Tracey L. Giannouris, MA
January 13, 2020
Fish oil supplements for cardiovascular (CV) protection have been a controversial topic for years. Recently, Vascepa (Amarin), a prescription fish oil comprising high-dose icosapent ethyl, received an expanded indication from the US Food and Drug Administration (FDA) for CV risk reduction in some patients with elevated triglyceride (TG) levels. Given that not all fish oil products — prescription or over-the-counter — are alike, here are five important things to know about their use.
1. Icosapent ethyl is the only prescription omega-3 approved for CV reduction.
With its expanded indication, icosapent ethyl can now be used as an adjunct to statin therapy to reduce CV events in patients with elevated TG levels (≥150 mg/dL) and established atherosclerotic cardiovascular disease (ASCVD) or diabetes and at least two other CV risk factors. This recommendation is based on outcomes from REDUCE-IT, which demonstrated a 25% reduced risk of major CV events in patients receiving icosapent ethyl, and a 35% reduced risk reduction in participants with a history of ASCVD.
This concentrated eicosapentaenoic acid (EPA)-only prescription omega-3 polyunsaturated fatty acid (PUFA) was associated with higher rate of atrial fibrillation and bleeding in REDUCE-IT, and although it is noted in the prescribing information under warnings and precautions, the FDA did not think these effects warranted a contraindication.
Previous studies of lower doses (1g) of combined EPA/docosahexaenoic acid (DHA) pills did not show a reduction in outcomes in at-risk patients without prior CVD, even in those with diabetes. Higher doses of other omega-3 formulations may reduce CV events, but that remains to be tested in clinical studies. The ongoing STRENGTH trial of high-dose (4g) omega-3 carboxylic acid/EPA in patients who are at high CV risk with elevated TG levels is expected to be completed in late 2020.
Whether TG lowering alone or additional pleiotropic anti-inflammatory, antithrombotic effects explain the level of CV risk reduction seen in REDUCE-IT is a subject of debate.
2. Although the currently available prescription fish oils are effective in lowering TG levels, differences exist among products with respect to formulation and effect.
The available prescription fish oils are not true fish oil products, but rather are different formulations of omega-3 fatty acids derived from fish oil. Five prescription omega-3 PUFA are currently available in the United States, four of which are approved by the FDA to lower serum TG levels (Table), and one of which (Vascazen, Pivotal Therapeutics) is an FDA-regulated medical food for omega-3 deficiency in patients with CVD.
Table. Currently Available FDA-Approved Omega-3 PUFA Formulations
|Brand Name||Formulation||EPA (g) per 1 g capsule||DHA (g) per 1 g capsule||Omega-3 dose (g) per 4 g|
|Epanova||Omega-3-carboxylic acids/DHA||0.55||0.2||3.0 EPA+DHA|
|Lovaza||Omega-3 acid ethyl esters/DHA||0.43||0.345||3.1 EPA/DHA|
|Omtryg||Omega-3 acid ethyl esters/DHA||0.43*||0.345*||3.1 EPA/DHA|
|Vascepa||Icosapent ethyl||0.88||0||1.0 EPA|
|*Amount per 1.2 g capsule|
Although all of the prescription omega-3 PUFA have similar TG lowering effects, variations exist with respect to their effects on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels. Studies have shown that the DHA-containing omega-3 PUFA increase LDL-C and may moderately increase HDL-C, whereas studies have shown the EPA-only omega-3 PUFA significantly lowers serum TG levels without increasing LDL-C in patients both on and off statin therapy, and it modestly decreases HDL-C.
3. Prescription fish oils are not indicated for all patients with elevated TG levels.
With the exception of the EPA/DHA medical food formulation and the use of high-dose icosapent ethyl for the reduction of CV events, the currently available prescription fish oils are approved by the FDA as an adjunct to dietary intervention for adult patients with very high TG levels (≥ 500 mg/dL). The American Heart Association (AHA) Science Advisory on omega-3 fatty acids for the management of hypertriglyceridemia notes that "for all degrees of triglyceride elevation, treatment or elimination of secondary causes and intensive diet and lifestyle changes are recommended before direct pharmacotherapy."
