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 determine the differences of 6 versus 12 months of administration of n-3 ethly esters (EE) both on the glycemic parameters and on plasma lipoprotein
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, or arterial hypertension.

  • Patients with fasting glucose <7.7 mmol/L (140 mg/dL) and altered oral glucose 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), history of vascular or non vascular brain disease, severe hyperlipidemia with drug treatment, severe hypertension with antihypertensive treatment, MI in past 3 month, or unstable angina.

 TC > 300 mg/dL, TG > 400 mg/dL

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

Pre-Study/Wash Out Phase (4 weeks):

Patients followed an isocaloric diet, maintained stable body weight, concomitant therapy was stabilized and no hypolipidemic drugs prescribed.

Study Phase 1 (double blind phase): 

  • Double blind phase where pateints were divided into 2 groups.
  • Months 0-2: patients received conventional therapy and instructed to take 1 capsule TID of ESAPENT (totaling 1530 mg EPA, 1050 mg DHA) or corresponding placebo (olive oil) TID.
  • Months 2-6: patients were instructed to reduce dosage of both ESAPENT or placebo  to 1 capsule BID (totaling: 1020 mg EPA and 700 mg DHA)
  • Months 2,4, and 6, lipid and glucose levels taken
  • Month 6, Insulin (radioimmunoasay) and HgA1c measured.

Study Phase 2 (open phase): 

  • At month 7 through month 12, all patients received 1 capsule BID (2g) of ESAPENT
  • Months 9 and 12 lipid and glucose levels takes
  • Month 12, Insulin (radioimmunoasay) and HgA1c measured

Compliance

The drug was taken regularly in most participants.  A total of 77 participants (45 in n-3 EE group and 32 in placebo group[17 during double blind phase and 15 in opne phase]) did not take the drug regularly

Statistical Analysis

 Statistical analysis were carried out according to "intent to treat" and per protocal" At months 6 and 12, changes in lipid metabolism were evaluated according to ANOVA for repeated measures or ANCOVA for repeated measurements. Nominal significance level of 0.05 was kept for each analysis.

Further analysis looked at NIDDM/IGT and type of hyperlipoproteinemia (IIB or IV). HDL-C was also looked at within TG analysis.

Data Collection Summary:

TC, TG levels (by enzyme methods), HDL-C (selective precipitation with dextran-Mg Cl2), LDL-C (Friedewald formula), fasting glucose levels by assay.  At three participating centers, EPA, DHA, and red blood cells were monitored in all patients

Description of Actual Data Sample:

       Total 935 patients participated in this study through 63 centers distributed throughout Italy. 470 patients in the n-3 EE group and 465 in the placebo group. At end of 6 months, 67 participants stopped treatment (28 in n-3 EE group and 39 in placebo group). Final total of 868 patients for the double blind phase.  In the second phase (months 7 through 12). 70 participants stopped treatment (36 in the n-3 EE groups and 34 in the group assigned the drug treatment in that last 6 months).

Characteristics of Participants in the open phase
Characteristics

Group A (n=442)

(Prior n-3 EE)

Group B (n=426)

(Prior Placebo group)

Sex

Male

Female

 

165

277

 

163

263

Age (year)

mean

 58.2 +/-9.09  58.8+/-8.99

Body Weight (kg)

Month 6

Month 12

 

73.5 +/-10.38

73.5+/-10.33

 

 73.2 +/-10.10

73.3+/-9.90

Type of hyperlipoproteinemia

Type IIB

Type IV

 

65%

35%

 

65%

35%

Additional Risk Factors

NIDDM

Arterial hypertension

 

43%

67%

 

44%

68%

Causes stated for participants leaving the study include: lack fo willingness of the patient to contnue the protocal, sever intercurrent illnesses, and worsening NIDDM.

 

Summary of Results:

 Overall, this study found a small reduction in total cholesterol for the whole pateint sample during the open phase. LDL-C increased in the first 6 months for the n-3 EE group, however, minimal change of LDL-C was found at 12 months in the n-3 group.  HDL-C saw a moderate rise in the first 6 months in both the n-3 EE and placebo group, and during the open phase (final 6 months), HDL-C showed an overall rise of +7.4% in all groups (P< 0.001).  TG reduction was seen in the n-3 group during the first 6 months( ~21.5 % reduction P<0.001) and at the 12 month mark TG further decreased resulting in a 25.2% total reduction.  A reducation by 19.5% in TG was also seen in the placebo group during the second phase of the study.  Researchers also found no difference after 12 months of treatment in fasting glucose levels in patients from either group. No significant canges were nnoted in blood pressure levels.

Researchers further subgrouped participants into 4 groups: Type IIB hyperlipoproteinemia/Non NIDDM (n=164), Type IB hyperlipoproteinemia/NIDDM (n=123), Type IV hyperlipoproteinemia/Non NIDDM (n=86), and Type IV hyperlipoproteinemia/NIDDM (n=70).

 In the last 6 months of treatment:

  • Participants with Type IIB saw a total cholesterol reduction of 4.15% (P<0.001)  in Non-NIDDM and 3.8% in NIDDM (P<0.001).
  • NIDDM participants (both types) saw no change in LDL-C during the open phase, however, LDL-C rose 15.9% in Non NIDDM and type IV participants (P<0.002)
  • In the first 6 months, HDL-C rose significantly in male NIDDM participants when compared to normoglycemics treated with placebo (respectively 8.31% vs 4.53%, P <0.05). Also, HDL-C increase was seen (statistically significant) with NIDDM and in Non NIDDM, both with IIB and IV hyperlipoproteinemia (all P<0.001)
  • NIDDM participants with type IV hyperlipoproteinemia saw the greatest reduction in TG followed by Non NIDDM participants with type IV hyperlipoproteinemia.
  • TG responses vs baseline HDL-C levels in both NIDDM and Non NIDDM participants showed no difference. (-22% vs-18.2% respectively; P: n.s.)

 Other Findings

Throughout the entire study, 12 clinical events occured; six in the n-3 EE group and six in the placebo group.  5 deaths occured (from cancer, CVA, or unkonwn origin). Other clinical events included a severe angina crisis in participant with severe coronary disease, TIA, CVA,and paralytic ileum during the first 6 months.

 55 participants during the 12 months experienced side effects. The most frequent side effects were at teh G.I. level,i.e. halitosis, nausea, vomiting, diarrhea and epigastric pain.

 

 

Author Conclusion:

Authors conclude that prolongation of treatment (beyond 6 months) of low dose n-3 EE (2 gm/d) was associated both with a significant progressive reducation of triglyceridemia and no apparent harmful effects on glycemic control. In addition, a positive effect on HDL-C levels was found.  At 12 months there was not a significant difference in HDL-C levels increasing between the n-3 EE and placebo groups in   Overall LDL-C levels did not rise.

Authors also noted that the cholesterol regulating effects of n-3 EE intake may result in significant cholesterol reducation, particularly in populations with low dietary fat consumption.  The participateing population may hold many characteristics of the metabolic syndrome and achievement of sustained TG reduction plus other favorable lipoprotein chagnes is indicated by low/moderate dise of n-3 fatty acids givin in the form of EE.

Funding Source:
Reviewer Comments:

Well done study. Limitations included lack of generalization of the findings due to the design of the study and te selection criteria (elxclusion of obese individuals and those with unstable disease). Also, diabetic participants for the most part were undergoing hypoglycemic treatment.

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%.) 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? 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? ???
  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)? 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? 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