Icosapent ethyl: prescription-grade eicosapentaenoic acid to reduce cardiovascular risk

Atherosclerotic cardiovascular (CV) disease remains a leading cause of morbidity and mortality in Australia, imposing a substantial burden on healthcare expenditure.¹ Despite advances in the management of modifiable CV risk factors, such as intensive lowering of LDL cholesterol (LDL-C) with high-intensity statins, ezetimibe and proprotein convertase subtilisin/kexin type 9-directed therapies, residual risk remains a significant challenge for many patients.^2,3 This residual risk is multifactorial, often driven by thrombotic, lipid, metabolic and inflammatory pathways, which has catalysed the search for novel pharmacotherapies that can mitigate CV risk beyond targeting traditional risk factors.² In particular, hypertriglyceridaemia is common in patients with CV disease and is associated with an increased risk of CV events despite optimal statin treatment.^4,5

Omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can lower triglyceride levels and may have additional pleiotropic cardioprotective properties, but their role in CV prevention continues to be debated.^6-8 EPA and DHA differ in their effects on cell membrane structure, lipid oxidation, inflammation and endothelial function.⁸ Notably, the cell membrane-stabilising effects of EPA may be neutralised when co-administered with DHA.⁹ Clinical trials that have evaluated various formulations of EPA and DHA in combination have not shown a significant reduction in CV events compared with placebo, except for the Protection against Incidences of Serious Cardiovascular Events Study (PISCES) in haemodialysis patients, as summarised in Table 1Table 1..^10-14 On the other hand, the Japan EPA Lipid Intervention Study (JELIS) and Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial (REDUCE-IT) demonstrated that EPA-only formulations significantly reduces CV events, as summarised in Table 2Table 2..^15,16

As a result, icosapent ethyl, an esterified EPA derived from fish oil, has become the first prescription-grade EPA to be approved by the US Food and Drug Administration (FDA) to reduce the risk of atherosclerotic CV disease in adults.¹⁷ Icosapent ethyl was subsequently approved by the TGA in November 2022 and is currently subsidised on the PBS under specific criteria (Box 1Box 1. and Box 2Box 2.).¹⁸ Furthermore, icosapent ethyl is recommended by several national and international guidelines for the prevention of CV events in eligible high-risk patients.^19-23

What is the evidence for its cardiovascular benefit?

The effect of icosapent ethyl, prescribed at 2 g twice daily, on CV outcomes was assessed in the multinational REDUCE-IT trial.¹⁶ The trial randomised 8179 patients with established CV disease or diabetes plus at least one other CV risk factor, who had fasting triglyceride levels of 1.5 to 5.6 mmol/L, controlled LDL-C levels of 1.1 to 2.6 mmol/L and who were on statin therapy.¹⁶ After a median follow up of 4.9 years, the primary endpoint (a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation or unstable angina) was significantly reduced compared with placebo (17.2% vs 22.0%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.68–0.83; p <0.001), with a number needed to treat of 21 to prevent one CV event.¹⁶ Moreover, the key secondary endpoint (a composite of CV death, nonfatal myocardial infarction or nonfatal stroke) was significantly reduced compared with placebo (11.2% vs 14.8%; HR 0.74; 95% CI, 0.65–0.83; p <0.001), as was CV death (4.3% vs 5.2%; HR 0.80; 95% CI, 0.66–0.98; p = 0.03).¹⁶

Prespecified analyses of REDUCE-IT have demonstrated that icosapent ethyl significantly reduced the burden of first, subsequent and total ischaemic events for each individual component of the composite primary endpoint.²⁴ Subsequent analyses of REDUCE-IT have identified groups likely to derive greater absolute benefit, including those with prior myocardial infarction, prior coronary artery bypass graft surgery, prior percutaneous coronary intervention, recent acute coronary syndrome, estimated glomerular filtration rate of less than 60 mL/min/1.73 m² and cardiovascular–kidney–metabolic syndrome.^25-31 Moreover, icosapent ethyl provided similar CV risk reduction in patients with and without heart failure, irrespective of lipoprotein(a) levels, and across different types of background statin therapy in REDUCE-IT.^32-34 Cost-effectiveness analyses have also demonstrated that icosapent ethyl is cost effective for CV prevention, particularly in patients with CV disease, and yielded more quality-adjusted life-years than standard care.^35-37

