Effects of icosapent ethyl on lipoprotein particle concentration and size ...

Journal of Clinical Lipidology (2015) 9, 377–383

Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (the ANCHOR Study) Christie M. Ballantyne, MD*, Rene A. Braeckman, PhD, Harold E. Bays, MD, John J. Kastelein, MD, PhD, James D. Otvos, PhD, William G. Stirtan, PhD, Ralph T. Doyle Jr., BA, Paresh N. Soni, MD, PhD, Rebecca A. Juliano, PhD Baylor College of Medicine and the Houston Methodist DeBakey Heart and Vascular Center, Houston, TX, USA (Dr Ballantyne); Amarin Pharma Inc., Bedminster, NJ, USA (Drs Braeckman, Stirtan, Soni, Juliano, and Mr Doyle); Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY, USA (Dr Bays); Academic Medical Center, Amsterdam, The Netherlands (Dr Kastelein); and LipoScience, Raleigh, NC, USA (Dr Otvos) KEYWORDS: Apolipoprotein B; Eicosapentaenoic acid; High-density lipoproteins; Hypertriglyceridemia; Icosapent ethyl; Low-density lipoproteins; Omega-3 fatty acid; Statin; Triglycerides

BACKGROUND: Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved at a dose of 4 g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (TG $ 500 mg/dL). OBJECTIVE: In this prespecified exploratory analysis from the ANCHOR study of patients at high cardiovascular risk with TG $ 200 and ,500 mg/dL despite statin control of low-density lipoprotein cholesterol, we assessed the effects of IPE on lipoprotein particle concentration and size and examined correlations of atherogenic particles with apolipoprotein B (ApoB). METHODS: Nuclear magnetic resonance spectroscopy was used to measure lipoprotein particle concentration and size. RESULTS: Compared with placebo (n 5 211), IPE 4 g/day (n 5 216) significantly reduced concentrations of: total (12.2%, P 5 .0002), large (46.4%, P , .0001), and medium (12.1%, P 5 .0068) very-low-density lipoprotein (VLDL) particles; total (7.7%, P 5 .0017) and small (13.5%, P , .0001) LDL particles; and total (7.4%, P , .0001) and large (31.0%, P , .0001) high-density lipoprotein particles. Atherogenic lipoprotein particles (total VLDL and total LDL) correlated with ApoB at baseline (R2 5 0.57) and week 12 (R2 5 0.65) as did total LDL particle concentration at baseline (R2 5 0.53) and week 12 (R2 5 0.59). Compared with placebo, IPE 4 g/day significantly reduced VLDL (7.7%, P , .0001) and high-density lipoprotein (1.2%, P 5 .0014) particle sizes with a modest but significant increase in LDL particle size (0.5%, P 5 .0031).

This study was designed and sponsored by Amarin Pharma Inc., Bedminster, NJ, USA. The role of the funding source, Amarin Pharma Inc., is detailed under the author contributions section. * Corresponding author. Baylor College of Medicine, 6565 Fannin St., MSA 601, Houston, TX 77030.

E-mail address: [email protected] Submitted August 28, 2014. Accepted for publication November 23, 2014.

1933-2874/Ó 2015 National Lipid Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/3.0/). http://dx.doi.org/10.1016/j.jacl.2014.11.009

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Journal of Clinical Lipidology, Vol 9, No 3, June 2015 CONCLUSIONS: Compared with placebo, treatment with IPE 4 g/day for 12 weeks reduced key atherogenic lipoprotein particle concentrations. At both baseline and end of study, atherogenic lipoprotein concentrations correlated with ApoB. Ó 2015 National Lipid Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/3.0/).

