Icosapent Research Articles

Beneficial effects of eicosapentaenoic acid on the metabolic profile of obese female mice entails upregulation of HEPEs and increased abundance of enteric Akkermansia muciniphila

Eicosapentaenoic acid (EPA) ethyl esters are of interest given their clinical approval for lowering circulating triglycerides and cardiometabolic disease risk. EPA ethyl esters prevent metabolic complications driven by a high fat diet in male mice; however, their impact on female mice is less studied. Herein, we first investigated how EPA influences the metabolic profile of female C57BL/6J mice consuming a high fat diet. EPA lowered murine fat mass accumulation, potentially through increased biosynthesis of 8-hydroxyeicosapentaenoic acid (HEPE), as revealed by mass spectrometry and cell culture studies. EPA also reversed the effects of a high fat diet on circulating levels of insulin, glucose, and select inflammatory/metabolic markers. Next, we studied if the improved metabolic profile of obese mice consuming EPA was associated with a reduction in the abundance of key gut Gram-negative bacteria that contribute toward impaired glucose metabolism. Using fecal 16S-ribosomal RNA gene sequencing, we found EPA restructured the gut microbiota in a time-dependent manner but did not lower the levels of key Gram-negative bacteria. Interestingly, EPA robustly increased the abundance of the Gram-negative Akkermansia muciniphila, which controls glucose homeostasis. Finally, predictive functional profiling of microbial communities revealed EPA-mediated reversal of high fat diet-associated changes in a wide range of genes related to pathways such as Th-17 cell differentiation and PI3K-Akt signaling. Collectively, these results show that EPA ethyl esters prevent some of the deleterious effects of a high fat diet in female mice, which may be mediated mechanistically through 8-HEPE and the upregulation of intestinal Akkermansia muciniphila.

META-ANALYSIS OF 17 CLINICAL TRIALS USING OMEGA-3 FATTY ACIDS IN PATIENTS WITH CARDIOVASCULAR DISEASE

BACKGROUND Cardiovascular disease (CVD) is the primary cause of mortality worldwide. Ischemic events associated with CVD are causatively related to vascular inflammation and atherothrombosis. Certain omega-3 fatty acids, such as eicosapentaenoic acid (EPA), are thought to have anti-inflammatory and anti-thrombotic properties. Icosapent ethyl (IPE) is an ethyl ester of EPA, currently approved by Health Canada as prescription IPE. At 4 g/d, IPE significantly reduced clinical events in high-risk patients with diabetes and other risk factors of CV disease in the REDUCE-IT trial. Previous clinical trials, with the majority of them administering a combination of EPA and the O3FA, docosahexaenoic acid (DHA), have been conducted with mixed outcomes. This study aimed to determine whether O3FA formulations of EPA alone versus mixed combinations can confer protection in patients with CVD. METHODS AND RESULTS The meta-analysis included 13 randomized controlled trials with endpoints including non-fatal myocardial infarction (MI), coronary heart disease (CHD) death, total CHD, CVD death, total CVD, total stroke and major vascular events. The pooled rate ratios (RRs) were calculated using a fixed method. This meta-analysis also included 4 clinical trials that assessed the effect of omega-3 fatty acids on coronary plaque volume and stability. All trials involved formulations with EPA alone or in combination with DHA. Out of 17 trials using omega-3 fatty acids in patients with CVD risk, 5 employed EPA alone, all of which (100%) met the defined endpoints. The remaining 12 trials used a combination of EPA and DHA, of which only 4 (33%) met the defined endpoints, but only in patients where statin use was not prespecified. The differences in outcomes did not correlate with triglyceride lowering. CONCLUSION In a meta-analysis of O3FA trials, the formulation of EPA alone as icosapent ethyl (IPE) was superior to mixtures containing DHA in statin-treated patients. The benefits with IPE are attributed to potential anti-inflammatory, anti-oxidant and anti-thrombotic actions. Elucidating such mechanisms for EPA will lead to further insights into our understanding of atherosclerosis and strategies for CVD treatment. Cardiovascular disease (CVD) is the primary cause of mortality worldwide. Ischemic events associated with CVD are causatively related to vascular inflammation and atherothrombosis. Certain omega-3 fatty acids, such as eicosapentaenoic acid (EPA), are thought to have anti-inflammatory and anti-thrombotic properties. Icosapent ethyl (IPE) is an ethyl ester of EPA, currently approved by Health Canada as prescription IPE. At 4 g/d, IPE significantly reduced clinical events in high-risk patients with diabetes and other risk factors of CV disease in the REDUCE-IT trial. Previous clinical trials, with the majority of them administering a combination of EPA and the O3FA, docosahexaenoic acid (DHA), have been conducted with mixed outcomes. This study aimed to determine whether O3FA formulations of EPA alone versus mixed combinations can confer protection in patients with CVD. The meta-analysis included 13 randomized controlled trials with endpoints including non-fatal myocardial infarction (MI), coronary heart disease (CHD) death, total CHD, CVD death, total CVD, total stroke and major vascular events. The pooled rate ratios (RRs) were calculated using a fixed method. This meta-analysis also included 4 clinical trials that assessed the effect of omega-3 fatty acids on coronary plaque volume and stability. All trials involved formulations with EPA alone or in combination with DHA. Out of 17 trials using omega-3 fatty acids in patients with CVD risk, 5 employed EPA alone, all of which (100%) met the defined endpoints. The remaining 12 trials used a combination of EPA and DHA, of which only 4 (33%) met the defined endpoints, but only in patients where statin use was not prespecified. The differences in outcomes did not correlate with triglyceride lowering. In a meta-analysis of O3FA trials, the formulation of EPA alone as icosapent ethyl (IPE) was superior to mixtures containing DHA in statin-treated patients. The benefits with IPE are attributed to potential anti-inflammatory, anti-oxidant and anti-thrombotic actions. Elucidating such mechanisms for EPA will lead to further insights into our understanding of atherosclerosis and strategies for CVD treatment.

