EAL

DM: Omega-3 Fatty Acids (2014)

Citation:

Holman RR, Paul S, Farmer A, Tucker L, Stratton IM, Neil HA, Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes Study Group. Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes (AFORRD): a randomized controlled trial. Diabetologia, 2009; 52 (1): 50-59.

Study Design:

Randomized Controlled Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

The aim of the present study was to examine the impact of statin or mega-3 ethyl esters 90 (omega-3 ethyl esters) on estimated cardiovascular disease risk in community based type 2 diabetes subjects without known CVD and not taking lipid-lowering therapy.

Inclusion Criteria:

Patients with type 2 diabetes for at least three months
Aged 18 years or older
No known CVD events
Not taking lipid-lowering drugs.

Exclusion Criteria:

Taking lipid-lowering therapy
Triacylglycerol over 8.0mmol per L
Impaired hepatic function [alanine aminotransferase (ALT) greater than two times the upper limit of normal]
Uncontrolled diabetes (HbA_1cover 10%)
Uncontrolled hypertension (blood pressure persistently over 160/100mmHg)
Elevated creatine kinase (more than three times the upper limit of normal).

Description of Study Protocol:

Recruitment: Patients were recruited from primary care clinics and were participants of the AFORRD trial
Design: A randomized controlled two-by-two factorial trial
Blinding used: Patients and study staff were masked to the study medication group assignemnts.

Intervention

A total of 800 eligible patients were randomized to double-blind study medication two weeks after their screening visit
Computerized central randomization was used to allocate them in a two-by-two factorial manner to atorvastatin (Lipitor, 20mg per day) or matching placebo and, simultaneously, to omega-3 EE90 (Omacor, two grams per day) or matching placebo (olive oil, two grams per day)
Omega-3 capsules contained 46% EPA and 38% DHA
Lipid profiles were measured at entry and at four months, with CVD risks estimated using the UK Prospective Diabetes Study risk engine
A central computer randomized 800 patients in 59 UK general practices to atorvastatin (N=401, 20mg per day) or placebo (N=399) and omega-3 EE90 (N=397, two grams per day) or placebo (N=403) in a concealed factorial manner.

Statistical Analysis

The X² and Wilcoxon tests were used for categorical and continuous variables respectively to compare between-group differences
A 10-year CVD risk was estimated from age, duration of diagnosed diabetes, sex, self-reported ethnicity, smoking status, HbA_1c, systolic BP and total cholesterol-to-HDL-C ratio, using the UKPDS risk engine
Study medication interaction effects were analyzed using the general linear model.

Data Collection Summary:

Timing of Measurements

Baseline measurements for HbA_1c and lipid profile were conducted
At four months, HbA_1c and lipid profile were collected.

Dependent Variables

HbA_1c (measured by liquid chromatography)
Total cholesterol
HDL-cholesterol (HDL-C kit)
LDL-cholesterol
TG (colorimetric)
Blood pressure.

Independent Variables

Omega-3 supplementation.

Control Variables

All demographic variables.

Description of Actual Data Sample:

Initial N

Total: 800
Atorvastatin + omega-3: 200
Atorvastatin + placebo: 201
Omega-3 + placebo: 197
Placebo + placebo: 202.

Attrition (Final N)

Total: 732 (8.5% attrition)
Atorvastatin + omega-3: 188
Atorvastatin + placebo: 183
Omega-3 + placebo: 183
Placebo + placebo: 178.

Age

Mean age was 63.5±11.7 years and 57% were males (N=459 out of 800).

Ethnicity

90.4% were white.

Anthropometrics

Mean BMI was 30.8±6.2kg/m² and was not different among groups
Mean WC was 103±14cm and was not different among groups.

Summary of Results:

Key Findings

Of 732 patients with four months of data, more allocated to atorvastatin (N=371), compared with placebo (N=361), achieved LDL-C of less than 2.6mmol per L (91% vs. 24%, P<0.001) and had estimated 10-year CVD risks of less than 20% (38% vs. 26%, P<0.001)
No differences were noticed between Omega-3 and Placebo Groups for participants achieving triacyglycerol below 1.5mmol per L (65% vs. 60%, P=0.18) or estimated 10-year CVD risks below 20% (34% vs. 30%, P=0.18)
There was a reduction in mean triacylglyceraol of 0.09mmol per L (5.6%, P=0.003) but no significant changes in LDL-C, 10-year CVD risk, total cholesterol, systolic or diastolic blood pressure of HbA_1c.

Author Conclusion:

Omega-3 has no impact on CVD risk factors
Triglycerides levels do indicate some reduction after omega-3 supplementation levels, however other lipids labs show no change after omega-3 supplementation.

Funding Source:

Industry:

Pharmaceutical/Dietary Supplement Company:

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)	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?	Yes
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?	N/A
	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?		No
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes