The New England Journal of Medicine January 03, 2019

Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (REDUCE-IT)

Deepak L. Bhatt, P. Gabriel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Steven B. Ketchum et al.

Bottom Line

In high-risk patients with elevated triglycerides despite statin therapy, high-dose highly purified icosapent ethyl significantly reduced the risk of major ischemic events, including cardiovascular death, compared to placebo.

Key Findings

1. A primary end-point event (composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) occurred in 17.2% of the icosapent ethyl group compared to 22.0% of the placebo group (HR 0.75; 95% CI, 0.68 to 0.83; P<0.001), yielding a number needed to treat (NNT) of 21.

2. The key secondary end point (composite of cardiovascular death, nonfatal MI, or nonfatal stroke) occurred in 11.2% of the icosapent ethyl group versus 14.8% of the placebo group (HR 0.74; 95% CI, 0.65 to 0.83; P<0.001).

3. Cardiovascular death was significantly lower in the icosapent ethyl group at 4.3% compared to 5.2% in the placebo group (HR 0.80; 95% CI, 0.66 to 0.98; P=0.03).

4. Hospitalization for atrial fibrillation or flutter was significantly more common in the icosapent ethyl group (3.1% vs. 2.1%, P=0.004).

5. Serious bleeding events occurred slightly more frequently in the icosapent ethyl group (2.7% vs. 2.1%), although this difference did not reach statistical significance (P=0.06).

Study Design

Design

RCT

Double-Blind

Sample

8,179

Patients

Duration

4.9 yr

Median

Setting

Multicenter, International

Population Patients aged 45 years or older with established cardiovascular disease, or 50 years or older with diabetes and at least one additional risk factor, receiving stable statin therapy, with fasting triglyceride levels of 135 to 499 mg/dL and LDL-C of 41 to 100 mg/dL.

Intervention Icosapent ethyl 2 g administered twice daily (total daily dose, 4 g).

Comparator Matching mineral oil placebo administered twice daily.

Outcome A composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

Study Limitations

• The use of a mineral oil placebo raised concerns that it may have negatively affected statin absorption or increased inflammatory markers (CRP) and LDL-C in the control arm, though investigators concluded the modest LDL differences could not explain the 25% relative risk reduction.

• The trial cohort was overwhelmingly white (approximately 90%), which may limit the generalizability of the findings to other racial and ethnic groups.

• Baseline use of non-statin lipid-lowering therapies, such as ezetimibe or PCSK9 inhibitors, was very low because they were either relatively new or not widely standard practice at the time of trial design.

Clinical Significance

REDUCE-IT established icosapent ethyl (high-dose purified EPA) as a highly effective adjunctive therapy for reducing residual cardiovascular risk in statin-treated patients with established ASCVD or diabetes and moderate hypertriglyceridemia. Unlike over-the-counter mixed omega-3 supplements (EPA/DHA) or fibrates, which largely failed to show outcome benefits in contemporary trials, this specific formulation and high dosage successfully reduced ischemic events, including cardiovascular death, altering lipid management guidelines.

Historical Context

Prior to REDUCE-IT, targeting hypertriglyceridemia to lower cardiovascular risk had yielded frustratingly mixed or negative results; large outcomes trials for fibrates (like ACCORD-Lipid), niacin (AIM-HIGH, HPS2-THRIVE), and low-dose mixed omega-3 fatty acids failed to demonstrate significant ASCVD benefit on top of statins. The open-label JELIS trial in Japan had earlier suggested a benefit for purified EPA combined with statins, but it lacked a true placebo and was conducted in a population with high baseline dietary fish intake. REDUCE-IT rigorously proved the clinical efficacy of 4g/day of pure icosapent ethyl in a Western, statin-treated population, reshaping the therapeutic landscape for residual lipid risk.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why did the REDUCE-IT trial use highly purified icosapent ethyl (an EPA derivative) instead of a standard over-the-counter fish oil supplement containing both EPA and DHA?

Key Response

Over-the-counter fish oils contain DHA, which is known to increase LDL cholesterol levels, whereas EPA does not. Furthermore, OTC supplements have lower concentrations of active omega-3s, requiring an impractical pill burden to reach the 4g/day dose used in the trial. This highlights basic lipid metabolism and the distinct pharmacological profiles of specific omega-3 fatty acids.

Resident

Based on the REDUCE-IT inclusion criteria, which specific patient populations in a clinical setting should be prescribed icosapent ethyl, and what are the key adverse effects to monitor?

Key Response

Candidates include patients with established cardiovascular disease or diabetes with at least one additional risk factor, who are on maximally tolerated statin therapy, and have fasting triglycerides between 135 and 499 mg/dL. Residents must monitor for an increased risk of atrial fibrillation and bleeding events, which were significantly higher in the treatment arm.

Fellow

The cardiovascular event reduction in REDUCE-IT (25% relative risk reduction) was disproportionately large compared to the relatively modest reduction in triglyceride levels. What mechanisms, aside from triglyceride lowering, likely explain the cardiovascular benefits of icosapent ethyl?

Key Response

The benefit cannot be explained by triglyceride reduction alone. EPA integrates into cell membranes, increasing structural stability, reducing endothelial dysfunction, decreasing oxidative stress, and dampening inflammatory pathways (evidenced by a reduction in high-sensitivity CRP). It may also favorably alter plaque morphology and reduce macrophage accumulation.

Attending

How does the REDUCE-IT trial fundamentally shift the paradigm regarding the residual cardiovascular risk hypothesis, and how do you reconcile its positive findings with the negative results of trials using niacin, fibrates, or low-dose mixed omega-3s?

Key Response

Previous trials targeting residual risk via triglyceride-lowering or HDL-raising (niacin, fibrates) or low-dose mixed EPA/DHA failed to show CV benefit. REDUCE-IT shifted the focus from merely correcting the lipid panel to utilizing high-dose, purified EPA as a targeted pharmacotherapy for its systemic plaque-stabilizing and anti-inflammatory properties, separating the drug's true mechanism from simple triglyceride reduction.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The choice of mineral oil as the placebo in REDUCE-IT has been heavily debated. How might the use of mineral oil have compromised the internal validity of the trial, and what statistical or methodological approaches could be used to adjust for this potential confounding?

Key Response

Mineral oil was observed to increase LDL-C and hsCRP in the placebo group, potentially exaggerating the relative benefit of icosapent ethyl by acting as an active comparator with negative effects. A methodological critique would involve mediation analysis or sensitivity analyses comparing event rates in placebo patients who had the largest biomarker increases versus those who did not, to estimate the true isolated effect size of the active drug.

Journal Editor

As an editor handling the REDUCE-IT manuscript, how would you require the authors to address the increased incidence of atrial fibrillation and bleeding, and what secondary analyses would you mandate to ensure the risk-benefit ratio is accurately portrayed?

Key Response

An editor would demand rigorous transparency regarding safety signals, as the active arm had a significantly higher rate of hospitalization for atrial fibrillation and a trend toward serious bleeding. The editor would require a Number Needed to Treat versus Number Needed to Harm analysis, and a breakdown of whether the cardiovascular benefits (such as stroke reduction) definitively outweighed the potentially stroke-provoking atrial fibrillation risk.

Guideline Committee

Given the REDUCE-IT findings, how should clinical guidelines be updated regarding the use of non-statin therapies for cardiovascular risk reduction, specifically delineating between icosapent ethyl and other triglyceride-lowering agents?

Key Response

REDUCE-IT provides strong evidence for using icosapent ethyl in statin-treated patients with ASCVD or diabetes and triglycerides above 135 mg/dL to reduce ASCVD risk. Guidelines must explicitly differentiate icosapent ethyl, which is recommended for CV risk reduction, from fibrates, niacin, and OTC fish oil, which are not recommended for CV risk reduction, though fibrates remain indicated for severe hypertriglyceridemia above 500 mg/dL to prevent pancreatitis.

Clinical Landscape

Noteworthy Related Trials

2007

JELIS Trial

n = 18,645 · Lancet

Tested

Highly purified EPA 1.8g daily

Population

Hypercholesterolemic Japanese patients on statins

Comparator

Statin alone

Endpoint

Major coronary events

Key result: EPA treatment significantly reduced major coronary events by 19 percent compared to statin therapy alone.

2020

STRENGTH Trial

n = 13,078 · JAMA

Tested

Omega-3 carboxylic acids (EPA + DHA) 4g daily

Population

Statin-treated patients with high CV risk, hypertriglyceridemia, and low HDL

Comparator

Corn oil placebo

Endpoint

MACE (CV death, MI, stroke, coronary revascularization, or unstable angina)

Key result: The trial was stopped early for futility because the EPA and DHA combination did not significantly reduce MACE compared to placebo.

2022

PROMINENT Trial

n = 10,497 · NEJM

Tested

Pemafibrate 0.2mg twice daily

Population

T2DM patients with hypertriglyceridemia and low HDL

Comparator

Placebo

Endpoint

4-point MACE (CV death, nonfatal MI, ischemic stroke, or coronary revascularization)

Key result: Pemafibrate effectively lowered triglycerides but did not reduce the incidence of major adverse cardiovascular events compared to placebo.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis