A Comprehensive Monograph on Icosapent Ethyl: From Molecular Pharmacology to a New Paradigm in Cardiovascular Risk Reduction

Executive Summary

Icosapent ethyl (IPE), marketed under the brand names Vascepa® and Vazkepa®, is a high-purity, prescription-grade ethyl ester of eicosapentaenoic acid (EPA), a naturally occurring omega-3 fatty acid.[1] Its formulation as a single-molecule, EPA-only product distinguishes it fundamentally from over-the-counter fish oil supplements and other prescription omega-3 fatty acid therapies, which typically contain a mixture of EPA and docosahexaenoic acid (DHA). This distinction is clinically paramount, as IPE avoids the elevation in low-density lipoprotein cholesterol (LDL-C) that can be associated with DHA-containing products.[4]

The medication holds two primary indications approved by the U.S. Food and Drug Administration (FDA) and other global regulatory bodies. The first is as an adjunct to diet for the reduction of triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (TG levels $ \geq 500 \text{ mg/dL} $). The second, and more transformative, indication is as an adjunct to maximally tolerated statin therapy to reduce the risk of major adverse cardiovascular events in high-risk adult patients with elevated triglycerides (TG levels $ \geq 150 \text{ mg/dL} $).[2]

The therapeutic landscape for managing residual cardiovascular risk was fundamentally redefined by the landmark Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT). This large-scale, multinational study provided definitive evidence that treatment with 4 grams per day of IPE resulted in a statistically robust and clinically significant 25% relative risk reduction in the primary composite endpoint of major adverse cardiovascular events (MACE) in a high-risk, statin-treated population.[11] The magnitude of this benefit suggests that the therapeutic effects of IPE extend well beyond simple triglyceride reduction. The mechanism is believed to be multifaceted, involving pleiotropic effects such as anti-inflammatory, anti-platelet, and cell membrane-stabilizing actions, which are likely driven by the substantial increase in systemic EPA levels and a consequent favorable shift in the EPA-to-arachidonic acid (AA) ratio.[15]

From a safety perspective, IPE is generally well-tolerated. The primary safety considerations, identified and quantified within the REDUCE-IT trial, are a small but statistically significant increased risk of atrial fibrillation or atrial flutter and an increased risk of bleeding events. The bleeding risk is most pronounced when IPE is used concomitantly with other antithrombotic agents, necessitating careful patient monitoring.[13]

Clinically, IPE represents the first non-LDL-focused lipid-modifying therapy to demonstrate a significant reduction in cardiovascular events in a large-scale, randomized controlled outcomes trial. This achievement has established a new pillar of treatment for managing residual atherothrombotic risk in appropriately selected patients. Consequently, IPE has earned strong, Class I and Level A recommendations in major international clinical practice guidelines, which explicitly state that its proven benefits should not be extrapolated to other omega-3 fatty acid products.[19]

Drug Identification and Physicochemical Properties

A precise understanding of the chemical entities involved is foundational to appreciating the pharmacology and clinical application of this therapy. It is critical to distinguish between icosapent, the active fatty acid, and icosapent ethyl, the administered pharmaceutical prodrug.

Distinction Between Icosapent and Icosapent Ethyl

Icosapent (Eicosapentaenoic Acid, EPA)

Icosapent is the biologically active molecule, identified by DrugBank ID DB00159 and CAS Number 10417-94-4.20 It is an omega-3 polyunsaturated fatty acid (PUFA) characterized by a 20-carbon aliphatic chain containing five

cis double bonds.[21] Its systematic International Union of Pure and Applied Chemistry (IUPAC) name is (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic acid.[1] As an omega-3 fatty acid, the first double bond is located at the third carbon atom from the methyl (omega) end of the chain.[21]

Icosapent is a naturally occurring component of marine fish oils and functions as a vital micronutrient and nutraceutical.[20] In human physiology, it serves as a precursor for the synthesis of the prostaglandin-3 and thromboxane-3 families of eicosanoids, which possess anti-inflammatory and anti-aggregatory properties, contrasting with the pro-inflammatory eicosanoids derived from arachidonic acid.[20]

Icosapent Ethyl (IPE)

Icosapent ethyl, identified by DrugBank ID DB08887, is the pharmaceutical agent used in clinical practice.2 It is a synthetic ethyl ester derivative of EPA, functioning as a prodrug designed to enhance stability and facilitate consistent oral delivery.2 After oral administration, IPE undergoes hydrolysis (de-esterification) by digestive enzymes in the gastrointestinal tract, releasing the active EPA molecule for absorption into the systemic circulation.2 In 2016, the U.S. FDA recognized the highly purified, single-molecule formulation of IPE as a new chemical entity, formally distinguishing it from other fish oil-derived products.26

The development of a highly purified ethyl ester prodrug is a deliberate and critical pharmaceutical strategy. Natural fatty acids like EPA can be susceptible to oxidation and degradation. Esterification of the carboxylic acid group protects this reactive site, improving the molecule's chemical stability and ensuring a longer shelf-life, which is essential for a pharmaceutical product. Furthermore, this process allows for the creation of a standardized, high-purity active pharmaceutical ingredient that can be precisely dosed and formulated into soft gelatin capsules. This consistency and purity, validated through rigorous manufacturing processes approved by regulatory agencies, is what elevates IPE from a variable dietary supplement to a reliable, evidence-based prescription medication. The conversion of the prodrug back to the active EPA in the gut ensures that the intended therapeutic molecule is delivered to the site of absorption. This entire pharmaceutical refinement process was a key step in transforming a natural compound into a therapeutic agent capable of undergoing rigorous clinical testing and gaining regulatory approval for specific medical indications.

Nomenclature and Identifiers

The nomenclature for these molecules is extensive, reflecting their roles in chemistry, nutrition, and pharmacology.

• Icosapent (EPA): Also known as eicosapentaenoic acid, timnodonic acid, and all-cis-5,8,11,14,17-icosapentaenoic acid.[1]
• Icosapent Ethyl (IPE): Also known as ethyl eicosapentaenoate, icosapento, icosapentum, and the code name AMR101. Commercial brand names include Vascepa® and Vazkepa®.[1]

A comprehensive list of systematic and database identifiers is provided in Table 1 to facilitate unambiguous identification and cross-referencing in research and clinical databases.

