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Hypertriglyceridemia: HELP
Articles by John J. P. Kastelein
Based on 14 articles published since 2010
(Why 14 articles?)
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Between 2010 and 2020, J. J. Kastelein wrote the following 14 articles about Hypertriglyceridemia.
 
+ Citations + Abstracts
1 Editorial FISHing for the Miracle of Eicosapentaenoic Acid. 2019

Kastelein, John J P / Stroes, Erik S G. ·From the Academic Medical Center, University of Amsterdam, Amsterdam. ·N Engl J Med · Pubmed #30444682.

ABSTRACT: -- No abstract --

2 Review Moving Targets: Recent Advances in Lipid-Lowering Therapies 2019

Larsen, Lars E / Stoekenbroek, Robert M / Kastelein, John J P / Holleboom, Adriaan G. ·From the Department of Vascular Medicine, Amsterdam University Medical Center, The Netherlands. ·Arterioscler Thromb Vasc Biol · Pubmed #30676072.

ABSTRACT: Statin therapy has delivered tremendous value to society by improving the burden of atherosclerotic cardiovascular disease. Nonetheless, atherosclerotic cardiovascular disease remains the leading cause of death globally. Technological advances such as in the field of genomics have revolutionized drug discovery and development and have revealed novel therapeutic targets to lower low-density lipoprotein cholesterol (LDL-C), as well as other detrimental lipids and lipoproteins. Therapeutic LDL-C lowering prevents atherosclerotic cardiovascular disease with an effect size proportional to absolute LDL-C reductions and time of exposure. This understanding supports the notion that reducing cumulative LDL-C exposure should be a key therapeutic target. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibiting monoclonal antibodies provides the possibility of reducing LDL-C to very low levels. Novel therapeutic platforms such as RNA inhibition present opportunities to combine robust lipid lowering with infrequent dosing regimens, introducing therapies with vaccine-like properties. The position of lipid-lowering therapies with targets other than LDL-C, such as Lp(a) [lipoprotein(a)], TRL (triglyceride-rich lipoproteins), and remnant cholesterol, will likely be determined by the results of ongoing clinical trials. Current evidence suggests that reducing Lp(a) or TRLs could attenuate atherosclerotic cardiovascular disease risk in specific categories of patients. This review provides an overview of the latest therapeutic developments, focusing on their mechanisms, efficacy, and safety.

3 Review Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial. 2018

Nicholls, Stephen J / Lincoff, A Michael / Bash, Dianna / Ballantyne, Christie M / Barter, Philip J / Davidson, Michael H / Kastelein, John J P / Koenig, Wolfgang / McGuire, Darren K / Mozaffarian, Dariush / Pedersen, Terje R / Ridker, Paul M / Ray, Kausik / Karlson, Björn W / Lundström, Torbjörn / Wolski, Kathy / Nissen, Steven E. ·South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia. · Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, Ohio. · Baylor College of Medicine, Houston, Texas. · University of New South Wales, Sydney, Australia. · University of Chicago, Chicago, Illinois. · Academic Medical Center, Amsterdam, The Netherlands. · Deutsches Herzzentrum München, Technische Universität München, and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. · Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas. · Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts. · Oslo University Hospital, Oslo, Norway. · Harvard Medical School, Boston, Massachusetts. · Imperial College of London, London, UK. · Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · AstraZeneca Pharmaceuticals, Gothenburg, Sweden. ·Clin Cardiol · Pubmed #30125052.

ABSTRACT: It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.

4 Clinical Trial Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. 2015

Gaudet, Daniel / Alexander, Veronica J / Baker, Brenda F / Brisson, Diane / Tremblay, Karine / Singleton, Walter / Geary, Richard S / Hughes, Steven G / Viney, Nicholas J / Graham, Mark J / Crooke, Rosanne M / Witztum, Joseph L / Brunzell, John D / Kastelein, John J P. ·From the Department of Medicine, Université de Montréal and Ecogene-21 Clinical Research Centre, Chicoutimi, QC, Canada (D.G., D.B., K.T.) · Isis Pharmaceuticals, Carlsbad (V.J.A., B.F.B., W.S., R.S.G., S.G.H., N.J.V., M.J.G., R.M.C.), and the Department of Medicine, University of California, San Diego, La Jolla (J.L.W.) - both in California · the Department of Medicine, University of Washington, Seattle (J.D.B.) · and the Department of Vascular Medicine, Academic Medical Center, Amsterdam (J.J.P.K.). ·N Engl J Med · Pubmed #26222559.

