Omega-3 fatty acids for cardiovascular event lowering

Abstract

Low-density lipoprotein cholesterol (LDL-C) is the main target for therapeutics aimed at reducing the risk of atherosclerotic cardiovascular disease (ASCVD) and downstream cardiovascular (CV) events. However, multiple studies have demonstrated that high-risk patient populations harbour residual risk despite effective LDL-C lowering. While data support the causal relationship between triglycerides and ASCVD risk, triglyceride-lowering therapies such as omega-3 fatty acids have shown mixed results in CV outcomes trials. Notably, icosapent ethyl, a purified formulation of eicosapentaenoic acid (EPA), has garnered compelling evidence in lowering residual CV risk in patients with hypertriglyceridaemia and treated with statins. In this review, we summarize studies that have investigated omega-3-fatty acids for CV event lowering and discuss the clinical implementation of these agents based on trial data and guidelines.

Graphical Abstract

omega-3 fatty acids, atherosclerotic cardiovascular disease, icosapent ethyl

Introduction

Atherosclerotic cardiovascular disease (ASCVD) continues to be the leading cause of mortality in the United States (US).¹ Lowering low-density lipoprotein cholesterol (LDL-C) is the predominant focus for reducing the risk of developing ASCVD and downstream cardiovascular (CV) events.² However, even with effective LDL-C lowering, residual risk remains in high-risk patient populations, such as those with type 2 diabetes mellitus, metabolic syndrome, and obesity.^3,4 Studies have demonstrated that additional apolipoprotein B-containing lipoproteins, such as triglyceride (TG)-rich lipoproteins, may contribute to the pathogenesis of atherosclerosis via multiple mechanisms.⁵ High TGs can be used as a marker for elevated levels of these TG-rich lipoproteins, and growing clinical evidence has associated hypertriglyceridaemia with residual ASCVD risk.^6–9 Data supporting the causal relationship between TG and ASCVD have led to a focus on targeting hypertriglyceridaemia to incrementally lessen the risk of future CV events. Yet, lipid-lowering therapies for hypertriglyceridaemia, such as fibrates and niacin, have not shown benefit in mitigating CV risk when used in conjunction with statins.^10–12

In addition to fibrates and niacin, omega-3 fatty acids can effectively lower TG levels. Mechanisms include reducing the rate of fatty acid incorporation into very-low-density lipoprotein (VLDL) and stimulating activity of lipoprotein lipase.¹³ Omega-3 fatty acids took centre stage when several trials showed inconsistent results in lowering CV events. The potential benefit of omega-3 fatty acids in decreasing CV events may be beyond that of their TG-lowering effects; it has been hypothesized that the pleiotropic effects of omega-3-fatty acids can lead to reduction in atherosclerosis.¹⁴ Omega-3 fatty acids exist in several sources: plant products such as nuts, vegetable oils, chia seeds, walnuts, and flax seeds are dietary sources of omega-3 fatty acids in the form of alpha-linolenic acid (ALA).¹⁵ ALA is converted to docosahexaenoic acid (DHA) via enzymatic steps, which include eicosapentaenoic acid (EPA) as an intermediary. EPA and DHA can also exist in dietary sources such as fish.¹⁶ Omega-3 fatty acids are often consumed in the form of fish oil supplements. Although these supplements have gained popularity, their impact on mitigating CV risk is limited due to lack of regulation in processing and unclear quality.¹⁷ Finally, omega-3 fatty acids exist in highly concentrated purified formulations, available with prescriptions such as icosapent ethyl, that have been studied in recent major clinical trials.

Past trials of omega-3 fatty acids to improve CV outcomes have been inconsistent in their results, with potential contributing factors including variability in trial design, patient population, and omega-3-fatty acid composition and dosing. In this review, we summarize the studies that have investigated omega-3-fatty acids for CV event lowering and discuss practical implications of trial data to the clinical setting (Graphical abstract).

