Advertisement

Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Atherogenic Lipid/Lipoprotein, Apolipoprotein, and Inflammatory Parameters in Patients With Elevated High-Sensitivity C-Reactive Protein (from the ANCHOR Study)

Open AccessPublished:June 06, 2019DOI:https://doi.org/10.1016/j.amjcard.2019.05.057
      Icosapent ethyl is pure prescription eicosapentaenoic acid approved at 4 g/day as an adjunct to diet to reduce triglycerides (TG) in adults with TG ≥500 mg/dl. Elevated high-sensitivity C-reactive protein (hsCRP) is associated with increased cardiovascular risk. The 12-week ANCHOR study randomized 702 statin-treated patients at increased cardiovascular risk with TG 200 to 499 mg/dl despite low-density lipoprotein cholesterol (LDL-C) control (40 to 99 mg/dl). This post hoc analysis assessed 246 ANCHOR patients with baseline hsCRP ≥ 2.0 mg/L randomized to icosapent ethyl 4 g/day (n = 126; approved dose) or placebo (n = 120). Without increasing LDL-C, icosapent ethyl significantly reduced median TG (−20%; p < 0.0001), non–high-density lipoprotein cholesterol (−12.3%; p < 0.0001), total cholesterol (−11.1%; p < 0.0001), high-density lipoprotein cholesterol (−5.2%; p = 0.0042), very LDL-C (−21.0%; p < 0.0001), very low-density lipoprotein TG (−22.9%; p < 0.0001), remnant lipoprotein cholesterol (−23.0%; p = 0.0125), apolipoprotein B (−7.4%; p = 0.0021), apolipoprotein C-III (−16%; p < 0.0001), oxidized LDL (−13.7%; p = 0.0020), lipoprotein-associated phospholipase A2 (−19.6%; p < 0.0001), and hsCRP (−17.9%; p = 0.0213) versus placebo, while interleukin-6 and intercellular adhesion molecule-1 were not significantly changed. Eicosapentaenoic acid increased with icosapent ethyl 4 g/day +637% in plasma and +632% in red blood cells versus placebo (both p < 0.0001). Icosapent ethyl exhibited a safety profile similar to placebo. In conclusion, in statin-treated patients with hsCRP ≥ 2.0 mg/L and TG 200 to 499 mg/dl at baseline, icosapent ethyl 4 g/day significantly and safely reduced TG and other atherogenic and inflammatory parameters without increasing LDL-C versus placebo.
      Elevated high-sensitivity C-reactive protein (hsCRP), a known biomarker of systemic inflammation, is associated with increased cardiovascular (CV) risk.
      • Kaptoge S
      • Di Angelantonio E
      • Lowe G
      • Pepys MB
      • Thompson SG
      • Collins R
      • Danesh J
      C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis.
      Major associations have supported inclusion of hsCRP ≥ 2.0 mg/L in CV risk assessment.
      • Goff Jr., DC
      • Lloyd-Jones DM
      • Bennett G
      • Coady S
      • D'Agostino Sr., RB
      • Gibbons R
      • Greenland P
      • Lackland DT
      • Levy D
      • O'Donnell CJ
      • Robinson J
      • Schwartz JS
      • Shero ST
      • Smith Jr., SC
      • Sorlie P
      • Stone NJ
      • Wilson PW
      2013 ACC/AHA Guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Jacobson TA
      • Ito MK
      • Maki KC
      • Orringer CE
      • Bays HE
      • Jones PH
      • McKenney JM
      • Grundy SM
      • Gill EA
      • Wild RA
      • Wilson DP
      • Brown WV
      National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1-full report.
      Clinical studies suggest that reduction in CVD risk factors, including hsCRP, is associated with decreased risk of recurrent CV events.
      • Ridker PM
      • Cannon CP
      • Morrow D
      • Rifai N
      • Rose LM
      • McCabe CH
      • Pfeffer MA
      • Braunwald E
      C-reactive protein levels and outcomes after statin therapy.
      • Nissen SE
      • Tuzcu EM
      • Schoenhagen P
      • Crowe T
      • Sasiela WJ
      • Tsai J
      • Orazem J
      • Magorien RD
      • O'Shaughnessy C
      • Ganz P
      Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease.
      • Morrow DA
      • de Lemos JA
      • Sabatine MS
      • Wiviott SD
      • Blazing MA
      • Shui A
      • Rifai N
      • Califf RM
      • Braunwald E
      Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial.
      • Ridker PM
      • Everett BM
      • Thuren T
      • MacFadyen JG
      • Chang WH
      • Ballantyne C
      • Fonseca F
      • Nicolau J
      • Koenig W
      • Anker SD
      • Kastelein JJP
      • Cornel JH
      • Pais P
      • Pella D
      • Genest J
      • Cifkova R
      • Lorenzatti A
      • Forster T
      • Kobalava Z
      • Vida-Simiti L
      • Flather M
      • Shimokawa H
      • Ogawa H
      • Dellborg M
      • Rossi PRF
      • Troquay RPT
      • Libby P
      • Glynn RJ
      Antiinflammatory therapy with canakinumab for atherosclerotic disease.
      Eicosapentaenoic acid (EPA) is an omega-3 fatty acid that lowers triglycerides (TG) and TG-rich lipoproteins with or without statin therapy.
      • Nelson JR
      • Wani O
      • May HT
      • Budoff M
      Potential benefits of eicosapentaenoic acid on atherosclerotic plaques.
      In the ANCHOR study of adults with residually high TG (200 to 499 mg/dl) despite stable statin therapy, icosapent ethyl (pure ethyl ester of EPA; Vascepa, Amarin Pharma Inc, Bedminster, NJ) significantly reduced TG, demonstrated a safety profile similar to placebo, and significantly improved lipid, lipoprotein, and oxidative and inflammatory parameters.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      • Bays HE
      • Ballantyne CM
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
      • Ballantyne CM
      • Braeckman RA
      • Bays HE
      • Kastelein JJ
      • Otvos JD
      • Stirtan WG
      • Doyle Jr., RT
      • Soni PN
      • Juliano RA
      Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (the ANCHOR Study).
      • Ballantyne CM
      • Bays HE
      • Philip S
      • Doyle RTJ
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      • Juliano RA
      Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies.
      • Ballantyne CM
      • Bays HE
      • Braeckman RA
      • Philip S
      • Stirtan WG
      • Doyle Jr., RT
      • Soni PN
      • Juliano RA
      Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies.
      The purpose of this post hoc analysis was to examine the effects of icosapent ethyl 4 g/day (approved dose) compared with placebo on TG, hsCRP, and other atherogenic parameters in the subgroup of patients from ANCHOR with baseline hsCRP ≥ 2.0 mg/L.

