Do patients benefit from omega-3 fatty acids?

Omega-3 fatty acids (O3FAs) possess beneficial properties for cardiovascular (CV) health and elevated O3FA levels are associated with lower incident risk for CV disease (CVD.) Yet, treatment of at-risk patients with various O3FA formulations has produced disparate results in large, well-controlled and well-conducted clinical trials. Prescription formulations and fish oil supplements containing low-dose mixtures of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have routinely failed to prevent CV events in primary and secondary prevention settings when added to contemporary care, as shown most recently in the STRENGTH and OMEMI trials. However, as observed in JELIS, REDUCE-IT, and RESPECT-EPA, EPA-only formulations significantly reduce CVD events in high-risk patients. The CV mechanism of action of EPA, while certainly multifaceted, does not depend solely on reductions of circulating lipids, including triglycerides (TG) and LDL, and event reduction appears related to achieved EPA levels suggesting that the particular chemical and biological properties of EPA, as compared to DHA and other O3FAs, may contribute to its distinct clinical efficacy. In vitro and in vivo studies have shown different effects of EPA compared with DHA alone or EPA/DHA combination treatments, on atherosclerotic plaque morphology, LDL and membrane oxidation, cholesterol distribution, membrane lipid dynamics, glucose homeostasis, endothelial function, and downstream lipid metabolite function. These findings indicate that prescription-grade, EPA-only formulations provide greater benefit than other O3FAs formulations tested. This review summarizes the clinical findings associated with various O3FA formulations, their efficacy in treating CV disease, and their underlying mechanisms of action.

Eicosapentaenoic Acid: between Cardiovascular Benefits and the Risk of Atrial Fibrillation.

In recent years, scientific research has increasingly focused on the cardiovascular benefits of omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplements. The most promising results emerged from the new trials on a high-dose eicosapentaenoic acid (EPA)-only approach, instead of the previously prescribed therapy with EPA + docosahexaenoic acid (DHA). The evidence of the reduction of cardiovascular events in patients at high cardiovascular risk with EPA is intriguing. However, physicians have expressed concern about the potential high risk of atrial fibrillation (AF) occurrence due to such an approach. This study aims to investigate the current evidence on the cardiovascular benefits of EPA and its association with atrial arrhythmogenesis. Current guidelines consider EPA (as IPE) treatment for selected patients but with no specific indication regarding AF risk evaluation. We propose a flowchart that could be a starting point for the future development of an algorithm to help clinicians to prescribe EPA safely and effectively, especially in patients at high risk of incipient AF.

Real-world safety of icosapent ethyl: analysis based on spontaneous reports in FAERS database.

BACKGROUND: The triglyceride-lowering drug, icosapent ethyl (IPE), was granted a new indication for the reduction of atherosclerotic cardiovascular disease risk in 2019. This study aimed to investigate the safety profile of IPE by mining the FDA Adverse Event Reporting System (FAERS) database. METHODS: The reporting odds ratio was used to analyze IPE's adverse events (AEs) based on the FAERS data from July 2012 to December 2022. We described the characteristics of AE reports and evaluated the clinical prioritization of AEs. Then we defined and analyzed nine interested adverse drug reactions (ADRs) in both overall and subgroups, and investigated the times to onset. RESULTS: The findings of our study strengthen the evidence for an increased risk of atrial fibrillation using IPE. IPE alone may not increase the risk of bleeding unless combined with antithrombotic drugs. Similar to statins, IPE alone can increase the risk of musculoskeletal pain, drug-related hepatic disorders, and hyperglycemia, but the risk could not double when IPE was combined with statins. Most ADRs occur in the early stage of treatment. CONCLUSIONS: This study provides a comprehensive real-world safety profile of IPE, which indicates that IPE is well-tolerated.

Omega-3 fatty acid supplements and risk of atrial fibrillation and 'micro-atrial fibrillation': A secondary analysis from the OMEMI trial.

BACKGROUND & AIMS: Recent randomized clinical trials have raised concerns regarding potential off target adverse effects from supplementation of n-3 polyunsaturated fatty acids (PUFA) on atrial fibrillation (AF) risk. We aimed to assess risk and potential mediators of AF and 'micro-AF' from n-3 PUFA in post-myocardial infarction (MI) patients. METHODS: In the OMEMI trial, 70-82 y. o. patients with a recent MI were randomized to 1.8 g/day of eicosapentaenoic-/docosahexaenoic acid (EPA/DHA) or placebo (corn oil) for two years. New-onset AF and 'micro-AF' was recorded by clinical detection and by screening with Zenicor thumb-ECG (adjudicated by blinded investigators). Serum EPA and DHA were measured at baseline and study end. RESULTS: At baseline, 759 of 1014 (75%) patients had no AF history. These patients were aged 75 ± 4 years and 71% were male. During follow-up, 43 patients developed new-onset AF (39 clinically-detected and 4 by thumb-ECG screening). In addition, 27 patients had episodes of micro-AF, yielding a total of 70 patients with new-onset AF or 'micro-AF'. In the n-3 PUFA group 46 (11.9%) had AF/'micro-AF' (28 AF, 18 'micro-AF') and in the placebo group 24 (6.5%) had AF/micro-AF (15 AF, 9 micro-AF); HR 1.90 (95%CI 1.16-3.11), P = 0.011. Changes in serum EPA (but not DHA) mediated the effect from n-3 PUFA on AF risk, explaining 65% of the association. CONCLUSION: Supplementation of n-3 PUFA post MI increases the risk of 'micro-AF' and AF, and increases in EPA seems to be an important mediator of the treatment effect from n-3 PUFA on the risk of AF. STUDY REGISTRATION: OMEMI Study; ClinicalTrails.gov identifier: NCT0184194.

A Critical Review of Icosapent Ethyl in Cardiovascular Risk Reduction.

Icosapent ethyl (IPE) was the first fish oil product the US Food and Drug Administration (FDA) approved to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in adults. IPE is an esterified version of eicosapentaenoic acid (EPA) and acts as a prodrug in the body to exert its effects. IPE affects the body primarily through triglyceride (TG) reduction and was initially indicated for hypertriglyceridemia in addition to statin therapy or for patients with statin intolerances. Various studies have investigated this agent, and multiple subanalyses have been conducted since the FDA approval. These subanalyses have assessed factors such as sex, statin therapy, high-sensitivity C-reactive protein levels (hs-CRP), and various inflammatory biomarkers in groups of patients taking IPE. This article aims to provide a critical review of the clinical data available regarding cardiovascular benefits of IPE in patients with ASCVD and its value as a treatment option for patients with elevated TG levels.

Cardiovascular Benefits of Icosapent Ethyl in Patients With and Without Atrial Fibrillation in REDUCE-IT.

Background In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), icosapent ethyl (IPE) versus placebo) reduced cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization, but was associated with increased atrial fibrillation/atrial flutter (AF) hospitalization (3.1% IPE versus 2.1% placebo; P=0.004). Methods and Results We performed post hoc efficacy and safety analyses of patients with or without prior AF (before randomization) and with or without in-study time-varying AF hospitalization to assess relationships of IPE (versus placebo) and outcomes. In-study AF hospitalization event rates were higher in patients with prior AF (12.5% versus 6.3%, IPE versus placebo; P=0.007) versus without prior AF (2.2% versus 1.6%, IPE versus placebo; P=0.09). Serious bleeding rates trended higher in patients with (7.3% versus 6.0%, IPE versus placebo; P=0.59) versus without prior AF (2.3% versus 1.7%, IPE versus placebo; P=0.08). With IPE, serious bleeding trended higher regardless of prior AF (interaction P value [Pint]=0.61) or postrandomization AF hospitalization (Pint=0.66). Patients with prior AF (n=751, 9.2%) versus without prior AF (n=7428, 90.8%) had similar relative risk reductions of the primary composite and key secondary composite end points with IPE versus placebo (Pint=0.37 and Pint=0.55, respectively). Conclusions In REDUCE-IT, in-study AF hospitalization rates were higher in patients with prior AF especially in those randomized to IPE. Although serious bleeding trended higher in those randomized to IPE versus placebo over the course of the study, serious bleeding was not different regardless of prior AF or in-study AF hospitalization. Patients with prior AF or in-study AF hospitalization had consistent relative risk reductions across primary, key secondary, and stroke end points with IPE. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01492361; Unique Identifier: NCT01492361.

Icosapent ethyl alleviates acetic acid-induced ulcerative colitis via modulation of SIRT1 signaling pathway in rats.

Ulcerative colitis (UC) is a global inflammatory bowel disease. This study aimed to assess the effects of icosapent ethyl on acetic acid-induced colitis in rats as well as the underlying mechanisms involved. 36 male Wister rats were equally divided into six groups: control, UC, mesalamine 100 mg/kg, icosapent 150mg/kg, icosapent 300 mg/kg, and EX527-icosapent 300 mg/kg groups. Except for control group, UC was induced by acetic acid instillation into colon. Drugs were administered once daily for one week then under thiopental anaesthesia, colons were excised. Colitis macroscopic and microscopic scores were assessed. A part of colon was homogenized for detection of malondialdehyde (MDA), inerleukin1 (IL-1ß), tumor necrosis factor (TNF-α), superoxide dismutase (SOD), phosphorylated Akt (pAkt) and caspase 3 levels. Silent information regulator 1 (SIRT1), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2 (Nrf2) mRNA expressions were detected. Mallory-stained colonic sections were examined for collagen fibres detection. Immunohistochemistry of NF-κB and p53 expressionsin colonic sections were assessed. Acetic acid induced colitis with increments in MDA, IL-1ß, TNF-α, and caspase 3 levels while decreased SOD, pAkt, SIRT1, HO-1, and Nrf2 with increased collagen fibres as well as NF-κB and p53. Icosapent decreased macro& microscopic colitis scores, MDA, IL-1ß, TNF-α, and caspase 3 levels while increased SOD, pAkt, SIRT1, HO-1, and Nrf2 with decreased collagen fibres as well as NF-κB and p53. The effects of icosapent 300 mg/kg were similar to mesalamine. Icosapent effects were antagonized by EX527. Icosapent alleviated acetic acid-induced colitis via its anti-inflammatory, antioxidant, and anti-apoptotic effects mediated in part by SIRT1 pathway activation.

Potential effects of icosapent ethyl on cardiovascular outcomes in cigarette smokers: REDUCE-IT smoking.

AIMS: Cigarette smoking is among the most well-established risk factors for adverse cardiovascular outcomes. We sought to determine whether icosapent ethyl (IPE), a highly purified form of eicosapentaenoic acid with antiatherothrombotic properties, may reduce the excessive risk of cardiovascular disease (CVD) attributable to smoking. METHODS AND RESULTS: Reduction of Cardiovascular Events with Icosapent Ethyl Trial (REDUCE-IT) was a multinational, double-blind trial that randomized 8179 statin-treated patients with elevated triglycerides and CV risk to IPE or placebo, with a median follow-up period of 4.9 years. Icosapent ethyl reduced the primary composite endpoint [CV death, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or hospitalization for unstable angina] by 25% (P < 0.0001). In the current analyses, the effect of IPE was evaluated in REDUCE-IT using post hoc analyses based on smoking history. Groups were classified as current smokers (n = 1241), former smokers (n = 3672), and never smokers (n = 3264). Compared with placebo, IPE use in combined current and former smokers (n = 4913) was associated with significant reductions in time to the primary composite endpoint {hazard ratio: 0.77 [95% confidence interval (CI): 0.68-0.87]; P < 0.0001} and in total events [rate ratio: 0.71 (95% CI: 0.61-0.82); P < 0.0001]. These benefits remained significant when subdivided into current and former smokers (P = 0.04, P = 0.005), with reductions in the key secondary composite endpoint (P < 0.0001) and in the individual components of CV death or non-fatal MI (P = 0.04, P = 0.01) and fatal or non-fatal MI (P = 0.009, P = 0.01), respectively. Benefits were consistent and significant in non-smokers as well. Overall, there were similar estimated rates of first occurrences of primary CVD endpoints in current smokers (23.8%) and former smokers (23.0%) assigned to IPE compared with never smokers on placebo (25.7%). CONCLUSION: In REDUCE-IT, IPE treatment was associated with a reduced risk of CV events in current and former smokers to levels observed in never smokers. While smoking cessation should always be recommended, these data raise the possibility that IPE treatment may attenuate CV hazards attributable to smoking.

Comparing the effects of docosahexaenoic and eicosapentaenoic acids on cardiovascular risk factors: Pairwise and network meta-analyses of randomized controlled trials.

BACKGROUND: Evidence from clinical trial studies suggests that docosahexaenoic acids (DHA) may have greater potential effects on improving cardiovascular risk factors than eicosapentaenoic acid (EPA). However, this evidence has not yet been meta-analyzed and quantified. The aim of this study was to evaluate and compare the effect of DHA and EPA monotherapy on cardiovascular risk factors based on paired and network meta-analysis. METHODS: Relevant articles published up to January 2022 were systematically retrieved from relevant databases. We included all Randomized Controlled Trials (RCTs) on adults that directly compared the effects of DHA with EPA and RCTs of indirect comparisons (DHA and EPA monotherapy compared to control groups). Data were pooled by pairwise and network meta-analysis and expressed as mean differences (MDs) with 95% CIs. The study protocol was registered with PROSPERO (Registration ID: CRD42022328630). RESULTS: Network meta-analysis of comparisons of DHA and EPA suggested significant comparable effects only on LDL-C (MD EPA versus DHA = -8.51 mg/L; 95% CI: -16.67; -0.35). However, the Network meta-analysis not show a significant effect for other risk factors. Furthermore, pairwise meta-analysis of direct comparisons of DHA and EPA showed significant difference in their effects on plasma glucose (MD EPA versus DHA = -0.31 mg/L; 95% CI: -0.60, -0.02), Insulin (MD EPA versus DHA = -2.14 mg/L; 95% CI: -3.26, -1.02), but the results were not significant for risk factors. CONCLUSION: Our findings suggest that both EPA and DHA act similarly on the markers under study, with slight changes in plasma glucose, insulin, and LDL-C.

Long-term safety and efficacy of MND-2119 (self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester) in patients with hypertriglyceridemia: Results from a multicenter, 52-week, open-label study.

BACKGROUND: In Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E which can be administered once-daily. OBJECTIVE: The objective of this study was to investigate the safety and efficacy of long-term administration of MND-2119 in hypertriglyceridemia patients. METHODS: In this multicenter, 52-week, open-label study, patients with high triglyceride (TG) (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=61) or MND-2119 4 g/day (n=61). RESULTS: The incidence of adverse events in MND-2119 2 g/day and MND-2119 4 g/day was 70.5% and 62.3%, respectively, and the incidence of adverse drug reactions was 9.8% and 8.2%, respectively. There were no notable problems in the safety assessments of both treatment groups. By Week 4, TG levels had decreased from baseline in both groups, and the TG reducing effect continued up to Week 52 (mean percentage change from baseline in TG at Week 52 [two-sided 95% confidence interval]: MND-2119 2 g/day: -16.71% [-26.61, -6.81], MND-2119 4 g/day: -21.01% [-27.86, -14.16]). In both groups, plasma EPA concentration at Week 4 was maintained up until Week 52 and the plasma EPA concentration at Week 52 was 200.5 ± 54.7 µg/mL in MND-2119 2 g/day and 308.6 ± 98.6 µg/mL in MND-2119 4 g/day. CONCLUSION: Long-term administration of MND-2119 was not associated with any safety-related problems. TG levels decreased by Week 4, and the TG reducing effect continued up to Week 52.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

Big Fish or No Fish; Eicosapentaenoic Acid and Cardiovascular Disease.

Benefits of omega 3 fatty acids for cardiovascular and other diseases have been touted for more than 50 years. The one clear clinical benefit of these lipids is the reduction of circulating levels of triglycerides, making them a useful approach for the prevention of pancreatitis in severely hypertriglyceridemic patients. After a series of spectacularly failed clinical trials that were criticized for the choice of subjects and doses of omega 3 fatty acids used, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) using a high dose of icosapent ethyl (IPE) reported a reduction in cardiovascular disease (CVD) events. However, this trial has generated controversy due to the use of mineral oil in the control group and the associated side effects of the IPA. This review will focus on the following topics: What are the epidemiologic data suggesting a benefit of omega 3 fatty acids? What might be the mechanisms for these benefits? Why have the clinical trials failed to resolve whether these fatty acids provide benefit? What choices should a clinician consider?

Icosapent ethyl for reduction of persistent cardiovascular risk: a critical review of major medical society guidelines and statements.