SUBSTANTIAL CARDIOVASCULAR RISK REDUCTION WITH ICOSAPENT ETHYL REGARDLESS OF DIABETES STATUS OR BMI: REDUCE-IT BMI

BACKGROUND REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 grams daily or placebo. IPE reduced the primary (CV death, myocardial infarction [MI], stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, MI, stroke) endpoints 25% and 26%, respectively (each p < 0.000001). At baseline, median body mass index (BMI) was 30.8 kg/m2, and 58.5% of REDUCE-IT patients had diabetes mellitus (DM). In patients with DM, the primary and key secondary endpoints were reduced 23% and 30%, respectively (each p≤0.00005). METHODS AND RESULTS We evaluated if BMI modulated CV risk reduction with IPE in patients with or without DM. In the full cohort, similar CV risk reduction was observed across the prespecified endpoint testing hierarchy (interaction p=ns for all), and relative safety between treatment groups was generally consistent. In persons with or without DM, similar reductions in the primary endpoint were observed across BMI categories (Figure), with similar findings in the key secondary endpoint (interaction p=ns for all). CONCLUSION The significant cardiovascular risk reduction provided by IPE 4g/day is consistent across BMI in patients with and without DM. REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 grams daily or placebo. IPE reduced the primary (CV death, myocardial infarction [MI], stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, MI, stroke) endpoints 25% and 26%, respectively (each p < 0.000001). At baseline, median body mass index (BMI) was 30.8 kg/m2, and 58.5% of REDUCE-IT patients had diabetes mellitus (DM). In patients with DM, the primary and key secondary endpoints were reduced 23% and 30%, respectively (each p≤0.00005). We evaluated if BMI modulated CV risk reduction with IPE in patients with or without DM. In the full cohort, similar CV risk reduction was observed across the prespecified endpoint testing hierarchy (interaction p=ns for all), and relative safety between treatment groups was generally consistent. In persons with or without DM, similar reductions in the primary endpoint were observed across BMI categories (Figure), with similar findings in the key secondary endpoint (interaction p=ns for all). The significant cardiovascular risk reduction provided by IPE 4g/day is consistent across BMI in patients with and without DM.