The placebo used in REDUCE-IT contained prescription-grade mineral oil to mimic the colour and consistency of icosapent ethyl.¹⁶ Small increases in triglyceride levels (2.2% at one year), LDL-C levels (10.2% at one year) and high-sensitivity C-reactive protein levels (from 2.1 mg/L to 2.8 mg/L at two years) were observed in the placebo group, which has generated some debate about whether the mineral oil placebo was inert.^16,38,39 However, these biomarker increases were not significantly associated with CV outcomes according to the independent Data and Safety Monitoring Committee of REDUCE-IT.³⁸ Independent analyses by the FDA indicated that the effect of these increased biomarkers on the primary endpoint was numerically small, would not account for the 25% relative risk reduction, and was therefore unlikely to change the overall study conclusions.^38,40 Moreover, the JELIS trial of Japanese patients with hypercholesterolaemia did not administer mineral oil as placebo and showed a significant CV benefit of EPA-only supplementation.¹⁵

More recently, the Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy – Statin and Eicosapentaenoic Acid (RESPECT-EPA) evaluated icosapent ethyl in 2506 Japanese patients with coronary artery disease and a low EPA/arachidonic acid ratio and who were on statin therapy.⁴¹ Icosapent ethyl resulted in a numerically lower risk of the primary endpoint that did not reach statistical significance (Table 2Table 2.).⁴¹ On the other hand, the secondary endpoint (a composite of sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalisation and coronary revascularisation, or coronary revascularisation) was significantly lower with icosapent ethyl compared with placebo (6.6% vs 9.7%; HR, 0.73; 95% CI, 0.55–0.97).⁴¹ It is important to note that the RESPECT-EPA trial used a lower dose of icosapent ethyl (1.8 g daily), had a smaller sample size than REDUCE-IT and JELIS, and was likely underpowered because of the high discontinuation rate of the study drug and the higher dropout rate in the treatment compared with the control group.^41,42

What are the mechanisms of cardiovascular benefit?

In REDUCE-IT, triglyceride levels decreased by a median of 18.3% in the icosapent ethyl group and increased by 2.2% in the placebo group after one year.¹⁶ Although residual hypertriglyceridaemia was an inclusion criterion for REDUCE-IT, the reduction in CV risk with icosapent ethyl was similar across baseline and the treatment achieved target triglyceride levels.^16,43 This finding suggests that mechanisms of icosapent ethyl beyond its lowering of triglyceride levels, such as its antithrombotic, anti-inflammatory, antioxidant and atherosclerotic plaque-stabilising effects, may be contributing factors, as shown in the FigureFigure..^6,8 However, the exact mechanisms of CV benefit remain unclear. Among patients in REDUCE-IT, icosapent ethyl had minimal effects on biomarkers associated with CV disease, such as interleukin-1 beta, interleukin-6, high-sensitivity C-reactive protein, oxidised LDL-C, homocysteine, lipoprotein(a) and lipoprotein- associated phospholipase A2.⁴⁴ Moreover, icosapent ethyl reduced the rate of CV endpoints irrespective of baseline LDL-C in REDUCE-IT.⁴⁵ As such, further studies will be needed to determine whether icosapent ethyl provides CV benefits in patients with LDL-C and triglyceride levels outside of the REDUCE-IT trial inclusion criteria. Preliminary data suggest that on-treatment (or achieved) EPA levels may correlate inversely with risk of CV events; however, plasma EPA levels are not currently routinely measured.^41,42

