Omega-3 Free Fatty Acids Research Articles

Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: The EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial

Omega-3 fatty acids in free fatty acid form have enhanced bioavailability, and plasma levels are less influenced by food than for ethyl ester forms. The aim was to evaluate the safety and lipid-altering efficacy in subjects with severe hypertriglyceridemia of an investigational pharmaceutical omega-3 free fatty acid (OM3-FFA) containing eicosapentaenoic acid and docosahexaenoic acid. This was a multinational, double-blind, randomized, out-patient study. Men and women with triglycerides (TGs) ≥ 500 mg/dL, but <2000 mg/dL, took control (olive oil [OO] 4 g/d; n = 99), OM3-FFA 2 g/d (plus OO 2 g/d; n = 100), OM3-FFA 3 g/d (plus OO 1 g/d; n = 101), or OM3-FFA 4 g/d (n = 99) capsules for 12 weeks in combination with the National Cholesterol Education Program Therapeutic Lifestyle Changes diet. Fasting serum TGs changed from baseline by -25.9% (P < .01 vs OO), -25.5% (P < .01 vs OO), and -30.9% (P < .001 vs OO) with 2, 3, and 4 g/d OM3-FFA, respectively, compared with -4.3% with OO. Non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol-to-HDL-C ratio, very low-density lipoprotein cholesterol, remnant-like particle cholesterol, apolipoprotein CIII, lipoprotein-associated phospholipase A2, and arachidonic acid were significantly lowered (P < .05 at each OM3-FFA dosage vs OO); and plasma eicosapentaenoic acid and docosahexaenoic acid were significantly elevated (P < .001 at each OM3-FFA dosage vs OO). With OM3-FFA 2 and 4 g/d (but not 3 g/d), low-density lipoprotein cholesterol was significantly increased compared with OO (P < .05 vs OO). High-sensitivity C-reactive protein responses with OM3-FFA did not differ significantly from the OO response at any dosage. Fewer subjects reported any adverse event with OO vs OM3-FFA, but frequencies across dosage groups were similar. Discontinuation due to adverse event, primarily gastrointestinal, ranged from 5% to 7% across OM3-FFA dosage groups vs 0% for OO. OM3-FFA achieved the primary end point for TG lowering and secondary end point of non-HDL-C lowering at 2, 3, and 4 g/d in persons with severe hypertriglyceridemia. This trial was registered at www.clinicaltrials.gov as NCT01242527.

A Highly Bioavailable Omega-3 Free Fatty Acid Formulation Improves the Cardiovascular Risk Profile in High-Risk, Statin-Treated Patients With Residual Hypertriglyceridemia (the ESPRIT Trial)

BackgroundA novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia. ObjectiveThis study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non–HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease. MethodsIn this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥200 mg/dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events. ResultsIn the 627 subjects in the intention to treat sample, non–HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (–3.9% and –6.9%, respectively) compared with OO (–0.9%) (both, P < 0.05), as were TG levels (–14.6% and –20.6%, respectively, vs –5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) (P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d. ConclusionsOM3-FFA was well tolerated and lowered non–HDL-C and TG levels at both 2- and 4-g/d dosages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental improvements compared with 2 g/d. ClinicalTrials.gov identifier: NCT01408303.

AstraZeneca Bolsters Late-Stage Cardiovascular Disease Pipeline with Omthera Pharmaceuticals Purchase

In its second cardiovascular disease-focused purchase of 2013, AstraZeneca has agreed to acquire Omthera Pharmaceuticals for approximately US$323 M plus Contingent Value Rights that equate to approximately US$120 M in total. With the acquisition, AstraZeneca will gain Omthera’s sole product candidate Epanova™, an omega-3 free fatty acid composition that has successfully completed two Phase III trials in patients with hypertriglyceridaemia and which will face competition in the prescription omega-3 market from GlaxoSmithKline’s Lovaza® (omega-3-acid ethyl esters) and Amarin’s Vascepa® (icosapent ethyl).

Abstract 19030: Apolipoprotein C-III is Significantly Reduced by Prescription Omega-3 Free Fatty Acids (Epanova) in Patients with Severe Hypertriglyceridemia and Changes Correlate with Increases in LDL-C: A Sub-analysis of the EVOLVE trial

Background: Apolipoprotein C-III (apoC-III) inhibits lipoprotein lipase activity and hepatic uptake of triglyceride-rich lipoproteins. Elevated levels of apoC-III have been found to be an independent predictor for CHD risk and genetically reduced apoC-III is associated with protection from CHD, making apoC-III a therapeutic target. Omega-3 fatty acid formulations containing docosahexaenoic acid (DHA) have been shown to increase LDL-C in patients with severe hypertriglyceridemia (HTG). Clinical data suggest that eicosapentaenoic acid (EPA) alone, which lowers triglycerides to a similar extent as EPA + DHA, does not raise LDL-C, but also fails to lower apoC-III. Materials: The EVOLVE trial evaluated 2, 3, and 4 g/d of a novel omega-3 free-fatty acid (FFA) formulation containing both EPA + DHA compared with 4 g/d of olive oil. In 399 patients with severe HTG we evaluated the effects on plasma apoC-III levels and the correlations between change in apoC-III and change in plasma lipids (TG, LDL-C) after 12-weeks of therapy. Results: Epanova 2, 3, and 4 g/d produced significant median reductions in apoC-III by 9 (p=0.02), 13 (p=0.006), and 15% (p&lt;0.001), respectively, compared to olive oil (+5%). Epanova produced significant (p&lt;0.001) median reductions in triglycerides (TG) of 26, 22, and 31%, respectively, compared to 10% for olive oil, and significant (p&lt;0.001) median increases in LDL-C of 21, 16, 26%, respectively, compared to 10% for olive oil. There was a significant positive correlation between percent changes in apoC-III and triglycerides (r=0.603, p&lt;0.001) and a significant negative correlation between percent changes in apoC-III and LDL-C concentrations (r=-0.28, p&lt;0.001). Conclusion: A novel omega-3 FFA formulation containing both EPA and DHA significantly lowered apoC-III levels in addition to reducing TG levels. An increase in LDL-C correlated with the reduction in apoC-III. Since EPA alone does not appear to lower apoC-III, these results support the hypothesis that DHA has specific effects in lowering apoC-III and that the mechanism by which DHA increases LDL-C may be related to its effect to lower apo CIII.

Abstract 18775: Low Levels of Omega-3s In Hispanics Due to Genetic and Dietary Factors Can be Significantly Improved with a Highly Bioavailable Omega-3 Free-fatty Acid Formulation

Background: Hispanic Americans have low fish consumption compared to non-Hispanics. In addition to dietary intake, LC-PUFA plasma levels are affected by FADS1 gene polymorphisms. FADS1 genes code for desaturases that convert MC-PUFAs (linoleic, alpha-linoleic acid) to LC-PUFAs (arachidonic acid (AA), eicosapentaenoic acid (EPA)). The single nucleotide polymorphism (SNP), rs174546 in the FADS1 gene has previously been shown to be associated with variations in plasma EPA and AA and triglycerides levels . The present study evaluated the prevalence of the rs174546 SNP genotypes (CC, CT, TT) and corresponding plasma EPA, DHA and AA levels after treatment with an omega-3 free-fatty acid (FFA) formulation in a population of healthy Hispanic volunteers. Methods: Forty six Hispanic participants in a statin pharmacokinetic study received 40 mg of simvastatin with and without a 4g daily dose of omega-3 FFA (primarily EPA and DHA ) for two weeks in a cross over study. Plasma samples were collected prior to and at the end-of-treatment in the omega-3 FFA arm for analysis of EPA, DHA, and AA. Results: Prior to treatment the Hispanic population had a higher prevalence of TT homozygotes (41%) compared to CC homozygotes (24%) corresponding to significantly different levels of EPA (CC=18 ug/mL; CT=11 ug/mL; TT=7 ug/mL, p &lt;0.0001) and AA (CC=266 ug/mL; CT=202 ug/mL; TT=167 ug/mL, p &lt;0.0001) across genotypes. In response to Omega-3 FFA therapy a substantial increase in EPA was observed, with the largest percent increase in the TT genotype (TT:1054%, CT:573%, CC:253%, p&lt;0.0001). Baseline plasma DHA levels were low suggesting comparable dietary fish intake and changes were similar across genotypes (CC:39%, CT:55%, TT:67%, p=0.2134). Conclusion: In contrast to other ethnicities, the T allele in FADS1 polymorphism, rs174546 is the major allele in Hispanics and the TT genotype is associated with low levels of EPA. This difference in LC-PUFA levels can be exacerbated with low dietary omega-3 intake and may explain the high prevalence of hypertriglyceridemia in Hispanics. Our data suggests that treatment with a highly bioavailable omega-3 FFA may result in significant improvement in omega-3 levels in the Hispanic population.

