EAL

DLM: Elevated Triglycerides and Omega-3 Fatty Acids (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the effect of low-dose n-3 fatty acid treatment on lipid and lipoprotein concentrations, and secondly to evaluate the associated effects on the clinical abnormalities of hypertriglyceridemia, particularly altered glucose metabolism and arterial hypertension.

Inclusion Criteria:

Males (age 45-75y) and females (age 55-80y) with hyperlipoproteinemia type IIB (serum TC >7.21 mmol/L [270 mg/dL]) or IV (serum TC < or= 7.21 mmol/L [270 mg/dL]) assoiciated with at least one additional risk factor: impaired glucose tolerance, NIDDM years, or arterial hypertension.

Patients with fasting glucose <7.7 mmol/L (140 mg/dL) and altered oral glocse tolerance were defined as having imparied glucose.
Patients with diabetes greater than 2 years who were also in metabolic control with or without pharmocological treatment were defined as having NIDDM.
Patients treated with antihypertensive drugs or who had more than one systolic blood pressure >/= 160 mmHg, a diastolic blood pressure>/= 95 mm Hg, or both, independent of drug treatment were considered to have arterial hypertension.

Exclusion Criteria:

Patients with severe intercurrent aliments, renal disease, taking insulin, intestinal malabsorption, duodenal ulcer not responsive to therapy, obese individuals (BMI>/=30 kg/m²), noncompliant or unreliable patients, history of vascular or non vascular brain disease (epilepsy, alcoholism), hyperlipidemia with drug treatment, hypertension with antihypertensive treatment, MI in past 3 month, or unstable angina.

Description of Study Protocol:

This was a multicentered and multistage double blind study involving 63 clinical centers throughout Italy. Each centred invited the first 16-20 patients who met inclusion criteria to participate in the study. Each center was counted as one unit and then assigned a random number. Each number was assigned to either treatment group is such a way as to balance the number of patients assigned to each treatment.

The use of hypolipidemic agents was restricted in all participating centers, no change in dose of scheduled oral hypoglycenic or antihypertensive agents was allowed in the 6 months of the study.

4 week wash-out period

Patients followed an isoenergetic diet to maintain a stable body weight; concomitant threrapy was stabilized and no hypolipdemic drugs were prescribed.
All patients recieved dietary instruction to reduce the amount of arachindonic acid-rich food items (eggs, heart, liver, and lungs ) to no more than once a week.

Baseline Visit

Patients recieved n-3 ethyl ester preparation three times a day (total of 1530 mg EPA and 1050 mg DHA) or a corresponding placebo (olive oil) also given three times a day.

*Note: the daily amount of EPA + DHA corresponded to the approx. amount of 150g fresh salmon or 300g albacore tuna.

Fasting blood samples
Blood Pressure evaluated
Urine and hematologic analysis

2, 4, and 6 month visits

After 2 months, the dose of EPA + DHA was reduced to one capsule twice a day (1020 mg EPA and 700 mg DHA) till end of 6 months. Placebo was also reduced to one capsule twice a day.

*Note: Patients were advised to swallow the capsule before their main meals.

Fasting blood samples
Blood pressure
6 month, also urine and hematologic analysis

Compliance

Complaince was was assessed by pill counting

Statistical Analysis

Analysis of data was preformed both according to the "intent to treat" and "per protocal" criteria. Patients in the study less than 6 months, the last value was calculated. Inferential analysis was preformed by mixed-factorial analysis of varience for repeated measures analysis of variance. Data was represented by mean standard diviations.

Data Collection Summary:

Baseline Visit

Complete laboratory analysis including urine and hematologic analysis, complete lipid and lipoprotein (TC, triacylglycerol concentration, HDL-C, LDL-C using Friedewald formula)
Fasting glucose
HbA_1c was measured in NIDDM individuals.
2-hour oral glucose tolerance test (75gm) was given to the group with impaired glucose tolerance.
Blood pressure (measured 3 times in the sitting position by ausculatatory technique. Each measurement was recorded with the means forthe final calculation)

2, 4, and 6 month visits

Complete lipid and lipoprotein evaluation
Fasting glucose
Blood pressure
At 6 month visit, urine and hematologic analysis was repeated

At 3 participating centers, concentration of EPA and DHA (gas-liquid chromatography after chlorform-methanol extraction and transmethylation) in plasma and RBCs were monitored in all patients.

Description of Actual Data Sample:

935 participants invloved in the study.