Intravascular imaging studies have previously demonstrated that EPA may mediate the regression of plaques and stabilisation of thin-cap fibroatheroma.^46,47 More recently, cardiac imaging studies have provided further mechanistic data.^48,49 The Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy (EVAPORATE) trial randomised 80 patients with coronary atherosclerosis, hypertriglyceridaemia (triglyceride levels of 1.5 to 5.6 mmol/L) and LDL-C levels inclusive of 1.0 to 3.0 mmol/L, who were receiving statin therapy, to either 4 g daily of icosapent ethyl or placebo with mineral oil.⁴⁸ The trial demonstrated that icosapent ethyl decreased low-attenuation (at-risk) plaque volume after 18 months (including fibrous, fibrofatty, total noncalcified and total plaque volumes) compared with placebo, as measured by cardiac CT angiography, with no significant differences in the change in LDL-C or triglyceride levels.⁴⁸ Analyses have also demonstrated that icosapent ethyl improved fractional flow reserve, derived from cardiac CT angiography, at nine and 18 months compared with placebo.⁴⁹ These findings suggest that a favourable impact on atherosclerotic plaque and coronary physiology may be a mechanism leading to the reduction in CV events with icosapent ethyl.

When and in whom should the therapy be used?

The TGA-approved indications for icosapent ethyl aligns with trial inclusion criteria for REDUCE-IT and is shown in Box 1Box 1.. PBS-prescribing criteria are shown in Box 2Box 2., noting that a fasting triglyceride level is required. Icosapent ethyl is not currently PBS subsidised for the TGA indication of patients with diabetes and at least one additional CV risk factor who do not have established CV disease. Icosapent ethyl can also be considered, as a prescription omega-3 fatty acid, for lowering triglyceride levels and the risk of pancreatitis in patients with persistent severe hypertriglyceridaemia (>5.6 mmol/L), based on guideline recommendations, although it is not TGA approved for this indication.^18,21,50

If the patient does not fulfil the PBS criteria, they may be prescribed icosapent ethyl via a private prescription (cost as of April 2026: $154.43 per 120 capsules or about $5 per day at the recommended dose; refer to https://www.pbs.gov.au for updated information). Icosapent ethyl is prescribed as a daily oral dose of four capsules, taken as two 998 mg capsules twice daily, and should be taken with or following a meal, as this may assist with the management of potential gastrointestinal side effects. The PBS authority streamlined code is 15889 for initial treatment and 15927 for continuing treatment. Continuing treatment does not require LDL-C or triglyceride criteria.

What are the side effects and important precautions to consider?

In REDUCE-IT, the overall rates of adverse events and serious adverse events leading to discontinuation of icosapent ethyl or placebo did not differ significantly between the groups.¹⁶ However, icosapent ethyl was associated with a greater risk of atrial fibrillation (5.3% vs 3.9%).¹⁶ An increased risk of new-onset atrial fibrillation was also observed in the RESPECT-EPA trial (icosapent ethyl 3.1% vs control 1.6%;  p = 0.017).⁴¹ In a meta-analysis of randomi- sed trials examining CV outcomes with omega-3 fatty acids, an increased risk of atrial fibrillation was demonstrated, with the risk being greatest in trials testing doses greater than 1 g/day.⁵¹ Notably, the majority of cases of atrial fibrillation or flutter in REDUCE-IT occurred in patients with a history of these conditions.^52,53 In patients with a history of prior atrial fibrillation or flutter who are currently in sinus rhythm, the benefit of icosapent ethyl should be balanced against the increased risk of atrial arrhythmia. In the setting of persistent or chronic atrial fibrillation, these considerations may be less important. After commencing icosapent ethyl, patients with a history of paroxysmal atrial fibrillation or flutter should be advised to report palpitations that may herald the onset of an atrial arrhythmia, and an ECG should be performed when clinically indicated.

