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Kaiser Permanente Colorado, School of Pharmacy at Denver
Health Sciences Center
Colorado Permanente Medical Group
University of Colorado Health Sciences Center, Denver, Colorado
Clinical Advisor-Clinical Pharmacy Programs, Humana Inc., Louisville, Kentucky
Address reprint requests to: Kari L. Olson, PharmD, BCPS, Kaiser Permanente Colorado-Clinical Pharmacy Cardiac Risk Service, 16601 East Centretech Parkway, Aurora, CO 80011. E-mail: kari.olson{at}kp.org
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ABSTRACT |
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Methods: This was a prospective, randomized, double-blind study comparing DHA to DHA + EPA in patients with CAD and triglycerides greater than 200 mg/dL. Subjects were randomized to either 1000 mg of DHA or 1252 mg of DHA + EPA for eight weeks. Baseline and eight-week laboratories were drawn to assess changes in the fasting lipid profile. The primary objective was to evaluate the change in triglycerides between the two groups at eight weeks.
Results: A total of 116 subjects were enrolled; 57 in the DHA group and 59 in the DHA + EPA group. Baseline characteristics were similar between groups. The mean age was 69.4 ± 9.1 years and 70.7% were male. Triglycerides decreased by an average of 21.8% in the DHA group (p < 0.001) and 18.3% in the DHA + EPA group (p < 0.001). The difference between groups was not significant. A greater proportion of subjects in the DHA group achieved triglyceride goal (less than 150 mg/dL) compared to the DHA + EPA group (24.6% versus 10.2%, p < 0.05).
Conclusions: Our results indicate that the American Heart Association recommended cardioprotective dose of omega-3 fatty acids can also significantly lower triglycerides in patients with CAD. There do not appear to be significant differences in triglyceride-lowering between DHA only and DHA + EPA combination products when dosing is based on DHA.
Key words: coronary artery disease, hypertriglyceridemia, omega-3 fatty acids
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSACKNOWLEDGMENTSREFERENCES |
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Omega-3 fatty acids, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from marine sources, have received much attention in recent years. Epidemiological, observational, and clinical studies provide evidence that regular omega-3 fatty acid consumption is associated with a decrease in morbidity and mortality from CAD [6–12]. Reviews of human studies show that omega-3 fatty acids can also lower triglycerides [13–15]. GISSI-Prevenzione, the largest prospective, randomized study to date, demonstrated that daily supplementation with 850 to 882 mg of omega-3 fatty acids in a 1:1.2 ratio of DHA/EPA among 2836 patients surviving a recent (
3 months) myocardial infarction reduced the risk of death, non-fatal myocardial infarction, and stroke by 15% compared to placebo at 3.5 years [12]. Triglycerides were statistically significantly decreased by only 3.4% in the omega-3 fatty acid group compared to control [12]. While these results provide clinical support for the use of omega-3 fatty acids in reducing coronary events, they may not be applicable to patients with stable CAD and elevated triglycerides. The American Heart Association recommends 1000 mg of omega-3 fatty acid supplements daily for heart protection in CAD patients and 2000 to 4000 mg daily for triglyceride reduction [16].
Questions regarding the use of omega-3 fatty acid supplements remain. Studies have evaluated the triglyceride-lowering effects of omega-3 fatty acids using moderate to high doses, however, the optimal dose and DHA/EPA ratio has yet to be defined. Furthermore, conflicting data exist as to which component, DHA, EPA, or a combination of both, is most responsible for lowering triglycerides. To our knowledge, a comparison of DHA to a combination of DHA + EPA has not been evaluated. The purpose of this study was to evaluate the efficacy of DHA compared to a combination of DHA + EPA for triglyceride reduction in patients with CAD and elevated triglycerides.
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METHODS |
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Subject Selection
Patients identified and enrolled in this study were followed by the Clinical Pharmacy Cardiac Risk Service (CPCRS) of KPCO. CPCRS is a pharmacist-managed, physician-supervised service that monitors over 11,000 patients with CAD [17]. CPCRS assists primary care physicians and cardiology teams with the implementation and long-term management of all evidence-based cardiac risk reduction treatment strategies (antiplatelet therapy, lipid-lowering therapy, beta-blockers post-myocardial infarction, and angiotensin converting enzyme inhibitors) [17].
