Not All Fish Oils Are Created Equal: Insight From REDUCE-IT

Fish oils are among the most well recognized health supplements and are omnipresent in health food aisles across the United States. Yet despite their popularity, the cardiovascular benefits of the active ingredient in fish oils, omega-3 fatty acids (FA), have long been controversial owing to differing results from several previous cardiovascular outcomes trials. (CVOT). Given the different formulations, dosages and patient populations studied, these trials have allowed researchers and physicians to better understand the pharmacologic and clinical nuances of omega-3 FA in cardioprotection. Data from the randomized controlled trial Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) further adds to the growing body of evidence on the use of omega-3 FA and reinforces the notion that not all fish oils are created equal.1

Omega-3 fatty acids are a family of polyunsaturated fatty acids (PUFA) of which three major types are needed by humans: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).2 ALA is an essential fatty acid and must be consumed through dietary sources, largely from nuts, vegetable oils, flax seeds and leafy vegetables. EPA and DHA can be synthesized from ALA though a significant portion is also derived from the diet, mainly from oily fish or fish oil supplements.3 As a supplement, fish oils come in many forms including ethyl esters, acylglycerols, triacylglycerols and phospholipid forms containing varying proportion of EPA and DHA.4 Omega-3 fats are integral in cellular function, influencing membrane structure and function, cell signaling and gene expression. Moreover, various pleotropic effects have been described to be associated with omega-3 FA consumption, including reduction of resting heart rate and blood pressure as well as anti-thrombosis and anti-inflammatory properties.5

Highly purified omega-3 FA formulations either containing a mixture of DHA/EPA or EPA alone have been approved by the Food and Drug Administration (FDA) and are available as prescribed therapies for treatment of severe hypertriglyceridemia (≥500 mg/dL).6,7 The rationale of treating elevated triglycerides (TGs) from a cardioprotection perspective lies in reduction of residual atherosclerotic cardiovascular disease (ASCVD) risk in patients with hypertriglyceridemia even after achieving LDL cholesterol (LDL-C) below goal levels with statin therapy.8 It is thought that while large TG-rich particles likely are not atherogenic, smaller TG containing remnant particles, especially after hydrolysis to cholesteryl ester-enriched byproducts, can permeate vessel walls and promote atherosclerosis.9 Thus, it has been hypothesized that reduction in TGs can provide additional cardioprotective benefit beyond LDL-C lowering.

There have been multiple CVOTs assessing the efficacy of omega-3 FA in reducing CV events. GISSI Prevenzione (GISSI-P) assessing omega-3 ethyl esters 1g/day in patients with recent myocardial infarction (MI) showed significant reduction of primary endpoint (death, nonfatal MI and nonfatal stroke) in patients on omega-3 FA before statin and other medical therapies were part of the definition of guideline directed medical therapy.10 Likewise, GISSI Heart Failure (GISSI-HF), assessing patients with chronic heart failure, showed significant reduction in primary endpoints of all-cause mortality and heart failure hospitalization in patients on 1g/day of omega-3 ethyl ester.11 However, these earlier studies enrolled a low number of patients on concomitant statin therapy (5% and 22% at start of study for GISSI-P and GISSI-HF respectively) with lower rates of revascularization. Subsequent trials involving similar doses and formulations but with a larger proportion of patients on a background of statin therapy, other medical therapies for ASCVD risk reduction, such as dual antiplatelet therapy, and therapies like ACE-I and beta blockers did not show significant efficacy.12 Most recently, ASCEND (A Study of Cardiovascular Events iN Diabetes), assessing 15,480 patients with diabetes mellitus without ASCVD, showed no significant difference in risk for major vascular events (nonfatal MI, stroke, transient ischemic attack, vascular death) among patients taking 1g/day omega-3 FA compared with placebo at a mean follow-up of 7.4 years.13 Around 75% of the patients in the ASCEND study were on statin therapy with a mean non-HDL-C of 113mg/dL (LDL-C and TGs not available).

Given the biochemical differences between EPA and DHA that portend to possibly distinct anti-oxidant and membrane modulatory properties, omega-3 formulations with EPA alone have also been developed and evaluated with respect to cardiovascular outcomes. In 2007, investigators published results from JELIS (Effect of Eicosapentaenoic Acid [EPA] on Major Cardiovascular Events in Hypercholesterolemic Patients: the Japan EPA Lipid Intervention Study), which assessed the efficacy of purified EPA 1.8g (without DHA) in combination with low-intensity statin therapy in 18,645 Japanese patients with hypercholesterolemia (mean baseline total cholesterol 7.11mmol/L [~275mg/dL]) compared with statin therapy alone.14 The median TG level at baseline for the EPA group was 1.73mmol/L (~153mg/dL) and 1.74mmol/L (~154mg/dL) for the control group. JELIS showed a significant reduction in major coronary events defined as sudden cardiac death, fatal and non-fatal MI, unstable angina and revascularization (HR 0.81, 95% CI 0.69-0.95). The reduction in events was in the setting of modest TG lowering (by 9% from baseline in the EPA group and by 4% in controls, p <0.0001) and without differences in reduction of LDL cholesterol levels. Subgroup analysis showed a more pronounced reduction in events in patients with mixed dyslipidemia with TGs ≥150mg/dL and HDL-C < 40mg/dL (HR 0.47, 95% CI 0.23-0.98).15

REDUCE-IT was a phase III multi-centered randomized control trial to evaluate the efficacy of highly purified ethyl ester of EPA, icosapent ethyl, at 2g twice daily (4g total daily dose) versus placebo (mineral oil) in reduction of major cardiovascular events (composite of cardiovascular death, non-fatal MI, nonfatal stroke, coronary revascularization or unstable angina requiring hospitalization).1 The study included 8,179 participants with either established ASCVD (70.7% of the participants) or diabetes mellitus plus additional ASCVD risk factors (29.3% of participants), who were concurrently treated with statins. Patients included in the trial had fasting TG levels of ≥150mg/dL and <500mg/dL as well as LDL-C levels of >40mg/dL and ≤100mg/dL, and were not on any additional lipid lowering medications other than statins (±ezetimibe).16 It should be noted that the lower inclusion cutpoint for fasting TG was amended to ≥200mg/dL early in the study to increase the enrollment of patients with more significant TG elevations. Enrolled participants in the study had a median age of 64 years; over 70% of the participants were men and more than 90% were white race. Median baseline TG levels were 216.5 mg/dL (IQR: 176.5-272.0) and 216.0 mg/dL (IQR: 175.5-274.0) in the icosapent ethyl and placebo groups respectively, while the median baseline LDL-C levels were 74.0 mg/dL (IQR: 61.5-88.0) and 76.0 mg/dL (IQR: 63.0-89.0) respectively. Approximately 93% of both active drug group and placebo group were on either moderate or high intensity statin therapy.1

The median follow-up was 4.9 years during which the primary endpoint occurred in 17.2% of patients in the active treatment group on icosapent ethyl 2g twice daily and 22.0% of the placebo group (HR 0.75; 95% CI, 0.68-0.83; p <0.001). The absolute risk reduction (ARR) in primary efficacy end point was 4.8% with a number needed to treat of 21 to avoid one primary endpoint event over a median follow-up time period of 4.9 years. Individual secondary endpoints of cardiovascular death (HR 0.80; 95% CI, 0.66-0.98; p = 0.03; ARR = 0.9%), fatal or non-fatal MI (HR 0.69; 95% CI, 0.58-0.81; p <0.001; ARR = 2.6%), fatal or nonfatal stroke (HR 0.72; 95% CI, 0.55-0.93; p = 0.01; ARR = 0.9%), urgent or emergent revascularization (HR 0.65; 95% CI, 0.55-0.78; p <0.001; ARR = 2.5%) and hospitalization for unstable angina (HR 0.68; 95% CI, 0.53-0.87; p = 0.002; ARR = 1.2%) were also significantly reduced in the icosapent ethyl group compared to placebo. However, the secondary endpoint of death from any cause was not significantly different between groups (HR 0.87; 95% CI, 0.74-1.02).

Treatment with icosapent ethyl was also noted to have significant effect on lipids and metabolic profile. TG were lowered by 18.3% (-39.0 mg/dL) at year 1 and 21.6% (-45.0 mg/dL) at last visit for the icosapent ethyl group compared with an increase of 2.2% (4.5 mg/dL) at year 1 and reduction of 6.5% (-13.0 mg/dL) at last visit for placebo. At last visit, the LDL-C in the icosapent ethyl group was reduced by 1.2% (-1.0 mg/dL) while the LDL-C in the placebo arm increased by 6.5% from baseline (5.7 mg/dL). This was thought to be possibly due to the use of mineral oil as placebo. High sensitivity C-reactive protein (hs-CRP) was reduced by 12.6% (-0.2 mg/L) in the icosapent ethyl arm compared with a rise of 29.9% (0.4 mg/L) in the placebo arm.

