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Macrovascular Residual Risk Studies

14 October 2016
Icosapent ethyl (eicosapentaenoic acid ethyl ester) reduces remnant cholesterol: Results from the MARINE and ANCHOR studies
Treatment reduced remnant-like particle cholesterol, with greater effects in patients on statins, especially moderate to high intensity statins.
Ballantyne CM, Bays HE, Philip S et al. Icosapent ethyl (eicosapentaenoic acid ethyl ester): Effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies. Atherosclerosis 2016;253:81-7.
Objective: To evaluate the effects of icosapent ethyl on calculated and directly measured remnant-like particle cholesterol (RLP-C) in an analysis of the MARINE and ANCHOR studies.
Study design: Exploratory analysis of these two Phase III randomized, double-blind, placebo-controlled studies. In the MARINE study, stable statin therapy with or without ezetimibe was permitted but not mandatory. In the ANCHOR study, all patients were at high cardiovascular risk and on a stable statin dose (atorvastatin, rosuvastatin, or simvastatin with or without ezetimibe) at baseline. Patients in each study were randomly allocated to treatment with icosapent ethyl 4 g/day or 2 g/day, or placebo. The duration of treatment was 12 weeks.
Study population: Patients with elevated triglycerides (≥500 and <2000 mg/dL [≥5.65 and <22.6 mmol/L] in MARINE (n=229, 25% on statin); statin-stabilized triglycerides (≥200 and <500 mg/dL [≥2.26 and <5.65 mmol/L] and low-density lipoprotein cholesterol [LDL-C] ≥40 and <100 mg/dL [≥1.04 and <2.59 mmol/L] in ANCHOR (n=702, 93% on medium or higher intensity statins).
Efficacity measure: Primary: Percent change from baseline to study end in directly measured RLP-C levels (MARINE, n = 218; ANCHOR, n = 252) and calculated RLP-C levels in the intention-to-treat populations.
Methods: Direct RLP-C was measured by immunoseparation assay. Calculated RLP-C was determined as total cholesterol – (high-density lipoprotein cholesterol) – (LDL-C, either measured or calculated).

Data were analysed by intention-to-treat including all patients with a baseline triglyceride value. The median differences in percent changes from baseline for RLP-C were estimated using the Hodges-Lehmann method, with the Wilcoxon rank sum test used to calculate p values. Subgroup analyses were conducted by baseline triglycerides in each study, by statin use in the MARINE study, and by statin intensity (lower vs medium/higher) in the ANCHOR study. Correlation analyses used Pearson correlation coefficients. The pre-specified level of statistical significance was 0.05. 
Main results:

Briefly, icosapent ethyl significantly reduced RLP-C (both direct measurement or calculated) compared with placebo in patients from both studies. The effects were greater with the 4 g/day dose (median reduction versus placebo 26-32% versus 15-17%). Importantly, the effects of treatment were greater in patients with higher baseline triglycerides (MARINE), and on statins, notably moderate to high intensity statins versus lower intensity statins (ANCHOR) (Table).


Table. Median percent change from baseline to week 12 in RLP-C versus placebo


Icosapent ethyl

4 g/day

Icosapent ethyl

2 g/day

Direct RLP-C



MARINE study



ITT population

-29.8, p=0.004

-14.9, p=0.15

Statin use

-56.8, p=0.02

-41.6, p=0.15

No statin use

-21.4, p=0.046

-8.5, 0.44

Baseline triglycerides



   ≤750 mg/dL

-26.1, p=0.057

-7.3, 0.66

   >750 mg/dL

-37.5, p=0.02

-25.4, p=0.10




ANCHOR study



ITT population

-25.8, p=0.0001

-16.7, p=0.015

Statin intensity




-11.9, p=0.52

+2.7, p=0.83

   Moderate to high

-26.7, p=0.0002

-17.3, p=0.014

Study median triglyceride



   <259 mg/dL

-22.2, p=0.026

-16.4, p=0.11

   ≥259 mg/dL

-30.6, p=0.001

-18.0, p=0.066




Calculated RLP-C

(based on measured LDL-C)




-28.9, p=0.0002



-31.7, p=<0.0001


Authors’ conclusion: Icosapent ethyl 4 g/day significantly reduced calculated and directly measured RLP-C levels versus placebo in patients with elevated TG levels from the MARINE and ANCHOR studies.


A growing body of evidence shows that elevated RLP-C levels are associated with increased risk for atherosclerotic cardiovascular disease in high risk patients, even in those on statin treatment,1,2 and makes the case for considering high RLP-C as a contributor to lipid-related residual cardiovascular risk.3-5  Importantly, it should be emphasised that these lipoproteins are highly atherogenic, as cholesterol-rich remnant lipoprotein particles carry about 5 times as much cholesterol as LDL particles. Treatments that are effective in lowering RLP-C may offer potential to reduce this risk.

The current report shows that icosapent ethyl, a high-purity prescription form of eicosapentaenoic acid ethyl ester, is effective in reducing RLP-C in patients with very high triglycerides, with or without concomitant statin treatment (MARINE), as well as those with high triglycerides despite statin therapy (ANCHOR). In these studies, icosapent ethyl 4 g/day reduced RLP-C by about 30% (range 26-32%). Importantly, the effects of treatment appeared to be greater in patients with higher triglycerides at baseline, as well as patients on moderate to higher intensity statins. In addition, icosapent ethyl has been shown to lower triglycerides and improve other atherogenic lipid parameters including non-high-density lipoprotein cholesterol and apolipoprotein B, without an elevation in LDL-C levels compared with placebo.6,7 Taken together, therefore, these data lend support to the proposal that this treatment may be effective in the management of lipid-related residual cardiovascular risk that persists despite statin therapy.  

 The question that remains, however, is whether this therapy will reduce cardiovascular outcomes in patients with elevated triglycerides despite statin therapy, as in ANCHOR. The ongoing prospective outcomes study REDUCE-IT8 will provide answers to this highly pertinent question. 


1.  Varbo A, Benn M, Tybjaerg-Hansen A et al.  Remnant cholesterol as a causal risk factor for ischemic heart disease.  J Am Coll Cardiol 2013;61:427-36.

2. Varbo A, Benn M, Smith GD et al. Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease. Circ Res 2015;116:665-73.

3. Nguyen SV, Nakamura T, Kugiyama K, High remnant lipoprotein predicts recurrent cardiovascular events on statin treatment after acute coronary syndrome. Circ J 2014;78:2492-500.

4. Joshi PH, Khokhar AA, Massaro JM et al.  Remnant lipoprotein cholesterol and incident coronary heart disease: the jackson heart and framingham offspring cohort studies, J Am Heart Assoc 2016;

5. Jepsen AK, Langsted A, Varbo A et al. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease, Clin Chem 2016;62:593-604.

6. Bays HE, Ballantyne CM, Kastelein JJ et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial), Am. J. Cardiol 2011;108:682-90.

7. Ballantyne CM, Bays HE, Kastelein JJ et al., Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study), Am J Cardiol 2012;110:984-92.

8. A Study of AMR101 to Evaluate its Ability to Reduce Cardiovascular Events in High Risk Patients with Hypertriglyceridemia and on Statin (REDUCE-IT). Identifier: NCT01492361.

Key words residual cardiovascular risk; triglycerides; remnant cholesterol; icosapent ethyl; eicosapentaenoic acid ethyl ester