Adult patients enrolled in CPCRS with a history of CAD (defined as acute myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous coronary intervention, and/or a cardiac catheterization showing 
50% occlusion of one or more coronary vessels) were eligible to participate. Subjects with two consecutive triglyceride levels between 200 and 750 mg/dL, a LDL-C level less than 100 mg/dL, and a thyroid stimulating hormone (TSH) level within normal limits (0.32–5.50 IU/ml) within the past year were considered for enrollment. Concomitant use of statins, thiazide diuretics, beta-blockers, estrogen, levothyroxine, and/or oral corticosteroids was permitted if the doses of these medications remained unchanged during the two months prior to enrollment. Patients were excluded for the following reasons: pregnant or breastfeeding; documented history of alcoholism within the previous year; glycosylated hemoglobin (HbA1c) >8.5% within the past six months; taking omega-3 fatty acid supplements in doses of greater than 400 mg DHA per day; receiving >5 mg prednisone (or equivalent) per day; hospitalized for any reason within the previous two months; and failure to provide written informed consent.
Procedures
Invitation letters and consent documents were mailed to potential study subjects who met initial entry criteria identified through a computer-generated list from the CPCRS patient-tracking database. Upon receiving signed informed consent from interested subjects, the medical record of each was further screened for study eligibility. Baseline fasting lipid panel (FLP), alanine aminotransferase (ALT), creatine kinase (CK), fasting blood glucose (FBG), TSH (if not performed within the previous year), and HbA1c (for subjects with diabetes mellitus, if not done within the previous six months) values were obtained for each potential study subject. Subjects who continued to meet laboratory entry criteria were enrolled and randomized.
Participants were randomized to receive either 1000 mg per day of DHA or 1252 mg per day (1000 mg of DHA) of DHA + EPA for eight weeks using a computer generated list of random numbers. Study supplements had been previously analyzed by an independent laboratory to determine the exact amount of DHA and EPA contained per capsule for each product. Products with the same lot number were used throughout the study. Participants and investigators were blinded to treatment allocation. Study supplements were mailed to participants by an individual not directly involved with the study and were labeled as either "Supplement A" or "Supplement B." Study participants were instructed to maintain their current diet, exercise habits, and alcohol intake throughout the eight-week study period. FLP, ALT, CK, and FBG measurements were obtained for each participant at study entry and at an eight-week follow-up laboratory visit.
Outcome Measures
The primary outcome measure was the change in triglyceride concentration from baseline to week eight between groups. Secondary outcomes included changes in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C concentrations from baseline to week eight, and the proportion of subjects achieving the triglyceride goal of less than 150 mg/dL at follow-up. Proportions of subjects with elevations in ALT levels greater than three times the upper limit of normal (>120 IU/L), CK levels greater than the upper limit of normal (>209 mg/dL), and FBG levels greater than the upper limit of normal (>110 mg/dL) at follow-up were assessed as safety parameters for each treatment.
A standardized telephone questionnaire was administered at the eight-week follow-up to assess how well study participants tolerated the study supplements and the adequacy of study blinding. The questionnaire was administered by an individual not directly involved with the study. Questionnaire results were obtained from all but two subjects in the DHA + EPA group who could not be reached. Adherence to study supplements was assessed through capsule counts. Subjects were considered adherent if they took greater than or equal to 90% of their study supplement over the eight-week study period. Capsule counts were obtained for all but 21 subjects (14 in the DHA + EPA group and 7 in the DHA group) who failed to return their study supplement vials.
Statistical Analysis
It was determined that a sample size of 50 participants in each treatment group would be required to detect a difference of 20% in the primary outcome measure using an 
= 0.05 and a ß = 0.2. All statistical analyses were performed using SAS (Cary, NC) and data were analyzed on an intention-to-treat basis. Subject characteristic data was assessed at time of enrollment. Descriptive statistics were used for subject characteristic data with proportions, means ± standard deviations (SD), or medians reported where appropriate. The distributions of continuous variables were assessed for the normality of their distributions. Appropriate parametric (i.e., paired t-tests, student’s t-test) or non-parametric (i.e., Wilcoxon signed rank test, Wilcoxon rank-sum test) statistical tests were performed to assess differences in mean or median values within and between groups, respectively. The McNemar’s and chi-squared tests of association were utilized to assess differences in proportions of dichotomous outcomes within and between groups, respectively. As the randomization resulted in no clinically meaningful, statistically significant baseline differences between the groups, additional analyses to adjust for residual bias were not performed.
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RESULTS |
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DISCUSSION |
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Hypertriglyceridemia can be difficult to manage within the CAD population. Fibric acid derivatives and niacin are commonly used for triglyceride-lowering but pose an increased risk for adverse events such as myopathy and rhabdomyolysis when used in combination with statin therapy [4,5]. In many cases, the risk of combination therapy with statins and fibric acid derivatives outweighs the potential clinical benefit. Omega-3-fatty acids appear to be an effective option for lowering triglycerides in patients with CAD receiving statins without increasing the risk of serious adverse events, but the optimal dose remains unknown. The results of our study demonstrate that the recommended daily dose of 2000 mg to 4000 mg of omega-3 fatty acids for triglyceride reduction may not be necessary when dosing is based on DHA [16].