Physicochemical Properties

Icosapent is described as a colorless liquid, while the pharmaceutical product, icosapent ethyl, is formulated as an oily liquid within soft gelatin capsules.[1] Both molecules are highly lipophilic, a property essential for their absorption with fatty foods and their incorporation into lipid structures such as lipoproteins and cell membranes. The partition coefficient (LogP) for icosapent is reported as 6.1, indicating its strong preference for lipid environments over aqueous ones.[20] The detailed physicochemical properties are summarized in Table 1.

Table 1: Comparative Physicochemical Properties of Icosapent and Icosapent Ethyl

Property	Icosapent (Active Moiety)	Icosapent Ethyl (Prodrug)
Common Names	Eicosapentaenoic acid (EPA), Timnodonic acid	Ethyl eicosapentaenoate, Vascepa®, Vazkepa®
IUPAC Name	(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic acid	ethyl (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoate
DrugBank ID	DB00159	DB08887
CAS Number	10417-94-4	86227-47-6
Chemical Formula	$ C_{20}H_{30}O_{2} $	$ C_{22}H_{34}O_{2} $
Molecular Weight	302.45 g/mol	330.50 g/mol
SMILES	$ CC/C=C\backslash C/C=C\backslash C/C=C\backslash C/C=C\backslash C/C=C\backslash CCCC(=O)O $	$ CC/C=C\backslash C/C=C\backslash C/C=C\backslash C/C=C\backslash C/C=C\backslash CCCC(=O)OCC $
InChIKey	JAZBEHYOTPTENJ-JLNKQSITSA-N	SSQPWTVBQMWLSZ-AAQCHOMXSA-N
Physical Description	Colorless liquid	Oily liquid in soft gelatin capsules

Data compiled from sources [1], and.[24]

Pharmacology and Mechanism of Action

The pharmacological effects of icosapent ethyl are extensive, encompassing both direct lipid-modifying actions and a range of pleiotropic effects that are believed to contribute significantly to its cardiovascular benefits.

Mechanism of Action for Triglyceride Reduction

The primary lipid-modifying effect of icosapent ethyl is the robust reduction of plasma triglyceride levels. This is not achieved through a single pathway but rather a coordinated series of actions on hepatic lipid metabolism, which collectively decrease the production and enhance the clearance of triglyceride-rich lipoproteins.[2]

• Inhibition of VLDL-TG Synthesis and Secretion: The liver is the primary site of de novo triglyceride synthesis and the production of very low-density lipoproteins (VLDL), which are the main carriers of triglycerides in the bloodstream. EPA has been shown to reduce the hepatic synthesis and/or secretion of VLDL-triglycerides (VLDL-TG), thereby lowering the flux of new triglycerides into the circulation.[2]
• Inhibition of DGAT: A key molecular target in this process is acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT). This enzyme catalyzes the final and rate-limiting step in the synthesis of triglycerides. By inhibiting DGAT, EPA directly curtails the liver's ability to produce triglycerides.[2]
• Increased Fatty Acid β-Oxidation: EPA promotes the mitochondrial breakdown of fatty acids for energy production, a process known as β-oxidation. This action effectively shunts fatty acids away from the triglyceride synthesis pathway, reducing the available substrate pool for VLDL assembly.[2]
• Enhanced Triglyceride Clearance: Some evidence suggests that EPA may also enhance the clearance of triglycerides from the circulation by increasing the activity of plasma lipoprotein lipase (LPL). LPL is an enzyme located on the surface of capillaries that hydrolyzes triglycerides within VLDL particles, facilitating their removal from the blood.[2]

Pharmacodynamics and Pleiotropic Effects

The clinical benefits of icosapent ethyl, particularly the profound reduction in cardiovascular events observed in the REDUCE-IT trial, are not fully explained by its triglyceride-lowering effect alone. This points to the importance of its broader pharmacodynamic and pleiotropic actions.

A clear dose-dependent relationship has been established in clinical studies. The pivotal Phase 3 trials, MARINE and ANCHOR, demonstrated that higher doses of IPE lead to proportionally greater increases in plasma and red blood cell (RBC) concentrations of EPA. These increases in EPA concentration, in turn, correlate strongly and significantly with the magnitude of triglyceride reduction.[3] The approved 4 g/day dose consistently achieves plasma EPA concentrations exceeding 170 µg/mL, a level that appears to be a therapeutic threshold for eliciting a significant clinical effect.[15]

One of the most critical mechanisms underlying IPE's pleiotropic effects is the modulation of the eicosanoid pathway. Eicosanoids are potent signaling molecules involved in inflammation and thrombosis. They are synthesized from 20-carbon polyunsaturated fatty acids, primarily the omega-6 fatty acid arachidonic acid (AA) and the omega-3 fatty acid EPA.[22] EPA directly competes with AA for the same metabolic enzymes, namely cyclooxygenase (COX) and lipoxygenase (LOX).[20] When systemic EPA levels are increased through IPE supplementation, there is a competitive shift in eicosanoid production:

• Metabolism of AA produces pro-inflammatory and pro-thrombotic molecules like prostaglandin E2 ($ PGE_2 ),thromboxaneA2( TXA_2 ),andleukotrieneB4( LTB_4 $).
• Metabolism of EPA produces alternative eicosanoids, such as prostaglandin I3 ($ PGI_3 )andleukotrieneB5( LTB_5 $), which are significantly less inflammatory and promote vasodilation and inhibition of platelet aggregation.[20]

This favorable shift in the eicosanoid balance is a key proposed mechanism for the anti-inflammatory and anti-thrombotic benefits that contribute to the reduction in ischemic events. Other potential mechanisms include direct antioxidant effects, improved endothelial function, and stabilization of atherosclerotic plaque by altering the lipid composition of cell membranes.1

Pharmacokinetics (Absorption, Distribution, Metabolism, and Excretion)

The pharmacokinetic profile of icosapent ethyl is characterized by its conversion to the active moiety, extensive distribution, and a long elimination half-life.