      Methods

      ANCHOR (NCT01047501) was a phase 3, multicenter, placebo-controlled, randomized, double-blind, 12-week clinical study conducted at 97 sites in the United States from December 2009 to February 2011.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      Study design and participant eligibility criteria were previously reported.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      Briefly, eligible adults had high CV risk and residually high TG (200 to 499 mg/dl) despite controlled low-density lipoprotein cholesterol (LDL-C; 40–99 mg/dl) on stable statin therapy (atorvastatin, rosuvastatin, or simvastatin; with or without ezetimibe).
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      High CVD risk was defined as a history of coronary artery disease (i.e., history of myocardial infarction, unstable or stable angina, coronary artery interventions, or clinically significant myocardial ischemia), noncoronary forms of clinical atherosclerosis (i.e., peripheral arterial disease, abdominal aortic aneurysm, or carotid artery disease), or type 1 or 2 diabetes mellitus.
      The design included a 4- to 6-week diet and lifestyle-stabilization lead-in period during which other TG-lowering medications were washed out and statin therapy was stabilized for baseline measurement determination.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      Patients were randomized to icosapent ethyl 4 g/day, icosapent ethyl 2 g/day, or matched placebo. This post hoc analysis evaluated the subgroup of 246 patients from the ANCHOR intent-to-treat (ITT) population with baseline hsCRP ≥ 2.0 mg/L who were randomized to icosapent ethyl 4 g/day (the US Food and Drug Administration−approved dose) or placebo.
      The ITT population was defined as all randomized patients who had a baseline TG measurement, received ≥1 dose of study drug, and had ≥1 postrandomization efficacy measurement. ANCHOR was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The appropriate institutional review boards approved the protocol, and all patients provided written informed consent.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      Efficacy variables included the median difference in percent change from baseline to week 12 between the icosapent ethyl 4 g/day and placebo groups for fasting plasma TG (primary variable), total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, very low-density triglycerides, remnant lipoprotein cholesterol (RLP-C), non-HDL-C, apolipoprotein B, apolipoprotein C-III (Apo C-III), lipoprotein-associated phospholipase A2 (Lp-PLA2), hsCRP, oxidized low-density lipoprotein (ox-LDL), interleukin-6 (IL-6), intercellular adhesion molecule-1, and plasma and red blood cell concentrations of EPA. These parameters were measured as previously described (LDL-C and RLP-C were not calculated but were measured by beta-quantification and immunoseparation assays, respectively).
      • Bays HE
      • Ballantyne CM
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
      ,
      • Ballantyne CM
      • Bays HE
      • Braeckman RA
      • Philip S
      • Stirtan WG
      • Doyle Jr., RT
      • Soni PN
      • Juliano RA
      Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies.
      • Bays HE
      • Ballantyne CM
      • Kastelein JJ
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      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).
      • Brinton EA
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Braeckman RA
      • Soni PN
      Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study.
      • Braeckman RA
      • Manku MS
      • Bays HE
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on plasma and red blood cell fatty acids in patients with very high triglyceride levels (results from the MARINE study).
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects.
      The protocol prespecified that EPA levels were to be measured with liquid chromatography using tandem mass spectroscopy methodology in approximately the first 216 patients in ANCHOR with complete sample datasets.
      The evaluation of safety included monitoring of treatment-emergent adverse events (TEAEs), defined as any AEs that began after the first dose of study medication or that worsened in severity during the double-blind treatment period. TEAEs reported herein included total TEAEs and those occurring in ≥3% of patients in any treatment group of the overall ANCHOR study population (i.e., nausea, diarrhea, nasopharyngitis, and arthralgia).
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      The present subgroup analysis of patients with baseline hsCRP ≥ 2.0 mg/L was not prespecified in the ANCHOR study protocol. Similar to the analyses conducted in the full study population, these post hoc analyses were primarily performed as in the ITT population. Median differences in percent change from baseline between the icosapent ethyl 4 g/day and placebo groups for the primary efficacy variable and additional assessments were estimated with the Hodges-Lehmann method (p values from the Wilcoxon rank sum test for treatment comparisons), where departures from normality were observed; for normally distributed parameters, an analysis of covariance model was used with least squares means and standard errors. Missing values were imputed using the last-observation-carried-forward method. For all post hoc analyses, the alpha level for statistical significance was 0.05. Safety analyses were based on the safety population (all randomized patients who received ≥1 dose of the study drug). These analyses were conducted with SAS/STAT 9.22 software (SAS Institute Inc, Cary, NC).

      Results

      ANCHOR randomized 702 statin-treated patients to icosapent ethyl 4 g/day, icosapent ethyl 2 g/day, or placebo.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      Median baseline hsCRP for the icosapent ethyl 4 g/day, 2 g/day, and placebo arms of the full ANCHOR cohort were 2.2, 2.0, and 1.8 mg/L, respectively. The present post hoc subgroup analysis included 246 patients from the ANCHOR ITT group with baseline hsCRP ≥ 2.0 mg/L randomized to receive icosapent ethyl 4 g/day (n = 126) or placebo (n = 120). Four patients in the icosapent ethyl 4 g/day group and 6 patients in the placebo group discontinued study medication. Baseline characteristics were similar in the icosapent ethyl 4 g/day and placebo groups (Table 1). Median (interquartile range) hsCRP at baseline was 3.9 (3.2) mg/L in the icosapent ethyl 4 g/day group and 4.6 (4.4) mg/L in the placebo group.
      Table 1Baseline characteristics of patients from ANCHOR ITT population with baseline hsCRP ≥2.0 mg/L
      There were no significant differences in baseline characteristics among treatment groups in the total randomized ANCHOR population (hsCRP was an exploratory endpoint and was not tested).
      VariableIcosapent Ethyl

      4 g/day

      (n = 126)
      Placebo

      (n = 120)
      Age, mean (SD) (years)60.2 (9.7)61.0 (9.9)
      Male72 (57.1%)64 (53.3%)
      Female54 (42.9%)56 (46.7%)
      White124 (98.4%)116 (96.7%)
      Body mass index, mean (SD) (kg/m2)33.7 (5.1)34.0 (5.2)
      Diabetes mellitus93 (73.8%)92 (76.7%)
      Atorvastatin use24 (19.1%)20 (16.7%)
      Rosuvastatin use30 (23.8%)31 (25.8%)
      Simvastatin use72 (57.1%)69 (57.1%)
      Low statin intensity
      Lower-intensity statin regimens, simvastatin 5 to 10 mg; medium-intensity statin regimens, rosuvastatin 5 to 10 mg, atorvastatin 10 to 20 mg, simvastatin 20 to 40 mg, simvastatin 10 to 20 mg plus ezetimibe 5 to 10 mg; higher-intensity statin regimens, rosuvastatin 20 to 40 mg, atorvastatin 40 to 80 mg, simvastatin 80 mg, simvastatin 40 to 80 mg plus ezetimibe 5 to 10 mg.
      9 (7.1%)8 (6.7%)
      Medium statin intensity
      Lower-intensity statin regimens, simvastatin 5 to 10 mg; medium-intensity statin regimens, rosuvastatin 5 to 10 mg, atorvastatin 10 to 20 mg, simvastatin 20 to 40 mg, simvastatin 10 to 20 mg plus ezetimibe 5 to 10 mg; higher-intensity statin regimens, rosuvastatin 20 to 40 mg, atorvastatin 40 to 80 mg, simvastatin 80 mg, simvastatin 40 to 80 mg plus ezetimibe 5 to 10 mg.
      80 (63.5%)74 (61.7%)
      High statin intensity
      Lower-intensity statin regimens, simvastatin 5 to 10 mg; medium-intensity statin regimens, rosuvastatin 5 to 10 mg, atorvastatin 10 to 20 mg, simvastatin 20 to 40 mg, simvastatin 10 to 20 mg plus ezetimibe 5 to 10 mg; higher-intensity statin regimens, rosuvastatin 20 to 40 mg, atorvastatin 40 to 80 mg, simvastatin 80 mg, simvastatin 40 to 80 mg plus ezetimibe 5 to 10 mg.
      37 (29.4%)38 (31.7%)
      hsCRP, median (IQR) (mg/L)
      n = 120 for the icosapent ethyl 4 g/day group and n = 115 for the placebo group.
      3.9 (3.2)4.6 (4.4)
      hsCRP = high-sensitivity C-reactive protein; ITT = intent-to-treat; IQR = interquartile range; SD = standard deviation.
      low asterisk There were no significant differences in baseline characteristics among treatment groups in the total randomized ANCHOR population (hsCRP was an exploratory endpoint and was not tested).
      Lower-intensity statin regimens, simvastatin 5 to 10 mg; medium-intensity statin regimens, rosuvastatin 5 to 10 mg, atorvastatin 10 to 20 mg, simvastatin 20 to 40 mg, simvastatin 10 to 20 mg plus ezetimibe 5 to 10 mg; higher-intensity statin regimens, rosuvastatin 20 to 40 mg, atorvastatin 40 to 80 mg, simvastatin 80 mg, simvastatin 40 to 80 mg plus ezetimibe 5 to 10 mg.
      n = 120 for the icosapent ethyl 4 g/day group and n = 115 for the placebo group.
      In patients with hsCRP ≥ 2.0 mg/L at baseline, and compared with placebo, icosapent ethyl 4 g/day significantly reduced the primary endpoint of fasting TG by 19.9% (p < 0.0001; Table 2, Figure 1), as well as non-HDL-C, total cholesterol, HDL-C, very low-density lipoprotein cholesterol, very low-density triglycerides, and RLP-C as compared with placebo (p values ranging from 0.0125 to <0.0001), without increasing LDL-C (p = 0.1162; Table 2, Figure 1). Apolipoproteins (apolipoprotein B and apolipoprotein C-III) and markers of oxidation and inflammation (hsCRP, ox-LDL, and Lp-PLA2) also significantly decreased with icosapent ethyl 4 g/day as compared with placebo (p values ranging from 0.0213 to <0.0001; Table 2, Figure 1). Changes in IL-6 and intercellular adhesion molecule-1 were small and statistically insignificant when compared with placebo (Table 2, Figure 1). Icosapent ethyl 4 g/day significantly increased mean EPA in plasma and red blood cells (Table 3).
      Table 2Effects of icosapent ethyl 4 g/day on lipids/lipoproteins, apolipoproteins, and markers of oxidation and inflammation in patients from ANCHOR ITT population with baseline hsCRP ≥2.0 mg/L
      ParameterIcosapent ethyl 4 g/dayPlacebo
      BaselineEnd of treatmentChange from baseline, %BaselineEnd of treatmentChange from baseline, %Median difference in % change from baseline, icosapent ethyl 4 g/day vs placebo, %, p value
      Lipids/Lipoproteins
       TG (mg/dl) (primary efficacy variable)
        n = 126, 120267.8 (97.0)220.8 (110.0)−16.6 (32.3)267.5 (86.8)280.5 (118.8)+5 (44.4)−19.9, <0.0001
       LDL-C (mg/dl)
        n = 126, 11981.0 (23.0)83.5 (34.0)+2.8 (28.9)84.0 (24.0)88.0 (28.0)+9.2 (36.1)−5.0, 0.1162
       Non-HDL-C (mg/dl)
        n = 126, 120128.5 (29.0)125.0 (41.0)−4.5 (22.0)131.5 (29.0)136.0 (42.5)+9.7 (32.7)−12.3, <0.0001
       TC (mg/dl)
        n = 126, 120167.0 (37.0)166.0 (41.0)−2.6 (15.8)170.0 (34.0)182.5 (47.5)+9.2 (24.0)−11.1, <0.0001
       HDL-C (mg/dl)
        n = 126, 12036.5 (12.0)36.0 (13.0)−2.1 (18.8)39.0 (11.0)39.0 (15.5)+5.6 (19.6)−5.2, 0.0042
       VLDL-C (mg/dl)
        n = 126, 11945.5 (20.0)38.0 (20.0)−11.8 (49.2)42.0 (21.0)49.0 (29.0)+11.1 (63.4)−21.0, <0.0001
       VLDL-TG (mg/dl)
        n = 126, 119196.5 (92.0)154.5 (100.0)−18.7 (52.4)190.0 (95.0)205.0 (129.0)+4.6 (67.2)−22.9, <0.0001
       RLP-C (mg/dl)
      RLP-C and ox-LDL were measured in approximately the first 35% of patients randomized in the ANCHOR study.
        n = 43, 4014.0 (5.0)10.0 (6.0)−26.3 (45.0)14.0 (6.0)13.0 (5.0)+3.8 (67.8)−23.0, 0.0125
      Apolipoproteins
       Apo B (mg/dl)
      Apo B and Apo C-III were measured in the subgroup of all patients with available archived plasma samples from the ANCHOR study.13
        n = 120, 11593.0 (21.5)93.5 (24.5)−0.5 (15.4)91.0 (23.0)99.0 (22.0)+6.5 (26.4)−7.4, 0.0021
       Apo C-III (mg/dl)
      Apo B and Apo C-III were measured in the subgroup of all patients with available archived plasma samples from the ANCHOR study.13
        n = 114, 10615.4 (5.0)14.0 (5.0)−7.7 (28.1)15.1 (4.4)16.2 (5.6)+6.8 (33.4)−16.0, <0.0001
      Markers of Oxidation and Inflammation
       Ox-LDL (U/L)
      RLP-C and ox-LDL were measured in approximately the first 35% of patients randomized in the ANCHOR study.