Per their FDA-approved indication, omega-3 PUFA products are for adult patients. Although prescription-strength omega-3 PUFA appear to be well tolerated in pediatric patients, studies to date have not shown significant efficacy in lowering TG levels in this patient population.
Because the prescription omega-3 PUFA are derived from fish sources, they are contraindicated for use in patients in whom there is a known hypersensitivity to fish or shellfish.
Although not a contraindication, per the FDA product label, caution should be exercised when prescribing omega-3 PUFA to patients with hepatic impairment, and it is recommended that alanine aminotransferase and aspartate aminotransferase levels be monitored because some formulations of EPA/DHA can increase serum levels of these enzymes.
4. Over-the-counter (OTC) marine-based products are not a substitute for prescription omega-3 PUFA for reducing TG levels.
Although they may serve a supplementary role to diet, OTC marine oil-based omega-3 fatty acids, such as fish oil, calanus oil, and krill oil, are neither recommended nor indicated as a substitute for prescription omega-3 PUFA to lower serum TG levels or as a treatment for any disease.
The FDA-approved prescription omega-3 PUFA contain pharmaceutical-strength doses of highly purified, regulated levels of DHA/EPA combined, or EPA alone. OTC marine oils contain much lower, subtherapeutic amounts of omega fatty acids (even those products claiming to be double- or triple-strength), and because these products are not reviewed, approved, or monitored by the FDA, there are no assurances as to their quality, potency, and safety.
Furthermore, OTC marine oils contain a variety of other nontherapeutic ingredients — in some cases, cholesterol, oxidized fatty acids, or contaminants. Patients taking these marine oils also risk exposure to higher levels of oxidative products, and some of these supplements have been found to contain high levels of saturated fats, which interfere with the purported beneficial effects of these products. Omega-3 PUFA supplements that have been voluntarily tested to confirm content independently carry the US Pharmacopeial Convention symbol on the label.
With more than 100 OTC marine oil-based dietary supplements available and marketed to consumers, one expert analysis from the American College of Cardiology noted the temptation for some patients to switch from higher-cost prescription PUFA to a less expensive OTC supplement. To facilitate adherence to the prescribed marine-based oil and dissuade patients from switching to an OTC supplement, the authors of this analysis recommend physicians provide information about available coverage assistance.
5. Prescription omega-3 PUFA may prove cost-effective by reducing clinical and economic burden.
With respect to cost, the average retail price for a 30-day supply of Lovaza (4 g EPA/DHA) is $202.39; for a 30-day capsule supply of Vascepa the cost is about $348 to $364 (or about $245 with manufacturer coupon). These costs may be offset by some private insurance plans, Medicare, and Medicaid.
The clinical burden of severe hypertriglyceridemia is associated with substantial healthcare costs. In the US, the annual economic burden associated with high TG is estimated to be $10.7 billion. Previous studies suggest that the cost of prescription omega-3 PUFA could be offset by the beneficial effects, such as reduced CV morbidity and mortality as well as a reduced risk of pancreatitis, kidney disease, and diabetes-related events in patients with very high triglycerides.
More recently, results from nonprofit analyses confirmed the cost-effectiveness of icosapent ethyl as an adjunct to statin therapy. An analysis of data from REDUCE-IT demonstrated that icosapent ethyl had "better outcomes at lower health care costs" ($4.16/day for payer-eligible patients), making it not only cost-effective but also cost-saving compared with placebo.
Tracey L. Giannouris, MA, is a freelance medical/clinical editor in Flemington, New Jersey. She has worked on various peer-reviewed and continuing medical education publications in both human and animal healthcare for nearly two decades.