• Absorption: Icosapent ethyl is administered orally as an ethyl ester prodrug. Following administration with food, which is essential for its absorption, the ester bond is hydrolyzed by lipases in the gut. This releases the active metabolite, EPA, which is then absorbed in the small intestine. From there, it enters the systemic circulation primarily through the thoracic duct lymphatic system, similar to other dietary fatty acids.[2] The peak plasma concentration (Tmax) of total EPA is achieved approximately 5 hours after oral administration.[2]
• Distribution: Once absorbed, EPA is widely distributed throughout the body. It is highly incorporated into complex lipids; less than 1% of circulating EPA exists as an unesterified (free) fatty acid. The vast majority is esterified into phospholipids, triglycerides, and cholesteryl esters, which are then transported within lipoproteins or incorporated into the phospholipid membranes of cells, including red blood cells.[2] This extensive incorporation into tissues is reflected by its large steady-state volume of distribution (Vz/F) of approximately 88 liters.[2]
• Metabolism: The primary metabolic pathway for EPA is β-oxidation, which occurs mainly in the liver. This is the same catabolic process used by the body to break down other endogenous and dietary fatty acids into acetyl-Coenzyme A, which can then enter the Krebs cycle to produce energy.[2] A crucial aspect of its metabolism is that metabolism mediated by the Cytochrome P450 (CYP) enzyme system is only a minor pathway of elimination.[25]
• Excretion: Icosapent ethyl and its active metabolite EPA are not excreted by the kidneys.[2] The elimination half-life (T1/2) of total EPA from plasma is very long, estimated to be approximately 89 hours. The total plasma clearance (CL/F) is approximately 684 mL/hr.[2]

The pharmacokinetic and pharmacodynamic properties of IPE converge to create a uniquely favorable profile for its target patient population. The fact that its metabolism bypasses the heavily utilized CYP450 enzyme system is of profound clinical importance. Patients with established cardiovascular disease are almost invariably on complex medication regimens that include statins, antiplatelet agents, antihypertensives, and antidiabetic drugs, many of which are substrates, inhibitors, or inducers of CYP enzymes. The low potential for IPE to cause pharmacokinetic drug-drug interactions, as confirmed in studies with CYP substrates like rosiglitazone and atorvastatin, means it can be safely added to these existing therapies without the need for dose adjustments of other critical medications.[25] This "low-interaction" profile provides a significant practical advantage in clinical management.

Simultaneously, IPE exerts a "high-impact" pharmacodynamic effect. The 25% relative risk reduction in major adverse cardiovascular events observed in REDUCE-IT far exceeds what would be predicted based solely on its modest ~20% reduction in triglycerides.[13] This discrepancy strongly supports the conclusion that its powerful pleiotropic effects—such as the modulation of the eicosanoid pathway—are the primary drivers of its clinical benefit. Therefore, IPE can be conceptualized as an agent that safely integrates into complex therapeutic regimens due to its benign pharmacokinetic profile, while adding a unique and substantial layer of cardiovascular protection through potent pharmacodynamic mechanisms that extend beyond lipid lowering.

Table 2: Summary of Pharmacokinetic Parameters for Total Plasma EPA after Steady-State Dosing of Icosapent Ethyl (4 g/day)

Pharmacokinetic Parameter	Value (Mean ± SD or Median)	Description
$ T_{max} $ (Time to Peak Concentration)	5 hours	Time after dosing at which the maximum plasma concentration is reached.
$ C_{max} $ (Peak Concentration)	347.2 ± 112.5 µg/mL	The maximum concentration of total EPA observed in the plasma.
$ AUC_{0–24} $ (Area Under the Curve)	6,519 ± 1,963 µg•h/mL	A measure of total drug exposure over a 24-hour dosing interval.
$ T_{1/2} $ (Elimination Half-life)	89.3 ± 42.0 hours	The time required for the plasma concentration of EPA to decrease by half.
CL/F (Apparent Clearance)	683.7 ± 280.6 mL/h	The volume of plasma cleared of the drug per unit of time.
$ V_{z}/F $ (Apparent Volume of Distribution)	88.4 ± 55.2 L	A theoretical volume representing the extent of drug distribution in the body.

Data represent steady-state parameters for the 4 g/day dose (2 g BID) group from the pharmacokinetic study in healthy volunteers [3] and DrugBank.[2]

Clinical Efficacy and Landmark Trials

The clinical evidence supporting the use of icosapent ethyl is robust, built upon foundational trials establishing its lipid-lowering efficacy and culminating in a landmark cardiovascular outcomes trial that redefined its role in modern cardiology.

The REDUCE-IT Trial: A Definitive Analysis

The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) is the cornerstone of IPE's indication for cardiovascular risk reduction and serves as its primary differentiator from all other lipid-modifying therapies targeting triglycerides.[11]

Trial Design and Methodology

REDUCE-IT was a large-scale, multinational, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of IPE in reducing ischemic events. The trial enrolled 8,179 high-risk patients who were already on stable statin therapy.12 The key inclusion criteria were designed to select a population with significant residual cardiovascular risk:

• Age and Risk Category: Patients aged 45 years or older with established cardiovascular disease (the secondary prevention cohort) or patients aged 50 years or older with diabetes mellitus and at least one additional cardiovascular risk factor (the high-risk primary prevention cohort).
• Lipid Criteria: Fasting triglyceride levels between 135 mg/dL and 499 mg/dL, and low-density lipoprotein cholesterol (LDL-C) levels between 41 mg/dL and 100 mg/dL.[13]

Eligible patients were randomized in a 1:1 ratio to receive either icosapent ethyl at a dose of 4 grams per day (administered as 2 grams twice daily with food) or a matching placebo.[37] The study was event-driven, with a median follow-up duration of 4.9 years.[13]

Primary and Key Secondary Outcomes

The results of the REDUCE-IT trial were unequivocally positive and demonstrated a profound benefit of IPE therapy.

• Primary Endpoint: The primary composite endpoint was the time to first occurrence of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization. An event from this composite occurred in 17.2% of patients in the icosapent ethyl group compared to 22.0% of patients in the placebo group. This represented a highly statistically significant 25% relative risk reduction (RRR) (Hazard Ratio 0.75; 95% Confidence Interval [CI] 0.68-0.83; $ P < 0.001 $).[12]
• Key Secondary Endpoint: The key secondary endpoint was a hard composite of cardiovascular death, non-fatal MI, or non-fatal stroke. Treatment with IPE resulted in a 26% RRR for this endpoint, with an event rate of 11.2% in the IPE group versus 14.8% in the placebo group (HR 0.74; 95% CI 0.65-0.83; $ P < 0.001 $).[12]

Further Efficacy Endpoints and Subgroup Analyses

Prespecified hierarchical testing of other secondary endpoints revealed consistent and significant benefits across a range of ischemic events. Notably, IPE treatment led to a statistically significant 20% RRR in cardiovascular death (4.3% vs. 5.2%; HR 0.80; 95% CI 0.66-0.98; $ P = 0.03 $) and a 31% RRR in non-fatal MI (HR 0.69; 95% CI 0.58-0.81; $ P < 0.001 $).13 The benefit of IPE was remarkably consistent across numerous prespecified subgroups, including patients with a history of prior MI. In this high-risk subgroup, IPE reduced the primary endpoint by 26% (HR 0.74) and, importantly, reduced the risk of cardiovascular death by 30%.37

Pivotal Trials in Hypertriglyceridemia (MARINE and ANCHOR)

Prior to the REDUCE-IT trial, the efficacy of IPE in lowering triglycerides was established in two pivotal Phase 3 trials, MARINE and ANCHOR. These studies provided the evidence for its initial FDA approval for severe hypertriglyceridemia.[3]

• The MARINE Trial: This study evaluated IPE in patients with severe hypertriglyceridemia (baseline TG levels $ \geq 500 \text{ mg/dL} $ and $ \leq 2000 \text{ mg/dL} $). The results showed that IPE at a dose of 4 g/day significantly reduced median triglyceride levels by 27% from baseline compared to placebo. A critically important finding from this trial was that this substantial triglyceride reduction was achieved without a concomitant increase in LDL-C levels, a common and undesirable side effect of other omega-3 fatty acid formulations containing DHA.[3]
• The ANCHOR Trial: This study assessed IPE in patients with high triglycerides (baseline TG levels $ \geq 200 \text{ mg/dL} $ and $ < 500 \text{ mg/dL} $) who were already on stable statin therapy and had well-controlled LDL-C. In this population, IPE at 4 g/day reduced median triglyceride levels by 18% from baseline compared to placebo. Furthermore, in this patient group, IPE treatment also resulted in a small but statistically significant reduction in LDL-C levels.[3]

Table 3: The REDUCE-IT Trial - Design and Key Efficacy Outcomes

Component	Description
Study Design	Multinational, randomized, double-blind, placebo-controlled, event-driven trial
Patient Population	N = 8,179; Patients on stable statin therapy with elevated triglycerides (135-499 mg/dL) and either established CVD or diabetes with other risk factors.
Intervention	Icosapent Ethyl 4 g/day (2 g BID with food) vs. Matching Placebo
Median Follow-up	4.9 years
Efficacy Endpoint	IPE Group Event Rate
Primary Composite Endpoint	17.2%
(CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina)
Key Secondary Composite Endpoint	11.2%
(CV death, non-fatal MI, or non-fatal stroke)
Cardiovascular Death	4.3%
Non-fatal Myocardial Infarction	6.5%
Non-fatal Stroke	2.8%

Data compiled from sources [12], and.[14]

Clinical Application and Dosing

The robust clinical data for icosapent ethyl have led to specific approved indications, a well-defined dosing regimen, and strong recommendations within major international treatment guidelines.

Approved Indications

Icosapent ethyl has two distinct, FDA-approved indications based on the evidence from its pivotal clinical trials.

• Cardiovascular Risk Reduction: Based on the landmark results of the REDUCE-IT trial, IPE is indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization. This indication is for adult patients who have elevated triglyceride levels ($ \geq 150 \text{ mg/dL} $) and either established cardiovascular disease or diabetes mellitus with two or more additional risk factors for cardiovascular disease.[2]
• Severe Hypertriglyceridemia: Based on the results of the MARINE trial, IPE is indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (defined as TG levels $ \geq 500 \text{ mg/dL} $).[2] It is important to note that the effect of IPE on the risk for pancreatitis in this patient population has not been determined.[8]

Dosage, Administration, and Brand Formulations

The dosing and administration of icosapent ethyl are standardized to ensure optimal efficacy and absorption.

• Recommended Dosage: The recommended and clinically studied dose for both approved indications is 4 grams per day. This dose is administered as 2 grams taken twice daily with food.[4] Administration with a meal is a critical instruction, as the lipophilic nature of the drug requires the presence of fats for efficient absorption.
• Dosage Forms: Icosapent ethyl is available as liquid-filled soft gelatin capsules in two strengths: 0.5 gram and 1 gram.[4] The total daily dose of 4 grams can be achieved by taking either two 1-gram capsules twice daily or four 0.5-gram capsules twice daily.[4]
• Administration Instructions: Patients should be advised to swallow the capsules whole. The capsules should not be broken open, crushed, chewed, or dissolved, as this could alter the absorption profile of the medication.[8]
• Brand Names: The primary brand name for icosapent ethyl in the United States is Vascepa®. In the European Union, it is marketed as Vazkepa®.[1]

Guideline Recommendations

Following the publication of the REDUCE-IT trial, icosapent ethyl has been rapidly and strongly incorporated into major international clinical practice guidelines for cardiovascular risk reduction. A key consensus among these leading medical societies is that the clinical results observed with IPE are specific to this high-purity, EPA-only formulation and should not be generalized or extrapolated to any other omega-3 fatty acid product, including other prescription mixtures or dietary supplements.[19]

• American College of Cardiology (ACC) / American Heart Association (AHA): An AHA Science Advisory identified IPE as the first non-LDL-focused lipid therapy to demonstrate cardiovascular benefit and recommended it be considered first-line therapy for patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) whose triglycerides remain elevated despite maximally tolerated statin therapy and lifestyle changes.[19]
• American Diabetes Association (ADA): The ADA's Standards of Medical Care in Diabetes gives icosapent ethyl a Level "A" recommendation for use in patients with diabetes and ASCVD or other cardiovascular risk factors who are on a statin with controlled LDL-C but have elevated triglycerides (135-499 mg/dL).[19]
• European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS): These guidelines recommend that icosapent ethyl (2g twice daily) should be considered for high-risk patients with established cardiovascular disease whose triglyceride levels remain between 135 mg/dL and 499 mg/dL despite statin treatment.[19]
• National Lipid Association (NLA) and American Association of Clinical Endocrinologists (AACE): Both societies provide strong recommendations for the addition of IPE 4 g/day for cardiovascular risk reduction in high-risk and very-high-risk patients on maximally tolerated statins with persistent hypertriglyceridemia (TG 135-499 mg/dL).[19]

Safety Profile, Tolerability, and Risk Management

The safety and tolerability of icosapent ethyl have been extensively evaluated in its clinical development program, most notably in the large and long-term REDUCE-IT trial. While generally well-tolerated, there are specific risks that require clinical attention and patient counseling.

Adverse Events Profile

Common Adverse Effects

The most frequently reported adverse events that occurred more often with icosapent ethyl than with placebo in clinical trials are generally mild to moderate in severity. These include:

• Musculoskeletal pain and arthralgia (joint pain): This was one of the most common complaints.[17]
• Peripheral edema: Swelling of the hands, legs, or feet due to fluid buildup.[17]
• Constipation:.[17]
• Gout:.[17]

Serious Adverse Events of Clinical Significance

Two serious adverse events were identified in the REDUCE-IT trial that warrant particular attention.

• Atrial Fibrillation or Atrial Flutter: Treatment with IPE was associated with a statistically significant increased risk of atrial fibrillation (AFib) or atrial flutter requiring hospitalization. In the REDUCE-IT trial, this occurred in 3.1% of patients receiving IPE compared to 2.1% of patients receiving placebo.[17] The risk appears to be higher in patients who have a prior history of AFib or atrial flutter.[17] Clinicians should monitor patients for symptoms suggestive of an arrhythmia, such as palpitations, lightheadedness, dizziness, chest discomfort, or shortness of breath.[17]
• Bleeding: IPE is associated with an increased risk of bleeding events. In REDUCE-IT, any bleeding event was reported in 11.8% of patients in the IPE group versus 9.9% in the placebo group.[17] The risk of serious bleeding events (e.g., gastrointestinal bleeding) was also slightly higher, occurring in 3.1% of IPE patients versus 2.5% of placebo patients.[17] This risk is amplified in patients who are taking concomitant antithrombotic medications, such as antiplatelet agents (e.g., aspirin, clopidogrel) or anticoagulants (e.g., warfarin, direct oral anticoagulants). In patients on these concurrent therapies, serious bleeding occurred in 3.4% of the IPE group versus 2.6% of the placebo group.[16]

Contraindications, Warnings, and Precautions

• Contraindication: The only absolute contraindication to the use of icosapent ethyl is a known hypersensitivity (e.g., an anaphylactic reaction) to the drug or any of its components.[19]
• Warnings and Precautions:
• Fish and/or Shellfish Allergy: Icosapent ethyl is derived from fish oils. Although it is not definitively known whether patients with allergies to fish or shellfish are at an increased risk of an allergic reaction to the highly purified product, the prescribing information advises that it should be used with caution in this population.[18]
• Hepatic Impairment: As with other omega-3 fatty acid therapies, liver enzymes (alanine aminotransferase and aspartate aminotransferase) should be monitored periodically in patients with hepatic impairment.[33]

Drug-Drug and Drug-Food Interactions

• Pharmacodynamic Interactions: The most clinically significant drug interaction is the increased risk of bleeding when IPE is co-administered with other drugs that affect hemostasis. This includes anticoagulants (e.g., warfarin, apixaban, rivaroxaban) and antiplatelet agents (e.g., aspirin, clopidogrel).[2] The mechanism is a pharmacodynamic synergism, as EPA itself possesses mild antiplatelet properties, which can potentiate the effects of these other medications.[52] Patients on such combination therapy require close monitoring for signs and symptoms of bleeding.
• Pharmacokinetic Interactions: A key advantage of IPE is its low potential for pharmacokinetic drug-drug interactions. Because its metabolism occurs primarily via β-oxidation rather than the Cytochrome P450 (CYP450) enzyme system, it is not expected to interfere with the metabolism of the many drugs that are CYP substrates.[25] This has been confirmed in dedicated drug interaction studies, which found no significant pharmacokinetic interaction between IPE and CYP substrates like atorvastatin and rosiglitazone.[25]
• Drug-Food Interactions: There are no specific foods that are contraindicated or must be avoided while taking icosapent ethyl. However, a critical administration instruction is that the medication must be taken with food to ensure its adequate absorption.[4] Beyond this, patients are advised to adhere to a heart-healthy diet that is low in fat and cholesterol as part of their comprehensive management strategy.[27]

Table 4: Summary of Key Adverse Reactions from the REDUCE-IT Trial

Adverse Reaction	Icosapent Ethyl (N=4089) Incidence %	Placebo (N=4090) Incidence %
Atrial Fibrillation/Flutter (requiring hospitalization)	3.1%	2.1%
Any Bleeding Event	11.8%	9.9%
Serious Bleeding Event	3.1%	2.5%
Peripheral Edema	7.8%	5.8%
Constipation	5.4%	3.6%
Musculoskeletal Pain	4.3%	3.2%
Gout	4.3%	3.3%

Data compiled from sources [17], and.[13]

Comparative Analysis and Market Context

Icosapent ethyl occupies a unique position in the therapeutic armamentarium for cardiovascular disease, a status defined by its distinct chemical composition, its unparalleled evidence base from clinical outcomes trials, and its specific regulatory journey.

Icosapent Ethyl vs. Other Omega-3 Formulations

The clinical superiority of icosapent ethyl over other omega-3 fatty acid products, both prescription and over-the-counter, stems from several key differentiators.