Characteristics of Participants
Characteristics	EPA + DHA (n=294M, 176 F)	Placebo (n=289M, 176F)
Age (Y) Women Men	62.1 +/- 7.12 55.8 +/- 9.35	55.8 +/- 9.35 57.0 +/-9.54
Type of hypercholesterolemia (%) Type IIB Type IV	65 35	65 35
Additional Risk Factors NIDDM Impaired glucose tolerance Arterial Hypertension	44 11 68	45 11 68
Body Weight (kg) Baseline 6 months	74.0 +/-10.44 73.5+/- 10.38	73.7 +/-10.08 73.2 +/-10.10

Baseline lipids, fasting glucose and blood pressure:

	EPA+DHA (n=470)	Placebo (n=465)
Total Cholesterol (mmol/L):	6.05 +/- 0.84	6.04 +/- 0.86
HDL-C (mmol/L):	1.03 +/- 0.25	1.03 +/-0.25
Triacylglycerol (mmol/L):	3.32 +/- 0.89	3.36 +/-0.96
Fasting glucose (mmol/L)	6.6 +/- 2.1	6.7 +/-2.0
Blood Pressure (mm Hg) Systolic Diastolic	145.7 +-/ 14.5 86.5 +/-8.2	144.8 +/- 14.9 85.5 +/- 8.1

67 participants interupted treatment. 28 in the EPA+DHA group and 39 in the placebo group. Body weight in kg was measured at baseline and at 6 months for both groups. EPA+DHA 74.0 =/-2044 at

Summary of Results:

Treatment had no significant effect on Total cholesterol. LDL-C concentrations raised in both groups; n-3 esters (6.0%) and placebo (3.0%). However, triacylglycerol concentrations significantly lowered 21.53 % in n-3 esters groups compared with 6.54% in the placebo group at the end of 6 months (P<0.0001). Of note, the greatest reduction occured within the first 2 months. Patients with impaired glucose tolerance or NIDDM showed no different triacylglycerol response.

LDL increased in both groups; 6% in fish oil and 3% in plcebo (P=0.048 for difference between groups)

Participants were also divided into 2 groups: those with and without low HDL-C concentrations (</=0.91 mmol/L). n-3 esters reduced concentrations significantly, but in NIDDM participants the percentage of triacylglycerol reduction was greater in those with HDL-C </= 0.91 mmol/L (-23.3%) than in those with HDL-C >0.91 mmol/L (-16.9%; P<0.05). Normoglycemic participants showed no difference in triacylglycerol response related to HDL-C concentrations. Overall, the study found a small increase in HDL-C in both groups (males with impaired glucose tolerance or NIDDM treated with n-3 esters had the greatest increase in HDL-C).

No effect on n-3 ethyl ester treatment ws observed on any of the major glycemic indexes: fasting glucose, HbA_1c,insulinemia, and oral glucose tolerance. Essentially these indexes remained the same at basline to 6 months.

Three centers collected EPA and DHA concentrations in plasma and RBCs. Plasma and RBC concentrations were similar at baseline and after 6 months of EPA+DHA treatment, the centers found significant changes in the n-3 fatty acid content of both plasma and RBCs. EPA showed a more significant rise than DHA from baseline (214%; p <0.0001 and 31%; P<0.001 respectively).

Author Conclusion:

This study concluded that n-3 ethyl esters can procide a suitable option for lowering plasma tricylglycerol concentraions in a range similar to that reported by several investigators, and using higher doses of either n-3 ethyl esters or fish-oil triacylglycerol resulted in modest changes in LDL-C concentrations in normolipidemic or hypertriglyceridemic patients. Also, the effect of n-3 fatty acids on HDL-C concentrations is small, however, the study did not evaluate the changes in the HDL subfractions that may play a role in HDL-C increase in NIDDM and glucose tolerance.

The authors noted that n-3 fatty acids may act in a way similar to that of fibrates; by lowering cholesterol only in hypercholerolemic patients with an LDL-C raising effect in hypertriglceridemia.

The lack of effect on glucose metabolism of n-3 ethyl esters in participants with impaired glycemic control rules out concern about the prescription of n-3 ethyl ester containing products to diabetics.

Funding Source:

Reviewer Comments:

This information along with a information reported from various other studies indicates that patients with hypertriglyceridemia dna bnormal glucose metabolism respond well to a moderate daily dose on n-3 ethyl esters without impairment of glycemic control.

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)	Yes
	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?		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%.)	???
	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?	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?	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?	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?	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)?	Yes
	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?	N/A
	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?	No
	10.2.	Was the study free from apparent conflict of interest?	Yes