        n = 46, 3954.1 (14.8)54.1 (17.2)−2.9 (20.9)53.3 (16.0)62.4 (17.9)+14.7 (25.6)−13.7, 0.0020
       Lp-PLA2 (ng/ml)
        n = 120, 113184.5 (54.5)163.0 (59.0)−13.3 (16.3)192.0 (61.0)203.0 (74.0)+7.3 (24.6)−19.6, <0.0001
       hsCRP (mg/L)
        n = 120, 1153.9 (3.2)3.7 (3.6)−10.5 (70.1)4.6 (4.4)5.4 (7.2)+8.0 (77.3)−17.9, 0.0213
       IL-6 (pg/ml)
        n = 46, 383.4 (2.8)2.8 (2.5)−1.6 (57.9)4.2 (2.7)4.0 (4.2)−1.7 (66.6)−4.2, 0.7463
       ICAM-1 (ng/ml)
        n = 46, 38288.5 (107.0)300.5 (116.0)+3.3 (12.1)304.5 (130.0)307.5 (149.0)+2.2 (12.9)+1.1, 0.5621
      Apo B = apolipoprotein B; Apo C-III = apolipoprotein C-III; HDL-C = high-density lipoprotein cholesterol; hsCRP = high-sensitivity C-reactive protein; ICAM-1 = intercellular adhesion molecule-1; IL-6 = interleukin-6; ITT = intent-to-treat; LDL-C = low-density lipoprotein cholesterol; Lp-PLA2 = lipoprotein-associated phospholipase A2; non-HDL-C = non–high-density lipoprotein cholesterol; ox-LDL = oxidized low-density lipoprotein; RLP-C = remnant lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides; VLDL-C = very low-density lipoprotein cholesterol; VLDL-TG = very low-density lipoprotein triglycerides.
      Data are presented as medians (interquartile ranges) for end point values. Median differences in percent changes from baseline versus placebo are Hodges-Lehmann medians. Patient numbers are presented as the number of patients in the icosapent ethyl 4 g/day group and the placebo group, respectively.
      low asterisk RLP-C and ox-LDL were measured in approximately the first 35% of patients randomized in the ANCHOR study.
      Apo B and Apo C-III were measured in the subgroup of all patients with available archived plasma samples from the ANCHOR study.
      • Ballantyne CM
      • Bays HE
      • Braeckman RA
      • Philip S
      • Stirtan WG
      • Doyle Jr., RT
      • Soni PN
      • Juliano RA
      Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies.
      Figure 1
      Figure 1Change in levels of lipids/lipoproteins, apolipoproteins, and markers of oxidation and inflammation (patients from the ANCHOR ITT population with baseline hsCRP ≥2.0 mg/L). Values represent median of difference in percent change from baseline to week 12 for icosapent ethyl 4 g/day versus placebo. *p < 0.0001; p < 0.01; p < 0.05; NS, not significant versus placebo. Apo B = apolipoprotein B; Apo C-III = apolipoprotein C-III; HDL-C = high-density lipoprotein cholesterol; hsCRP = high-sensitivity C-reactive protein; ICAM-1 = intercellular adhesion molecule-1; IL-6 = interleukin-6; ITT = intent-to-treat; LDL-C = low-density lipoprotein cholesterol; Lp-PLA2 = lipoprotein-associated phospholipase A2; non-HDL-C = non–high-density lipoprotein cholesterol; ox-LDL = oxidized low-density lipoprotein; RLP-C = remnant lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides; VLDL-C = very low-density lipoprotein cholesterol; VLDL-TG = very low-density lipoprotein triglycerides.
      Table 3Change in plasma and RBC EPA in patients from ANCHOR ITT population with baseline hsCRP ≥2.0 mg/L
      Includes only patients with available EPA data at both baseline and week 12; EPA was measured in approximately the first 216 ANCHOR patients with complete sample datasets as prespecified.
      ParameterIcosapent ethyl 4 g/dayPlacebo
      Baseline, mean (SD)End of treatment, mean (SD)Change from baseline, LS mean (SE)Baseline, mean (SD)End of treatment, mean (SD)Change from baseline, LS mean (SE)Change from baseline, LS mean, icosapent ethyl 4 g/day vs placebo, %, p value
      Plasma EPA, µg/ml
       n = 41, 3829.4 (20.4)179.1 (72.9)+157.0 (8.7)25.5 (14.8)29.7 (13.1)+11.9 (8.8)+637.0, <0.0001
      RBC EPA, µg/ml
       n = 39, 3511.2 (5.5)67.2 (29.3)+57.6 (3.4)10.0 (6.2)9.0 (4.4)+1.0 (3.5)+631.6, <0.0001
      EPA = eicosapentaenoic acid; hsCRP = high-sensitivity C-reactive protein; ITT = intent-to-treat; LS = least squares; RBC = red blood cell; SD = standard deviation; SE = standard error.
      Patient numbers are presented as the number of patients in the icosapent ethyl 4 g/day group and the placebo group, respectively.
      low asterisk Includes only patients with available EPA data at both baseline and week 12; EPA was measured in approximately the first 216 ANCHOR patients with complete sample datasets as prespecified.
      As with the overall ANCHOR population, the safety profile of icosapent ethyl 4 g/day was similar to placebo in this subgroup analysis of patients with baseline hsCRP ≥ 2.0 mg/L (Table 4). In this subgroup analysis of patients with baseline hsCRP ≥ 2.0 mg/L, the only TEAE reported in ≥3% of patients receiving icosapent ethyl 4 g/day was diarrhea, occurring in 5 (3.8%) patients compared with 8 (6.5%) patients in the placebo group (Table 4). In the overall ANCHOR population, diarrhea, nausea, nasopharyngitis, and arthralgia were the most commonly reported TEAEs (occurring in ≥3% of any treatment group), and arthralgia was the only of these TEAEs that occurred with higher frequency in the icosapent ethyl treatment groups than in the placebo group.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      These TEAEs occurred at similar rates in this subgroup analysis of patients with baseline hsCRP ≥ 2.0 mg/L (icosapent ethyl 4 g/day vs placebo groups, respectively: nausea [2.3% vs 2.4%], nasopharyngitis [0.8% vs 4.8%], and arthralgia [2.3% vs 0%]) (Table 4). One patient each in the icosapent ethyl 4 g/day and placebo groups discontinued due to an AE (icosapent ethyl 4 g/day: subarachnoid hemorrhage, ruptured cerebral aneurysm, and brain edema; placebo: headache), none of which were considered related to study drug by the treating investigator.
      Table 4Adverse events in patients from the ANCHOR safety population with baseline hsCRP ≥2.0 mg/L
      Preferred TermPatients With TEAEs
      Icosapent ethyl 4 g/day

      (n = 131)
      Placebo

      (n = 124)
      Any TEAE60 (45.8%)60 (48.4%)
      Nausea
      TEAEs (irrespective of causality) occurring in ≥3% of all patients in the entire safety population of the ANCHOR study (in any treatment group).9
      3 (2.3%)3 (2.4%)
      Diarrhea
      TEAEs (irrespective of causality) occurring in ≥3% of all patients in the entire safety population of the ANCHOR study (in any treatment group).9
      5 (3.8%)8 (6.5%)
      Nasopharyngitis
      TEAEs (irrespective of causality) occurring in ≥3% of all patients in the entire safety population of the ANCHOR study (in any treatment group).9
      1 (0.8%)6 (4.8%)
      Arthralgia
      TEAEs (irrespective of causality) occurring in ≥3% of all patients in the entire safety population of the ANCHOR study (in any treatment group).9
      Most commonly reported adverse event listed in the icosapent ethyl prescribing information.26
      3 (2.3%)0 (0.0%)
      hsCRP = high-sensitivity C-reactive protein; TEAE = treatment-emergent adverse event.
      low asterisk TEAEs (irrespective of causality) occurring in ≥3% of all patients in the entire safety population of the ANCHOR study (in any treatment group).
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      Most commonly reported adverse event listed in the icosapent ethyl prescribing information.

      Vascepa [package insert]. Bedminster, NJ: Amarin Pharma Inc., 2017.

      Discussion

      This post hoc analysis of statin-treated patients with high CV risk, TG 200 to 499 mg/dl, and hsCRP ≥ 2.0 mg/L at baseline suggests icosapent ethyl 4 g/day significantly reduces TG and other atherogenic and inflammatory parameters without increasing LDL-C versus placebo. Results are generally similar to those in the entire ANCHOR population.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      • Bays HE
      • Ballantyne CM
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
      • Ballantyne CM
      • Bays HE
      • Philip S
      • Doyle RTJ
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      • Juliano RA
      Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies.
      • Ballantyne CM
      • Bays HE
      • Braeckman RA
      • Philip S
      • Stirtan WG
      • Doyle Jr., RT
      • Soni PN
      • Juliano RA
      Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies.
      Icosapent ethyl 4 g/day also demonstrated similar improvement in TG and other atherogenic/inflammatory parameters in other ANCHOR subpopulations including diabetes mellitus,
      • Brinton EA
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Braeckman RA
      • Soni PN
      Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study.
      women,
      • Mosca L
      • Ballantyne CM
      • Bays HE
      • Guyton JR
      • Philip S
      • Doyle Jr., RT
      • Juliano RA
      Usefulness of icosapent ethyl (eicosapentaenoic acid ethyl ester) in women to lower triglyceride levels (results from the MARINE and ANCHOR trials).
      chronic kidney disease,
      • Vijayaraghavan K
      • Szerlip HM
      • Ballantyne CM
      • Bays HE
      • Philip S
      • Doyle RT
      • Juliano RA
      • Granowitz C
      Icosapent ethyl reduces potentially atherogenic lipid and inflammatory markers in high-risk statin-treated patients with stage 3 chronic kidney disease and persistent high triglycerides [abstract].
      and women with diabetes mellitus.
      • Brinton EA
      • Ballantyne CM
      • Guyton JR
      • Philip S
      • Doyle Jr., RT
      • Juliano RA
      • Mosca L
      Lipid effects of icosapent ethyl in women with diabetes mellitus and persistent high tiglycerides on statin treatment: ANCHOR trial subanalysis.
      EPA is incorporated into cell membranes and atherosclerotic plaque, where it alters cellular inflammation, oxidation, and signaling pathways that promote atherosclerosis.
      • Nelson JR
      • Wani O
      • May HT
      • Budoff M
      Potential benefits of eicosapentaenoic acid on atherosclerotic plaques.
      • Borow KM
      • Nelson JR
      • Mason RP
      Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.
      Prior studies suggest that purified EPA may have anti-inflammatory effects in addition to improving lipid levels in patients with high CV risk.
      • Nelson JR
      • Wani O
      • May HT
      • Budoff M
      Potential benefits of eicosapentaenoic acid on atherosclerotic plaques.
      • Bays HE
      • Ballantyne CM
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
      • Borow KM
      • Nelson JR
      • Mason RP
      Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.
      EPA treatment has been associated with improvements in several markers of inflammation, including the ratio of EPA to arachidonic acid (EPA/AA), ox-LDL, Lp-PLA2, adiponectin, IL-6, IL-10, monocyte chemoattractant protein-1, and pentraxin-3, a marker of local arterial inflammation.
      • Nelson JR
      • Wani O
      • May HT
      • Budoff M
      Potential benefits of eicosapentaenoic acid on atherosclerotic plaques.
      • Bays HE
      • Ballantyne CM
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
      • Borow KM
      • Nelson JR
      • Mason RP
      Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.
      In the overall ANCHOR population, icosapent ethyl 4 g/day significantly improved hsCRP, Lp-PLA2, ox-LDL, and the EPA/AA ratio.
      • Bays HE
      • Ballantyne CM
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
      • Braeckman R
      • Manku MS
      • Ballantyne CM
      • Stirtan WG
      • Soni PN
      Effects of AMR101, a pure eicosapentaenoic omega-3 fatty acid, on the fatty acid profile in plasma and red blood cells in statin-treated patients with persistent high triglycerides (results from the ANCHOR study) [abstract].
      Although EPA lowered hsCRP in the ANCHOR and MARINE trials (MARINE included patients with TG 500 to 2000 mg/dl with or without statin therapy), similar hsCRP reductions were not observed in trials evaluating EPA and DHA mixtures in patients with high or very high TG.
      • Bays HE
      • Ballantyne CM
      • Braeckman RA
      • Stirtan WG
      • Soni PN
      Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
      ,
      • Kastelein JJP
      • Maki KC
      • Susekov A
      • Ezhov M
      • Nordestgaard BG
      • Machielse BN
      • Kling D
      • Davidson MH
      Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial.
      • Dunbar RL
      • Nicholls SJ
      • Maki KC
      • Roth EM
      • Orloff DG
      • Curcio D
      • Johnson J
      • Kling D
      • Davidson MH
      Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: a randomized, controlled, double-blind trial.

      Omtryg Medical Reviews Food and Drug Administration Website: Food and Drug Administration; Center for Drug Evaluation and Research, 2014.

      Previous reports support icosapent ethyl as having safety and tolerability similar to that of placebo.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      • Bays HE
      • Ballantyne CM
      • Kastelein JJ
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      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).
      In pooled analyses of randomized, double-blind icosapent ethyl clinical trials including the ANCHOR study, the only AE reported in >2% of patients and at a rate greater than placebo was arthralgia (reported in 2.3% of patients receiving icosapent ethyl vs 1.0% of patients receiving placebo).

      Vascepa [package insert]. Bedminster, NJ: Amarin Pharma Inc., 2017.

      Safety data in the present post hoc subanalysis of patients from ANCHOR with hsCRP ≥ 2.0 mg/L at baseline were consistent with the safety profile of icosapent ethyl and data from the overall ANCHOR population.
      • Ballantyne CM
      • Bays HE
      • Kastelein JJ
      • Stein E
      • Isaacsohn JL
      • Braeckman RA
      • Soni PN
      Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).
      As observed in clinical trials in the statin-treated population, elevated hsCRP appears to be a marker of patients at higher risk of coronary events,
      • Ridker PM
      • Cannon CP
      • Morrow D
      • Rifai N
      • Rose LM
      • McCabe CH
      • Pfeffer MA
      • Braunwald E
      C-reactive protein levels and outcomes after statin therapy.
      • Nissen SE
      • Tuzcu EM
      • Schoenhagen P
      • Crowe T
      • Sasiela WJ
      • Tsai J
      • Orazem J
      • Magorien RD
      • O'Shaughnessy C
      • Ganz P
      Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease.
      • Morrow DA
      • de Lemos JA
      • Sabatine MS
      • Wiviott SD
      • Blazing MA
      • Shui A
      • Rifai N
      • Califf RM
      • Braunwald E
      Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial.
      • Ridker PM
      • Everett BM
      • Thuren T
      • MacFadyen JG
      • Chang WH
      • Ballantyne C
      • Fonseca F
      • Nicolau J
      • Koenig W
      • Anker SD
      • Kastelein JJP
      • Cornel JH
      • Pais P
      • Pella D
      • Genest J
      • Cifkova R
      • Lorenzatti A
      • Forster T
      • Kobalava Z
      • Vida-Simiti L
      • Flather M
      • Shimokawa H
      • Ogawa H
      • Dellborg M
      • Rossi PRF
      • Troquay RPT
      • Libby P
      • Glynn RJ
      Antiinflammatory therapy with canakinumab for atherosclerotic disease.
      and the inflammation pathway is being evaluated as a potential therapeutic target for atherosclerotic CVD.
      • Ridker PM
      • Everett BM
      • Thuren T
      • MacFadyen JG
      • Chang WH
      • Ballantyne C
      • Fonseca F
      • Nicolau J
      • Koenig W
      • Anker SD
      • Kastelein JJP
      • Cornel JH
      • Pais P
      • Pella D
      • Genest J
      • Cifkova R
      • Lorenzatti A
      • Forster T
      • Kobalava Z
      • Vida-Simiti L
      • Flather M
      • Shimokawa H
      • Ogawa H
      • Dellborg M
      • Rossi PRF
      • Troquay RPT
      • Libby P
      • Glynn RJ
      Antiinflammatory therapy with canakinumab for atherosclerotic disease.
      The recent Canakinumab Antiinflammatory Thrombosis Outcome Study in statin-treated patients with persistent hsCRP ≥ 2.0 mg/L adds support for the hypothesis that inflammation plays a role in atherothrombosis and is a modifiable risk factor, showing improved hsCRP and a reduction in CV events in patients treated with canakinumab, an anti-inflammatory therapy targeted at a cytokine upstream of hsCRP in the inflammatory cascade.
      • Ridker PM
      • Everett BM
      • Thuren T
      • MacFadyen JG
      • Chang WH
      • Ballantyne C
      • Fonseca F
      • Nicolau J
      • Koenig W
      • Anker SD
      • Kastelein JJP
      • Cornel JH
      • Pais P
      • Pella D
      • Genest J
      • Cifkova R
      • Lorenzatti A
      • Forster T
      • Kobalava Z
      • Vida-Simiti L
      • Flather M
      • Shimokawa H
      • Ogawa H
      • Dellborg M
      • Rossi PRF
      • Troquay RPT
      • Libby P
      • Glynn RJ
      Antiinflammatory therapy with canakinumab for atherosclerotic disease.
      CV outcomes data of pure EPA in statin-treated patients with high residual CV risk and elevated hsCRP have not been reported. In the recently completed Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT; NCT01492361), icosapent ethyl 4 g/day resulted in a significant reduction in major adverse CV events compared with placebo (hazard ratio, 0.75; 95% confidence interval, 0.68 to 0.83; p < 0.001) over a median follow-up time of 4.9 years.
      • Bhatt DL
      • Steg G
      • Miller M
      • Brinton EA
      • Jacobson TA
      • Ketchum SB
      • Doyle Jr, RT
      • Juliano RA
      • Jiao L
      • Granowitz C
      • Tardif JC
      • Ballantyne CM
      Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
      In REDUCE-IT, loghsCRP decreased by a median of 21.8% (p < 0.0001) from baseline to the year 2 in the icosapent ethyl 4 g/day group and by 0.0% (p = 0.9203) in the placebo group, resulting in a 22.5% median between-group decrease for icosapent ethyl 4 g/day versus placebo (p < 0.0001). In REDUCE-IT, reductions in hsCRP levels may have contributed to the observed CV risk reduction. Based on REDUCE-IT results, the American Diabetes Association recommends that icosapent ethyl be considered for reducing CV risk in statin-treated patients with controlled LDL-C, TG 135 to 499 md/dl, diabetes, and atherosclerotic CV disease or other cardiac risk factors (Level A recommendation).