Elevated TGs and CV risk

Hypertriglyceridaemia is highly prevalent in the US; 21.1% of adults had high TG levels (≥150 mg/dL) in data from 2015 to 2018.¹ Hypertriglyceridaemia can occur due to increased production of triglyceride-rich lipoproteins (TRLs), and therefore TG concentrations can be considered as a marker of apolipoprotein B (apoB) pro-atherogenic lipoproteins.¹⁸ Recently, several genetic and genome-wide analysis studies have linked plasma TG levels (a modifiable risk factor) to the development of ASCVD.^19,20 In one Mendelian randomization study, one standard deviation increase in TG levels was associated with a 54% increase in the risk for myocardial infarction (MI).^21,22 Furthermore, data from prospective studies in European populations have indicated a significant association between TG levels and coronary heart disease (CHD) risk, with one meta-analysis demonstrating an adjusted odds ratio of 1.72 [95% confidence interval (CI) 1.56–1.90] for individuals with TG values in the top third of the population compared with those in the bottom third.⁶ However, older studies have shown this association to be attenuated after adjustment for other lipoproteins, such as high-density lipoprotein cholesterol (HDL-C).⁶ Klempfner et al demonstrated that in a cohort of 15 355 patients from the Bezafibrate Infarction Prevention (BIP) trial, 22-year mortality risk for patients with severe hypertriglyceridaemia (≥500 mg/dL) was increased by 68% vs. patients with low-normal TG (<100 mg/dL). This was after adjustment for covariates including HDL-C.²³ Additionally, in an observational longitudinal cohort study using electronic health record data, patients with ASCVD and statin-controlled LDL-C were more likely to have non-fatal MI and coronary or peripheral revascularization over mean follow-up of 5 years in the high TG group.²⁴ In a retrospective administrative claims analysis of more than 20 000 statin-treated patients with diabetes and/or ASCVD, the cohort with high TG had increased risk of major CV events (HR 1.35, 95% CI 1.225–1.485) along with higher average total healthcare cost per month and rate of inpatient hospital stay.²⁵ These studies support the notion that elevated TG contribute to residual CV risk in statin-treated patients.

Despite epidemiologic, genetic, and clinical evidence for increased CV risk with hypertriglyceridaemia, attempts to reduce this risk using agents that lower TGs, such as fibrates and niacin, have been disappointing.^10,26,27 In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal CV events, non-fatal MI, or non-fatal stroke compared with simvastatin alone in a patient population with type 2 diabetes mellitus.¹⁰ Similarly, in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global health Outcomes) trial, in patients with established CV disease, the combination of niacin and LDL-lowering therapy did not reduce CV events; though, niacin showed a trend towards benefit in the subset of patients within the highest TG tertile (≥198 mg/dL) in a post hoc analysis.²⁶ However, no difference in incidence of major vascular events between groups (15.1 vs. 15.5%) was found among high TG patients in the HPS2-THRIVE (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) trial, which investigated niacin and laropiprant vs. placebo.¹² Furthermore, in the PROMINENT (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabetes) study, randomization of patients with type 2 diabetes mellitus taking moderate to high intensity statins with TG levels 200–499 mg/dL and HDL-C ≤ 40 mg/dL to pemafibrate—a selective peroxisome proliferator-activated receptor α modulator—did not reduce CV events as compared to placebo, despite lowering TG levels.²⁸

Mechanisms of action of omega-3-fatty acids

Lowering of TGs

Omega-3 fatty acids can lower TG by reducing VLDL production, increasing VLDL clearance, and stimulating lipoprotein lipase.¹³ The MARINE (Multi-centre, plAcebo-controlled, Randomized, double-blINd, a 12-week study with an open-label Extension) trial demonstrated that 4 g/day of icosapent ethyl (a highly purified omega-3 fatty acid with >96% EPA) reduced placebo-corrected TG levels by 33.1% without increasing LDL-C in patients (n = 229) with fasting TG >500 mg/dL.²⁹ Furthermore, the ANCHOR [Effect of AMR101 (Ethyl Icosapentate) on Triglyceride Levels in Patients on Statins With High Triglyceride Levels] trial also confirmed the safety of icosapent ethyl and its ability to decrease TG levels in high-risk statin-treated patients (n = 702) with residual high TG (200–500 mg/dL) despite LDL-C < 100 mg/dL. The median placebo-adjusted change in TG levels from baseline was 21.5% with 4 g/day of icosapent ethyl.³⁰ TG lowering has also been demonstrated in trials of mixed omega-3 fatty acids containing both EPA and DHA. In the EVOLVE (EpanoVa fOR Lowering Very high triglyceridEs) trial, TGs were lowered from baseline by 25.5–30.9% with various doses of the mixed omega-3 fatty acid formulation in patients with TG ≥ 500 mg/dL.³¹ Of note, LDL-C was significantly increased (19 vs. 3% in placebo) with 2 and 4 g/day omega-3 fatty acid formulations, but there was no increase in circulating concentrations of atherogenic lipoprotein particles as evidenced by no change in apoB concentrations.³¹

