Icosapent ethyl use in clinical practice: current and future directions

Introduction

Originally, icosapent ethyl (IPE) was developed as a treatment for hypertriglyceridaemia.² However, in the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT),³ IPE significantly decreased the risk of ischaemic events (including cardiovascular [CV] death) by ~25% after a median follow-up of 4.9 years. The study included patients with fasting triglyceride (TG) levels of 1.7 to 5.6 mmol/L (150 to 499 mg/dL) and low-density lipoprotein cholesterol (LDL-C) levels of 1.1 to 2.6 mmol/L (41 to 100 mg/dL) who were on optimum statin treatment. Interestingly, this reduction in CV risk was independent of TG lowering. This opened up the discussion about the possible mechanisms behind the risk-lowering effects of the drug.³

Based on the results of REDUCE-IT, IPE is generally well tolerated, with a similar distribution of people between the two groups (IPE [81.8%] and mineral oil placebo [81.3%]) reporting adverse events, except in the case of atrial fibrillation and peripheral oedema, which was significantly higher in the IPE group than the placebo group. However, in the IPE group, there was a significant reduction in the rates of anaemia, diarrhoea and gastrointestinal adverse events.^1,3

IPE and cardiovascular risk reduction: what’s next?

IPE affects lipids by increasing the activity of lipoprotein lipase and decreasing liver lipogenesis.⁴ However, IPE also has well-known anti-inflammatory properties,⁵ and CV risk reduction in REDUCE-IT³ was more related to the reduction of anti-inflammatory markers rather than triglyceride lowering. Therefore, it is likely that IPE may be targeting the residual inflammatory risk, although this hypothesis needs to be proven by prospective studies that will evaluate the impact of IPE on coronary vessel inflammation. Importantly, the use of mineral oil as the placebo in REDUCE-IT and the increased event rate observed in the placebo group of the trial has raised the question of whether the observed benefit of IPE was enhanced by the potentially detrimental effect of the placebo treatment. This makes the mechanistic investigation of IPE’s CV effects even more imperative.

Cardiovascular inflammation assessment

Cardiovascular inflammation can be evaluated either by measuring less specific, but easy to apply, surrogate circulating biomarkers (e.g., high-sensitivity C-reactive protein [hsCRP]) or by using more sophisticated imaging methods like positron emission tomography or computed tomography.⁶ Indeed, a recently developed imaging method utilises attenuation indexing of the perivascular adipose tissue from coronary computed tomography angiography images, to generate a quantitative metric of coronary inflammation, the fat attenuation index (FAI)^7,8 and the respective FAI Score.⁹ The FAI and FAI Score capture the residual inflammatory risk¹⁰ and can be used to monitor responsiveness of coronary inflammation (and the associated risk) to treatments.¹¹ Upcoming clinical trials are expected to evaluate the responsiveness of coronary inflammation and the residual inflammatory risk to IPE treatment in the near future.

Expanding the indications of IPE use

Another open question that needs addressing, is that of the rather restrictive indications for the use of IPE in the UK. Indeed, the NICE guidance indicates the use of IPE only in patients with TG levels ≥1.7 mmol/L (≥150 mg/dL), who are taking statins and who have established CV disease.¹ Although this target population comes from the inclusion criteria of REDUCE-IT, it does not take into account the fact that CV disease risk reduction in that trial was independent of the patients’ baseline TG levels.³ Opening the label to all patients presenting as high risk would be something worth considering as more data accumulate, in order to support the dissociation of IPE treatment from TG levels. In any case, adding IPE to optimum statin treatment (administered either based on high absolute risk or as treatment of hyperlipidaemia) should remain the preferred strategy. Another interesting population that may benefit from IPE, could be those intolerant to statins who are at high risk based on either conventional risk calculators (e.g., QRISK^®3, the European Society of Cardiology Systematic COronary Risk Estimation [ESC-SCORE2]) or enhanced risk calculators that use imaging to also take into account the residual inflammatory risk (e.g., CaRi-HEART^TM).⁹ Patients with diabetes could also be further investigated as a target population of IPE treatment,¹² even if their absolute 10-year risk is low; this proposal was introduced based on the sensitivity analyses of the diabetic population within REDUCE-IT.¹³