Serious bleeding events occurred in 2.7% of patients in the icosapent ethyl group compared with 2.1% in the placebo group (p = 0.06), with no fatal bleeding events in either group.¹⁶ There were no significant differences between the icosapent ethyl and placebo groups in the rates of adjudicated haemorrhagic stroke (0.3% vs 0.2%; p = 0.55), serious central nervous system bleeding (0.3% vs 0.2%; p = 0.42) or gastrointestinal bleeding (1.5% vs 1.1%; p = 0.15).¹⁶ The modestly higher rate of bleeding events with icosapent ethyl may be consistent with the proposed antithrombotic and antiplatelet mechanism of action. Patients taking concomitant antithrombotic agents such as antiplatelets, warfarin and direct-acting oral anticoagulants may be at increased risk of bleeding and should be asked periodically if they have experienced symptoms of bleeding. In patients not taking antithrombotic agents, the rate of serious bleeding with icosapent ethyl is very low (0.2%) and is reportedly similar to placebo (see Australian Product Information). In addition, consideration should be given to timing the commencement of icosapent ethyl with de-escalation of antithrombotic therapies, such as de-escalating dual antiplatelet therapy to monotherapy. The risks and benefits of continuing icosapent ethyl should be discussed with the patient if symptoms suggestive of bleeding occur.

Icosapent ethyl should be used with caution in patients with a known hypersensitivity to fish, shellfish or both. Icosapent ethyl is contraindicated in patients with hypersensitivity to the active substance, soy products or any of the excipients. Limited data are available on the use of icosapent ethyl in pregnant women (category B1). There is also a low potential for clinically significant drug–drug interactions involving the cytochrome P450 enzyme system. No dose adjustment is necessary based on age, or renal or hepatic impairment. In patients with hepatic impairment, aspartate aminotransferase and alanine aminotransferase levels should be monitored as clinically indicated before the start of treatment and at appropriate intervals during treatment.

Conclusion

Icosapent ethyl is an esterified EPA that can significantly reduce CV events in statin-treated patients with hypertriglyceridaemia and established CV disease, or with diabetes and at least one other CV risk factor. The mechanisms through which icosapent ethyl results in CV protection remain unclear; however, several mechanisms have been proposed, including antithrombotic, anti-inflammatory, antioxidant and atherosclerotic plaque-stabilising effects. The therapy has been approved by the TGA, is subsidised on the PBS under specific criteria, and is recommended by several guidelines for the prevention of CV events in eligible high-risk patients. Potential side effects of icosapent ethyl include atrial fibrillation and bleeding, but its overall safety profile is favourable. Icosapent ethyl should be recommended for CV prevention in eligible high-risk patients.  MT

COMPETING INTERESTS: Dr Lan has received research funding from Sanofi as part of a Clinical Fellowship in Endocrinology and Diabetes; has received education support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Seqirus, Eli Lilly, Novartis, Novo Nordisk and Pfizer; has received speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, CSL Seqirus, Eli Lilly, Menarini, Novartis, Novo Nordisk and Sanofi; and has participated in advisory boards for Eli Lilly. Associate Professor Nelson has received research support from AstraZeneca, Amgen, Eli Lilly and Novartis; and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Seqirus, Eli Lilly, GSK, Novartis, Novo Nordisk, Sanofi Pasteur and Vaxxinity. Professor Playford has received research support from Novartis, AstraZeneca, Edwards LifeSciences, Eli Lilly, Bristol Meyer Squibb, Echo IQ Ltd and Pfizer; and speaker honoraria from Amgen, Novartis, GSK, Eli Lilly, CSL Seqirus and Novo Nordisk. Professor Watts has received grants or honoraria from Amgen, Arrowhead, AstraZeneca, CSL Seqirus, Esperion, Novartis, Novo Nordisk, Pfizer, Sanofi-Regeneron and Silence Therapeutics.

This article is for general information purposes only, and the full Product Information should be consulted before prescribing any of the mentioned medications.

References