Mechanisms beyond TG lowering

The benefits of omega-3- fatty acids extend beyond that of TG lowering, and the full range of biological effects remain to be fully investigated. Current hypotheses include pleiotropic effects mediated by EPA and downstream anti-inflammatory and antithrombotic effects. EPA has been shown to diminish markers of inflammation, which is one of the drivers of atherosclerosis. The MARINE and ANCHOR trials of icosapent ethyl suggest anti-inflammatory effects with reduction in oxidized LDL, lipoprotein-associated phospholipase A₂ (Lp-PLA2), and high-sensitivity C-reactive protein (hsCRP).³² There are also differences between EPA and DHA in their effects on lipid oxidation and endothelial function,^33–35 likely mediated by variations in the way they integrate into the cell membrane^36–38 (Figure 1). EPA stabilizes the phospholipid bilayer by allowing cholesterol to remain more evenly distributed while DHA affects membrane fluidity by promoting formation of disordered domains, which subsequently disrupts the cell membrane.³⁹ Reducing the cholesterol-rich domains mediated by EPA may alleviate inflammation and improve endothelial dysfunction. Given that atherosclerosis is the product of endothelial dysfunction and inflammation and is associated with changes in membrane lipid structure with increased permeability, lipid oxidation, and generation of reactive oxygen species, the ability to modulate these pathways with EPA is promising.^40,41

Figure 1

Differences in eicosapentaenoic acid and docosahexaenoic acid. Eicosapentaenoic acid and docosahexaenoic acid are different in their tissue distributions, effects on membrane structure, and ability to modulate inflammation, oxidative stress, and endothelial dysfunction.

Randomized trials of omega-3 fatty acids

There have been several randomized clinical trials of omega-3 fatty acids for CV event lowering (Table 1). The GISSI-P (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Prevenzione) trial randomized patients with recent MI to omega-3 fatty acid supplements (1 g mixture of EPA and DHA) and demonstrated a reduction in the composite outcome of death, non-fatal MI, and stroke by 10%. However, only 5% of patients were on statins at baseline, making it less generalizable to current clinical practice.⁴² A constellation of subsequent large scale clinical trials failed to show benefit of omega-3 fatty acids. The ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial investigated a population of patients at high risk for CV events who had impaired glucose tolerance or diabetes; randomization of patients to 1 g capsule of ethyl esters of omega-3 fatty acids with median follow-up of 6.2 years demonstrated a lowering of TG levels by 14.5 mg/dL but showed no difference in the primary outcome of death from CV causes between groups. In this trial, 53% of patients were on a statin at baseline.⁴³

Table 1

CV outcomes of trials of mixed omega-3 fatty acids

Trial (year)	# of patients	Patient population	% Baseline statin use	Intervention	Primary results
GISSI—P (1999)	11, 324	Recent MI (≤3 months)	5%	Synthetic α-tocopherol (850–882 mg EPA + DHA ethyl ester) vs. no supplement	Composite endpoint of all-cause death, non-fatal MI, and non-fatal stroke
					RR 10%; 95% CI 1–18; P = 0.048
OMEGA (2010)	3, 851	Admitted for acute MI	94%	1 g omega-3 fatty acid ethyl ester (460 mg EPA + 380 mg DHA) vs. olive oil placebo	Sudden cardiac death
					1.5 vs. 1.5%; P = 0.84
ORIGIN (2012)	12, 536	Impaired fasting glucose or diabetes, high risk for CV events	53%	1 g omega-3 fatty acid capsule (465 mg EPA + 375 mg DHA) vs. olive oil placebo	CV mortality
					9.1 vs. 9.3%
					HR 0.98; 95% CI 0.87–1.10; P = 0.72
ASCEND Omega-3 (2018)	15, 450	With diabetes and no ASCVD	75%	1 g omega-3 fatty acid (EPA + DHA) vs. olive oil placebo	MACE (vascular death, MI, stroke/TIA)
					8.9 vs. 9.2%
					Rate ratio 0.97; 95% CI 0.87–1.08
					P = 0.55
VITAL (2019)	25, 871	No known CVD	35%	1 g omega-3 fatty acid (EPA + DHA) vs. olive oil placebo	Major CV events (composite of MI, stroke, death from CV causes)
					HR 0.92; 95% CI 0.8–1.06; P = 0.24
STRENGTH (2020)	13, 078	High-risk for CV event; on statin for at least 4 weeks; LDL <100 or treated with maximally tolerated statin; TG 180–500 mg/dL	100%	4 g omega-3 carboxylic acid (EPA + DHA) vs. corn oil placebo	Composite of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or UA requiring hospitalization
			50% high-intensity
					12 vs. 12.2%
					HR 0.99; 95% CI 0.9–1.09; P = 0.84
OMEMI (2020)	1, 027	Patients age 70 to 82 years with recent acute MI (2–8 weeks)	97%	1.8 g omega-3 fatty acid (930 mg EPA + 660 mg DHA) vs. corn oil placebo	Non-fatal acute MI, unscheduled revascularization, stroke, all-cause death, heart failure hospitalization
					21.4 vs. 20%
					HR 1.08; 95% CI 0.82–1.41; P = 0.6

TG, triglyceride; MI, myocardial infarction; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; GISSI-P Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico Prevenzione; RR, relative risk; CI, confidence interval; ORIGIN, Outcome Reduction with an Initial Glargine Intervention; CV, cardiovascular; HR, hazard ratio; ASCEND, A Study of Cardiovascular Events in Diabetes; ASCVD, atherosclerotic cardiovascular disease; TIA, transient ischaemic attack; VITAL, Vitamin D and Omega-3 Trial; STRENGTH, Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridaemia; UA, unstable angina; OMEMI, Omega-3 Fatty acids in Elderly with Myocardial Infarction.

The ASCEND (A Study of Cardiovascular Events in Diabetes)-Omega 3 trial also investigated patients with diabetes, but its population consisted of patients without evidence of ASCVD. Patients were randomized (n = 15 480) to 1 g of omega-3 fatty acids or a placebo of olive oil. During a mean follow-up of 7.4 years, there was no difference in the primary endpoint of first serious vascular event, defined as composite of MI, stroke, transient ischaemic attack, or vascular death (rate ratio 0.97; 95% CI 0.87–1.08). However, in exploratory analyses, there were fewer vascular deaths in the fatty acid group vs. placebo (rate ratio 0.81; 95% CI 0.67–0.99).⁴⁴ Another primary prevention trial, VITAL (Vitamin D and Omega-3 Trial), involved 25 871 participants who received supplementation with omega-3 fatty acids vs. placebo and found that during a median follow-up of 5.3 years, there was no difference in incidence of major adverse CV events (HR 0.92; 95% CI 0.8–1.06). Although, in secondary endpoint analyses, there was lower incidence of total MI (HR 0.72; 95% CI 0.59–0.9) and composite CHD (HR 0.83; 95% CI 0.71–0.97).⁴⁵

Other contemporary trials have also been unable to demonstrate CV protection with omega-3 fatty acids. For example, in the STRENGTH (Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridaemia) trial—comprised of 13 078 patients at high CV risk with hypertriglyceridaemia and low levels of HDL-C—4 g/day of omega-3 carboxylic acid (a formulation of EPA and DHA) did not show any benefit in the primary composite outcome when compared to a placebo of corn oil.⁴⁶ Additionally, in the OMEMI (Omega-3 Fatty acids in Elderly with Myocardial Infarction) trial, which investigated patients with recent acute MI aged 70–82, there was no reduction in events with 1.9 g of EPA + DHA.⁴⁷ Data from meta-analyses have also been mixed; one study demonstrated no significant association of omega-3 fatty acids with fatal or non-fatal CHD or any major vascular events.⁴⁸ However, in a meta-analysis of 18 randomized controlled trials and 16 prospective studies, there was reduction with EPA + DHA in CHD in higher-risk populations with elevated TG and LDL-C, though there was no decrease in CHD in the overall population.⁴⁹ Another meta-analysis, which did not include STRENGTH and OMEMI, found a lower risk of MI, total CHD, and total cardiovascular disease (CVD) with omega-3 fatty acids yet there was no association seen for stroke.⁵⁰ Furthermore, a meta-analysis of 40 studies of EPA + DHA supplements showed lower risk of MI (RR 0.87; 95% CI 0.8–0.96) with number needed to treat (NNT) of 272. Nevertheless, there was no association with overall CVD events. There was a dose-effect relationship seen with the EPA + DHA formulations; each additional 1 g/day was associated with risk reduction of 9% in MI,⁵¹ which raises the question of whether one cause of discrepancies in trials is the varying concentrations of omega-3 fatty acids utilized.

Overall, the trials of omega-3 fatty acids have differed considerably in terms of the population studied (primary prevention vs. secondary prevention) as well as in baseline characteristics, including statin use and baseline TG levels. Furthermore, all of the trials discussed thus far have included a combination of EPA and DHA, and the meta-analyses above included studies with wide heterogeneity in the composition of omega-3 fatty acids. Given differential effects of EPA and DHA, the formulations used may considerably affect results. Moreover, the threshold concentration of EPA achieved within the trial may be a relevant factor given the evidence of a dose response; several of these trials had lower-dose preparations which may have diluted any potential benefit.⁵²

Randomized trials of EPA

While the trials discussed above included combined formulations of EPA and DHA, the JELIS (Japan EPA Lipid Intervention Study) trial in 2007 specifically investigated 1.8 g of EPA vs. statin therapy (low-dose 10 mg pravastatin or 5 mg simvastatin) in a patient population comprised mostly of those without a history of CVD. There was a 19% relative risk reduction in ASCVD events at a median follow-up of 4.6 years. The outcome was driven by a statistically significant reduction in hospitalizations for unstable angina while no other individual endpoints (such as non-fatal MI, stroke, revascularization, or CV mortality) were significantly different. Limitations of this trial include lack of placebo and lack of use of high-intensity statin as comparison. Remarkably, the diminished coronary events seen with EPA were irrespective of reduction of LDL-C, indicating that other factors influence these beneficial effects. Furthermore, EPA was most effective in the high TG (≥150 mg/dL) and low HDL (<40 mg/dL) group of patients, in which there was a 52% reduction in ASCVD events.^53,54

Building off of the results of JELIS, REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), evaluated 2 g twice daily of icosapent ethyl (purified stable ethyl ester of EPA) vs. placebo in 8179 patients with CVD or diabetes and CVD risk factors. The population consisted of patients with median LDL of 75 mg/dL and TG of 135–500 mg/dL.⁵⁵ The trial demonstrated risk reduction by 25% in CVD events, including death, MI, stroke, revascularization, or hospitalization for unstable angina (17.2% in intervention vs. 22% in placebo, HR 0.75; 95% CI 0.68 to 0.83, P < 0.001) with a median follow-up of 4.9 years.⁵⁶ The total utilized dose of 4 g daily was a higher dose than prior trials, and the formulation of a highly purified EPA ethyl ester also differed from prior trials that had failed to show benefit with omega-3 fatty acids. In comparison, JELIS had used a lower dose of icosapent ethyl—1.8 g. Nevertheless, there were equivalent plasma EPA levels seen in JELIS as with the 4 g of icosapent ethyl used in REDUCE-IT.⁵⁶ In terms of safety, there were more hospitalizations for atrial fibrillation and atrial flutter in the intervention group in REDUCE-IT, though rates were overall low.⁵⁷ There was also a trend towards higher difference overall rates of serious adverse bleeding events with icosapent ethyl (2.7 vs. 2.1%, P = 0.06).⁵⁶

The CV benefits of icosapent ethyl are quite robust, and this was demonstrated by consistent and significant reductions in CV events as determined by independent, blinded clinical endpoint committee adjudication as well as investigator-reported assessments.⁵⁸ Also, benefit was consistent early on in the study and persisted across pre-specified interim analyses.⁵⁹ Several investigations from REDUCE-IT have also established the generalizability of the results to various patient populations. A pre-specified analysis of patients enrolled in the trial in the US showed strong risk reductions with no heterogeneity between US and non-US subgroups, underscoring US patients derive as much benefit from the medication as seen in the overall trial.⁶⁰ Furthermore, while other lipid-lowering therapies may have less efficacy and higher adverse events in patients with chronic kidney disease (CKD), icosapent ethyl was shown to reduce ischaemic events across a range of estimated glomerular filtration rate (eGFR) and CKD status. Tolerability and safety were also consistent. Though bleeding rates and atrial fibrillation/flutter event rates were higher with decreasing eGFR, the relative risks with icosapent ethyl were similar across eGFR categories.⁶¹

In addition, the ability of icosapent ethyl to address residual risk for CV outcomes after coronary artery bypass grafting (CABG) was demonstrated in a subgroup analysis of patients that showed a decrease in the primary endpoint with absolute risk reduction of 6.2% and NNT of 16 in those with prior CABG (22.5% of trial population).⁶² Similarly, patients who have undergone percutaneous coronary intervention (PCI) are one of the more high-risk groups in danger of subsequent CV events. 41.7% of REDUCE-IT participants had prior PCI, and a post hoc analysis demonstrated a 34% reduction in the primary composite end point (HR 0.66).⁶³ Another post hoc analysis investigated benefit in patients with prior MI (45.2% of population) and revealed a reduction in the primary endpoint from 26.1% to 20.2% with icosapent ethyl vs. placebo (HR 0.74; 95% CI 0.65–0.85). There was a 35% relative risk reduction in total ischaemic events, 34% reduction in MI, 30% reduction in CV death, and 20% reduction in all-cause mortality.^64,65 There were similar reductions in endpoints in those who did or did not have a history of prior coronary revascularization.^64,65 Proof of benefit in such high-risk populations adds to the growing body of evidence in support of icosapent ethyl.

Furthermore, in a pre-specified analysis, there was a reduction in total primary endpoint events (rate ratio 0.70; 95% CI 0.62–0.78), which highlights the substantial decrease in first, subsequent, and total ischaemic events with icosapent ethyl.⁶⁶ Also, analyses have demonstrated no difference in outcomes based on baseline TG levels.⁶⁷ This benefit across ischaemic endpoints regardless of baseline TG levels further substantiates the hypothesis that the benefit from icosapent ethyl stems from mechanisms of action beyond TG lowering. In REDUCE-IT REVASC, a sub-analysis, reduction was demonstrated in elective, urgent, and emergent coronary revascularization along with a decrease in the need for PCI and CABG.⁶⁸ This emphasizes the impacts of EPA on direct atherothrombotic burden.

The results of REDUCE-IT have garnered controversy due to lack of benefit seen in other contemporary trials of high-dose omega-3 fatty acids, such has the STRENGTH trial. Postulations include clinical significance of the different placebos used between the two trials. There have been theories regarding whether the positive results of icosapent ethyl may be due to theoretical negative effects of the mineral oil placebo used in REDUCE-IT, given that net change in LDL-C was –1.2% in those allocated to icosapent ethyl compared to 10.9% in those in the mineral oil group.⁵⁶ Notwithstanding, other studies have provided no evidence that mineral oil affects absorption of other medications (e.g. statins).^14,69 Additionally, no difference in progression of total plaque and total non-calcified plaque volume by coronary computed tomography angiography (CCTA) has been reported in mineral oil placebo participants compared to non-mineral oil placebo participants.⁷⁰ The consistent benefit seen for icosapent ethyl across different statin types, including hydrophilic and hydrophobic statins, further argues against an interaction between mineral oil and statin absorption.⁷¹

The differing results in REDUCE-IT and STRENGTH are unlikely to be due to placebo alone, but rather stem from the inherent biological differences in the omega-3 fatty acid formulations used. The carboxylic acid used in STRENGTH has variable absorption depending on dietary fat content compared to the ethyl ester of EPA used in REDUCE-IT. Icosapent ethyl also has 25% more EPA per dose than the omega-3 carboxylic acid used in STRENGTH, which explains the 61% higher blood levels of EPA in REDUCE-IT vs. STRENGTH.⁷² The fundamental differences in EPA as compared to DHA may also explain the differential results. EPA is known to have more potent antioxidant effects as compared to DHA and can also decrease macrophage accumulation and inflammatory markers, all of which modulate atherosclerosis.^14,73,74 EPA treatment of endothelial cells has shown anti-inflammatory and cytoprotective cellular changes.⁷⁵ Likewise, data from a meta-analysis of randomized controlled trials of omega-3 fatty acids confirm this difference between EPA monotherapy and EPA and DHA combinations. In this analysis, there was higher relative risk reductions in CV mortality, non-fatal MI, CHD events, and revascularization with EPA monotherapy.⁷⁶ Overall, the anti-inflammatory and antithrombotic effects of EPA along with modulation of endothelial dysfunction may contribute to reducing the development of atherosclerosis and stabilizing atherosclerotic plaque.^73,77 An in vitro study demonstrated that EPA significantly inhibited LDL oxidation by 75% while DHA, in comparison, exhibited lower antioxidant activity.⁷⁸ However, the exact causal mechanisms to explain the benefit detected in REDUCE-IT still remain uncertain. A sub-study of REDUCE-IT indicated that icosapent ethyl had minimal effects on biomarkers associated with atherosclerosis (homocysteine, oxidized-LDL-C, interleukin-6, Lp-PLA2, hsCRP, interleukin-1β) though there were small absolute increases in certain biomarkers, including hsCRP, in patients in the mineral oil placebo group over time.⁷⁹ However, an experimental model showed that neither mineral nor corn oil affected LDL oxidation.⁷⁸

The aforementioned trials investigated icosapent ethyl in a mixed primary and secondary prevention population. In contrast, the RESPECT-EPA (Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy—Statin and Eicosapentaenoic Acid) trial specifically examined the utility of icosapent ethyl in a secondary prevention population; 2506 Japanese patients with stable coronary artery disease and EPA/arachidonic acid ratio below 0.4 were randomized to 1.8 g icosapent ethyl plus statin or to statin therapy alone. Rate of the primary endpoint of CV death, non-fatal MI, non-fatal cerebral infarction, unstable angina, and coronary revascularization was the same across groups at two years of follow-up, but there was a trend towards benefit with icosapent ethyl at six years in the primary endpoint (10.9 vs. 14.9%, HR 0.785; 95% CI 0.616–1.001, P = 0.055) and a nominally significant reduction in the secondary endpoint of sudden cardiac death, MI, unstable angina, or coronary revascularization (8 vs. 11.3%, P = 0.031).⁸⁰ Despite being underpowered, the trial adds to existing evidence showing benefit of EPA in decreasing coronary events regardless of the placebo group.

Several imaging studies have confirmed the benefit of EPA formulations in regards to atherosclerosis. The CHERRY (Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography) trial consisted of 193 patients in Japan who had undergone PCI; icosapent ethyl in combination with pitavastatin showed significant reduction in atheroma volume (assessed via intravascular ultrasound) compared to pitavastatin alone. The baseline TG levels in this trial were not high (mean TG of 110 mg/dL in intervention group), further proving that EPA can stabilize plaques.⁸¹ Furthermore, in the EVAPORATE (Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy) trial, 4 g/day of icosapent ethyl decreased rates of plaque progression using CCTA and affected plaque volume and composition in a trial of 80 patients. The primary endpoint of low-attenuation plaque—a component of vulnerable plaque—was significantly reduced with icosapent ethyl compared with placebo. This reduction in plaque progression without significant difference in LDL-C or TG further supports the pleiotropic and non-lipid effects of omega-3 fatty acids.^82,83 However, there were no significant differences in the Agatston score progression rates, so it was unclear if icosapent ethyl modified calcified plaque volume.⁸³ Notably, Bittner et al. showed in a study of 71 patients that low levels of omega-3-fatty acids (EPA + DHA) had significant inverse association with early onset of coronary artery calcium.⁸⁴ While EVAPORATE specifically investigated plaque burden, a recent sub-study utilizing data from the trial demonstrated that icosapent ethyl also led to significant benefits in coronary physiology compared with placebo. Improvement in fractional flow reserve (FFR), derived from CCTA, was seen at 9 months and sustained at 18-month follow-up.⁸⁵

Clinical perspective and practical implications

While REDUCE-IT and its sub analyses provide compelling evidence for the benefit of icosapent ethyl in lowering residual CV risk, the next challenge is the implementation of the medication in daily clinical practice.⁸⁶ Food and Drug Administration (FDA) approval of the medication was initially for severe hypertriglyceridaemia (>500 mg/dL) but expanded to include indications for CVD risk reduction after REDUCE-IT.⁸⁷ Now, it is approved as an adjunct to maximally tolerated statin therapy in patients with fasting or non-fasting TG >150 mg/dL and established CVD or diabetes and more than two CVD risk factors. There are no particular criteria for LDL-C levels, as icosapent ethyl provides CV benefit regardless of baseline LDL-C.

Several studies have placed the trial in the context of real-world clinical practice. In one study of 2 424 865 adults in Ontario with hypertriglyceridaemia and controlled LDL-C, 25% of the cohort potentially qualified for icosapent ethyl.⁸⁸ Similarly, a study from the CLARIFY (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) registry supported the generalizability of REDUCE-IT; 15% of patients with established coronary artery disease were eligible for the medication.⁸⁹ Also, in a large contemporary Canadian cohort of patients with a history of CABG and currently on statin, 26.4% would be eligible for icosapent ethyl according to REDUCE-IT and FDA criteria.⁹⁰ In another study applying the results of REDUCE-IT to patients hospitalized for MI in France, it was demonstrated that 12.5% of patients could benefit from icosapent ethyl.⁹¹ Furthermore, icosapent ethyl was seen as cost effective in an economic evaluation analysis from REDUCE-IT. Treatment yielded more quality-adjusted life years than standard care and was projected to cost save over a lifetime with a 58.4% probability of costing less and being more effective.⁹²