• Compositional Purity: The defining feature of IPE is its composition. It is a highly purified, single-molecule product containing only the ethyl ester of eicosapentaenoic acid (EPA). In contrast, all other prescription omega-3 formulations (e.g., Lovaza®, Omtryg®, Epanova®) and all dietary fish oil supplements are mixtures that contain both EPA and docosahexaenoic acid (DHA).[5]
• Effect on LDL-C: This compositional difference has a direct and critical clinical consequence. The DHA component in mixed omega-3 products has been consistently shown to raise levels of low-density lipoprotein cholesterol (LDL-C), which is an undesirable effect in patients being treated for dyslipidemia and cardiovascular risk.[6] Icosapent ethyl, being devoid of DHA, does not cause this increase in LDL-C. In fact, in some patient populations, it has been shown to produce a small but significant reduction in LDL-C, providing a distinct therapeutic advantage.[5]
• Cardiovascular Outcome Data: Icosapent ethyl is the only omega-3 fatty acid therapy that has been proven to significantly reduce major adverse cardiovascular events in a large, prospective, randomized, placebo-controlled cardiovascular outcomes trial (REDUCE-IT).[5] This high level of evidence, demonstrating a reduction in hard clinical endpoints like cardiovascular death and myocardial infarction, is absent for all EPA/DHA mixtures and dietary supplements. This evidence gap is why major clinical guidelines explicitly state that the findings of REDUCE-IT cannot be extrapolated to other products.[19]

The journey of icosapent ethyl from a natural fish oil component to a globally approved, evidence-based pharmaceutical represents a significant achievement in drug development. It illustrates a paradigm shift, transforming a substance often viewed as a "natural" or "supplement" commodity into a rigorously tested, high-value therapeutic agent. This transformation was achieved through a deliberate, multi-step process. First, the company developed a highly purified, single-molecule prodrug (IPE) to ensure consistency, stability, and purity far exceeding that of any supplement.[26] Second, they conducted rigorous Phase 3 trials (MARINE, ANCHOR) to secure an initial, specific indication for severe hypertriglyceridemia, establishing a regulatory foothold.[39] Third, and most critically, they made a substantial investment in the massive, long-term REDUCE-IT trial to prove a benefit on hard clinical outcomes—a high-risk, high-reward strategy that no other omega-3 product sponsor had successfully completed.[11] The unequivocally positive result of this trial led to the landmark FDA label expansion and subsequent EMA approval, which were followed by strong guideline recommendations that cemented IPE's unique and protected place in therapy.[10] This entire process—purification, pharmaceutical formulation, rigorous clinical testing, and evidence-based regulatory approval—is what elevated IPE from the crowded and undifferentiated field of omega-3s to a distinct, indispensable therapeutic agent for cardiovascular risk reduction.

Regulatory Trajectory

The regulatory history of icosapent ethyl reflects its clinical development, with an initial approval for a lipid-lowering indication followed by a landmark expansion based on cardiovascular outcomes data.

U.S. Food and Drug Administration (FDA)

• July 26, 2012: The FDA granted its initial approval for Vascepa® (icosapent ethyl) as an adjunct to diet for the treatment of adult patients with severe hypertriglyceridemia (TG $ \geq 500 \text{ mg/dL} $). This approval was based on the positive efficacy and safety data from the MARINE trial.[9]
• December 13, 2019: Following a review of the compelling results from the REDUCE-IT trial, the FDA approved a significant label expansion for Vascepa®. The new indication was for cardiovascular risk reduction in high-risk, statin-treated patients. This made IPE the first and only drug approved by the FDA specifically for this purpose, marking a major milestone in cardiovascular pharmacotherapy.[9]

European Medicines Agency (EMA)

• March 26, 2021: The European Commission, following a positive recommendation from the EMA's Committee for Medicinal Products for Human Use (CHMP), granted marketing authorization for Vazkepa® (icosapent ethyl) for the indication of cardiovascular risk reduction across the European Union.[24] The EMA also recognized icosapent ethyl as a new active substance, which entitled it to a period of regulatory data protection in the EU market.[46]

Table 5: Comparative Profile of Prescription Omega-3 Fatty Acid Formulations

Feature	Icosapent Ethyl (Vascepa®/Vazkepa®)	Omega-3-Acid Ethyl Esters (e.g., Lovaza®)
Active Ingredients	Eicosapentaenoic Acid (EPA) ethyl ester only	EPA ethyl ester and Docosahexaenoic Acid (DHA) ethyl ester
EPA Content (per 1g capsule)	≥960 mg	~465 mg
DHA Content (per 1g capsule)	0 mg	~375 mg
Primary Indications	1. Cardiovascular Risk Reduction 2. Severe Hypertriglyceridemia (TG ≥500 mg/dL)	Severe Hypertriglyceridemia (TG ≥500 mg/dL)
Effect on Triglycerides (TG)	Significant Reduction	Significant Reduction
Effect on LDL-C	Neutral or slight reduction	Can significantly increase LDL-C
CV Outcome Trial Evidence	Positive (REDUCE-IT): 25% RRR in MACE	No dedicated, large-scale trial demonstrating MACE reduction

Data compiled from sources [5], and.[6]

Conclusion and Future Directions

Icosapent ethyl has emerged as a pivotal therapy in cardiovascular medicine, fundamentally altering the approach to managing residual risk in patients with atherosclerotic cardiovascular disease. Its clinical and regulatory journey has successfully established it not merely as a triglyceride-lowering agent, but as a multifaceted cardiovascular protective therapy with a unique and robust evidence base.

The profile of icosapent ethyl is defined by its high-purity, EPA-only composition, which confers a distinct advantage over mixed omega-3 fatty acid products by avoiding the detrimental increase in LDL-cholesterol. Its favorable pharmacokinetic profile, characterized by metabolism that bypasses the CYP450 system, minimizes the risk of drug-drug interactions, making it a safe and practical addition to the complex medication regimens common in high-risk cardiovascular patients. The therapeutic benefit, however, is driven by potent pleiotropic mechanisms—including anti-inflammatory and anti-thrombotic effects via modulation of the eicosanoid pathway—that extend far beyond its lipid-modifying properties.