      American Diabetes Association issues critical updates to the 2019 standards of medical care in diabetes. Arlington, VA, 2019.

      The strength of the findings from these analyses in statin-treated patients with hsCRP ≥ 2.0 mg/L and high TG at baseline is limited due to the modest sample size and the post hoc nature of the analysis. In addition, although icosapent ethyl 4 g/day improved CV risk parameters in this subgroup of patients with hsCRP ≥ 2.0 mg/L from the ANCHOR study, the study was not designed to determine effects on CV events. Prospectively designed CV outcomes studies are needed to ascertain whether these changes will translate into lower CVD morbidity and mortality.

      Disclosures

      Dr Miller discloses serving as advisor and steering committee member (REDUCE-IT) for Amarin Pharma Inc. Dr Ballantyne discloses the following relations: has received research grants (paid to institution, not individual) from Akcea, Amarin Pharma Inc, Amgen, Esperion, Novartis, Regeneron, and Sanofi-Synthelabo; and has received honoraria from Akcea, Amarin Pharma Inc, Amgen, Astra Zeneca, Eli Lilly, Esperion, Matinas BioPharma Inc, Merck, Novartis, Pharmam Inc, Regeneron, and Sanofi-Synthela bo. Dr Bays discloses the following relations: has received research grants from Acasti, Akcea, Amarin Pharma Inc, Amgen, AstraZeneca, Esperion, LIB Therapeutics, MedImmune, Merck, Omthera, Pfizer, Regeneron, and Sanofi; has served as a consultant/advisory board member for Aegerion, Amarin Pharma Inc, Amgen, Esperion, Regeneron, and Sanofi; and has served as a speaker for Acasti, Amgen, Kowa, Regeneron, and Sanofi. Dr Granowitz, Mr Doyle, Dr Juliano, and Dr Philip disclose employment with and stock ownership in Amarin Pharma Inc.

      Acknowledgments

      Editorial assistance was provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by Amarin Pharma Inc, Bedminster, NJ.