Overall rates of adverse events were not significantly different between the icosapent ethyl and placebo groups. The icosapent ethyl group did have lower rates of gastrointestinal adverse events (33.0% vs. 35.1%, p = 0.04) and anemia (4.7 vs. 5.8%) compared with placebo. The rates of atrial fibrillation (5.3% vs. 3.9%, p = 0.003) and peripheral edema (6.5% vs. 5.0%, p = 0.002) were noted to be significantly higher in the icosapent ethyl group compared to placebo. Rates of serious adverse bleeding events were 2.7% in the icosapent ethyl arm and 2.1% in the placebo arm (p = 0.06), with no significant differences in rates of central nervous system or gastrointestinal bleeding.

From a clinical perspective, the promising results from REDUCE-IT build on the finding of JELIS, further suggesting that a pure EPA formulation may offer cardioprotection, targeting a non-LDL-C reduction strategy to reduce residual cardiovascular risk with an improvement in a composite primary endpoint and secondary endpoint of cardiovascular mortality in a moderate to high risk patient population. Though the dose of EPA used in REDUCE-IT was higher than in JELIS, previous analysis showed that circulating EPA levels were similar between a daily dose of 4g in a western population compared to the 1.8g daily dose in the Japanese population in JELIS.17 An important distinction of REDUCE-IT is that the trial targeted higher levels of TGs, where fish oil and other triglyceride lowering therapies are likely to show the most benefit. REDUCE-IT patients had appreciably higher baseline TG levels compared to those in JELIS (median of 216mg/dL vs. 153mg/dL respectively), with more than double the percent reduction in TGs in REDUCE-IT. Moreover, LDL-C was overall well-controlled in REDUCE-IT with 93% of patients on either moderate or high intensity statin therapy, compared to JELIS where LDL-C levels were much higher and the majority of patients were on low-intensity statins. These observations add support to findings from Mendelian randomization studies suggesting that elevated TGs is not only a risk marker but even in the setting of well-controlled LDL-C, represents a residual risk factor for ASCVD.18,19 Interestingly, subgroup analysis from REDUCE-IT did not show significant heterogeneity of effect difference in primary endpoint between icosapent ethyl groups with baseline TG levels of >150 mg/dL versus <150 mg/dL. These findings of similar effect size even in patients with baseline TG levels of <150 mg/dL with icosapeny ethyl group are interesting and call into question whether the ideal cut-off for normal TG levels should be even lower than 150 mg/dL. In that respect, prior epidemiologic studies have shown that the risk associated with triglycerides increases even in the range of 90-175 mg/dL.20

As Bhatt et al. postulate, reduction of ASCVD events irrespective of attained TG levels suggest that mechanisms outside of TG reduction may also be involved. The attenuation of the rise in hs-CRP over the REDUCE-IT trial period support previously described anti-inflammatory effects of EPA,21,22 although there was significant elevation in hs-CRP levels in the placebo arm. Meanwhile, EPA is also known to affect platelet aggregation, which may account for the increase in bleeding events.23,24 Other potential pleotropic effects of EPA that have been previously described include promoting endothelial function and plaque stability.9 It will be interesting in follow-up studies of REDUCE-IT data to explore the mechanisms of icosapent ethyl, such as effects on traditional risk factors like blood pressure, blood glucose and insulin resistance, as well as effects on levels of various biomarkers and metabolites related to cardiovascular disease.

With regard to safety outcomes, it was reassuring that the drug was well tolerated from a gastrointestinal standpoint (which has led to compliance problems in other trials), with lower rates of gastrointestinal adverse effects compared with placebo (33.0% vs. 35.1%). The increase in rates of atrial fibrillation and peripheral edema will impact patient selection for icosapent ethyl in the clinical setting. It is unknown what the mechanism for the increase in AF incidence is, but it is an association that has previously been observed in other studies with EPA supplementation. Regardless, despite the statistical significance, the absolute increase in event rate was only 1.4%, which given the magnitude of benefit in cardiovascular risk reduction favors icosapent ethyl from a net clinical efficacy benefit. The lack of difference in rates of new heart failure (HR 0.95; 95% CI, 0.77-1.17) or heart failure hospitalization (HR 0.97; 95% CI, 0.77-1.22) between the icosapent ethyl and placebo groups is reassuring that the higher incidence of atrial fibrillation was less likely to lead to heart failure hospitalizations. Future studies examining echo data and biomarkers such as NT-proBNP could be performed to assess for more subtle changes that may be induced as a result of atrial remodeling leading to higher clinical atrial fibrillation.

The modest increase in bleeding events may be due to effect on formation and signaling of thromboxane A2, an important mediator of platelet aggregation.23,24 An increase in bleeding events was also observed in the JELIS study, albeit at a lower rate (1.1% in the EPA group and 0.6% in controls). It should be noted that only 13% of the EPA group and 14% of the control group were on antiplatelet therapy at baseline in JELIS. Though not reported, a majority of REDUCE-IT patients had established ASCVD and presumably a significant number of these patients were on aspirin and some potentially on dual antiplatelet therapy. The interaction between icosapent ethyl with antiplatelet and anticoagulation medications warrant further investigation to ensure safety of use in these patients.