A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: The ECLIPSE (Epanova® compared to Lovaza® in a pharmacokinetic single-dose evaluation) study

Omega-3 (OM-3) fatty acid products are indicated for the treatment of severe hypertriglyceridemia; however, the omega-3-acid ethyl ester (OM-3 EE) formulations require significant pancreatic lipase stimulation with high-fat meals for adequate intestinal absorption of the metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A novel omega-3 free fatty acid (OM-3 FFA) formulation (Epanova(®), Omthera Pharmaceuticals Inc., Princeton, NJ) was developed to maximize EPA and DHA bioavailability during a low-fat diet. To compare the relative bioavailability of EPA and DHA from single 4-gram doses of OM-3 FFA and a prescription OM-3 EE (Lovaza(®), GlaxoSmithKline, Research Triangle Park, NC). This was a randomized, open-label, single dose, 4-way crossover, bioavailability study of OM-3 FFA and OM-3 EE administered during periods of low-fat and high-fat consumption to 54 overweight adults. Bioavailability was determined by the ln-transformed area under the plasma concentration versus time curve (AUC(0-t)) during a 24-hour interval for EPA and DHA (baseline-adjusted). The baseline-adjusted AUC(0-t) for total EPA+ DHA during the low-fat period was 4.0-fold greater with OM-3 FFA compared with OM-3 EE (2650.2 vs 662.0 nmol·h/mL, respectively; P<.0001). During the high-fat period, AUC(0-t) for OM-3 FFA was approximately 1.3-fold greater than OM-3 EE (P < .0001). During the low-fat period, 30 of 51 (58.8%) subjects dosed with OM-3 FFA maintained an AUC(0-t) that was ≥50% of the respective high-fat AUC(0-t) in contrast to only 3 of 50 (6.0%) subjects dosed with OM-3 EE. During a low-fat consumption period, the OM-3 FFA formulation provided dramatically improved bioavailability over the OM-3 EE formulation in overweight subjects. These findings offer a potential therapeutic advantage of the OM-3 FFA formulation for the treatment of severe hypertriglyceridemia as these patients are expected to adhere to a low-fat diet.

A Topographical Map of the Causal Network of Mechanisms Underlying the Relationship Between Major Depressive Disorder and Coronary Heart Disease

Major depressive disorder (MDD) and coronary heart disease (CHD) are both clinically important public health problems. Depression is linked with a higher incidence of ischaemic cardiac events and MDD is more prevalent in patients with CHD. No single comprehensive model has yet described the causal mechanisms linking MDD to CHD. Several key mechanisms have been put forward, comprising behavioural mechanisms, genetic mechanisms, dysregulation of immune mechanisms, coagulation abnormalities and vascular endothelial dysfunction, polyunsaturated omega-3 free fatty acid deficiency, and autonomic mechanisms. It has been suggested that these mechanisms form a network, which links MDD and CHD. The aim of this review is to examine the causal mechanisms underlying the relationship between MDD and CHD, with the aim of constructing a topological map of the causal network which describes the relationship between MDD and CHD. The search term 'depression and heart disease' was entered into an electronic multiple database search engine. Abstracts were screened for relevance and individually selected articles were collated. This review introduces the first topological map of the causal network which describes the relationship between MDD and CHD. Viewing the causal pathways as an interdependent network presents a new paradigm in this field and provides fertile ground for further research. The causal network can be studied using the methodology of systems biology, which is briefly introduced. Future research should focus on the creation of a more comprehensive topological map of the causal network and the quantification of the activity between each node of the causal network.