The REDUCE-IT trial stands as a landmark achievement in cardiovascular research. It was the first study to successfully demonstrate that targeting a non-LDL pathway in statin-treated patients could yield a substantial reduction in hard ischemic events, including cardiovascular death. The trial's unequivocally positive results have filled a major unmet need in clinical practice and have firmly established icosapent ethyl as an essential, evidence-based tool for both secondary and high-risk primary prevention in appropriately selected patient populations.

The clinical application of icosapent ethyl requires a careful consideration of its risk-benefit profile. The profound reduction in ischemic events must be weighed against the small but statistically significant increased risks of atrial fibrillation and bleeding. For the high-risk populations defined by the REDUCE-IT inclusion criteria, the net clinical benefit is overwhelmingly positive, a conclusion strongly supported by its prominent inclusion in major international treatment guidelines.

Looking forward, several avenues for future research remain. While the clinical benefit is proven, further investigation is needed to fully elucidate the precise hierarchy and relative contributions of IPE's various pleiotropic effects to the overall reduction in cardiovascular events. Studies exploring its utility in other high-risk patient populations, such as those with established heart failure or in the acute post-myocardial infarction setting, could further expand its therapeutic role. Ultimately, the success of icosapent ethyl has not only provided clinicians with a powerful new tool but has also validated the broader therapeutic strategy of targeting pathways beyond LDL-cholesterol to continue to reduce the global burden of atherosclerotic cardiovascular disease.

Works cited

1. Icosapent | eicosapentaenoic acid | EPA | CAS#10417-94-4 - MedKoo Biosciences, accessed September 14, 2025, https://www.medkoo.com/products/8134
2. Icosapent ethyl: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 14, 2025, https://go.drugbank.com/drugs/DB08887
3. Pharmacokinetics of Eicosapentaenoic Acid in Plasma and Red ..., accessed September 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4467252/
4. Vascepa Dosage: Guidelines for Adults - GoodRx, accessed September 14, 2025, https://www.goodrx.com/vascepa/dosage
5. What is the difference between Icosapent ethyl (Eicosapentaenoic acid) and Omega-3 ethyl esters in the treatment of hypertriglyceridemia? - Dr.Oracle AI, accessed September 14, 2025, https://www.droracle.ai/articles/162835/what-is-the-difference-of-icosapent-ethyl-and-omega-3-ethyl-esters
6. A Comparative Overview of Prescription Omega-3 Fatty Acid ..., accessed September 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4671468/
7. Vascepa® (icosapent ethyl) - Prior Authorization ... - UHCprovider.com, accessed September 14, 2025, https://www.uhcprovider.com/content/dam/provider/docs/public/prior-auth/drugs-pharmacy/commercial/r-z/PA-Med-Nec-Vascepa.pdf
8. Dosing - VASCEPA® (icosapent ethyl), accessed September 14, 2025, https://vascepahcp.com/dosing/
9. Vascepa (icosapent ethyl) FDA Approval History - Drugs.com, accessed September 14, 2025, https://www.drugs.com/history/vascepa.html
10. FDA Approves Vascepa to Reduce Cardiovascular Risk - American College of Cardiology, accessed September 14, 2025, https://www.acc.org/latest-in-cardiology/articles/2019/12/16/16/41/fda-approves-vascepa-to-reduce-cardiovascular-risk
11. REDUCE-IT: findings and implications for practice - The British Journal of Cardiology, accessed September 14, 2025, https://bjcardio.co.uk/2023/05/reduce-it-findings-and-implications-for-practice/
12. Icosapent ethyl following acute coronary syndrome: the REDUCE-IT trial - Oxford Academic, accessed September 14, 2025, https://academic.oup.com/eurheartj/article/45/13/1173/7584871
13. REDUCE-IT: Does Icosapent Ethyl Represent New Pathway For Reducing CV Risk?, accessed September 14, 2025, https://www.acc.org/Latest-in-Cardiology/Articles/2018/11/07/15/19/sat-3pm-REDUCE-IT-aha-2018
14. REDUCE-IT USA | Circulation - AHA Journals, accessed September 14, 2025, https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.044440
15. Pharmacokinetics-pharmacodynamics of icosapent ethyl showing... - ResearchGate, accessed September 14, 2025, https://www.researchgate.net/figure/Pharmacokinetics-pharmacodynamics-of-icosapent-ethyl-showing-relationship-between-fasting_fig1_305273540
16. Real-world safety of icosapent ethyl: analysis based on spontaneous reports in FAERS database, accessed September 14, 2025, https://www.tandfonline.com/doi/pdf/10.1080/14740338.2023.2274946
17. Icosapent Side Effects: Common, Severe, Long Term - Drugs.com, accessed September 14, 2025, https://www.drugs.com/sfx/icosapent-side-effects.html
18. Icosapent Ethyl (Vascepa) for Hyperlipidemia/Hypercholesterolemia to Reduce Risk of Heart Attack and Stroke | AAFP, accessed September 14, 2025, https://www.aafp.org/pubs/afp/issues/2021/0115/p117.html
19. VASCEPA Guidelines, accessed September 14, 2025, https://vascepahcp.com/guidelines/
20. Icosapent | C20H30O2 | CID 446284 - PubChem, accessed September 14, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Icosapent
21. Eicosapentaenoic acid - Wikipedia, accessed September 14, 2025, https://en.wikipedia.org/wiki/Eicosapentaenoic_acid
22. Icosapent: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 14, 2025, https://go.drugbank.com/drugs/DB00159
23. Definition of ethyl icosapentate - NCI Drug Dictionary, accessed September 14, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/icosapent-ethyl
24. icosapent | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 14, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=refs&ligandId=7441
25. (PDF) Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Pharmacokinetic Parameters of Rosiglitazone in Healthy Subjects - ResearchGate, accessed September 14, 2025, https://www.researchgate.net/publication/264828998_Effects_of_Icosapent_Ethyl_Eicosapentaenoic_Acid_Ethyl_Ester_on_Pharmacokinetic_Parameters_of_Rosiglitazone_in_Healthy_Subjects
26. IPE Is the VASCEPA Difference, accessed September 14, 2025, https://www.vascepahcp.com/vascepa-difference/
27. Icosapent Ethyl Capsules: Package Insert / Prescribing Info, accessed September 14, 2025, https://www.drugs.com/pro/icosapent-ethyl-capsules.html
28. go.drugbank.com, accessed September 14, 2025, https://go.drugbank.com/drugs/DB08887#:~:text=Potential%20mechanisms%20of%20action%20include,increased%20plasma%20lipoprotein%20lipase%20activity.
29. What is Icosapent Ethyl used for? - Patsnap Synapse, accessed September 14, 2025, https://synapse.patsnap.com/article/what-is-icosapent-ethyl-used-for
30. Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Pharmacokinetic Parameters of Rosiglitazone in Healthy Subjects - PMC, accessed September 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4467261/
31. Icosapent ethyl: Eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies - PubMed, accessed September 14, 2025, https://pubmed.ncbi.nlm.nih.gov/27418543/
32. Vazkepa | European Medicines Agency (EMA), accessed September 14, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/vazkepa
33. Icosapent Ethyl (Vascepa) | Davis's Drug Guide - Nursing Central - Unbound Medicine, accessed September 14, 2025, https://nursing.unboundmedicine.com/nursingcentral/view/Davis-Drug-Guide/109833/all/icosapent_ethyl
34. Effect of Concomitant Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on the Pharmacokinetics of Atorvastatin - PMC, accessed September 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4281350/
35. Study Details | NCT01492361 | A Study of AMR101 to Evaluate Its ..., accessed September 14, 2025, https://clinicaltrials.gov/study/NCT01492361
36. REDUCE-IT Clinical Trial Results Presented and Published - Stern Cardiovascular, accessed September 14, 2025, https://www.sterncardio.com/news/reduce-it-clinical-trial-results-published
37. Prevention of Cardiovascular Events and Mortality With Icosapent ..., accessed September 14, 2025, https://www.jacc.org/doi/10.1016/j.jacc.2022.02.035
38. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial - PubMed, accessed September 14, 2025, https://pubmed.ncbi.nlm.nih.gov/28294373/
39. Icosapent ethyl: scientific and legal controversies - PMC, accessed September 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8070860/
40. Antihyperlipidemics - icosapent ethyl (Vascepa) - | WA.gov, accessed September 14, 2025, https://www.hca.wa.gov/assets/billers-and-providers/antihyperlipidemics-icosapent-ethyl.pdf
41. Icosapent ethyl (oral route) - Side effects & dosage - Mayo Clinic, accessed September 14, 2025, https://www.mayoclinic.org/drugs-supplements/icosapent-ethyl-oral-route/description/drg-20075707
42. Icosapent Ethyl Monograph for Professionals - Drugs.com, accessed September 14, 2025, https://www.drugs.com/monograph/icosapent-ethyl.html
43. Icosapent Uses, Side Effects & Warnings - Drugs.com, accessed September 14, 2025, https://www.drugs.com/mtm/icosapent.html
44. Icosapent Ethyl: MedlinePlus Drug Information, accessed September 14, 2025, https://medlineplus.gov/druginfo/meds/a613024.html
45. New REDUCE-IT® Analyses Presented at ESC 2025 Include Data Showing VASCEPA®/VAZKEPA® (Icosapent Ethyl) Therapy Resulted in 9% Fewer Total Hospitalizations & Reduces Cardiovascular Disease Risk in Certain High-Risk Patient Subgroups - Amarin Corp, accessed September 14, 2025, https://www.amarincorp.com/news-and-media/new-reduce-itr-analyses-presented-esc-2025-include-data-showing
46. Does European Commission approval of VAZKEPA grant regulatory exclusivity to Amarin for the label, accessed September 14, 2025, https://amarincorp.gcs-web.com/static-files/5e2225e2-f722-478a-8db8-0e46eb61f099
47. The 5 Vascepa Side Effects People Most Often Experience - GoodRx, accessed September 14, 2025, https://www.goodrx.com/vascepa/most-common-vascepa-side-effects
48. Vazkepa, INN-icosapent ethyl - European Medicines Agency, accessed September 14, 2025, https://www.ema.europa.eu/en/documents/product-information/vazkepa-epar-product-information_en.pdf
49. Learn About Safety & Side Effects | VASCEPA® (icosapent ethyl), accessed September 14, 2025, https://www.vascepa.com/about-vascepa/safety-and-side-effects/
50. Vascepa interactions: Other medications, alcohol, and more, accessed September 14, 2025, https://www.medicalnewstoday.com/articles/drugs-vascepa-interactions
51. Learn About Dosing Guidelines | VASCEPA® (icosapent ethyl), accessed September 14, 2025, https://www.vascepa.com/getting-started/dosing/
52. Vascepa (icosapent) dosing, indications, interactions, adverse ..., accessed September 14, 2025, https://reference.medscape.com/drug/vascepa-icosapent-999764
53. Drug Interaction Report - apixaban icosapent - Drugs.com, accessed September 14, 2025, https://www.drugs.com/interactions-check.php?drug_list=3407-0,3438-0&professional=1
54. Icosapent ethyl Advanced Patient Information - Drugs.com, accessed September 14, 2025, https://www.drugs.com/cons/icosapent-ethyl.html
55. Reference ID: 4057318 This label may not be the latest approved by FDA. For current labeling information, please visit https://, accessed September 14, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202057s019lbl.pdf
56. Icosapent ethyl capsules - Cleveland Clinic, accessed September 14, 2025, https://my.clevelandclinic.org/health/drugs/19677-icosapent-ethyl-capsules
57. Icosapent Interactions Checker - Drugs.com, accessed September 14, 2025, https://www.drugs.com/drug-interactions/icosapent.html
58. Ethyl eicosapentaenoic acid - Wikipedia, accessed September 14, 2025, https://en.wikipedia.org/wiki/Ethyl_eicosapentaenoic_acid
59. Learn About Amarin | VASCEPA® (icosapent ethyl), accessed September 14, 2025, https://www.vascepa.com/about-vascepa/history/