Furthermore, IPE was proven to significantly reduce ischaemic events in the subpopulation of REDUCE-IT with a history of myocardial infarction (MI).¹⁴ To further explore the potential of IPE in reducing the risk of recurrent MI or ischaemic events in this population, future clinical trials should focus more on secondary prevention. Moreover, clinical trials that would select patients based on either vascular inflammatory status (using the FAI) or based on IPE/EPA levels^15,16 would be informative.

IPE and other diseases with indirect cardiovascular implications

Autoimmune diseases

Chronic inflammatory/autoimmune diseases lead to increased CV disease risk.^17–19 Recent evidence suggests that EPA may prevent or even treat autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis, rheumatoid arthritis (RA) or even type 1 diabetes,²⁰ as discussed below:

• SLE. Multiple studies on SLE have demonstrated that omega-3 polyunsaturated fatty acids (n-3 PUFA) treatment may affect disease activity, improve endothelial function, and supress systemic inflammation.^21–26
• Multiple sclerosis. In cases of multiple sclerosis, n-3 PUFAs were able to promote remyelination; these protective and repairing effects were specifically related to EPA-derived metabolites and directly impact oligodendrocytes and neurons.²⁷
• Rheumatoid arthritis. In vitro studies have shown that exposure of T-cells from patients with RA to EPA and DHA inhibits the release of pro-inflammatory cytokines from these cells; therefore, n-3 PUFAs could potentially modulate inflammation and play a role in the treatment of RA.²⁸
• Inflammatory bowel disease. Inflammatory bowel disease (IBD) is often related to an increased level of n-6 PUFAs and consequent decreases of n-3 PUFAs, specifically, EPA.²⁹

Given the role of all these inflammatory diseases in CV risk,³⁰ it appears logical to assume that EPA, and specifically IPE, may have a role to play in preventing CV events in patients with autoimmune or inflammatory diseases.

Conclusions

REDUCE-IT came to change the landscape of pharmacological reduction of CV disease risk; IPE appears to provide an effective solution to improve CV outcomes, in addition to statin treatment. Although currently restricted to use in those patients with hypertriglyceridaemia on statins, it is clear that the beneficial effects of IPE are not only limited to this population. Future mechanistic studies are anticipated, which should shed light onto the exact mechanisms behind the risk reduction caused by this drug and support its broader use in both primary and secondary prevention.

Key messages

• Investigating the mechanisms by which icosapent ethyl (IPE) reduces cardiovascular risk may lead to its broader use in preventive cardiovascular medicine
• Upcoming studies will explore the responsiveness of cardiovascular inflammation to IPE
• As more data accumulates we will better understand the relationship of IPE to triglyceride levels

Conflicts of interest

CA is founder, shareholder and director of Caristo Diagnostics, a CT image analysis spinout company from the University of Oxford. CA has received honoraria from Amarin. CA is chair of the British Atherosclerosis Society. LV: none declared.

Lucrezia Volpe
Clinical Research Fellow at the University of Oxford

Charalambos Antoniades
BHF Chair of Cardiovascular Medicine at the University of Oxford

Acute Multidisciplinary Imaging and Interventional Centre, Division of Cardiovascular Medicine, University of Oxford, Level 6 West Wing, John Radcliffe Hospital, Headington, Oxford OX3 9DU
([email protected])

Articles in this supplement

Introduction
Triglyceride-rich lipoproteins and their role in cardiovascular disease
The evidence for fish oils and eicosapentaenoic acid in managing hypertriglyceridaemia
REDUCE-IT: findings and implications for practice

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