      References

        • Kaptoge S
        • Di Angelantonio E
        • Lowe G
        • Pepys MB
        • Thompson SG
        • Collins R
        • Danesh J
        C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis.
        Lancet. 2010; 375: 132-140
        • Goff Jr., DC
        • Lloyd-Jones DM
        • Bennett G
        • Coady S
        • D'Agostino Sr., RB
        • Gibbons R
        • Greenland P
        • Lackland DT
        • Levy D
        • O'Donnell CJ
        • Robinson J
        • Schwartz JS
        • Shero ST
        • Smith Jr., SC
        • Sorlie P
        • Stone NJ
        • Wilson PW
        2013 ACC/AHA Guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
        Circulation. 2014; 129: S49-S73
        • Jacobson TA
        • Ito MK
        • Maki KC
        • Orringer CE
        • Bays HE
        • Jones PH
        • McKenney JM
        • Grundy SM
        • Gill EA
        • Wild RA
        • Wilson DP
        • Brown WV
        National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1-full report.
        J Clin Lipidol. 2015; 9: 129-169
        • Ridker PM
        • Cannon CP
        • Morrow D
        • Rifai N
        • Rose LM
        • McCabe CH
        • Pfeffer MA
        • Braunwald E
        C-reactive protein levels and outcomes after statin therapy.
        N Engl J Med. 2005; 352: 20-28
        • Nissen SE
        • Tuzcu EM
        • Schoenhagen P
        • Crowe T
        • Sasiela WJ
        • Tsai J
        • Orazem J
        • Magorien RD
        • O'Shaughnessy C
        • Ganz P
        Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease.
        N Engl J Med. 2005; 352: 29-38
        • Morrow DA
        • de Lemos JA
        • Sabatine MS
        • Wiviott SD
        • Blazing MA
        • Shui A
        • Rifai N
        • Califf RM
        • Braunwald E
        Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial.
        Circulation. 2006; 114: 281-288
        • Ridker PM
        • Everett BM
        • Thuren T
        • MacFadyen JG
        • Chang WH
        • Ballantyne C
        • Fonseca F
        • Nicolau J
        • Koenig W
        • Anker SD
        • Kastelein JJP
        • Cornel JH
        • Pais P
        • Pella D
        • Genest J
        • Cifkova R
        • Lorenzatti A
        • Forster T
        • Kobalava Z
        • Vida-Simiti L
        • Flather M
        • Shimokawa H
        • Ogawa H
        • Dellborg M
        • Rossi PRF
        • Troquay RPT
        • Libby P
        • Glynn RJ
        Antiinflammatory therapy with canakinumab for atherosclerotic disease.
        N Engl J Med. 2017; 377: 1119-1131
        • Nelson JR
        • Wani O
        • May HT
        • Budoff M
        Potential benefits of eicosapentaenoic acid on atherosclerotic plaques.
        Vascul Pharmacol. 2017; 91: 1-9
        • Ballantyne CM
        • Bays HE
        • Kastelein JJ
        • Stein E
        • Isaacsohn JL
        • Braeckman RA
        • Soni PN
        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: 984-992
        • Bays HE
        • Ballantyne CM
        • Braeckman RA
        • Stirtan WG
        • Soni PN
        Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.
        Am J Cardiovasc Drugs. 2013; 13: 37-46
        • Ballantyne CM
        • Braeckman RA
        • Bays HE
        • Kastelein JJ
        • Otvos JD
        • Stirtan WG
        • Doyle Jr., RT
        • Soni PN
        • Juliano RA
        Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (the ANCHOR Study).
        J Clin Lipidol. 2015; 9: 377-383
        • Ballantyne CM
        • Bays HE
        • Philip S
        • Doyle RTJ
        • Braeckman RA
        • Stirtan WG
        • Soni PN
        • Juliano RA
        Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies.
        Atherosclerosis. 2016; 253: 81-87
        • Ballantyne CM
        • Bays HE
        • Braeckman RA
        • Philip S
        • Stirtan WG
        • Doyle Jr., RT
        • Soni PN
        • Juliano RA
        Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies.
        J Clin Lipidol. 2016; 10: 635-645
        • Bays HE
        • Ballantyne CM
        • Kastelein JJ
        • Isaacsohn JL
        • Braeckman RA
        • Soni PN
        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: 682-690
        • Brinton EA
        • Ballantyne CM
        • Bays HE
        • Kastelein JJ
        • Braeckman RA
        • Soni PN
        Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study.
        Cardiovasc Diabetol. 2013; 12: 100
        • Braeckman RA
        • Manku MS
        • Bays HE
        • Stirtan WG
        • Soni PN
        Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on plasma and red blood cell fatty acids in patients with very high triglyceride levels (results from the MARINE study).
        Prostaglandins Leukot Essent Fatty Acids. 2013; 89: 195-201
        • Braeckman RA
        • Stirtan WG
        • Soni PN
        Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects.
        Clin Pharmacol Drug Dev. 2014; 3: 101-108
        • Mosca L
        • Ballantyne CM
        • Bays HE
        • Guyton JR
        • Philip S
        • Doyle Jr., RT
        • Juliano RA
        Usefulness of icosapent ethyl (eicosapentaenoic acid ethyl ester) in women to lower triglyceride levels (results from the MARINE and ANCHOR trials).
        Am J Cardiol. 2017; 119: 397-403
        • Vijayaraghavan K
        • Szerlip HM
        • Ballantyne CM
        • Bays HE
        • Philip S
        • Doyle RT
        • Juliano RA
        • Granowitz C
        Icosapent ethyl reduces potentially atherogenic lipid and inflammatory markers in high-risk statin-treated patients with stage 3 chronic kidney disease and persistent high triglycerides [abstract].
        Circulation. 2017; 136: A15097
        • Brinton EA
        • Ballantyne CM
        • Guyton JR
        • Philip S
        • Doyle Jr., RT
        • Juliano RA
        • Mosca L
        Lipid effects of icosapent ethyl in women with diabetes mellitus and persistent high tiglycerides on statin treatment: ANCHOR trial subanalysis.
        J Womens Health (Larchmt). 2018; 27: 1170-1176
        • Borow KM
        • Nelson JR
        • Mason RP
        Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.
        Atherosclerosis. 2015; 242: 357-366
        • Braeckman R
        • Manku MS
        • Ballantyne CM
        • Stirtan WG
        • Soni PN
        Effects of AMR101, a pure eicosapentaenoic omega-3 fatty acid, on the fatty acid profile in plasma and red blood cells in statin-treated patients with persistent high triglycerides (results from the ANCHOR study) [abstract].
        Circulation. 2012; 126: A18549
        • Kastelein JJP
        • Maki KC
        • Susekov A
        • Ezhov M
        • Nordestgaard BG
        • Machielse BN
        • Kling D
        • Davidson MH
        Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial.
        J Clin Lipidol. 2014; 8: 94-106
        • Dunbar RL
        • Nicholls SJ
        • Maki KC
        • Roth EM
        • Orloff DG
        • Curcio D
        • Johnson J
        • Kling D
        • Davidson MH
        Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: a randomized, controlled, double-blind trial.
        Lipids Health Dis. 2015; 14: 98
      1. Omtryg Medical Reviews Food and Drug Administration Website: Food and Drug Administration; Center for Drug Evaluation and Research, 2014.

      2. Vascepa [package insert]. Bedminster, NJ: Amarin Pharma Inc., 2017.

        • Bhatt DL
        • Steg G
        • Miller M
        • Brinton EA
        • Jacobson TA
        • Ketchum SB
        • Doyle Jr, RT
        • Juliano RA
        • Jiao L
        • Granowitz C
        • Tardif JC
        • Ballantyne CM
        Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
        N Engl J Med. 2019; 380: 11-22
      3. American Diabetes Association issues critical updates to the 2019 standards of medical care in diabetes. Arlington, VA, 2019.