There are several potential reasons for the positive results of REDUCE-IT compared with other previously negative trials involving mixtures of EPA and DHA. EPA and DHA have different biochemical properties including effects on membrane bilayer structure, formation of cholesterol crystalline domains, LDL-C levels and platelet function.24-26 In addition, the higher dose of omega-3 FA studied in REDUCE-IT and higher triglyceride levels compared to previous trials may have led to a higher degree of efficacy in CV event reduction. A longer follow-up (4.9 years) in REDUCE-IT could also have contributed to rather larger ARR in primary end point seen in this study. The ongoing STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia ) trial, which aims to assess the efficacy and safety of omega-3 caboxylic acid, the first approved prescription drug with omega-3 in free fatty acid form, in a similar patient population will help to clarify some of the questions of how formulation and dosage of omega-3 FAs influence cardiovascular outcomes.27

One aspect of the REDUCE-IT trial design that has not yet been discussed above is the use of mineral oil in the placebo group. There is currently little evidence on direct impact of mineral oil on cardiovascular disease. However, there has been prior critique of the use of mineral oil as placebo due to possible decrease in absorption of medications including statins and possible adverse effect on the lipid profile.28 Though there was a slight upward drift of LDL-C and hs-CRP levels in the placebo arm through the course of the study, it is unlikely that the modest increase in LDL-C compared to the icosapent ethyl group can fully account for the degree of risk reduction in ASCVD outcomes for patients on icosapent ethyl. Finally, despite ~70% of the patients with established ASCVD, only 30% of the patients were on high-intensity statin therapy. These lower rates of high-intensity statin therapy use have also been noted in real-world ASCVD and diabetic populations and represent an opportunity to further improve ASCVD outcomes in these patients.29,30

Taken as a whole, the clinical implications of findings from REDUCE-IT are noteworthy. The rise in obesity and patients with metabolic syndrome around the world will likely increase the number of individuals with mixed lipid disorders and in particular those with elevated TGs. Even with the widespread use of statin therapy to target LDL-C, hypertriglyceridemia remains an independent risk factor for ASCVD and there continues to be a residual treatment gap in cardiovascular outcomes that needs to be closed. Thus, REDUCE-IT provides solid randomized clinical trial evidence that treating a high-risk population of secondary prevention patients or moderate to high risk primary prevention patients, as identified by elevated TGs, with icospent ethyl therapy improves both "hard" and "soft" endpoints, including a 20% RRR in cardiovascular mortality. While the magnitude of benefit was much larger than recent trials of non-statin therapies that have shown efficacy, REDUCE-IT also leaves us wondering whether the effect of icospent ethyl therapies may be due to non-TG- lowering mechanisms, such as a reduction in inflammation and platelet aggregation. Several additional trials on omega-3 FA are underway, which will continue to provide fresh perspectives on this "fishy" class of medications.


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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Anticoagulation Management and Atrial Fibrillation, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: alpha-Linolenic Acid, Anemia, Angina, Unstable, Aspirin, Atherosclerosis, Atrial Fibrillation, Atrial Remodeling, Biological Markers, Blood Glucose, Blood Platelets, Blood Pressure, Cardiovascular Diseases, Cholesterol, Cholesterol Esters, Cholesterol, LDL, C-Reactive Protein, Death, Sudden, Cardiac, Diabetes Mellitus, Docosahexaenoic Acids, Edema, Eicosapentaenoic Acid, Epidemiologic Studies, Esters, Fatty Acids, Nonesterified, Fatty Acids, Omega-3, Fish Oils, Flax, Follow-Up Studies, Glucose, Glycerides, Heart Failure, Heart Rate, Hemorrhage, Hospitalization, Hydrolysis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hypertriglyceridemia, Inflammation, Insulin Resistance, Ischemic Attack, Transient, Metabolic Syndrome X, Metabolome, Myocardial Infarction, Mineral Oil, Natriuretic Peptide, Brain, Numbers Needed To Treat, Patient Selection, Peptide Fragments, Obesity, Oxidants, Platelet Aggregation, Primary Prevention, Random Allocation, Research Personnel, Risk Factors, Secondary Prevention, Thrombosis, Thromboxane A2, Treatment Outcome, Triglycerides, United States Food and Drug Administration, Stroke, Plant Oils, Risk Reduction Behavior, Vegetables

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