EAL

DM: Omega-3 Fatty Acids (2014)

Citation:

Pan A, Sun J, Chen Y, Ye X, Li H, Yu Z, Wang Y, Gu W, Zhang X, Chen X, Demark-Wahnefried W, Liu Y, Lin X. Effects of a flaxseed-derived lignan supplement in type 2 diabetic patients: a randomized, double-blind, crossover trial. PLoS One. 2007; 2 (11): e1,148.

PubMed ID: 17987126

Study Design:

Randomized Crossover Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

The purpose of this study was to investigate the effect of a flaxseed-derived lignan supplement on indexes of glycemic control, insulin resistance and lipid profiles in type 2 diabetic patients.

Inclusion Criteria:

Between the ages of 50 and 79 years (women were required to be post-menopausal for one year)
LDL-cholesterol level of at least 2.9mmol per L
Diagnosis of type 2 diabetes, but not using exogenous insulin for glycemic control.

Exclusion Criteria:

Current or previous estrogen use
Regularly taking phytoestrogen-containing supplements
Antibiotic use in the preceding three months
Severe renal, liver, heart, pituitary, thyroid or mental diseases
Alimentary tract ulceration or diseases affecting absorption
History of cancer
History of drug or alcohol abuse.

Description of Study Protocol:

Recruitment: Type 2 diabetic patients were screened for inclusion at the local community medical service in urban districts of Shanghai
Design: Randomized placebo-controlled cross-over trial
Blinding used: Double-blind
Intervention: Subjects randomized to consume flaxseed-derived lignan capsules (360mg lignan per day) or placebo for 12 weeks, separated by an eight-week washout period before crossing over to the other intervention.

Statistical Analysis

Differences between values after 12-week intervention were analyzed in Stata 9.2 using a mixed model analysis of covariance with treatment and period as fixed factors, subjects as random factors and baseline measurements as covariates
Data that were not normally distributed, as assessed by Shapiro Wilks test, were naturally log-transformed prior to analysis
Pre and post differences in physical activity level and habitual energy intake were analyzed using ANOVA. Differences were considered significant at P<0.05.

Data Collection Summary:

Timing of Measurements

Measurements made at the beginning and the end of each two intervention periods.

Dependent Variables

Blood pressure and anthropometric parameters (height, weight, waist and hip circumferences) were measured and blood samples were taken
Indexes of glycemic control, insulin resistance and lipid profiles:
- Serum total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerol and glucose were measured using reagents
- HbA1c was determined by turbidometric immunoinhibition on packed red blood cells
- Plasma insulin was determined by radioimmunoassay and insulin resistance was calculated using the Homeostasis Model Assessment of Insulin Resistance method (HOMA-IR).
Urinary excretion of lignan metabolites and isoflavones was measured using a modified HPLC method
Lp(a) concentrations were measured in 245 serum samples, due to reagent shortage.

Independent Variables

Subjects randomized to consume flaxseed-derived lignan capsules (360mg lignan per day) or placebo for 12 weeks, separated by an eight-week washout period before crossing over to the other intervention
Dietary intakes were assessed using three-day food records, which ascertained intakes during two weekdays and one weekend day at four time-points throughout the study
All food records were reviewed for completeness and coded by the trained dietitians who were blinded to the study arms
Energy and nutrient intakes were calculated using the SY Nutrition Software, based on the local food composition database.

Control Variables

Physical activity level was evaluated by asking the average times per week spent on several common activities in the last month and each activity was assigned a metabolic equivalent value (MET).

Description of Actual Data Sample:

Initial N: 581 subjects screened for inclusion; 508 were excluded and 73 randomized
Attrition (final N): 68 completed study (34 in Group A and 34 in Group B)
Age: Mean, 63.2±7.4 years
Ethnicity: Not reported
Other relevant demographics: Mean waist circumference, 86.9±9.4cm
Anthropometrics: Mean BMI, 25.1kg/m²
Location: Shanghai.

Summary of Results:

Key Findings

The lignan supplement significantly improved glycemic control as measured by HbA_1c(-0.10±0.65% vs. 0.09±0.52%, P=0.001) compared to placebo, however no significant changes were observed in fasting glucose and insulin concentrations, insulin resistance and blood lipid profiles.
Urinary excretion of lignan metabolites (enterodiol and enterolactone) was significantly higher after the lignan supplement intervention, compared to baseline (14.2±18.1mcg per ml vs. 1.2±2.4mcg per ml, P<0.001)
Data also suggested minimal competition between lignan and isoflavones for bioavailability, when measured by the excretion concentrations.

Author Conclusion:

Daily lignan supplementation resulted in modest, yet statistically significant, improvements in glycemic control in type 2 diabetic patients, without apparently affecting fasting glucose, lipid profiles and insulin sensitivity
Further studies are needed to validate these findings and explore the efficacy of lignans on type 2 diabetes.

Funding Source:

Government:

Not-for-profit

Knowledge Program of the Chinese Academy of Sciences

Other non-profit:

Reviewer Comments:

The authors noted that a limitation of the present study is that the randomization was based upon the screening results (LDL-cholesterol) rather than the baseline measurements.

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?		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.)	N/A
	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?	Yes
	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?	Yes
	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?	Yes
	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)?	No
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	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?	Yes
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