ABSTRACT: BACKGROUND: Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline. RESULTS: A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study. CONCLUSIONS: We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).

5 Clinical Trial Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (the ANCHOR Study). 2015

Ballantyne, Christie M / Braeckman, Rene A / Bays, Harold E / Kastelein, John J / Otvos, James D / Stirtan, William G / Doyle, Ralph T / Soni, Paresh N / Juliano, Rebecca A. ·Baylor College of Medicine and the Houston Methodist DeBakey Heart and Vascular Center, Houston, TX, USA. Electronic address: cmb@bcm.tmc.edu. · Amarin Pharma Inc., Bedminster, NJ, USA. · Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY, USA. · Academic Medical Center, Amsterdam, The Netherlands. · LipoScience, Raleigh, NC, USA. ·J Clin Lipidol · Pubmed #26073397.

ABSTRACT: 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 = 211), IPE 4 g/day (n = 216) significantly reduced concentrations of: total (12.2%, P = .0002), large (46.4%, P < .0001), and medium (12.1%, P = .0068) very-low-density lipoprotein (VLDL) particles; total (7.7%, P = .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 (R(2) = 0.57) and week 12 (R(2) = 0.65) as did total LDL particle concentration at baseline (R(2) = 0.53) and week 12 (R(2) = 0.59). Compared with placebo, IPE 4 g/day significantly reduced VLDL (7.7%, P < .0001) and high-density lipoprotein (1.2%, P = .0014) particle sizes with a modest but significant increase in LDL particle size (0.5%, P = .0031). 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.

6 Clinical Trial Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). 2012

Bays, Harold E / Braeckman, Rene A / Ballantyne, Christie M / Kastelein, John J / Otvos, James D / Stirtan, William G / Soni, Paresh N. ·Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY 40213, USA. hbaysmd@aol.com ·J Clin Lipidol · Pubmed #23312052.

ABSTRACT: BACKGROUND: Icosapent ethyl (IPE; formerly AMR101) is a high-purity prescription form of eicosapentaenoic acid ethyl ester. In the MARINE study we evaluated the efficacy and safety of IPE in patients with very high triglycerides (TG; ≥500 mg/dL) and previously demonstrated significant reductions in TG levels with no significant increases in low-density lipoprotein (LDL) cholesterol levels. OBJECTIVES: In this follow-up, exploratory analysis, we report the effects of IPE on lipoprotein particle concentration and size. METHODS: MARINE was a phase 3, multicenter, placebo-controlled, randomized, double-blind, 12-week study. Hypertriglyceridemic patients (N = 229) were randomized to three treatment groups: IPE 4 g/day, IPE 2 g/day, or placebo. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy. RESULTS: Compared with placebo, IPE 4 g/day significantly reduced median concentrations of large very-low-density lipoprotein (VLDL; -27.9%; P = .0211), total LDL (-16.3%; P = .0006), small LDL (-25.6%; P < .0001), and total high-density lipoprotein (HDL; -7.4%; P = .0063) particles and reduced VLDL particle size (-8.6%; P = .0017). In this patient population with TG ≥500 mg/dL, IPE did not significantly change the overall sizes of LDL or HDL particles. CONCLUSION: IPE 4 g/day significantly reduced large VLDL, total LDL, small LDL, and total HDL particle concentrations and VLDL particle size in patients with TG ≥500 mg/dL. Changes in VLDL particle concentration and size reflect the TG-lowering effects of eicosapentaenoic acid. The reduction in LDL particle concentration with IPE is novel among ω-3 therapies and is consistent with the previously reported reduction in apolipoprotein B and lack of LDL-C increase with IPE in patients with very high TG levels. CLINICAL TRIAL REGISTRATION NUMBER: NCT01047683.

7 Clinical Trial Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). 2012

Ballantyne, Christie M / Bays, Harold E / Kastelein, John J / Stein, Evan / Isaacsohn, Jonathan L / Braeckman, Rene A / Soni, Paresh N. ·Baylor College of Medicine and the Methodist DeBakey Heart and Vascular Center, Houston, Texas, USA. cmb@bcm.tmc.edu ·Am J Cardiol · Pubmed #22819432.

ABSTRACT: AMR101 is an ω-3 fatty acid agent containing ≥96% pure icosapent-ethyl, the ethyl ester of eicosapentaenoic acid. The efficacy and safety of AMR101 were evaluated in this phase 3, multicenter, placebo-controlled, randomized, double-blinded, 12-week clinical trial (ANCHOR) in high-risk statin-treated patients with residually high triglyceride (TG) levels (≥200 and <500 mg/dl) despite low-density lipoprotein (LDL) cholesterol control (≥40 and <100 mg/dl). Patients (n = 702) on a stable diet were randomized to AMR101 4 or 2 g/day or placebo. The primary end point was median percent change in TG levels from baseline versus placebo at 12 weeks. AMR101 4 and 2 g/day significantly decreased TG levels by 21.5% (p <0.0001) and 10.1% (p = 0.0005), respectively, and non-high-density lipoprotein (non-HDL) cholesterol by 13.6% (p <0.0001) and 5.5% (p = 0.0054), respectively. AMR101 4 g/day produced greater TG and non-HDL cholesterol decreases in patients with higher-efficacy statin regimens and greater TG decreases in patients with higher baseline TG levels. AMR101 4 g/day decreased LDL cholesterol by 6.2% (p = 0.0067) and decreased apolipoprotein B (9.3%), total cholesterol (12.0%), very-low-density lipoprotein cholesterol (24.4%), lipoprotein-associated phospholipase A(2) (19.0%), and high-sensitivity C-reactive protein (22.0%) versus placebo (p <0.001 for all comparisons). AMR101 was generally well tolerated, with safety profiles similar to placebo. In conclusion, AMR101 4 g/day significantly decreased median placebo-adjusted TG, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, lipoprotein-associated phospholipase A(2), and high-sensitivity C-reactive protein in statin-treated patients with residual TG elevations.

8 Clinical Trial 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). 2011

Bays, Harold E / Ballantyne, Christie M / Kastelein, John J / Isaacsohn, Jonathan L / Braeckman, Rene A / Soni, Paresh N. ·Louisville Metabolic and Atherosclerosis Research Center, Kentucky, USA. hbaysmd@aol.com ·Am J Cardiol · Pubmed #21683321.

ABSTRACT: AMR101 is an omega-3 fatty acid agent containing ≥96% eicosapentaenoic acid ethyl ester and no docosahexaenoic acid. Previous smaller studies suggested that highly purified eicosapentaenoic acid lowered triglyceride (TG) levels without increasing low-density lipoprotein (LDL) cholesterol levels. TG-lowering therapies such as fibrates, and fish oils containing both eicosapentaenoic acid and docosahexaenoic acid, can substantially increase LDL cholesterol levels when administered to patients with very high TG levels (≥500 mg/dl). The present double-blind study randomized 229 diet-stable patients with fasting TG ≥500 mg/dl and ≤2,000 mg/dl (with or without background statin therapy) to AMR101 4 g/day, AMR101 2 g/day, or placebo. The primary end point was the placebo-corrected median percentage of change in TG from baseline to week 12. The baseline TG level was 680, 657, and 703 mg/dl for AMR101 4 g/day, AMR101 2 g/day, and placebo. AMR101 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76, p <0.0001) and AMR101 2 g/day by 19.7% (n = 73, p = 0.0051). For a baseline TG level >750 mg/dl, AMR101 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28, p = 0.0001) and AMR101 2 g/day by 32.9% (n = 28, p = 0.0016). AMR101 did not significantly increase the placebo-corrected median LDL cholesterol levels at 4 g/day (-2.3%) or 2 g/day (+5.2%; both p = NS). AMR101 significantly reduced non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein-associated phospholipase A(2), very low-density lipoprotein cholesterol, and total cholesterol. AMR101 was generally well tolerated, with a safety profile similar to that of the placebo. In conclusion, the present randomized, double-blind trial of patients with very high TG levels demonstrated that AMR101 significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels.

9 Article Differentiating Familial Chylomicronemia Syndrome From Multifactorial Severe Hypertriglyceridemia by Clinical Profiles. 2019

O'Dea, Louis St L / MacDougall, James / Alexander, Veronica J / Digenio, Andres / Hubbard, Brant / Arca, Marcello / Moriarty, Patrick M / Kastelein, John J P / Bruckert, Eric / Soran, Handrean / Witztum, Joseph L / Hegele, Robert A / Gaudet, Daniel. ·Akcea Therapeutics, Boston, Massachusetts. · BioBridges, Wellesley, Massachusetts. · Ionis Pharmaceuticals, Carlsbad, California. · Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. · Department of Medicine, Division of Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, AZ Amsterdam, Netherlands. · Institut E3M et IHU Cardiométabolique, Hôpital Pitié-Salpêtrière, Paris, France. · Manchester University Hospital NHS Trust, Manchester, England. · University of California, San Diego, La Jolla, California. · Robarts Research Institute, Western University, London, Ontario, Canada. · Department of Medicine, Université de Montréal and ECOGENE 21, Chicoutimi, Quebec, Canada. ·J Endocr Soc · Pubmed #31777768.

ABSTRACT: Context: Differentiation between familial chylomicronemia syndrome (FCS, type 1 hyperlipoproteinemia), a rare metabolic disorder, and the more common multifactorial severe hypertriglyceridemia (sHTG, type 5 hyperlipoproteinemia) is challenging because of their overlapping symptoms but important in patient management. Objective: To assess whether readily obtainable clinical information beyond triglycerides can effectively diagnose and differentiate patients with FCS from those with sHTG, based on well-curated data from two intervention studies of these conditions. Methods: The analysis included 154 patients from two phase 3 clinical trials of patients with sHTG, one cohort with genetically confirmed FCS (n = 49) and one with multifactorial sHTG (n = 105). Logistic regression analyses were performed to determine the ability of variables (patient demographics, medical history, and baseline lipids, individually or in sets) to differentiate the patient populations. Receiver operating characteristics were used to determine the variable sets with the highest accuracy (percentage of times actual values matched predicted) and optimal sensitivity and specificity. Results: The primary model diagnosed 45 of 49 patients with FCS and 99 of 105 patients with sHTG correctly. Optimal sensitivity for all available parameters (n = 17) was 91.8%, optimal specificity was 94.3%, and accuracy was 93.5%. Fasting low-density lipoprotein cholesterol (LDL-C) provided the highest individual predictability. However, a three-variable set of ultracentrifugally measured LDL-C, body mass index, and pancreatitis history differentiated the diseases with a near similar accuracy of 91.0%, and adding high-density lipoprotein cholesterol and very low-density lipoprotein cholesterol for a five-variable set provided a small incremental increase in accuracy (92.2%). Conclusions: In the absence of genetic testing, hypertriglyceridemic patients with FCS and sHTG can be differentiated with a high degree of accuracy by analyzing readily obtainable clinical information.

10 Article Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia. 2016

Kastelein, John J P / Hallén, Jonas / Vige, Runar / Fraser, David A / Zhou, Rong / Hustvedt, Svein Olaf / Orloff, David G / Bays, Harold E. ·Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. ·Cardiology · Pubmed #27160246.

ABSTRACT: OBJECTIVES: To evaluate the efficacy and safety of icosabutate, an oral, once-daily, first-in-class medication, in reducing non-high-density lipoprotein cholesterol (non-HDL-C) in patients with persistent hypertriglyceridemia despite statin therapy. METHODS: The study was designed to randomly assign 140 patients with fasting triglyceride levels ≥200 but <500 mg/dl on a stable dose of statin therapy to receive either masked icosabutate 600 mg once daily or a control for 12 weeks. The primary end point was a percentage change in non-HDL-C from baseline to 12 weeks. RESULTS: With icosabutate, non-HDL-C levels were reduced (-9.2%) when compared with the control (-0.4%) for a between-group difference of -7.4% (p = 0.02). Compared with the control, icosabutate reduced triglycerides (-27.0%, p < 0.001), very- low-density lipoprotein (VLDL) cholesterol (-31.5%, p < 0.001) and apolipoprotein C-III (-22.5%, p < 0.001). LDL-C levels did not change (0.5%, p = 0.87). HDL-C (10.2%, p < 0.001) was increased. After 113 subjects had been randomized, the study was terminated due to a partial clinical hold imposed by US regulators after observing QT prolongation at supratherapeutic doses of icosabutate in a dog study. In this study, adverse events were balanced between treatment arms, and there were no discontinuations due to adverse events. CONCLUSIONS: Icosabutate was efficacious in lowering non-HDL-C and other biomarkers of cardiovascular risk and was generally well tolerated.

11 Article Icosabutate for the treatment of very high triglycerides: A placebo-controlled, randomized, double-blind, 12-week clinical trial. 2016

Bays, Harold E / Hallén, Jonas / Vige, Runar / Fraser, David / Zhou, Rong / Hustvedt, Svein Olaf / Orloff, David G / Kastelein, John J P. ·L-MARC Research Center, Louisville, KY, USA. · Pronova BioPharma, Lysaker, Norway. · Medpace, Inc, Cincinatti, OH, USA. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: j.j.kastelein@amc.uva.nl. ·J Clin Lipidol · Pubmed #26892135.

ABSTRACT: BACKGROUND: Icosabutate is a structurally enhanced omega-3 fatty acid molecule developed with the aim of achieving improved triglyceride (TG)-lowering efficacy, increased potency, and preserved safety compared with conventional prescription omega-3 fatty acid. OBJECTIVE: To evaluate the efficacy and safety of icosabutate 600 mg once daily in patients with very high TGs. METHODS: After a 6-8 week run-in period, men and women with TG levels ≥ 500 mg/dL and ≤ 1500 mg/dL were randomized to double-blind treatment with placebo or icosabutate 600 mg for 12 weeks. The primary end point was % change from baseline in TGs at 12 weeks. RESULTS: A total of 87 subjects were randomized. At baseline, median TG (interquartile range) levels were 611 (543-878) and 688 (596-892) mg/dL, and the median change after 12 weeks of treatment was -51% and -17%, respectively, for a placebo-corrected change of -33% (P < .001). Adjusted for placebo, icosabutate significantly reduced very low-density lipoprotein cholesterol (-36%, P < .001), remnant lipoprotein cholesterol (-34%, P < .001), apolipoprotein (Apo) C-III (-35%, P < .001), trended toward reduced non-high-density lipoprotein cholesterol (-7%, P = .064); significantly increased high-density lipoprotein cholesterol (18%, P < .001) and low-density lipoprotein cholesterol (28%, P < .001), with a trend of an increased lipoprotein (a; 10%, P = .054). No changes were observed in total cholesterol, apolipoprotein B, or apolipoprotein A1. Fasting plasma glucose was unchanged, whereas fasting plasma insulin was reduced (P = .001) with icosabutate. Icosabutate was generally well tolerated. CONCLUSION: Treatment with icosabutate once daily significantly reduced TG, very low-density lipoprotein cholesterol, and Apo C-III levels in patients with very high TG levels. This trial was registered at www.clinicaltrials.gov as NCT01893515.

12 Article Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. 2014

Kastelein, John J P / Maki, Kevin C / Susekov, Andrey / Ezhov, Marat / Nordestgaard, Borge G / Machielse, Ben N / Kling, Douglas / Davidson, Michael H. ·Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Electronic address: j.j.kastelein@amc.uva.nl. · Biofortis Clinical Research, Addison, IL, USA. · Russian Cardiology Scientific Production Complex, Federal State University, Moscow, Russian Federation. · Copenhagen University Hospital, University of Copenhagen, Herlev, Denmark. · Omthera Pharmaceuticals, Inc, Princeton, NJ, USA. ·J Clin Lipidol · Pubmed #24528690.

ABSTRACT: BACKGROUND: Omega-3 fatty acids in free fatty acid form have enhanced bioavailability, and plasma levels are less influenced by food than for ethyl ester forms. OBJECTIVE: The aim was to evaluate the safety and lipid-altering efficacy in subjects with severe hypertriglyceridemia of an investigational pharmaceutical omega-3 free fatty acid (OM3-FFA) containing eicosapentaenoic acid and docosahexaenoic acid. METHODS: This was a multinational, double-blind, randomized, out-patient study. Men and women with triglycerides (TGs) ≥ 500 mg/dL, but <2000 mg/dL, took control (olive oil [OO] 4 g/d; n = 99), OM3-FFA 2 g/d (plus OO 2 g/d; n = 100), OM3-FFA 3 g/d (plus OO 1 g/d; n = 101), or OM3-FFA 4 g/d (n = 99) capsules for 12 weeks in combination with the National Cholesterol Education Program Therapeutic Lifestyle Changes diet. RESULTS: Fasting serum TGs changed from baseline by -25.9% (P < .01 vs OO), -25.5% (P < .01 vs OO), and -30.9% (P < .001 vs OO) with 2, 3, and 4 g/d OM3-FFA, respectively, compared with -4.3% with OO. Non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol-to-HDL-C ratio, very low-density lipoprotein cholesterol, remnant-like particle cholesterol, apolipoprotein CIII, lipoprotein-associated phospholipase A2, and arachidonic acid were significantly lowered (P < .05 at each OM3-FFA dosage vs OO); and plasma eicosapentaenoic acid and docosahexaenoic acid were significantly elevated (P < .001 at each OM3-FFA dosage vs OO). With OM3-FFA 2 and 4 g/d (but not 3 g/d), low-density lipoprotein cholesterol was significantly increased compared with OO (P < .05 vs OO). High-sensitivity C-reactive protein responses with OM3-FFA did not differ significantly from the OO response at any dosage. Fewer subjects reported any adverse event with OO vs OM3-FFA, but frequencies across dosage groups were similar. Discontinuation due to adverse event, primarily gastrointestinal, ranged from 5% to 7% across OM3-FFA dosage groups vs 0% for OO. CONCLUSIONS: OM3-FFA achieved the primary end point for TG lowering and secondary end point of non-HDL-C lowering at 2, 3, and 4 g/d in persons with severe hypertriglyceridemia. This trial was registered at www.clinicaltrials.gov as NCT01242527.

13 Article Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. 2012

Surendran, R P / Visser, M E / Heemelaar, S / Wang, J / Peter, J / Defesche, J C / Kuivenhoven, J A / Hosseini, M / Péterfy, M / Kastelein, J J P / Johansen, C T / Hegele, R A / Stroes, E S G / Dallinga-Thie, G M. ·Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. ·J Intern Med · Pubmed #22239554.

ABSTRACT: OBJECTIVES: The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to the loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG > 10 mmol L(-1) ), it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam. METHODS: The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls. RESULTS: In 46 patients (54%), rare DNA sequence variants were identified, comprising variants in LPL (n = 19), APOC2 (n = 1), APOA5 (n = 2), GPIHBP1 (n = 3) and LMF1 (n = 8). In 22 patients (26%), only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%). In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function. Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype. CONCLUSIONS: The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n = 3), APOC2 (n = 1) and APOA5 (n = 2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved our understanding of the molecular basis of this phenotype associated with acute pancreatitis and may help to guide future individualized therapeutic strategies.

14 Article The hypertriglyceridemic-waist phenotype and the risk of coronary artery disease: results from the EPIC-Norfolk prospective population study. 2010

Arsenault, Benoit J / Lemieux, Isabelle / Després, Jean-Pierre / Wareham, Nicholas J / Kastelein, John J P / Khaw, Kay-Tee / Boekholdt, S Matthijs. ·Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec. ·CMAJ · Pubmed #20643837.

ABSTRACT: BACKGROUND: Screening for increased waist circumference and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) has been proposed as an inexpensive approach to identify patients with excess intra-abdominal adiposity and associated metabolic abnormalities. We examined the relationship between the hypertriglyceridemic-waist phenotype to the risk of coronary artery disease in apparently healthy individuals. METHODS: A total of 21,787 participants aged 45-79 years were followed for a mean of 9.8 (standard deviation 1.7) years. Coronary artery disease developed in 2109 of them during follow-up. The hypertriglyceridemic-waist phenotype was defined as a waist circumference of 90 cm or more and a triglyceride level of 2.0 mmol/L or more in men, and a waist circumference of 85 cm or more and a triglyceride level of 1.5 mmol/L or more in women. RESULTS: Compared with participants who had a waist circumference and triglyceride level below the threshold, those with the hypertriglyceridemic-waist phenotype had higher blood pressure indices, higher levels of apolipoprotein B and C-reactive protein, lower levels of high-density lipoprotein cholesterol and apolipoprotein A-I, and smaller low-density lipoprotein particles. Among men, those with the hypertriglyceridemic-waist phenotype had an unadjusted hazard ratio for future coronary artery disease of 2.40 (95% confidence interval [CI] 2.02-2.87) compared with men who did not have the phenotype. Women with the phenotype had an unadjusted hazard ratio of 3.84 (95% CI 3.20-4.62) compared with women who did not have the phenotype. INTERPRETATION: Among participants from a European cohort representative of a contemporary Western population, the hypertriglyceridemic-waist phenotype was associated with a deteriorated cardiometabolic risk profile and an increased risk for coronary artery disease.