Introduction Icosapent ethyl (IPE; Vascepa; Amarin Pharma Inc., Bedminster, NJ) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved by the US Food and Drug Administration as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe ($500 mg/dL) hypertriglyceridemia.1 The Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 12-week study with an open-label Extension (MARINE) (N 5 229) demonstrated that, compared with placebo, IPE 4 g/day significantly reduced levels of TG (33.1%, P , .0001), total cholesterol (TC; 16.3%, P , .0001), non–high-density lipoprotein cholesterol (non-HDL-C; 17.7%, P , .0001), and apolipoprotein B (ApoB; 8.5%, P 5 .0019) in patients with very high TG levels ($500 and #2000 mg/dL) without significantly increasing lowdensity lipoprotein cholesterol (LDL-C).2 The ANCHOR study evaluated IPE in statin-treated patients at high risk for cardiovascular disease with persistently high TG ($200 and ,500 mg/dL) and wellcontrolled LDL-C ($40 and #115 mg/dL).3 Compared with placebo, IPE 4 g/day significantly (all P , .0001) reduced levels of TG (21.5%), TC (12.0%), non-HDL-C (13.6%), and ApoB (9.3%); LDL-C was also significantly reduced by 6.2% (P 5 .0067).3 Although the non-HDL-C–lowering effects of lipidlowering agents are central in clinical practice for the management of cardiovascular disease and risk, lipoprotein particle parameters and ApoB may also be clinically relevant and useful.4,5 Lipoprotein particle concentration, LDL particle size, and ApoB levels may influence atherogenicity and coronary heart disease risk.6–9 Indeed, LDL particle concentrations and/or ApoB have been included in recent treatment recommendations and consensus statements regarding lipid management.9–12 The objective of this prespecified exploratory analysis from the ANCHOR study was to assess the effects of IPE on lipoprotein particle concentration and size and to assess the correlation of LDL and total atherogenic particle concentrations with ApoB in statin-treated patients.

Methods ANCHOR was a phase 3, 12-week, multicenter, doubleblind, randomized, placebo-controlled study of IPE in

patients receiving atorvastatin, rosuvastatin, or simvastatin with or without ezetimibe and at high cardiovascular risk with TG levels $200 and ,500 mg/dL and LDL-C levels $40 and #115 mg/dL.3 Briefly, eligible patients aged .18 years entered a 4- to 6-week diet, lifestyle, and medication stabilization lead-in period with washout of prohibited non-statin lipid-altering medications (including fibrates, niacins, and omega-3 fatty acids). This was followed by a 2- to 3-week lipid-qualifying period after which patients entered the 12-week treatment period with IPE 4 g/day, IPE 2 g/day, or matched placebo.3 This brief report focuses on the Food and Drug Administration–approved dose of 4 g/day. Lipoprotein particle concentration and size were measured by nuclear magnetic resonance spectroscopy at LipoScience, Inc. (Raleigh, NC), as previously described.13 Statistical analyses were performed using SAS 9.2 software. The data set included values from the intent-to-treat (ITT) population, defined as all randomized patients who had a baseline TG primary efficacy end point measurement, received $1 dose of study drug, and had $1 postrandomization efficacy measurement. Patients with missing baseline or week 12 measurements were excluded. Lipoprotein particle end points were prespecified and exploratory with statistical significance predefined as P # .05; no adjustments were made for multiplicity. Medians and interquartile ranges were calculated for each treatment group at baseline, week 12, and for percent change from baseline at week 12. Between-treatment differences in percent change from baseline for each lipoprotein particle variable were examined using the Wilcoxon rank-sum test with Hodges-Lehmann medians presented. Lipid values and ApoB were assessed as previously described.3

Results Baseline characteristics were comparable across treatment groups in the ANCHOR study; most patients were white, overweight men younger than age 65 years with diabetes mellitus and were receiving medium- or highefficacy statin regimens. In this prespecified exploratory analysis of the ANCHOR study, 216 patients in the IPE 4 g/day group and 211 in the placebo group had evaluable lipoprotein particle samples, which represented 96% and 93% of the 4 g/day and placebo groups, respectively. In this subset of patients with lipoprotein data, baseline TG, LDL-

Ballantyne et al Table 1

IPE effects on lipoprotein particles

379

Median change in selected lipid end points from baseline to week 12 (patients with lipoprotein analysis) IPE 4 g/day (n 5 216)

Median change from baseline

Placebo (n 5 211)

Lipid end point (mg/dL)

Baseline

End of treatment

Change from baseline, %

Baseline

End of treatment


IPE 4 g/day vs placebo, %, P

TG

264.8 (90.3)

219.3 (91.3)

217.5 (30.4)

258.0 (80.5)

267.5 (141.0)

4.8 (43.6)

82.0 (24.0)

83.0 (31.0)

2.1 (27.0)

84.0 (27.0)

88.0 (31.0)

7.7 (31.2)

128.0 (32.5)

122.0 (37.0)

25.1 (21.4)

128.0 (34.0)

136.0 (42.0)

9.8 (27.2)

HDL-C

38.0 (12.0)

36.5 (13.0)

22.2 (18.5)

39.0 (12.0)

40.0 (14.0)

5.2 (22.0)

ApoB

92.5 (23.5)

90.0 (25.5)

22.2 (16.5)

92.0 (25.0)

98.0 (25.0)

7.0 (23.0)

221.1 ,.0001 25.2 .0225 213.5 ,.0001 25.0 .0005 28.8 ,.0001

LDL-C* Non-HDL-C

ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; IPE, icosapent ethyl; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. Data are presented as median (interquartile range) for end point values. Median percent changes vs placebo are Hodges-Lehmann medians. *n 5 210 for placebo.

C, non-HDL-C, HDL-C, and ApoB levels were similar between treatment groups and were consistent with those reported for the ITT population of the ANCHOR study (Table 1).3 Likewise, similar statistically significant reductions from baseline to week 12 in TG, LDL-C, non-HDL-C, HDL-C, and ApoB were observed with IPE 4 g/day compared with placebo in this analysis as in the ITT population from the ANCHOR study (Table 1).3 After 12 weeks of treatment, IPE 4 g/day significantly reduced concentrations of: total, large, and medium verylow-density lipoprotein (VLDL) particles; total and small LDL particles; and total and large HDL particles; and significantly increased the concentration of large LDL particles compared with placebo (Table 2). With regard to particle size, IPE 4 g/day significantly reduced VLDL and HDL and slightly increased LDL particle size compared with placebo (Table 2). At baseline and week 12, concentrations of atherogenic lipoproteins consisting of all VLDL and LDL particles correlated with ApoB concentration, as did total LDL particle concentrations (Fig. 1; all P , .0001).

Discussion This prespecified exploratory analysis of the ANCHOR study found that, compared with placebo, treatment with IPE 4 g/day reduced lipoprotein particle concentration in patients with TG $ 200 and ,500 mg/dL and LDL-C $40 and #115 mg/dL. The levels of LDL-C recorded at baseline would not generally be considered elevated and therefore were discordant with the increased concentrations of other atherogenic lipoproteins. This would be expected in a high-risk statin-treated patient population with persistently elevated TG levels and, presumably, with increased concentrations of TG-rich lipoproteins.14 Median baseline

LDL-C was 82 and 84 mg/dL in the IPE 4 g/day and placebo groups, respectively, and was thus well below the Adult Treatment Panel III target (relevant update at the time of the ANCHOR study) of ,100 mg/dL.15 Median baseline non-HDL-C was 128 mg/dL for both the IPE 4 g/day and placebo groups, just below the Adult Treatment Panel III target of 130 mg/dL.15 However, at baseline, median ApoB was 93 and 92 mg/dL for the IPE 4 g/day and placebo groups, respectively, and median total LDL particle concentration was 1131 and 1152 nmol/L for the IPE 4 g/day and placebo groups, respectively. Although LDL-C was well below 100 mg/dL and less than the 15th percentile of the population,16 LDL particle and ApoB concentrations remained at about the 40th percentile of the population17 and higher than suggested target levels,9,18 signifying an atherogenic lipid profile despite low LDL-C levels. The reductions in total VLDL particle concentration and size with IPE were consistent with its TG-lowering effects. After treatment with IPE 4 g/day, the magnitude of the reduction compared with placebo in total LDL particle concentration (7.7%, P 5 .0017) was consistent with the reductions in ApoB (8.8%, P , .0001) and LDL-C (5.2%, P 5 .0225) in this patient population. Although IPE 4 g/ day significantly increased LDL particle size, this was a modest change (0.5%, P 5 .0031). Smaller LDL particles may potentially be more atherogenic than larger LDL particles,19–21 but the clinical significance of the increase in LDL particle size observed here is unclear. Because each VLDL and LDL particle contains a single ApoB molecule,4 it was expected and confirmed that the concentrations of atherogenic (VLDL and LDL) particles as well as LDL particle concentrations correlated with ApoB levels at baseline and 12 weeks. Similar exploratory analyses from the MARINE study in patients with TG $ 500 and #2000 mg/dL showed that IPE 4 g/day significantly reduced the size of VLDL particles

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Journal of Clinical Lipidology, Vol 9, No 3, June 2015

Table 2

Median change from baseline to study end in lipoprotein particle concentration and size IPE 4 g/day (n 5 216) Baseline

Lipoprotein particle concentration Total VLDL, nmol/L 116.7 (66.6)

End of treatment


Baseline

End of treatment

110.0 (78.0)

22.5 (41.8)

111.2 (50.6)

122.0 (60.0)

Large VLDL, nmol/L

12.9 (10.7)

7.7 (7.6)

241.9 (57.2)

12.9 (9.7)

14.1 (13.2)

Medium VLDL, nmol/L

54.8 (37.2)

49.7 (41.8)

26.9 (59.3)

53.3 (29.9)

58.8 (36.1)

Small VLDL, nmol/L

43.9 (36.8)

46.8 (39.9)

8.3 (81.8)

41.4 (32.8)

45.3 (37.4)

Total LDL, nmol/L

1131 (369.5) 1191 (512.0)

3.8 (31.8)

1152 (353.0) 1287 (456.0)

IDL, nmol/L

51.5 (81.5)

63.0 (94.0)

Large LDL, nmol/L

113.5 (198.5) 172.5 (226.0)

Small LDL, nmol/L

894.0 (266.5) 902.5 (387.5)

Median change from baseline

Placebo (n 5 211)

23.7 (173.7)

55.0 (88.0)

55.0 (102.0)

55.2 (241.0) 113.0 (215.0) 166.0 (271.0) 21.1 (36.1)

902.0 (323.0) 978.0 (387.0)


IPE 4 g/day vs placebo, %, P

212.2 .0002 6.0 (101.1) 246.4 ,.0001 9.2 (56.3) 212.1 .0068 8.5 (70.0) 2.8 .6321 11.9 (31.6) 27.7 .0017 0.0 (194.8) 10.0 .3051 30.6 (200.4) 34.2 .0076 11.0 (39.0) 213.5 ,.0001 4.7 (16.2) 27.4 ,.0001 9.1 (50.4) 231.0 ,.0001 8.6 (81.8) 26.5 0.2245 1.6 (25.4) 22.8 .1267 7.9 (40.1)

Total HDL, mmol/L

34.3 (8.9)

32.6 (8.2)

24.0 (16.4)

34.8 (10.1)

35.5 (9.3)

Large HDL, mmol/L

2.5 (1.8)

1.9 (2.0)

221.6 (58.1)

2.8 (2.0)

2.9 (2.3)

Medium HDL, mmol/L

6.7 (6.0)

6.9 (4.8)

4.2 (69.4)

7.8 (5.6)

8.3 (7.3)

Small HDL, mmol/L

24.2 (6.4)

23.1 (6.7)

23.9 (21.9)

23.0 (8.1)

24.0 (7.4)

Lipoprotein particle size VLDL, nm

56.3 (8.3)

51.2 (8.4)

28.1 (13.7)

56.5 (10.0)

55.9 (11.3)

20.6 (14.3)

LDL,* nm

19.8 (0.5)

20.0 (0.6)

0.5 (2.5)

19.8 (0.6)

19.9 (0.5)

0.0 (2.5)

HDL, nm

8.7 (0.3)

8.6 (0.2)

21.1 (3.5)

8.7 (0.3)

8.7 (0.4)

0.0 (3.5)

27.7 ,.0001 0.5 .0031 21.2 .0014

HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; IPE, icosapent ethyl; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. Data are presented as median (interquartile range) for end point values. Median percent changes vs placebo are Hodges-Lehmann medians. Diameters are as follows: large VLDL (.60 nm); medium VLDL (42-60 nm); small VLDL (29-42 nm); IDL (23-29 nm); large LDL (20.5-23.0 nm); small LDL (18.0-20.5 nm); large HDL (9.4-14.0 nm); medium HDL (8.2-9.4 nm); and small HDL (7.3-8.2 nm). *n 5 215 for IPE 4 g/day.

(8.6%, P 5 .0017) and the concentrations of large VLDL (27.9%, P 5 .0211), total LDL (16.3%, P 5 .0006), small LDL (25.6%, P , .0001), and total HDL particles (7.4%, P 5 .0063) compared with placebo.13 As in the present study, the concentration of atherogenic particles correlated with ApoB at week 12 (R2 5 0.623, P , .0001).13 Results presented here for the ANCHOR study, together with data from the MARINE study, demonstrate that treatment with IPE 4 g/day decreases key atherogenic lipoprotein particle concentrations as well as ApoB. This may be of potential clinical benefit because atherogenic lipoprotein particle concentration and ApoB play important roles in atherogenicity and may be potentially useful in the management

of hypertriglyceridemic patients at increased coronary heart disease risk. Other exploratory analyses of the MARINE and ANCHOR studies demonstrated that IPE 4 g/day decreased Apo C-III22 as well as other key inflammatory markers associated with cardiovascular disease and atherosclerosis including oxidized LDL, lipoprotein-associated phospholipase A2, and high-sensitivity C-reactive protein compared with placebo.23 Recent outcome studies have called into question the benefit of raising HDL-C, and the HDL therapeutic focus has been shifting to whether there are benefits to altering HDL function that are not accurately reflected by HDL-C levels or particle concentration.24–26 In a comprehensive

Ballantyne et al


381

A

B

C

D

Figure 1 Correlations at baseline and week 12. Atherogenic particle concentration correlated with apolipoprotein B (ApoB) at (A) baseline (R2 5 0.57) and (B) week 12 (R2 5 0.65). Total low-density lipoprotein (LDL) particle concentration correlated with ApoB at (C) baseline (R2 5 0.53) and (D) week 12 (R2 5 0.59). For all correlations, P , .0001 and n 5 427. Bands show 95% confidence limits of the mean. Atherogenic particle concentration consisted of all very-low-density lipoprotein and LDL particles. IPE, icosapent ethyl.

consensus statement from the National Lipid Association on HDL, it was determined that further investigation was needed regarding the predictive utility of HDL subclass concentrations and the functional properties of individual HDL particle sizes and subfractions in the context of dyslipidemia.27 Therefore, the implications and clinical relevance of the small but significant change in HDL particle size observed in this analysis are unknown. Similarly, the recent American Heart Association and American College of Cardiology guidelines on cholesterol treatment defer guidance as to whether on-treatment markers such as LDL particles are useful for guiding treatment decisions, and identified these as critical questions, among many others that future guidelines could examine.28 However, the National Lipid Association recommendations for patient-centered management of dyslipidemia do provide guidance with regard to LDL particles, noting the clinical utility of measuring LDL particle concentration as an alternative to ApoB measurement and in cases where non-HDLC and LDL-C goals have been met.29 The statistically significant reduction in LDL particle concentration

observed with IPE 4 g/day in this analysis would coincide with such recommendations. The mechanisms by which IPE alters lipid and lipoprotein markers have not been fully elucidated. Studies suggest that EPA and docosahexaenoic acid (DHA) reduce hepatic VLDL production and secretion, and increase clearance of TG-rich lipoproteins.30 Mechanisms relating to these effects appear to include increased hepatic and skeletal b-oxidation, reduced ApoB100 secretion, increased lipoprotein lipase activity, and reduced free fatty acid release from adipose tissue.30 These results extend to the postprandial state, where reductions in TG and ApoB48 have been observed, likely owing in part to a decrease in ApoB48 secretion, an increase in chylomicron susceptibility to lipoprotein lipase, and decreased clearance competition from VLDL particles.31–34 From the limited clinical studies that elucidate EPA effects from those of DHA, DHA appears to increase LDL-C levels, whereas EPA does not.35,36 This could be in part because EPA appears to be more potent than DHA at inhibiting diacylglycerol acyl transferase37,38 and at

382 stimulating lipoprotein lipase and b-oxidation (both, at least in part, via peroxisome proliferator–activated receptor-a activation),38–40 thereby having potentially greater effects on TG synthesis and clearance. In addition, animal models suggest a down-regulation of the LDL receptor with DHA treatment, which is not observed with EPA treatment.41 Hence, it could be speculated that the observed reductions in LDL particle number with IPE treatment compared with placebo are due, at least in part, to reductions in TG production and increases in TG clearance, coupled with efficient LDL particle clearance. Such reductions in LDL particle number with IPE could be related to the finding that IPE did not raise LDL-C in either the MARINE or ANCHOR phase 3 clinical studies. Ultimately, it remains to be determined if the potentially beneficial effects of IPE on lipids, inflammation, and lipoproteins translate into reduction in cardiovascular events; the ANCHOR and MARINE studies were not designed to assess the effect of IPE on cardiovascular outcomes. However, the Japan EPA Lipid Intervention Study found that treatment with purified EPA in addition to statins reduced major coronary events in hypercholesterolemic patients.42,43 A large, ongoing, global, randomized, placebo-controlled phase 3 study (Reduction of Cardiovascular Events with EPA–Intervention Trial [REDUCE-IT; NCT01492361]) is evaluating the effect of IPE 4 g/day in high-risk, statin-treated patients with hypertriglyceridemia for prevention of cardiovascular events.44

Conclusions Compared with placebo, treatment with IPE 4 g/day for 12 weeks in statin-treated patients with persistently high TG levels ($200 and ,500 mg/dL) from the ANCHOR study reduced key atherogenic lipoprotein particle concentrations and increased LDL particle size. At both baseline and end of study, atherogenic lipoprotein concentrations correlated with ApoB. These effects are consistent with the TG-lowering activity of IPE, as demonstrated in the ANCHOR study, and extend the efficacy findings to date of IPE in statin-treated patients.

Acknowledgments Medical writing assistance was provided by Elizabeth Daro-Kaftan, PhD, of Peloton Advantage, LLC, Parsippany, NJ, USA, and funded by Amarin Pharma Inc., Bedminster, NJ, USA. Financial disclosures: Dr Ballantyne has received research/grant support from Abbott, Amarin Pharma Inc., Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi-Synthelabo, NIH, ADA, and AHA (all paid to institution, not individual), is a consultant for Abbott, Amarin Pharma Inc., Amgen, Cerenis, Esperion, GlaxoSmithKline, Kowa, Merck, Novartis, Omthera, Pfizer, Resverlogix, and Sanofi-Synthelabo.

Journal of Clinical Lipidology, Vol 9, No 3, June 2015 In the past 12 months, Dr Bays’ research site has received research grants from Alere, Amarin Pharma Inc., Amgen, Ardea, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, California Raisin Board, Catabasis, Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Forest, Gilead, Given, GlaxoSmithKline, Hanmi, Hisun, High Point Pharmaceuticals LLC, Hoffmann-La Roche, Home Access, Janssen, Merck, Metabolex, Nektar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Takeda, TIMI, Transtech Pharma, Trygg, Vivus, and WPU Pharmaceuticals. In the past 12 months, Dr Bays has served as a consultant and/or speaker for Amarin Pharma Inc., Amgen, AstraZeneca, Bristol Myers Squibb, Catabasis, Daiichi Sankyo, Eisai, Isis, Merck, Novartis, Omthera, Vivus, and WPU Pharmaceuticals. Dr Kastelein serves on the speakers bureaus of AstraZeneca, Merck Sharp & Dohme, Pfizer, and Roche, and is a consultant for Amarin Pharma Inc., AstraZeneca, Merck Sharp & Dohme, and Roche. Dr Otvos is an employee and stock shareholder of LipoScience, Inc. Drs Stirtan and Juliano are employees and stock shareholders of Amarin Pharma Inc. Drs Braeckman and Soni are former employees of Amarin Pharma Inc. Mr Doyle is an employee of Amarin Pharma Inc. Author Contributions. Study design: CMB, HEB. Data analysis/interpretation: CMB, RTD, WGS, RAJ, HEB. Drafting, critical revision, and approval of the manuscript: CMB, RTD, WGS, RAJ, HEB.

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