Acute Pancreatitis in Obesity: Adipokines and Dietary Fish Oil

Acute pancreatitis is a substantial clinical problem accounting for 240,000 hospital admissions yearly in the United States. Obesity is epidemic and is clearly an independent risk factor for increased severity of acute pancreatitis (AP). Adipose tissue is an endocrine organ that secretes a variety of metabolically active substances termed adipokines. However, the role of adipokines in modulating acute pancreatitis severity remains incompletely understood. Dietary fish oil is rich in omega-3 free fatty acids and attenuates adipose tissue-induced inflammation. Therefore, we hypothesized that feeding obese mice diets rich in fish oil would alter the adipokine milieu and attenuate the severity of pancreatitis. Lean (C57BL/6 J) and obese (LepDb) mice were fed either a soybean oil- or fish oil-rich diet for 4 weeks. AP was induced by six hourly intraperitoneal injections of cerulein (50 μg/kg). Serum adipokine levels were measured, and pancreatitis severity was assessed histologically and by measuring pancreatic concentrations of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), myleoperoxidase (MPO), and monocyte chemoattractant protein-1 (MCP-1). Obese mice developed more severe pancreatitis than lean mice. Fish oil significantly decreased serum leptin (lean and obese) and increased serum adiponectin (lean only). Fish oil did not alter the baseline pancreatic inflammatory milieu, nor did it change histologic or biochemical pancreatitis severity. These data demonstrate that a diet rich in fish oil altered the adipokine milieu in lean and congenitally obese mice; however, fish oil did not improve pancreatitis severity induced with cerulein hyperstimulation.

Omega-3 Fatty Acids for Maintenance of Remission of Crohn's Disease

Omega-3 Fatty Acids for Maintenance of Remission of Crohn's Disease

Omega-3 free fatty acids do not maintain remission of Crohn disease

Omega-3 free fatty acids do not maintain remission of Crohn disease

Omega-3 Free Fatty Acids for the Maintenance of Remission in Crohn Disease

Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542.

Cardiovascular Effects of Omega-3 Free Fatty Acids.

Omega-3 fatty acids are essential substances for the development and function of human organism. They cannot be synthesized in humans, and consequently have to be acquired from food, almost exclusively from fish. Omega-3 fatty acids exert potent anti-inflammatory and anti-atherosclerotic actions by interfering with the metabolism of arachidonic acid, modifying lipid composition (mainly lowering triglycerides), improving hemodynamics and reducing cardiac hypertrophy. Recently, clinical and experimental studies demonstrated an anti-arrhythmic effect and a significant impact on survival after myocardial infarction (MI). It follows that omega-3 fatty acids have been widely accepted for clinical use in patients with dyslipidemia or with atherosclerotic disease and in survivors of acute MI. This review briefly explores the metabolic mechanisms and the clinical effects of this class of substances and considers their use in patients with cardiovascular disease.

Coronary Heart Disease and Depression: The Next Steps

Abbreviations used in this article CHD coronary heart disease ENRICHD Enhancing Recovery in Coronary Heart Disease Patients CBT cognitive-behavioural therapy MI myocardial infarction SSRI selective serotonin reuptake inhibitor Since the exciting findings in the late 1980s and early 1990s that depression predicts prognosis in patients recovering from heart attacks, there has been little substantive advance in the treatment of mood disorders in patients with CHD. Although confirmatory epidemiologic studies have continued to appear (see the summary in the accompanying article by Frasure-Smith and Lesperance, 1), there has been little clinically relevant research. Because most clinical trials of antidepressants have excluded patients with medical comorbidity and because such patients, including those with CHD, often take multiple other medications that can interact with some antidepressants, the existing evidence base for depression treatment does not directly translate to CHD patients. The landmark ENRICHD Trial (2), funded by the United States National Heart, Lung and Blood Institute between 1996 and 2002, was designed as the first step in improving clinical treatment for post-Mi patients suffering from depression. At the same time, the ENRICHD Trial tested the hypothesis that treating depression with CBT, plus an SSRI antidepressant when needed, can improve cardiac prognosis. As summarized in the accompanying article (1), the results were disappointing. The usual care control group received a good deal of cointervention with antidepressants, and although overall differences in changes in depression were statistically significant, they were small. There was no evidence of a difference in cardiac events over the average follow-up period of 29 months. Since the publication of the results in 2003, researchers and clinicians have been wondering what the next step should be. Is it really possible to change depression symptoms in cardiac patients sufficiently to affect either the pathophysiology of cardiac disease or patient compliance with medical treatment and thus save lives? Imagine, for a moment, that the results of ENRICHD had been positive. What if, in addition to reducing depression symptoms, CBT plus sertraline as needed had resulted in better survival than usual care? Most of us working in behavioural cardiology would be a good deal happier and would probably have been much more productive over the last 3 years. However, what would we have known? We would have had a better idea of how to treat CHD patients suffering from depression, but we would not have known whether reducing depression symptoms per se results in decreased cardiac events. We also would not have known which component of the intervention was crucial for the reduction in cardiac events. This is because, like many other medical treatments, depression treatment-whether by CBT or SSRIs-has pleiotropic effects on body systems other than the brain, including the cardiovascular system. This means that the net effect on cardiac outcomes of any treatment for depression is likely to be at least as much a function of the sum of its impact on the cardiovascular mechanisms linking depression with prognosis as a function of its impact on depressive symptoms per se. As summarized in the accompanying review by Skala, Freedland, and Carney (3), in addition to the behavioural mechanism of adherence to medical advice and risk factor modification, there are reasonable data supporting that 5 biological mechanisms are involved in the link between depression and CHD: exaggerated platelet activation (4-7); reduced heart rate variability, reflecting increased sympathetic activity and (or) reduced vagal activity (8); increased innate inflammatory response (9,10); endothelial dysfunction (11,12); and reduced levels of omega-3 free fatty acids(13,14). Itis plausible that antidepressants have some effects on several of these mechanisms. …

Depression and Coronary Heart Disease

Beyond depression's impact on life quality, it is associated with both the incidence of coronary heart disease (CHD) and its prognosis. Depression is three times more common in CHD patients than in the general community. It is independently associated with at least a doubling in risk of subsequent cardiac events. Studies also show that it may precede the development of clinically evident CHD by many years. The mechanisms linking depression and CHD are currently unknown and likely to be complex. In addition to behavioral factors, changes in autonomic regulation, vascular disease of the brain, subchronic inflammation, reduced omega-3 free fatty acid levels, and enhanced platelet responsiveness may all be involved. Only one large clinical trial has attempted to alter CHD prognosis by treating depression. It succeeded in producing a small, but significant reduction in depression symptoms, but had no impact on subsequent CHD events. While debate continues about the causal relationship between CHD and depression, the best treatment strategy to improve prognosis in depressed CHD patients remains intensive modification of standard CHD risk factors in combination with treatment of depression to improve life quality.

Immune-enhancing diets for stressed patients with a special emphasis on arginine content: analysis of the analysis.

After two decades of intensive research, whether arginine-enriched diets for oral/enteral administration are beneficial or harmful for stressed patients remains uncertain. An American consensus and a meta-analysis provide divergent conclusions. The main goal of the present review is to analyze these documents. The so-called immune-enhancing diets have been found to be beneficial to postoperative patients. Nothing proves, however, that arginine is responsible for these beneficial effects since immune-enhancing diets contain other pharmacologically active components (e.g. omega3 free fatty acids, RNAs, antioxidant vitamins). In fact, arginine-enriched diets may be harmful in hemodynamically unstable patients and those presenting with multiple organ failure. In light of the current doubts and until convincing data are produced, immune-enhancing diets should not be used in unstable critically ill patients.