by elevated liver enzymes
  • MetS as defined by three or more of the following:
    • Fasting plasma glucose: 5.5 to 7.0mmol per L
    • TAG: 1.5mmol per L or more
    • HDL-C: Less than 1.0mmol per L (males) or less than 1.3 (females)
    • Systolic BP (SBP): 130mm Hg or more
    • Diastolic BP (DBP): 85mm Hg or more
    • On BP-lowering medication
    • Waist circumference (WC): more than 102cm (males) or more than 88cm (females).
Exclusion Criteria:
  • Anti-inflammatory or hypolipidemic medication, nutritional supplements, medical conditions
  • Fatty acid supplements including fish oils, evening primrose oil
  • High doses of antioxidant vitamins
  • Red rice yeast supplements
  • More than two servings of oily fish per week
  • Highly trained endurance athletes or more than three periods of intense exercise per week
  • Planning to start a special diet or lose weight
  • Weight change of 3kg or more within the last three months
  • Alcohol or drug abuse
  • Pregnancy, lactation or planning a pregnancy in next 12 months. 
Description of Study Protocol:


Completed centrally, according to age, gender and fasting plasma glucose concentration, applying Minimisation Program for Allocating Patients to Clinical Trials, Department of Clinical Epidemiology, The London Hospital Medical College.


Randomized controlled trial.

Blinding Used

Implied with measurements.


Subjects assigned to one of four isoenergetic diets differing in fat quantity and quality:

  • Two diets provided 38% energy from fat, one with high content (16% of energy) of SFA (HSFA diet) and the other with high content (20% energy) of MUFA (HMUFA diet)
  • The other two diets were low-fat, high-complex carbohydrate (LFHCC) diets that contained 28% energy from fat, with diet LFHCC n -3 including 1g to 2g per day supplement of very-long-chain marine n-3 PUFA and diet LFHCC and diet LFHCCC control including a control high-oleic acid sunflower-seed oil capsule.

Statistical Analysis

  • All data are presented as group means ± SE of the mean
  • Repeated measures ANOVA determined the effect of dietary fat modification on metabolic markers
  • Data were normalized by log, square root, inverse or sine transformation
  • Analyses were adjusted for between-subject factors: Sex, center and diet group with age and change of body weight as covariates
  • Significant time-diet and time x diet x gender interactions and significant main effects were investigated using Bonferroni post hoc tests
  • A Bonferroni correction was applied for multiple testing
  • Post hoc analysis was completed to determine whether habitual fat intake, defined as being above or below the median pre-intervention fat intake [36% of total energy intake, excluding subjects with the lowest (5%) and highest (5%) total fat intake], influenced the metabolic response. 
Data Collection Summary:

Timing of Measurements

Baseline and 12 weeks except for three-day food records, which were completed at six weeks.

Dependent Variables

  • Body weight: Calibrated scale
  • Waist circumference: Directly on skin in duplicate at the midpoint between supra iliac crest and lower rib margin at end of a normal expiration to nearest 0.1cm using a non-stretch tape measure
  • Hip circumference: In duplicate in nearest 0.1cm using non-restrictive tape measure, at the level of the greater trochanter without compressing the skin
  • Blood pressure: In seated position after five-minute rest, in duplicate using appropriately sized cuff before blood samples were taken
  • Lipid, apolipoprotein, glucose and inflammatory markers: Standard methods
  • Insulin-modified IV GTT
  • Health and lifestyle questionnaire: Habitual physical activity, smoking, alcohol intake.