INTRODUCTION: REDUCE-IT demonstrated that adding 4 g/day of icosapent ethyl (IPE; purified ethyl ester of eicosapentaenoic acid [EPA]) to statins substantially reduced cardiovascular disease (CVD) events, with few adverse effects. These data prompted numerous leading medical societies across five continents, including the American College of Cardiology, the European Society of Cardiology, and the Japanese Circulation Society, to update their guidelines or scientific/consensus statements to recommend use of IPE for primary and secondary prevention of CVD events. AREAS COVERED: This review discusses the incorporation of IPE into international guidelines and scientific statements, noting areas of consensus and distinction. As background, this review also describes the CVD benefits and risks of IPE as a statin adjunct, and outlines current data regarding the potential mechanisms of CVD risk reduction by EPA (as IPE) beyond triglyceride reduction. EXPERT OPINION/COMMENTARY: IPE is unique among 'triglyceride-lowering' treatments in having strong CVD outcomes data and, therefore, a broad international consensus among professional medical society guidelines and statements endorsing its use for CVD risk reduction in patients generally meeting REDUCE-IT inclusion criteria. IPE should be considered for CVD prevention as a statin adjunct in all such patients.Plain Language SummaryCardiovascular disease (CVD) remains the leading cause of death worldwide. Statin monotherapy is conventionally used first-line to reduce the risk of CV events, such as heart attacks and strokes, in patients with elevated cholesterol. However, considerable risk remains despite appropriate control of cholesterol levels with a statin. Consequently, research has focused on treatment of additional therapeutic targets to reduce this remaining CV risk. One such target is elevated blood triglyceride levels. Unfortunately, most drugs that lower triglyceride levels, such as niacin, fibrates, and mixed omega-3 fatty acids, have not reduced the risk of cardiovascular events in clinical trials when added to statin therapy. However, the omega-3 fatty acid eicosapentaenoic acid ('EPA') administered in highly purified form as icosapent ethyl (IPE) has emerged as the first omega-3 fatty acid, and the first triglyceride-lowering agent to prevent CV events when added to statins. This was demonstrated most notably in the pivotal REDUCE-IT trial, in which IPE reduced the risk of major CV events by 25% in high-risk patients with mildly to moderately elevated triglyceride levels despite statin-controlled cholesterol levels. The mechanisms responsible for this reduction in CV events appear to go far beyond lowering triglyceride levels alone. In light of the positive results from the REDUCE-IT trial, IPE was approved for CV disease risk reduction globally, including in the United States, Canada, European Union, and the United Kingdom, and its use is being increasingly endorsed in United States and international statements and guidelines for managing CV risk. Despite minor differences among guidelines, there is strong consensus that IPE should be considered for use in CVD prevention in all patients who meet the proposed criteria.

Efficacy and safety of self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (MND-2119) versus highly purified eicosapentaenoic acid ethyl ester in patients with hypertriglyceridemia: Results from a 12-week randomized, double-blind, active-controlled, phase 3 study.

BACKGROUND: In Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E, which can be administered once-daily. OBJECTIVE: The objective of this study was to assess non-inferiority in the efficacy of MND-2119 in patients with hypertriglyceridemia compared with highly purified EPA-E. METHODS: In this multicenter, 12-week, double-blind study, patients with high triglyceride (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=145), MND-2119 4 g/day (n=145), EPA-E 1.8 g/day (n=145) or EPA-E 2.7 g/day (n=145). The primary endpoint was percentage change in TG levels from baseline to end of treatment. RESULTS: MND-2119 2, 4 g/day and EPA-E 1.8, 2.7 g/day reduced TG levels from baseline by -10.09%, -15.51%, -9.30%, and -8.80%, respectively. The TG reduction rate of MND-2119 2 g/day was non-inferior to that of EPA-E 1.8 g/day (LS mean difference: -0.42, 95%CI: -5.76 to 4.91). Moreover, the TG reduction rate of MND-2119 4 g/day was superior to that of MND-2119 2 g/day (LS mean difference: -5.74, 95%CI: -10.59 to -0.89). There were no remarkable safety differences between MND-2119 2 g/day and EPA-E 1.8 g/day and between MND-2119 4 g/day and EPA-E 2.7 g/day. CONCLUSION: Non-inferiority of MND-2119 2 g/day to EPA-E 1.8 g/day for efficacy, and superiority of MND-2119 4 g/day over MND-2119 2 g/day for efficacy were verified. MND-2119 was safe and well tolerated.

Benefits of icosapent ethyl for enhancing residual cardiovascular risk reduction: A review of key findings from REDUCE-IT.

BACKGROUND: REDUCE-IT was a multinational, double-blind trial that randomized 8179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. IPE was associated with a substantial reduction in the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Since the original publication of the trial, there have been a myriad of additional analyses confirming the benefit of IPE in various patient groups. Our objectives in this review are to summarize the key findings of the REDUCE-IT trial and its subsequent analyses as well as to call for the reevaluation and expansion of current guidelines to incorporate IPE as a therapy for patients at elevated cardiovascular risk with mild or moderate hypertriglyceridemia.

Cholesterol crystals and atherosclerotic plaque instability: Therapeutic potential of Eicosapentaenoic acid.

Atherosclerotic plaques associated with acute coronary syndromes (ACS), i.e. culprit lesions, frequently feature a ruptured fibrous cap with thrombotic complications. On imaging, these plaques exhibit a low attenuation, lipid-rich, necrotic core containing cholesterol crystals and are inherently unstable. Indeed, cholesterol crystals are causally associated with plaque vulnerability in vivo; their formation results from spontaneous self-assembly of cholesterol molecules. Cholesterol homeostasis is a central determinant of the physicochemical conditions leading to crystal formation, which are favored by elevated membrane free cholesterol content in plaque endothelial cells, smooth muscle cells, monocyte-derived macrophages, and foam cells, and equally by lipid oxidation. Emerging evidence from imaging trials in patients with coronary heart disease has highlighted the impact of intervention involving the omega-3 fatty acid, eicosapentaenoic acid (EPA), on vulnerable, low attenuation atherosclerotic plaques. Thus, EPA decreased features associated with unstable plaque by increasing fibrous cap thickness in statin-treated patients, by reducing lipid volume and equally attenuating intraplaque inflammation. Importantly, atherosclerotic plaques rapidly incorporate EPA; indeed, a high content of EPA in plaque tissue is associated with decreased plaque inflammation and increased stability. These findings are entirely consistent with the major reduction seen in cardiovascular events in the REDUCE-IT trial, in which high dose EPA was administered as its esterified precursor, icosapent ethyl (IPE); moreover, clinical benefit was proportional to circulating EPA levels. Eicosapentaenoic acid is efficiently incorporated into phospholipids, where it modulates cholesterol-enriched domains in cell membranes through physicochemical lipid interactions and changes in rates of lipid oxidation. Indeed, biophysical analyses indicate that EPA exists in an extended conformation in membranes, thereby enhancing normal cholesterol distribution while reducing propagation of free radicals. Such effects mitigate cholesterol aggregation and crystal formation. In addition to its favorable effect on cholesterol domain structure, EPA/IPE exerts pleiotropic actions, including antithrombotic, antiplatelet, anti-inflammatory, and proresolving effects, whose plaque-stabilizing potential cannot be excluded. Docosahexaenoic acid is distinguished from EPA by a higher degree of unsaturation and longer carbon chain length; DHA is thus predisposed to changes in its conformation with ensuing increase in membrane lipid fluidity and promotion of cholesterol aggregation into discrete domains. Such distinct molecular effects between EPA and DHA are pronounced under conditions of high cellular cholesterol content and oxidative stress. This review will focus on the formation and role of cholesterol monohydrate crystals in destabilizing atherosclerotic plaques, and on the potential of EPA as a therapeutic agent to attenuate the formation of deleterious cholesterol membrane domains and of cholesterol crystals. Such a therapeutic approach may translate to enhanced plaque stability and ultimately to reduction in cardiovascular risk.

Impact of Icosapent Ethyl on Cardiovascular Risk Reduction in Patients With Heart Failure in REDUCE-IT.

Background Patients with heart failure (HF) are at high risk for atherosclerotic cardiovascular disease. Studies of atherothrombotic treatments in this population have been disappointing to date. Icosapent ethyl reduced the risk of atherosclerotic cardiovascular disease among a broad array of statin-treated patients at elevated risk for atherosclerotic cardiovascular disease. Whether the treatment benefits of icosapent ethyl are consistent among those with HF is unknown. Methods and Results REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized 8179 participants, including 1446 (17.7%) patients with a history of HF (icosapent ethyl, N=703; and placebo, N=743). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. We used Cox regression to estimate the risk of outcomes of participants with and without HF. We estimated the placebo-controlled change in triglycerides and hs-CRP (high-sensitivity C-reactive protein) from baseline to 2 years. Among 1446 patients with HF, median age was 63.0 years, median body mass index was 31.0 kg/m2, and more were men (69.3%). Icosapent ethyl reduced triglycerides (median reduction, 33.5 mg/dL, or 15.4%; P<0.0001) and hs-CRP (35.1%; P<0.0001) compared with placebo, similar to patients without HF (P-interaction>0.90). The treatment effect on the primary end point in patients with HF history (hazard ratio [HR], 0.87; 95% CI, 0.70-1.08) was consistent with the effects observed in patients without HF history (HR, 0.73; 95% CI, 0.65-0.81) (P-interaction=0.13). Conclusions In REDUCE-IT, icosapent ethyl provided similar improvements in triglyceride levels and hs-CRP as well as similar cardiovascular risk reduction in patients with and without HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Reducing residual cardiovascular risk in Europe: Therapeutic implications of European medicines agency approval of icosapent ethyl/eicosapentaenoic acid.

Atherosclerotic cardiovascular disease (ASCVD) and its atherothrombotic complications impose a substantial disease burden in Europe, representing a cost of €210 billion per year for the European Union. Hypertriglyceridemia, a major risk factor for premature ASCVD, is present in more than 20% of the European population, and is a key feature of atherogenic dyslipidemia. Recent findings from the Progression of Early Subclinical Atherosclerosis (PESA) cohort in Spain showed that even in apparently healthy, middle-aged individuals without a history of cardiovascular (CV) risk, elevated triglyceride levels are associated with subclinical atherosclerosis and arterial inflammation. Emerging evidence from epidemiologic and genetic studies supports an independent causative role of triglycerides, triglyceride-rich lipoproteins, and their remnants in this pathology. Icosapent ethyl (IPE) is a highly purified, stable ethyl ester of eicosapentaenoic acid (EPA) that was initially approved by the United States Food and Drug Administration to treat severe hypertriglyceridemia, and subsequently received an expanded indication to reduce the risk of CV events in adult statin-treated patients. Approval was based on the pivotal, randomized, placebo-controlled, double-blind Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), which showed that high-dose IPE (4 g/day) significantly reduced the risk of primary and secondary composite endpoints comprising major CV events and CV death relative to placebo. In 2021, the European Medicines Agency (EMA) approved IPE to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated triglyceride levels (≥1.7 mmol/L [≥150 mg/dL]) and established CV disease, or diabetes and at least one other CV risk factor. Clinical studies in Europe, which included patients with acute myocardial infarction, coronary artery disease, and those undergoing cardiac rehabilitation, established that 12.5% to 23.3% of these high-risk populations may benefit from treatment with IPE. Such clinical benefit may in part result from the moderate triglyceride-lowering properties of IPE/EPA; equally however, concentrations of atherogenic remnant particle-cholesterol are markedly reduced. Furthermore, IPE/EPA exerts pleiotropic actions beyond its lipid-lowering properties, which include modulation of endothelial function, attenuation of intra-plaque inflammation and oxidative stress, and reduction in macrophage accumulation. Plasma phospholipids, into which EPA is primarily incorporated and transported, appear to serve as precursors for a series of anti-inflammatory metabolites involving the resolvins RvE1 to RvE3, a pathway which may confer cardioprotective benefits. In addition, plaque imaging data from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) and the Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography (CHERRY) trials show that plaque stabilization may be favorably affected. These factors may act synergistically to stabilize atherosclerotic plaques and reduce CV risk. In addition to robust efficacy data, multiple cost-utility studies across several countries indicate that IPE/EPA is a cost-effective treatment option that is favorably situated relative to some common willingness-to-pay thresholds. This review will evaluate the relevance of hypertriglyceridemia to residual ASCVD burden in statin-treated dyslipidemic patients, the potential of IPE/EPA to reduce the risk of ASCVD and cardiovascular mortality in high-risk patient populations, and the mechanisms which may underlie these effects. Finally, the clinical implications of the EMA label for IPE will be critically appraised in light of the updated 2019 European Society of Cardiology/European Atherosclerosis Society guidelines on the management of dyslipidemia and the recent European Atherosclerosis Society consensus statement on triglyceride-rich lipoproteins and their remnants, together with considerations of its cost-effectiveness across several countries.