EICOSAPENTAENOIC ACID REDUCES EXPRESSION OF PLATELET ACTIVATION AND AGGREGATION PROTEINS IN PULMONARY AND VASCULAR ENDOTHELIUM DURING INFLAMMATION

BACKGROUND Atherothrombotic cardiovascular (CV) disease leads to platelet aggregation and thrombus formation. Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA), and was shown to reduce ischemic events in high-risk patients (REDUCE-IT). IPE is approved by Health Canada to reduce CV risk among patients with elevated TG levels as an add-on to maximally tolerated statin therapy. In this study, the effects of EPA on expression of proteins associated with platelet activation and aggregation were measured in cytokine (IL-6) treated pulmonary and vascular endothelial cells (ECs). METHODS AND RESULTS Human pulmonary ECs (PECs) and umbilical vein ECs (HUVECs) were treated with vehicle or EPA (40/10 µM in PECs/HUVECs) and IL-6 (12 ng/mL) for 24 h. Proteomic analysis was performed using liquid chromatography/mass spectroscopy that detected modulation of >1,000 proteins. Proteins which showed significantly (p < 0.05) greater than 1-fold change between treatment groups were further assessed. EPA significantly downregulated a total of 36 proteins involved in platelet activation, signaling, aggregation, in EC following cytokine exposure. Platelet endothelial cell adhesion molecule (PECAM) was downregulated in both HUVECs and PECs (1.2-fold) by EPA. In PECs, EPA significantly modulated 26 additional proteins related to platelet activation, including amyloid-beta precursor protein (1.1-fold decrease) and thrombin receptor (PAR-1,1.3-fold decrease). In HUVECs, the expression of nine other proteins were modulated related to platelet activation, including superoxide dismutase (1.6-fold increase). CONCLUSION EPA significantly reduced expression of multiple EC proteins required for platelet activation and aggregation, including PECAM in both pulmonary and vascular tissues. These findings indicate potential novel anti-platelet mechanisms for EPA that may account for reduced ischemic events in REDUCE-IT. Atherothrombotic cardiovascular (CV) disease leads to platelet aggregation and thrombus formation. Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA), and was shown to reduce ischemic events in high-risk patients (REDUCE-IT). IPE is approved by Health Canada to reduce CV risk among patients with elevated TG levels as an add-on to maximally tolerated statin therapy. In this study, the effects of EPA on expression of proteins associated with platelet activation and aggregation were measured in cytokine (IL-6) treated pulmonary and vascular endothelial cells (ECs). Human pulmonary ECs (PECs) and umbilical vein ECs (HUVECs) were treated with vehicle or EPA (40/10 µM in PECs/HUVECs) and IL-6 (12 ng/mL) for 24 h. Proteomic analysis was performed using liquid chromatography/mass spectroscopy that detected modulation of >1,000 proteins. Proteins which showed significantly (p < 0.05) greater than 1-fold change between treatment groups were further assessed. EPA significantly downregulated a total of 36 proteins involved in platelet activation, signaling, aggregation, in EC following cytokine exposure. Platelet endothelial cell adhesion molecule (PECAM) was downregulated in both HUVECs and PECs (1.2-fold) by EPA. In PECs, EPA significantly modulated 26 additional proteins related to platelet activation, including amyloid-beta precursor protein (1.1-fold decrease) and thrombin receptor (PAR-1,1.3-fold decrease). In HUVECs, the expression of nine other proteins were modulated related to platelet activation, including superoxide dismutase (1.6-fold increase). EPA significantly reduced expression of multiple EC proteins required for platelet activation and aggregation, including PECAM in both pulmonary and vascular tissues. These findings indicate potential novel anti-platelet mechanisms for EPA that may account for reduced ischemic events in REDUCE-IT.

Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT

BackgroundREDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. ObjectivesThe purpose of this study was to determine the effects of IPE on investigator-reported events. MethodsPotential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. ResultsThere was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. ConclusionsIPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361)

EICOSAPENTAENOIC ACID INHIBITS LIPOPOLYSACCHARIDE (LPS)-INDUCED MACROPHAGE ACTIVATION THROUGH A POTENTIAL CYCLOOXYGENASE PATHWAY

<h3>BACKGROUND</h3> Activated macrophages, characterized by increased inducible nitric oxide synthase (iNOS) expression, participate in atherosclerosis and its complications. Cyclooxygenase (COX) regulates iNOS activity. As both a substrate for and potential inhibitor of COX, the omega-3 fatty acid, eicosapentaenoic acid (EPA), may reduce iNOS activity. Icosapent ethyl is an ethyl ester of EPA, and was shown to reduce ischemic events in high-risk patients (REDUCE-IT). We tested the effects of EPA on iNOS activity in lipopolysaccharide (LPS)-activated macrophages. <h3>METHODS AND RESULTS</h3> Murine J774 macrophages were pretreated with vehicle, EPA (10, 20, 40 µM), (10 µM) for 2 h, then challenged with LPS (1.0 µg/ml). After 24 h, iNOS activity was measured by nitrite production using the Griess assay. As a positive control, the COX inhibitor diclofenac was tested (1.0 µg/ml). Treatment with LPS increased nitrite production by 465% (p < 0.001). EPA treatment reduced nitrite production in a significant, dose-dependent manner by 40-77% at 10-40 µM, respectively, compared to LPS-alone. EPA at the lowest concentration tested produced an effect similar to diclofenac, which reduced nitrite levels by 40% (p < 0.01). <h3>CONCLUSION</h3> EPA reduced LPS-induced macrophage activation in a dose-dependent manner that was reproduced to a lesser extent by diclofenac. These findings indicate a novel effect of EPA on both COX and iNOS activity. The ability of EPA to reduce macrophage activity may contribute to limiting atherothrombotic risk as evidenced in REDUCE-IT.

Clinical Management of Hypertriglyceridemia in the Prevention of Cardiovascular Disease and Pancreatitis.

Purpose of ReviewHypertriglyceridemia (HTG) is common and is a significant contributor to atherosclerosis and pancreatitis risk. Specific HTG treatments have had variable success in reducing atherosclerosis risk. Novel therapies for severe HTG treatment and pancreatitis risk reduction are likely to be available soon. These novel therapies are expected to have broader applications for more moderate HTG and atherosclerosis risk reduction as well.Recent FindingsNHANES 2012 data has confirmed a reduction in average triglyceride (TG) levels in the US population. Dietary modification and weight reduction when needed remain the core treatment elements for all individuals with HTG, while statin therapy is a foundational pharmacologic care for atherosclerotic cardiovascular disease (ASCVD) event risk reduction. In addition, the REDUCE-IT study provides evidence for additional benefit from the use of high-dose icosapent ethyl (IPE) on top of background medical therapy in adults with moderate HTG and ASCVD or type 2 diabetes mellitus (T2D) and additional ASCVD risk factors. However, treatment with eicosapentaenoic acid (EPA) combined with docosahexanoic acid (DHA) did not reduce ASCVD in a similar population studied in the STRENGTH trial. Furthermore, novel therapeutics targeting PPAR-ɑ, as well as ApoC-III and AngPTL3, effectively lower TG levels in individuals with moderate and severe HTG, respectively. These treatments may have applicability for reducing risk from ASCVD among individuals with chylomicronemia; in addition, ApoC-III and AngPTL3 treatments may have a role in treating individuals with the rare monogenic familial chylomicronemia syndrome (FCS) at risk for acute pancreatitis (AP).SummaryResidual ASCVD risk in individuals treated with contemporary care may be due in part to non-LDL lipid abnormalities including HTG. The findings from REDUCE-IT, but not STRENGTH, confirm that consumption of high-dose EPA may reduce ASCVD risk, while combination therapy of EPA plus DHA does not reduce ASCVD in a similar population. TG lowering likely reduces ASCVD risk in individuals with HTG, but ASCVD risk is multifactorial; the added benefit of IPE to contemporary preventive therapy is the consequence of differential non-TG biologic properties between the two fatty acids. Acute pancreatitis is more difficult to study prospectively since it is less common; however, TG lowering is likely critical for the care of at-risk individuals. Additional benefit from novel therapy that has an impact on this otherwise refractory condition is anticipated.

Icosapent ethyl: safely reducing cardiovascular risk in adults with elevated triglycerides

ABSTRACT Introduction In patients at high cardiovascular risk, the rate of events remains elevated despite traditional, evidence-based lipid-lowering therapy. Residual hypertriglyceridemia is an important contributor to this risk. However, prior medications with triglyceride-lowering effects have not reduced adverse clinical outcomes in the statin era. Areas covered The present review summarizes evidence and recommendations related to triglyceride-lowering therapy in the primary and secondary preventive settings. We provide an overview of findings from recent meta-analyses, important observational studies, and a detailed description of landmark trials, including the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT). We further review recommendations from current guidelines. Expert opinion Icosapent ethyl is a stable, highly purified ethyl ester of eicosapentaenoic acid that safely and effectively reduces cardiovascular events in the contemporary setting. It is prescribed at a dose of 2 grams twice daily and is indicated in patients at high cardiovascular risk who have fasting or non-fasting triglyceride levels ≥150 mg/dl despite maximally tolerated statin treatment, or in individuals with triglyceride levels ≥500 mg/dl. Conversely, omega-3 fatty acid preparations containing a combination of eicosapentaenoic acid and docosahexaenoic acid are not indicated for reduction of cardiovascular risk and should be actively deprescribed.

Omega-3 fatty acids for the prevention of atherosclerotic cardiovascular disease.

Marine-derived omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are a type of polyunsaturated fatty acids with many purported beneficial health effects including the prevention of atherosclerotic cardiovascular disease (ASCVD) events. Omega-3 fatty acid intake may be supplemented via dietary sources, as well as prescription or non-prescription products. Omega-3 fatty acids have been shown to reduce serum triglycerides, but there remains ongoing debate regarding the effect of omega-3 fatty acids on major adverse cardiovascular events in patients with established, or at risk of, ASCVD. Recent evidence from randomized, placebo-controlled trials has demonstrated that low-dose (1g daily or less) omega-3 fatty acids (DHA and EPA) do not reduce cardiovascular events or death in patients with or without established ASCVD. Contrarily, the REDUCE-IT trial demonstrated that a purified form of EPA ethyl esters (icosapent ethyl) at 4g daily reduced cardiovascular events and death in patients with ASCVD (or diabetes and multiple cardiovascular risk factors) and elevated triglycerides on background statin therapy. However, 4g daily of omega-3 carboxylic acids (DHA and EPA) did not show a cardiovascular benefit in the STRENGTH trial, which enrolled a similar population. The explanation for this observed discrepancy remains a source of contention and discourse. For now, icosapent ethyl has the most compelling evidence to support a cardiovascular benefit and should be considered in select patients who meet the REDUCE-IT criteria. Furthermore, alternative versions of omega-3 fatty acids should not be considered equivalent to icosapent ethyl. Patients taking an omega-3 fatty acid supplement should be monitored for potential adverse effects, including gastrointestinal disorders or bleeding, in addition to a possible increased risk of atrial fibrillation.

A randomized trial of icosapent ethyl in ambulatory patients with COVID-19

SummaryThe coronavirus disease 2019 (COVID-19) pandemic remains a source of considerable morbidity and mortality throughout the world. Therapeutic options to reduce symptoms, inflammatory response, or disease progression are limited. This randomized open-label trial enrolled 100 ambulatory patients with symptomatic COVID-19 in Toronto, Canada. Results indicate that icosapent ethyl (8 g daily for 3 days followed by 4 g daily for 11 days) significantly reduced high-sensitivity C-reactive protein (hs-CRP) and improved symptomatology compared with patients assigned to usual care. Specifically, the primary biomarker endpoint, change in hs-CRP, was significantly reduced by 25% among treated patients (−0.5 mg/L, interquartile range [IQR] [−6.9,0.4], within-group p = 0.011). Conversely, a non-significant 5.6% reduction was observed among usual care patients (−0.1 mg/L, IQR [−3.2,1.7], within-group p = 0.51). An unadjusted between-group primary biomarker analysis was non-significant (p = 0.082). Overall, this report provides evidence of an early anti-inflammatory effect of icosapent ethyl in a modest sample, including an initial well-tolerated loading dose, in symptomatic outpatients with COVID-19. ClinicalTrials.gov Identifier: NCT04412018.

Generalizability of the REDUCE-IT trial and cardiovascular outcomes associated with hypertriglyceridemia among patients potentially eligible for icosapent ethyl therapy: An analysis of the REduction of Atherothrombosis for Continued Health (REACH) registry

BackgroundThe REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) trial demonstrated that high-dose icosapent-ethyl reduced the risk of ischemic events in statin-treated patients with elevated triglycerides (TG) and either atherosclerotic cardiovascular disease (ASCVD) or diabetes plus at least one risk factor. Methods and resultsUsing data from REACH (Reduction of Atherothrombosis for Continued Health), a large international registry of outpatients with or at risk of ASCVD, we evaluated the proportion of patients potentially eligible for enrolment in REDUCE-IT and compared their outcomes to those excluded because of low TG. Among 62,464 patients with either ASCVD or diabetes enrolled in the REACH Registry, 1036/8418 (12.3%) patients in primary prevention and 6049/54046 (11.2%) patients in secondary prevention (11.3% overall) would have been eligible for inclusion in REDUCE-IT. Compared with patients excluded for low TG level, adjusted risk of the primary composite outcome of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina, or coronary revascularization was higher in the REDUCE-IT eligible group (HR:1.06, 95%CI:1.00–1.13, p = 0.04). In addition, unstable angina, non-fatal MI, percutaneous coronary intervention and coronary artery bypass grafting were also more frequent in the REDUCE-IT eligible group (HR:1.17, 95%CI:1.07–1.27, p < 0.001; HR:1.25, 95%CI:1.07–1.45, p < 0.001; HR:1.42, 95%CI:1.27–1.57, p < 0.001; HR:1.43, 95%CI:1.19–1.71, p < 0.001, respectively), whereas the adjusted risk of non-fatal stroke was lower (HR:0.64, 95%CI:0.54–0.75, p < 0.001). ConclusionIn this large international registry of patients with or at high-risk of ASCVD, 11.3% met the REDUCE-IT trial selection criteria. REDUCE-IT eligible patients were found to be at higher risk of cardiac atherothrombotic events, but at lower risk of stroke than trial-ineligible patients with lower TG.

Omega-3 and omega-6 fatty acids have distinct effects on endothelial fatty acid content and nitric oxide bioavailability

Treatment with high dose icosapent ethyl (IPE), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA), significantly reduced ischemic events in patients with either cardiovascular disease (CV) or diabetes plus other risk factors (REDUCE-IT) but the mechanism is not well understood. We compared the effects of EPA, docosahexaenoic acid (DHA), and the omega-6 fatty acid arachidonic acid (AA) on bioavailability of nitric oxide (NO) and fatty acid composition. Human umbilical vein endothelial cells (HUVECs) were pretreated with EPA, DHA, or AA (10 µM). Cells were stimulated with calcium ionophore and NO and peroxynitrite (ONOO−) were measured using porphyrinic nanosensors. Levels of EPA, DHA, AA and other fatty acids were measured by gas chromatography (GC). EPA treatment caused the greatest NO release (18%, p < 0.001) and reduction in ONOO− (13%, p < 0.05) compared to control; the [NO]/[ ONOO−] ratio increased by 35% (p < 0.001). DHA treatment increased NO levels by 12% (p < 0.01) but had no effect on ONOO− release. AA did not affect either NO or ONOO− release. Fatty acid treatments increased their respective levels in endothelial cells. EPA levels increased 10-fold to 4.59 mg/g protein (p < 0.001) with EPA treatment and the EPA/AA ratio increased by 10-fold (p < 0.001) compared to vehicle. Only EPA increased docosapentaenoic acid (DPA, omega-3) levels by 2-fold (p < 0.001). AA alone decreased the EPA/AA ratio 4-fold (p<0.001). These findings support a preferential benefit of EPA on endothelial function and omega-3 fatty acid content.

Improving Appropriate Use of Omega-3 Fatty Acids for Patients With Dyslipidemia: Effect of Online CME.

Hypertriglyceridemia is associated with an increased risk of atherosclerotic cardiovascular (CV) disease. Clinical trials have demonstrated the effectiveness of eicosapentaenoic acid ethyl ester (EPA), an omega-3 polyunsaturated fatty acid, on triglyceride lowering and on CV risk reduction. However, many clinicians have limited understanding of the effects of EPA and limited experience using EPA to reduce the risk of CV disease. An analysis was conducted to determine whether an online continuing medical education (CME) intervention could improve knowledge and competence of primary care physicians (PCPs) and cardiologists related to the role of EPA in management of CV risk in patients with dyslipidemia. The intervention comprised 2 online video-based CME activities. The effects of education were assessed for learners who completed 4 pre- and postassessment questions for each activity, using a matched pre-/postassessment design. For all questions combined, a McNemar's χ2 test assessed differences from pre- to postassessment. Matched-learner data indicated that 34% of PCPs improved their knowledge as a result of participating in the activities, and 42% had their knowledge reinforced. Among cardiologists, 28% improved their knowledge, and 61% had their knowledge reinforced. For these learner subsets, there was a significant 17% relative increase in self-assessed confidence in appropriate use of EPA for PCPs (n = 1644, P < 0.001) and a 12% increase for cardiologists (n = 524; P < 0.001). The improvements observed in this online CME intervention demonstrate the benefits of educating the appropriate target audience base and suggest that this type of intervention can translate into improvements in clinical care.

Omega-3 Fatty Acids and Cardiovascular Disease: A Narrative Review for Pharmacists.

Background:Atherosclerotic cardiovascular disease is a significant cause of morbidity and mortality worldwide. While use of statin therapy has improved management of lipids, an unmet need in reducing residual atherosclerotic cardiovascular disease risk and ischemic events persists. We provide an overview of the pharmacology of omega-3 fatty acids, omega-3 fatty acid cardiovascular outcomes trials, landmark clinical data and pharmacology of icosapent ethyl (a stable and highly purified ethyl ester of eicosapentaenoic acid), and the critical differences between fish oil supplements and prescription omega-3 fatty acids.Method:A PubMed literature review was conducted in April 2020 to identify articles discussing omega-3 fatty acid cardiovascular outcomes trials, pharmacology of icosapent ethyl, and the evaluation of fish oil dietary supplements and prescription omega-3 fatty acids.Results:Both eicosapentaenoic acid and docosahexaenoic acid have been widely associated with positive health benefits; however, data are inconsistent regarding the benefit of combination eicosapentaenoic acid and docosahexaenoic acid in patients with cardiovascular disease. Eicosapentaenoic acid, and specifically icosapent ethyl, has demonstrated atherosclerotic cardiovascular disease risk reduction among statin-treated patients. Important clinical differences exist between dietary supplement and prescription omega-3 fatty acid products.Conclusions:As research regarding the optimal management of dyslipidemia continues, additional therapy beyond statins is necessary to reduce atherosclerotic cardiovascular disease risk. In large cardiovascular outcomes trials, eicosapentaenoic acid has demonstrated cardiovascular benefit. Icosapent ethyl possesses a favorable efficacy and safety profile and should be considered as an adjunct to statin therapy to reduce ischemic event risk.

Managing dyslipidemia in patients with Type 2 diabetes

ABSTRACT Introduction Type 2 diabetes mellitus (T2DM) is associated with increased risk for atherosclerotic cardiovascular disease (ASCVD) which is partly related to atherogenic dyslipidemia with raised triglycerides, reduced high-density lipoprotein cholesterol levels, and accompanying lipid changes. Treatment of this dyslipidemia is regarded as a priority to reduce the ASCVD risk in T2DM. Areas covered This article reviews the relevant studies and guidelines from the publications related to this area. Expert opinion Lifestyle modification should always be encouraged, and statin treatment is indicated in most patients with T2DM based on the outcome of randomized controlled trials. If LDL-C goals are not achieved, first, ezetimibe and subsequently proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors should be added. Patients with T2DM derive greater benefits from ezetimibe and PCSK9 inhibitors due to their higher absolute ASCVD risk compared to patients without T2DM. If triglyceride levels remain elevated, a high dose of eicosapentaenoic acid ethyl ester should be added. Fibrates should be used for severe hypertriglyceridemia to prevent acute pancreatitis. Novel treatments including pemafibrate and inclisiran are undergoing cardiovascular outcome trials, and RNA-based therapies may help to target residual hypertriglyceridemia and high lipoprotein(a) with the long acting treatments offering potential improved adherence to therapy.

Optimal medical therapy after coronary artery bypass grafting: a primer for surgeons.

After coronary artery bypass grafting (CABG), patients remain at increased risk of cardiovascular events and death. Cardiac surgeons have the opportunity to reduce this risk by optimizing post-CABG patients' medical therapy. Recent developments in lipid-lowering, diabetes management, antithrombotic therapy, and anti-inflammatory therapy can significantly improve prognosis in patients with chronic coronary artery disease. PCSK-9 inhibitors should be used in patients with elevated LDL cholesterol despite maximally tolerated statin therapy. Icosapent ethyl should be considered in patients with elevated triglycerides despite maximally tolerated statin therapy. Long-acting GLP-1 receptor agonists or SLGT-2 inhibitors should be used in all post-CABG patients with type 2 diabetes. Intensified antithrombotic therapy with DAPT or DPI reduces MACE (and DPI reduces mortality) in patients with high atherosclerotic burden. Colchicine has not yet been incorporated into guidelines on OMT for stable CAD but it is reasonable to consider using it in high-risk patients. We review the foundations of optimal medical therapy after CABG, and summarize recent advances with a focus on practical application for the busy cardiac surgeon.

256-OR: Substantial Cardiovascular Risk Reduction with Icosapent Ethyl Regardless of Diabetes Status or BMI: REDUCE-IT BMI

Background: REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 grams daily or placebo. IPE reduced the primary (CV death, myocardial infarction [MI], stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, MI, stroke) endpoints 25% and 26%, respectively (each p Methods: We evaluated if BMI modulated CV risk reduction with IPE in patients with or without DM. Results: In the full cohort, similar CV risk reduction was observed across the prespecified endpoint testing hierarchy (interaction p=ns for all), and relative safety between treatment groups was generally consistent. In persons with or without DM, similar reductions in the primary endpoint were observed across BMI categories (Figure), with similar findings in the key secondary endpoint (interaction p=ns for all). Conclusion: The significant cardiovascular risk reduction provided by IPE 4g/day is consistent across BMI in patients with and without DM. Disclosure D. L. Bhatt: Research Support; Self; Afimmune Limited, Amarin Corporation plc, Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Idorsia Pharmaceuticals Ltd, Lexicon Pharmaceuticals, Inc., PLx Pharma Inc., Sanofi-Aventis. C. M. Ballantyne: Advisory Panel; Self; Amarin Corporation plc, Arrowhead Pharmaceuticals, Inc., Pfizer Inc., Consultant; Self; Amgen Inc., CSL Behring, Intercept Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Regeneron Pharmaceuticals Inc., Research Support; Self; Abbott, Amgen Inc., Ionis Pharmaceuticals, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc., Roche Diagnostic USA. E. A. Brinton: Consultant; Self; 89bio, Inc., DalCor Pharmaceuticals, Esperion, Novartis AG, Other Relationship; Self; Kowa Pharmaceuticals America, Inc., Speaker’s Bureau; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Amgen Inc., Esperion, Medicure. P. G. Steg: Consultant; Self; Amarin Corporation plc, Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation, Research Support; Self; Bayer AG, Sanofi, Servier Laboratories. S. B. Ketchum: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. R. A. Juliano: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. L. Jiao: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. R. T. Doyle: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. C. Granowitz: Employee; Self; Amarin Corporation plc. J. Tardif: Other Relationship; Self; Amarin Corporation plc, DalCor Pharmaceuticals, DalCor Pharmaceuticals, Sanofi, Research Support; Self; AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, REGENXBIO Inc., Servier Laboratories.

EPA’s pleiotropic mechanisms of action: a narrative review

ABSTRACT Treatment with icosapent ethyl 4 g/day, a highly purified and stable ethyl ester of eicosapentaenoic acid (EPA), demonstrated a significant reduction in atherosclerotic cardiovascular disease (ASCVD) events and death in REDUCE-IT. However, analyses of REDUCE-IT and meta-analyses have suggested that this clinical benefit is greater than can be achieved by triglyceride reduction alone. EPA therefore may have additional pleiotropic effects, including anti-inflammatory and anti-aggregatory mechanisms. EPA competes with arachidonic acid for cyclooxygenase and lipoxygenase, producing anti-inflammatory and anti-aggregatory metabolites rather than the more deleterious metabolites associated with arachidonic acid. Changing the EPA:arachidonic acid ratio may shift metabolic status from pro-inflammatory/pro-aggregatory to anti-inflammatory/anti-aggregatory. EPA also has antioxidant effects and increases synthesis of nitric oxide. Incorporation of EPA into phospholipid bilayers influences membrane structure and may help to prevent cardiac arrhythmias. Clinically, this may translate into improved vascular health, including regression of atherosclerotic plaque. Overall, EPA has a range of pleiotropic effects that contribute to a reduction in ASCVD.

Underlying mechanisms involved in the icosapent ethyl reduction of cardiovascular events still cannot be attributed to an anti-atherosclerotic effect.

Underlying mechanisms involved in the icosapent ethyl reduction of cardiovascular events still cannot be attributed to an anti-atherosclerotic effect.

The EVAPORATE trial provides important mechanistic data on plaque characteristics that have relevance to the REDUCE-IT results and clinical use of icosapent ethyl

The EVAPORATE trial provides important mechanistic data on plaque characteristics that have relevance to the REDUCE-IT results and clinical use of icosapent ethyl