Independent Variables

  • Subjects assigned to one of four previously described diets
  • Fat-modified food products were provided to all subjects to attain dietary fat targets in conjunction with their usual foods
  • A novel food exchange model was used to achieve the dietary targets
  • Spreads, cooking oil, baking fats, mayonnaise and biscuits were produced with a specific fatty acid profile to be used in the HSFA and HMUFA diet groups or low-fat spread and mayonnaise for the LFHCC groups
  • Volunteers were instructed to exchange any habitually used oils, fats or spreads with the study foods
  • Volunteers randomized to the HFSA diet were requested to consume only full-fat dairy foods and to replace one snack product usually eaten with a study HSFA cookie daily
  • This group was also asked to eat less carbohydrate
  • Subjects randomized to diet HMUFA, LFHCC and LFHCC n-3 were requested to consume only low-fat dairy products
  • Those on the HMUFA diet ate HMUFA mayonnaise or a handful of hazelnuts or cashews on replaced one normally eaten snack product with their choice of HMUFA biscuit
  • In the LFHCC and LFHCC n-3 diets, volunteers reduced their intake of high-fat snacks, ate two extra portions of complex carbohydrate daily and took the supplied capsules daily
  • They were encouraged to use cooking oil and baking fat to prepare dishes in their home
  • Diet counseling was given to the subjects and frequent monitoring and reinforcement was provided
  • Intervention foods were delivered to each volunteer every two weeks by their dietitian. 
Description of Actual Data Sample:
  • Initial N: 486 subjects
  • Attrition (final N): 417 (185 males, 232 females)
  • Age:
    • HSFA: 54.9 years
    • HMUFA: 54.62 years
    • LFHCC: 54.7 years
    • LFHCC: 55.39 years
  • Ethnicity: White Europeans
  • Anthropometrics:  Age, body weight, blood pressure, insulin and glucose levels were not different between dietary groups before intervention
  • Location: Eight European countries:
    • Ireland
    • UK
    • Norway
    • France
    • Netherlands
    • Spain
    • Poland
    • Sweden.
Summary of Results:

Key Findings

  • Dietary targets were largely achieved with significant isoenergetic reduction in dietary SFA, with replacement of MUFA or complex carbohydrates. Plasma oleic acid showed significant diet x time interaction (P=0.0005); levels increased following the HMUFA diet (P=0.033) and were lower after the HSFA and LFHCC n-3 diets (P=0.005). Enrichment of plasma EPA and DHA levels followed the LFHCC n-3 diet (P=0.005). Plasma n-6 PUFA levels were not changed. 
  • Reducing x diet interaction dietary SFA had no effect on insulin sensitivity, fasting insulin, glucose concentrations or HOMA-IR. A significant within-subject time (P=0.001) showed a small (less than 0.84kg or 1% body weight) but significant reduction in body weight following the LFHCC and LFHCC n-3 diets; therefore, change in body weight was controlled for in all analysis.  
  • Waist circumference, BMI and blood pressure were not significantly altered. Reducing dietary SFA had no effect on biomarkers of inflammation: Plasma CRP, IL-6, TNFx, sICAM-1, sVCAM-1, resistin, adiponectin, leptin, PAI-1 and tPA concentrations
  • Plasma TAG concentrations showed a significant diet x time interaction (P=0.006) whereby plasma TAG concentrations were lower after the HSFA and LFHCC n-3 diets (P=0.018 and P=0.005, respectively). Triglyceride-rich lipoprotein (TRL) TAG concentrations showed a diet x time interaction (P=0.049), with lower levels following the LFHCC n-3 diet only (P=0.032). TAG and TRL TAG showed a time x gender x diet interaction (P=0.017 and P=0.039, respectively). TAG and TRL TAG were reduced only in men after the HSFA and LFHCC n-3 diets (P=0.039 and P=0.02 (TAG), P=0.013 and P=0.008 (TRL TAG),  respectively).
  • Plasma NEFA showed a diet x time interaction approaching significance (P=0.061); post hoc analysis showed lower NEFA levels following the LFHCC n-3 diet (P=0.006). Plasma apo CIII showed a significant time x diet interaction (P=0.034); levels were reduced after the HSFA and LFHCC n-3 diets (P=0.014 and P=0.008, respectively). Neither plasma apo A1 nor apo B, apo B48, TRL apo B, apo CII or apo E were significantly altered by dietary fat modification. 
  • HDL-C but not TC or LDL-C showed a diet x time interaction (P=0.005). HDL-C was increased after both high-fat diets, HSFA and HMUFA (P<0.0005 and P=0.006, respectively), which improved the TC:HDL-C ratio (P=0.005  diet x time interaction). This ration was significantly improved after the LFHCC n-3 diet (P<0.005), mainly explained by lower TC levels.
Author Conclusion:

There was no effect of reducing SFA on insulin sensitivity in weight-stable obese metabolic syndrome subjects. Long-chain n-3 PUFA supplementation, in association with a low-fat diet, improved plasma triacylglycerol (TAG)-related metabolic syndrome profiles. 

Funding Source:
Government: EU 6 Framework Food Safety & Quality Programme, Norwegian Regional Health Authority
Norwegian Foundation for Health and Rehabilitation, Johan Throne Holst Foundation for Nutrition Research, Freia Medical Research Foundation
Other non-profit:
In-Kind support reported by Industry: Yes
Reviewer Comments:
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? Yes
  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? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) No
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  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? ???
  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%.) No
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? ???
  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? N/A
  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? Yes
  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? Yes
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)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  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? N/A
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