Several studies have evaluated the effects of omega-3-fatty acids, mostly derived from fish, among patients with hypertriglyceridemia [18–20]. One study evaluated patients with baseline triglycerides between 500 mg/dL and 2000 mg/dL and randomized them to 4000 mg of omega-3 fatty acids or placebo for four months [20]. Triglycerides were reduced by 45% compared to placebo (p <0.001) [20]. Another study compared the triglyceride-lowering properties of omega-3 fatty acids, 4000 mg per day, to those of gemfibrozil 1200 mg per day in 28 patients with elevated triglycerides. Both agents decreased triglyceride concentrations similarly [21].
There have been few studies that have specifically evaluated DHA alone in lowering triglycerides. One group of researchers reported a 16% reduction in triglycerides and a 16% increase in HDL-C using 1600 mg of DHA per day for six weeks in healthy vegetarian subjects [22]. Another group used 1700 mg of DHA per day for 15 weeks in normolipidemic subjects and reported similar results [23]. There has only been one published randomized, double-blind, placebo-controlled trial using DHA alone. In that study, 26 subjects with baseline triglycerides between 150 and 400 mg/dL received either 1250 mg or 2500 mg of DHA, or placebo daily for six weeks [24]. Triglycerides were significantly reduced by 21% and 18% with the 1250 mg and 2500 mg daily doses, respectively, compared to 3.5% with placebo (p <0.01) [24].
Omega-3 fatty acids (of various amounts of DHA and EPA) have also been evaluated to determine the contribution of each component (DHA and EPA) to the cardioprotective effects in patients with CAD. DHA has been associated with antiarrhythmic actions in animal and human experimental studies [25,26]. DHA can also significantly improve blood pressure and reduce heart rate [27]. On the other hand, EPA has been associated with an increase in heart rate [27,28]. Furthermore, when compared to EPA, DHA has been reported as having a greater effect on maintaining vascular function by enhancing vasodilator mechanisms [29].
Of note, in our study, although the DHA + EPA group consumed more total omega-3 fatty acids per day (1252 mg), the additional 252 mg of EPA appeared to offer no additional triglyceride-lowering benefit. The reason for this is unknown. It is possible that the additional 252 mg of EPA was not enough to impact triglyceride reduction. A larger dose of EPA may have produced a different result.
Our study is unique in that it evaluated a lower dose of omega-3 fatty acids to reduce triglycerides. This dose is also considered by the American Heart Association to be the cardioprotective dose [16]. The dose used in our study was based on the DHA component of the omega-3 fatty acids. All participants in our study had stable CAD and hypertriglyceridemia. Furthermore, the DHA only product that was used is derived from algae rather than fish oil and seemed to be better tolerated than the product derived from fish oil. To our knowledge, this is the only study comparing the triglyceride-lowering effects of DHA alone to DHA + EPA.
This study is not without limitations. We evaluated surrogate markers rather than clinical outcomes such as recurrent coronary events and mortality. Thus, it is not known whether the triglyceride-lowering effects of these agents would result in improved cardiovascular outcomes. However, the GISSI-Prevenzione study demonstrated a 15% reduction in death, non-fatal myocardial infarction, and stroke using 850 to 882 mg of combined DHA and EPA daily [12]. A meta-analysis of randomized controlled trials has shown similar benefits with dietary and non-dietary omega-3 fatty acids [30].
Given this study was only eight weeks in duration, it is uncertain if the triglyceride reduction seen with these omega-3 fatty acid supplements would be sustained for longer periods of time. Since there is evidence to show that omega-3 fatty acids can significantly lower triglycerides when compared to placebo [13,14,18,20,24], we did not include a placebo arm in our study. As a result, we can not be certain that triglycerides would not have decreased independently of the omega-3-fatty acid supplements. Adherence was assessed based on patient report and capsule counts. Although measures of plasma concentrations of DHA and EPA may have been more robust measures of adherence, due to logistical issues with the laboratory and cost, we were unable to conduct these analyses. No cost analysis was performed in this study. Future studies are needed to evaluate the cost-effectiveness of omega-3 fatty acids for decreasing triglycerides in the CAD population.
This study demonstrated significant triglyceride-lowering using a lower dose of omega-3 fatty acids than previously reported in the literature. Patients often complain of the fishy aftertaste of omega-3 fatty acid supplements. Algae-derived DHA products appear to be a better tolerated alternative. The higher cost of concentrated omega-3 fatty acid supplements may be offset if patients need to consume larger quantities of standard fish oil products (120 mg of DHA and 180 mg of EPA) in order to achieve similar triglyceride-lowering. Future studies with lower doses of standard products are needed.
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ACKNOWLEDGMENTS |
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Received January 4, 2006. Accepted April 18, 2006.
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