Following the results of REDUCE-IT and its several sub studies, guidelines have incorporated icosapent ethyl into their recommendations. The 2020 American Diabetes Association guidelines state that for patients on statins with well-controlled LDL-C and TG 135–499 mg/dL, addition of icosapent ethyl can be considered to reduce CV risk (level A recommendation).⁹³ However, the 2018 American College of Cardiology/American Heart Association guidelines were from before REDUCE-IT and therefore do not have any statement regarding icosapent ethyl. They do have a class IIa, B-NR recommendation in adults with persistent severe hypertriglyceridaemia (>500 mg/dL) to adhere to low-fat diet and consume omega-3 fatty acids.⁹⁴ In the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society guidelines for dyslipidemias, there is a Class IIa, LOE B for icosapent ethyl 2 g twice per day in combination with a statin in patients with TG levels 135–499 mg/dL despite statin therapy.⁹⁵ Furthermore, the 2021 ESC Prevention Guidelines recommend icosapent ethyl in high-risk patients if TG levels still elevated (>135 mg/dL) despite being on statins and adopting lifestyle measures (class IIb).⁹⁶ Similarly, the National Lipid Association guidelines also recommend icosapent ethyl in patients older than 45 with clinical ASCVD or older than 50 with diabetes and more than 1 risk factor with TG 135–499 mg/dL on maximally tolerated statin (class I, level B-R).⁹⁷

Other considerations for prescribing high-dose omega-3 fatty acids include the risk of atrial fibrillation, which was seen in REDUCE-IT (rate 5.3 vs. 3.9%, P = 0.003) and STRENGTH (new onset rate 2.2 vs. 1.3%, HR 1.69; 95% CI 1.29–2.21, P < 0.01). The rate of hospitalization for atrial fibrillation or flutter was also higher in patients taking icosapent ethyl (3.1 vs. 2.1%, P = 0.004) in REDUCE-IT. Therefore, in patients with poorly controlled atrial fibrillation or flutter the drug should likely be avoided.

In addition, patients may inquire about dietary sources of omega-3-fatty acids and fish oil supplements. In a prospective longitudinal study with ST-elevation MI patients, elevated marine omega-3-fatty acids (EPA) was inversely related to MACE and CV-hospital re-admission. Vegetable omega-3 (ALA) was also inversely related to all-cause mortality.⁹⁸ The findings support that consumption of foods rich in omega-3 fatty acids may be an effective strategy. However, in regards to fish oil supplements, the results from trials such as REDUCE-IT do not apply, as these supplements generally contain less omega-3 fatty acids than claimed and often have other types of saturated or oxidized fats that may interfere with potential benefits.⁹⁹

Conclusion and future directions

Patients treated with statins may have residual CV risk despite achievement of LDL-C goals. Hypertriglyceridaemia is a target for reducing this persistent CV risk. While trials of mixed omega-3 fatty acids have failed to exhibit CV event lowering, REDUCE-IT rigorously demonstrated the efficacy of a high-dose EPA preparation (icosapent ethyl) in patients with hypertriglyceridaemia on maximally tolerated statin with CVD or with diabetes and CVD risk factors. Given that the benefit of icosapent ethyl extends beyond its TG-lowering effects, further work is needed to understand the molecular mechanisms and pleiotropic actions. Next steps will also involve implementation of icosapent ethyl into the real-world setting and both identifying and addressing barriers to its clinical use. The future of utilizing omega-3 fatty acids in CV event lowering is also dependent on upcoming studies designed to evaluate the effect of icosapent ethyl in specific populations and identify which patients derive the most benefit.

Author contribution

G.K. and D.L.B. contributed to the conception or design of the work. G.K. drafted the manuscript. All authors contributed to the acquisition, analysis, or interpretation of data for the work. All authors critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Funding

None. Amarin paid the journal open access charges.

Author notes

Conflict of interest: G.K. has no disclosures. R.P.M. has received research funding or consulting from Amarin, Lexicon, Esperion, and HLS Therapeutics. Ph.G.S. has received grant support from Bayer/Janssen, Merck, Sanofi, Amarin, and Servier; has received fees for serving on a steering committee or executive steering committee from Bayer/Janssen, Amarin, Novartis, Boehringer Ingelheim, and Idorsia; has received lecture fees from Merck, Sanofi, Amgen, Bristol Myers Squibb, and AstraZeneca; has received fees for serving as co-chair of trials from Sanofi; has received consulting fees from Sanofi, Amarin, Amgen, Bristol Myers Squibb, Novartis, Regeneron, Eli Lilly, Novo Nordisk, and AstraZeneca; has received fees for serving on critical event committees from Bristol Myers Squibb and Pfizer; has received fees for serving as chair of a data monitoring committee from Servier; and has received fees for serving as chair of a registry from Servier. D.L.B. discloses the following relationships—Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, Hims, SFJ, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo.