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Hypertriglyceridemia: HELP
Articles from Multinational BioPharma
Based on 32 articles published since 2008
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These are the 32 published articles about Hypertriglyceridemia that originated from Multinational BioPharma during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2
1 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.

2 Review Development of triglyceride-lowering drugs to address residual cardiovascular risk: strategic and clinical considerations. 2018

Hallén, Jonas / Sreeharan, Nadarajah. ·Novartis Norge AS, Nydalen Alle 37, Oslo, Norway. · Institute of Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, James Clerk Maxwell Building, 57 Waterloo Road, London, UK. ·Eur Heart J Cardiovasc Pharmacother · Pubmed #30060063.

ABSTRACT: The prevalence of hypertriglyceridaemia is high and growing in several parts of the world. Hypertriglyceridaemia has a well-defined association with the risk of atherosclerotic cardiovascular (CV) disease and triglycerides represent a potential target for drugs aimed at mitigating CV risk. So far, no triglyceride-lowering pharmacological strategy has succeeded in conclusively showing the ability to modify clinical outcomes. This article discusses strategic and clinical aspects of development of triglyceride-lowering drugs to address CV disease.

3 Review Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review. 2017

Oscarsson, Jan / Hurt-Camejo, Eva. ·AstraZeneca Gothenburg, Pepparedsleden 1, SE-431 83, Mölndal, Sweden. Jan.Oscarsson@astrazeneca.com. · AstraZeneca Gothenburg, Pepparedsleden 1, SE-431 83, Mölndal, Sweden. ·Lipids Health Dis · Pubmed #28797250.

ABSTRACT: BACKGROUND: Epidemiological and genetic studies suggest that elevated triglyceride (TG)-rich lipoprotein levels in the circulation increase the risk of cardiovascular disease. Prescription formulations of omega-3 fatty acids (OM3FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce plasma TG levels and are approved for the treatment of patients with severe hypertriglyceridemia. Many preclinical studies have investigated the TG-lowering mechanisms of action of OM3FAs, but less is known from clinical studies. METHODS: We conducted a review, using systematic methodology, of studies in humans assessing the mechanisms of action of EPA and DHA on apolipoprotein B-containing lipoproteins, including TG-rich lipoproteins and low-density lipoproteins (LDLs). A systematic search of PubMed retrieved 55 articles, of which 30 were used in the review; 35 additional arrticles were also included. RESULTS: In humans, dietary DHA is retroconverted to EPA, while production of DHA from EPA is not observed. Dietary DHA is preferentially esterified into TGs, while EPA is more evenly esterified into TGs, cholesterol esters and phospholipids. The preferential esterification of DHA into TGs likely explains the higher turnover of DHA than EPA in plasma. The main effects of both EPA and DHA are decreased fasting and postprandial serum TG levels, through reduction of hepatic very-low-density lipoprotein (VLDL)-TG production. The exact mechanism for reduced VLDL production is not clear but does not include retention of lipids in the liver; rather, increased hepatic fatty acid oxidation is likely. The postprandial reduction in TG levels is caused by increased lipoprotein lipase activity and reduced serum VLDL-TG concentrations, resulting in enhanced chylomicron clearance. Overall, no clear differences between the effects of EPA and DHA on TG levels, or on turnover of TG-rich lipoproteins, have been observed. Effects on LDL are complex and may be influenced by genetics, such as APOE genotype. CONCLUSIONS: EPA and DHA diminish fasting circulating TG levels via reduced production of VLDL. The mechanism of reduced VLDL production does not involve hepatic retention of lipids. Lowered postprandial TG levels are also explained by increased chylomicron clearance. Little is known about the specific cellular and biochemical mechanisms underlying the TG-lowering effects of EPA and DHA in humans.

4 Review The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia. 2016

Backes, James / Anzalone, Deborah / Hilleman, Daniel / Catini, Julia. ·Atherosclerosis and LDL-Apheresis Center, School of Pharmacy, University of Kansas, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA. jbackes@kumc.edu. · AstraZeneca, Wilmington, DE, USA. · Creighton University, Omaha, NE, USA. ·Lipids Health Dis · Pubmed #27444154.

ABSTRACT: Hypertriglyceridemia (triglycerides > 150 mg/dL) affects ~25 % of the United States (US) population and is associated with increased cardiovascular risk. Severe hypertriglyceridemia (≥ 500 mg/dL) is also a risk factor for pancreatitis. Three omega-3 fatty acid (OM3FA) prescription formulations are approved in the US for the treatment of adults with severe hypertriglyceridemia: (1) OM3FA ethyl esters (OM3EE), a mixture of OM3FA ethyl esters, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Lovaza®, Omtryg™, and generics); (2) icosapent ethyl (IPE), EPA ethyl esters (Vascepa®); and (3) omega-3 carboxylic acids (OM3CA), a mixture of OM3FAs in free fatty acid form, primarily EPA, DHA, and docosapentaenoic acid (Epanova®). At approved doses, all formulations substantially reduce triglyceride and very-low-density lipoprotein levels. DHA-containing formulations may also increase low-density lipoprotein cholesterol. However, this is not accompanied by increased non-high-density lipoprotein cholesterol, which is thought to provide a better indication of cardiovascular risk in this patient population. Proposed mechanisms of action of OM3FAs include inhibition of diacylglycerol acyltransferase, increased plasma lipoprotein lipase activity, decreased hepatic lipogenesis, and increased hepatic β-oxidation. OM3CA bioavailability (area under the plasma concentration-time curve from zero to the last measurable concentration) is up to 4-fold greater than that of OM3FA ethyl esters, and unlike ethyl esters, the absorption of OM3CA is not dependent on pancreatic lipase hydrolysis. All three formulations are well tolerated (the most common adverse events are gastrointestinal) and demonstrate a lack of drug-drug interactions with other lipid-lowering drugs, such as statins and fibrates. OM3FAs appear to be an effective treatment option for patients with severe hypertriglyceridemia.

5 Review Acute pancreatitis during pregnancy: a review. 2014

Ducarme, G / Maire, F / Chatel, P / Luton, D / Hammel, P. ·Department of Obstetrics and Gynecology, Centre Hospitalier Departemental, La Roche sur Yon, France. · 1] Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie-Pancréatologie, Hôpital Beaujon, AP-HP, Clichy, France [2] Inserm U773-CRB3, Université Paris-Diderot, Clichy, France. · Department of Obstetrics and Gynecology, Hôpital Beaujon, AP-HP, Université Paris-Diderot, Clichy, France. ·J Perinatol · Pubmed #24355941.

ABSTRACT: This article aims to draw together recent thinking on pregnancy and acute pancreatitis (AP), with a particular emphasis on pregnancy complications, birth outcomes and management of AP during pregnancy contingent on the etiology. AP during pregnancy is a rare but severe disease with a high maternal-fetal mortality, which has recently decreased thanks to earlier diagnosis and some maternal and neonatal intensive care improvement. AP usually occurs during the third trimester or the early postpartum period. The most common causes of AP are gallstones (65 to 100%), alcohol abuse and hypertriglyceridemia. Although the diagnostic criteria for AP are not specific for pregnant patients, Ranson and Balthazar criteria are used to evaluate the severity and treat AP during pregnancy. The fetal risks from AP during pregnancy are threatened preterm labor, prematurity and in utero fetal death. In cases of acute biliary pancreatitis during pregnancy, a consensual strategy could be adopted according to the gestational age, and taking in consideration the high risk of recurrence of AP (70%) with conservative treatment and the specific risks of each treatment. This could include: conservative treatment in first trimester and laparoscopic cholecystectomy in second trimester. During the third trimester, conservative treatment or endoscopic retrograde cholangiopancreatography with biliary endoscopic sphincterotomy, and laparoscopic cholecystectomy in early postpartum period are recommended. A multidisciplinary approach, including gastroenterologists and obstetricians, seems to be the key in making the best choice for the management of AP during pregnancy.

6 Review Inhibitors of diacylglycerol acyltransferase: a review of 2008 patents. 2010

King, Andrew J / Judd, Andrew S / Souers, Andrew J. ·Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. ·Expert Opin Ther Pat · Pubmed #20021283.

ABSTRACT: BACKGROUND: Postprandial hypertriglyceridemia has been identified as a major independent risk factor for future cardiovascular events. Therefore, inhibition of triglyceride synthesis has enormous therapeutic potential in the treatment of metabolic disorders. Diacylglycerol acyltransferase (DGAT) enzymes catalyze the final and only committed step in triglyceride biosynthesis and have thus been identified as potential therapeutic targets to combat human cardio-metabolic diseases. OBJECTIVE/METHOD: Significant interest in DGAT-1 inhibitors has emerged in the last several years. To provide a perspective on the exciting features of this enzyme for targeting metabolic diseases, a summary of the biology and pharmacology surrounding the DGAT enzymes is presented. Following this is a discussion of the various chemotypes that have been disclosed within relevant patent applications published in 2008. Specifically, the similarities and differences of the chemical structures and the biological data that are provided to support the corresponding claims are presented. CONCLUSION: Small molecule and biologic-based DGAT inhibitors have been successfully used for the preclinical validation of DGAT enzymes as targets for the treatment of metabolic diseases. Given the advanced stage in which some of the chemical matter resides, it is expected that DGAT inhibitors will enter the clinic in the coming years.

7 Clinical Trial Attenuated suppression of lipolysis explains the increases in triglyceride secretion and concentration associated with basal insulin peglispro relative to insulin glargine treatment in patients with type 1 diabetes. 2018

Johansen, Rakel F / Søndergaard, Esben / Linnebjerg, Helle / Garhyan, Parag / Lam, Eric C Q / Porksen, Niels / Jacober, Scott J / Nielsen, Søren. ·Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark. · Eli Lilly and Company, Indianapolis, Indiana. · Formerly of Eli Lilly and Company, Singapore, Singapore. · Formerly of Eli Lilly and Company, Indianapolis, Indiana. ·Diabetes Obes Metab · Pubmed #28817248.

ABSTRACT: AIMS: To test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very-low-density lipoprotein (VLDL)-TG secretion and lipid oxidation, and decreased TG adipose tissue deposition. METHODS: In this open-label, randomized, 2-period crossover study, 14 patients with type 1 diabetes received once-daily, individualized, stable BIL or GL doses for 3 weeks. Palmitate flux was assessed using [9,10- RESULTS: The VLDL-TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than during GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means for VLDL-TG clearance and oxidation were 0.92 (95% confidence interval [CI] 0.72, 1.17) and 1.31 (95% CI 0.91, 1.90), respectively. The difference in LS means for VLDL-TG storage rate was -0.36 (95% CI -0.83, 0.12). CONCLUSIONS: BIL-treated patients had higher effective lipolysis, VLDL-TG secretion and VLDL-TG concentration compared with GL-treated patients, explaining the increased plasma TG concentrations reported previously. Data support attenuated effects of BIL on lipolysis, in addition to the recently described hepato-preferential glucodynamic effects.

8 Clinical Trial Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidaemia at high cardiovascular risk. 2017

Müller-Wieland, Dirk / Leiter, Lawrence A / Cariou, Bertrand / Letierce, Alexia / Colhoun, Helen M / Del Prato, Stefano / Henry, Robert R / Tinahones, Francisco J / Aurand, Lisa / Maroni, Jaman / Ray, Kausik K / Bujas-Bobanovic, Maja. ·Department of Internal Medicine I, University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany. dirmueller@ukaachen.de. · Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. · Institut du Thorax, CHU Nantes, Nantes, France. · Biostatistics and Programming Department, Sanofi, Chilly-Mazarin, France. · University of Edinburgh, Edinburgh, Scotland, UK. · Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. · University of California San Diego School of Medicine, Center for Metabolic Research, Veterans Affairs, San Diego Healthcare System, San Diego, CA, USA. · CIBERobn, Hospital Virgen de la Victoria, Málaga University, Málaga, Spain. · Sanofi, Bridgewater, NJ, USA. · Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. · Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK. · Sanofi, Paris, France. ·Cardiovasc Diabetol · Pubmed #28545518.

ABSTRACT: BACKGROUND: Type 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-high-density lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non-HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterol-lowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator. METHODS: DM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-C ≥100 mg/dl [≥2.59 mmol/l], and triglycerides ≥150 and <500 mg/dl [≥1.70 and <5.65 mmol/l]) with documented atherosclerotic cardiovascular disease or ≥1 additional cardiovascular risk factor. Participants were randomised (2:1) to alirocumab 75 mg every 2 weeks (Q2W) or lipid-lowering usual care on top of maximally tolerated statin (or no statin if intolerant). If randomised to usual care, investigators were able to add their pre-specified choice of one of the following to the patient's current statin regimen: ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid, in accordance with local standard-of-care. Alirocumab-treated individuals with non-HDL-C ≥100 mg/dl at week 8 will undergo a blinded dose increase to 150 mg Q2W at week 12. The primary efficacy endpoint is non-HDL-C change from baseline to week 24 with alirocumab versus usual care; other lipid levels (including LDL-C), glycaemia-related measures, safety and tolerability will also be assessed. Alirocumab will be compared to fenofibrate in a secondary analysis. RESULTS: Recruitment completed with 413 individuals randomised in 14 countries worldwide. Results of this trial are expected in the second quarter of 2017. CONCLUSIONS: ODYSSEY DM-DYSLIPIDEMIA will provide information on the efficacy and safety of alirocumab versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk using non-HDL-C as the primary efficacy endpoint. Trial registration NCT02642159 (registered December 24, 2015).

9 Clinical Trial AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes. 2016

Katz, L / Manamley, N / Snyder, W J / Dodds, M / Agafonova, N / Sierra-Johnson, J / Cruz, M / Kaur, P / Mudaliar, S / Raskin, P / Kewalramani, R / Pellacani, A. ·Amgen Inc., Thousand Oaks, CA, USA. · Amgen Ltd, Cambridge, UK. · Amgen Inc., Seattle, WA, USA. · Center for Metabolic Research, Veterans Administration San Diego Healthcare System, San Diego, CA, USA. · University of Texas Southwestern Medical Center, Dallas, TX, USA. ·Diabetes Obes Metab · Pubmed #26434934.

ABSTRACT: Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.

10 Clinical Trial 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. 2015

Dunbar, Richard L / Nicholls, Stephen J / Maki, Kevin C / Roth, Eli M / Orloff, David G / Curcio, Danielle / Johnson, Judith / Kling, Douglas / Davidson, Michael H. ·Division of Translational Medicine & Human Genetics, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 8046 Maloney Building, Philadelphia, PA, 19104-2699, USA. richard.dunbar@uphs.upenn.edu. · South Australian Health & Medical Research Institute, University of Adelaide, Adelaide, Australia. stephen.nicholls@sahmri.com. · Midwest Center for Metabolic & Cardiovascular Research, Chicago, IL, USA. kmaki@mc-mcr.com. · Sterling Research Group, Cincinnati, OH, USA. eroth@sterlingresearch.org. · Medpace, Inc., Cincinnati, OH, USA. d.orloff@medpace.com. · Omthera Pharmaceuticals, Princeton, NJ, USA. dcurcio319@gmail.com. · Omthera Pharmaceuticals, Princeton, NJ, USA. judithbjohnson@gmail.com. · Omthera Pharmaceuticals, Princeton, NJ, USA. douglaskling@gmail.com. · Omthera Pharmaceuticals, Princeton, NJ, USA. mdavidson@omthera.com. · AstraZeneca, Wilmington, DE, USA. mdavidson@omthera.com. ·Lipids Health Dis · Pubmed #26328624.

ABSTRACT: BACKGROUND: This study examined the effects of a mixture of highly bioavailable omega-3 carboxylic acids (OM3-CA) on nuclear magnetic resonance spectroscopy-assessed lipoprotein particle concentrations and sizes and other cardiovascular risk markers in statin-treated patients with fasting triglycerides (TG) ≥ 2.3 mmol/L (200 mg/dL) and <5.6 mmol/L (500 mg/dL) and at high cardiovascular risk. METHODS: After a diet lead-in and statin-stabilization period, 647 patients were randomly assigned to receive capsules of control (olive oil, OO) 4 g/d, OM3-CA 2 g/d (plus OO 2 g/d), or OM3-CA 4 g/d for 6 weeks. RESULTS: Compared with OO, low-density lipoprotein (LDL) particle size was increased with OM3-CA 2 g/d (p < 0.01) and 4 g/d (p < 0.001), and very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) particle sizes were decreased with both OM3-CA dosages vs. OO (p < 0.001 and p < 0.05 for VLDL and HDL, respectively). Total VLDL/chylomicron remnant particle concentration was reduced by 8.5 and 16.0 % with OM3-CA 2 and 4 g/d, respectively, vs. a 6.9 % reduction with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Total HDL particle concentration was also reduced by 1.5 and 3.2 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.6 % increase with OO (at least p < 0.05 for both comparisons). Changes in total LDL particle concentration were not significantly different for OO vs. OM3-CA at either dosage. Apolipoprotein (Apo) CIII levels decreased by 7.6 and 13.1 % with OM3-CA 2 and 4 g/d, respectively, vs. 3.2 % with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass was reduced by 6.2 and 10.7 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.1 % increase with OO (p < 0.001 for both vs. OO). There were no significant differences between treatments in high-sensitivity C-reactive protein responses. CONCLUSION: OM3-CA were associated with shifts in lipoprotein particle sizes and concentrations, and reductions in Apo CIII and Lp-PLA2, in patients with hypertriglyceridemia while taking a statin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01408303.

11 Article Discovery of a Novel Piperidine-Based Inhibitor of Cholesteryl Ester Transfer Protein (CETP) That Retains Activity in Hypertriglyceridemic Plasma. 2017

Yamada, Ken / Brousseau, Margaret / Honma, Wataru / Iimura, Akiko / Imase, Hidetomo / Iwaki, Yuki / Kawanami, Toshio / LaSala, Daniel / Liang, Guiqing / Mitani, Hironobu / Nonomura, Kazuhiko / Ohmori, Osamu / Pan, Meihui / Rigel, Dean F / Umemura, Ichiro / Yasoshima, Kayo / Zhu, Guoming / Mogi, Muneto. ·Novartis Institutes for BioMedical Research, Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139-4133, United States. · Novartis Institutes for BioMedical Research , Novartis Pharma K.K., Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan. · Novartis Institutes for BioMedical Research , Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, New Jersey 07936-1080, United States. ·J Med Chem · Pubmed #29035537.

ABSTRACT: Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.

12 Article Once-weekly administration of a long-acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non-human primates. 2017

Kim, Albert M / Somayaji, Veena R / Dong, Jennifer Q / Rolph, Timothy P / Weng, Yan / Chabot, Jeffrey R / Gropp, Kathryn E / Talukdar, Saswata / Calle, Roberto A. ·Pfizer Inc., Cambridge, Massachusetts, USA. · Pfizer Inc., Groton, Connecticut, USA. ·Diabetes Obes Metab · Pubmed #28573777.

ABSTRACT: AIMS: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes. METHODS: Participants received PF-05231023 or placebo intravenously once weekly for 4 weeks. Safety (12-lead ECGs, vital signs, adverse events [AEs], laboratory tests) and longitudinal weight assessments were performed. Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Cardiovascular safety studies were also conducted in telemetered rats and monkeys. Blood pressure (BP; mean, systolic and diastolic) and ECGs were monitored. RESULTS: A total of 107 people were randomized. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33%-43%) and increased HDL cholesterol (day 25, 15.7%-28.6%) and adiponectin (day 25, 1574 to 3272 ng/mL) across all doses, without significant changes in body weight (day 25, -0.45% to -1.21%). Modest decreases from baseline were observed for N-terminal propeptides of type 1 collagen (P1NP) on day 25, although C-telopeptide cross-linking of type 1 collagen (CTX-1) increased minimally. Systolic, diastolic BP, and pulse rate increased in a dose- and time-related manner. There were 5 serious AEs (one treatment-related) and no deaths. Three participants discontinued because of AEs. The majority of AEs were gastrointestinal. PF-05231023 increased BP and heart rate in rats, but not in monkeys. CONCLUSIONS: Once-weekly PF-05231023 lowered triglycerides markedly in the absence of weight loss, with modest changes in markers of bone homeostasis. This is the first report showing increases in BP and pulse rate in humans and rats after pharmacological administration of a long-acting FGF21 molecule.

13 Article Effect of Combination Cholesterol-Lowering Therapy and Triglyceride-Lowering Therapy on Medical Costs in Patients With Type 2 Diabetes Mellitus. 2017

Nichols, Gregory A / Reynolds, Kristi / Olufade, Temitope / Kimes, Teresa M / O'Keeffe-Rosetti, Maureen / Sapp, Daniel S / Anzalone, Deborah / Fortmann, Stephen P. ·Kaiser Permanente Center for Health Research, Science Programs Department, Portland, Oregon. Electronic address: greg.nichols@kpchr.org. · Kaiser Permanente Southern California, Department of Research and Development, Pasadena, California. · AstraZeneca LP, Health Economics and Outcomes Research, Wilmington, Delaware. · Kaiser Permanente Center for Health Research, Science Programs Department, Portland, Oregon. ·Am J Cardiol · Pubmed #27890243.

ABSTRACT: High triglyceride (TG) levels among patients with type 2 diabetes mellitus (DM) are associated with higher medical costs. We analyzed the economic impact of TG-lowering therapies and whether the association between medical costs and therapy differed according to TG reduction. We conducted an observational cohort study of 184,932 patients with diabetes mellitus who had a TG measurement between January 2012 and June 2013 and a second TG measurement 3 to 15 months later. We identified 4 therapy groups (statin monotherapy, TG-specific monotherapy, statin/TG-specific combination therapy, or no therapy) and stratified those groups by percent change in TG (increased ≥5%, change of ≤4.9%, decreased 5% to 29%, decreased ≥30%). We compared change in medical costs between the year before and after therapy, adjusted for demographic and clinical characteristics. Of the 184,932 total patients, 143,549 (77.6%) received statin monotherapy, 900 (0.5%) received TG-specific monotherapy, 1,956 (1.1%) received statin and TG-specific combination therapy, and 38,527 (20.8%) received no prescription lipid agents. After covariate adjustment, statin/TG-specific agent recipients had a mean 1-year total cost reduction of $1,110. The greatest cost reduction was seen among statin/TG-specific combination therapy patients who reduced TG levels by ≥30% (-$2,859). Statin monotherapy patients who reduced TG by ≥30% also had a large reduction in adjusted costs (-$1,079). In conclusion, we found a substantial economic benefit to treating diabetic patients with statin/TG-specific combination lipid therapy compared with monotherapy of either type or no lipid pharmacotherapy. A TG reduction of ≥30% produced a particularly large reduction in 1-year medical costs.

14 Article Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]. 2017

Kroon, Tobias / Baccega, Tania / Olsén, Arne / Gabrielsson, Johan / Oakes, Nicholas D. ·Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden tobias.kroon@astrazeneca.com. · AstraZeneca R&D, CVMD iMed, Gothenburg, Sweden. · Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden. ·J Lipid Res · Pubmed #27875257.

ABSTRACT: Nicotinic acid (NiAc) is a potent inhibitor of lipolysis, acutely reducing plasma free fatty acid (FFA) concentrations. However, a major FFA rebound is seen during rapid NiAc washout, and sustained exposure is associated with tolerance development, with FFAs returning to pretreatment levels. Our aim was to find a rational NiAc dosing regimen that preserves FFA lowering, sufficient to reverse nonadipose tissue lipid accumulation and improve metabolic control, in obese Zucker rats. We compared feeding-period versus fasting-period NiAc dosing for 5 days: 12 h subcutaneous infusion (programmable, implantable mini-pumps) terminated by gradual withdrawal. It was found that NiAc timed to feeding decreased triglycerides in liver (-47%; P < 0.01) and heart (-38%; P < 0.05) and reduced plasma fructosamine versus vehicle. During oral glucose tolerance test, plasma FFA levels were reduced with amelioration of hyperglycemia and hypertriglyceridemia. Furthermore, timing NiAc to feeding resulted in a general downregulation of de novo lipogenesis (DNL) genes in liver. By contrast, NiAc timed to fasting did not reduce tissue lipids, ameliorate glucose intolerance or dyslipidemia, or alter hepatic DNL genes. In conclusion, NiAc dosing regimen has a major impact on metabolic control in obese Zucker rats. Specifically, a well-defined NiAc exposure, timed to feeding periods, profoundly improves the metabolic phenotype of this animal model.

15 Article All-Cause and Acute Pancreatitis Health Care Costs in Patients With Severe Hypertriglyceridemia. 2017

Rashid, Nazia / Sharma, Puza P / Scott, Ronald D / Lin, Kathy J / Toth, Peter P. ·From the *Kaiser Permanente, Southern California Region, Drug Information Services, Downey, CA; †US Health Economics & Outcomes Research, Novartis Pharmaceuticals, Corporation, East Hanover, NJ; ‡Southern California Permanente Medical Group, Kaiser Permanente Southern California, West Los Angeles, CA; §CGH Medical Center, Sterling, IL; and ∥Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD. ·Pancreas · Pubmed #27518471.

ABSTRACT: OBJECTIVE: The aim of this study was to assess health care utilization and costs related to acute pancreatitis (AP) in patients with severe hypertriglyceridemia (sHTG) levels. METHODS: Patients with sHTG levels 1000 mg/dL or higher were identified from January 1, 2007, to June 30, 2013. The first identified incident triglyceride level was labeled as index date. All-cause, AP-related health care visits, and mean total all-cause costs in patients with and without AP were compared during 12 months postindex. A generalized linear model regression was used to compare costs while controlling for patient characteristics and comorbidities. RESULTS: Five thousand five hundred fifty sHTG patients were identified, and 5.4% of these patients developed AP during postindex. Patients with AP had significantly (P < 0.05) more all-cause outpatient visits, hospitalizations, longer length of stays during the hospital visits, and emergency department visits versus patients without AP. Mean (SD) unadjusted all-cause health care costs in the 12 months postindex were $25,343 ($33,139) for patients with AP compared with $15,195 ($24,040) for patients with no AP. The regression showed annual all-cause costs were 49.9% higher (P < 0.01) for patients with AP versus without AP. CONCLUSIONS: Patients who developed AP were associated with higher costs; managing patients with sHTG at risk of developing AP may help reduce unnecessary costs.

16 Article Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. 2016

Maki, Kevin C / Guyton, John R / Orringer, Carl E / Hamilton-Craig, Ian / Alexander, Dominik D / Davidson, Michael H. ·Midwest Center for Metabolic and Cardiovascular Research/MB Clinical Research, Glen Ellyn, IL, USA. Electronic address: kevin.maki@mxns.com. · Duke University School of Medicine, Durham, NC, USA. · University of Miami Miller School of Medicine, Miami, FL, USA. · Griffith and Flinders University Schools of Medicine, Queensland and South Australia, Australia. · EpidStat Institute, Ann Arbor, MI, USA. · AstraZeneca Pharmaceuticals, Wilmington, DE, USA. ·J Clin Lipidol · Pubmed #27578122.

ABSTRACT: BACKGROUND: Cardiovascular outcomes trials of fibrates, niacin, or omega-3 fatty acids alone, or added to a statin, have not consistently demonstrated reduced risk, but larger, statistically significant clinical benefits have been reported in subgroups with elevated triglycerides (TG) and/or elevated TG plus low high-density lipoprotein cholesterol (HDL-C). OBJECTIVE: To perform a meta-analysis of the effects of therapies targeting TG and TG-rich lipoprotein cholesterol on cardiovascular disease event risk in subjects with elevated TG or elevated TG paired with low HDL-C. METHODS: Publications were identified using PubMed, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, and Internet Stroke Center. Random-effects meta-analysis models were used to generate summary relative risk estimates and 95% confidence intervals. Heterogeneity was assessed by χ(2) and I(2) statistics, and the impact of each trial was assessed in one study-removed sensitivity analyses. RESULTS: Six trials of fibrates, 2 of niacin, 1 of fibrate + niacin, and 1 of omega-3 eicosapentaenoic acid ethyl esters were identified. For the prespecified primary cardiovascular disease or coronary heart disease end point used in each trial, the summary relative risk estimate (95% confidence interval) for subjects with elevated TG was 0.82 (0.73-0.91), p-heterogeneity = 0.13, I(2) = 36.2, and for subjects with elevated TG and low-HDL-C, it was 0.71 (0.63-0.81), p-heterogeneity = 0.52, I(2) = 0.0. There was no evidence of publication bias, and the results remained statistically significant when each individual trial was removed. CONCLUSION: Drugs that substantially, but not exclusively, lower TG and TG-rich lipoprotein cholesterol may have cardiovascular benefits in individuals with elevated TG, particularly if accompanied by low HDL-C.

17 Article Severe hypertriglyceridemia and factors associated with acute pancreatitis in an integrated health care system. 2016

Rashid, Nazia / Sharma, Puza P / Scott, Ronald D / Lin, Kathy J / Toth, Peter P. ·Kaiser Permanente, Southern California Region, Drug Information Services, Downey, CA, USA. Electronic address: Nazia.X.Rashid@kp.org. · Novartis Pharmaceuticals Corporation, US Health Economics & Outcomes Research, NJ, USA. · Southern California Permanente Medical Group, West Los Angeles, CA, USA. · Kaiser Permanente, Southern California Region, Drug Information Services, Downey, CA, USA. · CGH Medical Center, Sterling, IL, USA; Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Clin Lipidol · Pubmed #27578119.

ABSTRACT: OBJECTIVE: To evaluate patient characteristics, treatment patterns, comorbidities, and risk factors associated with the development of acute pancreatitis (AP) in patients with severe hypertriglyceridemia (HTG) in an integrated health care delivery system. METHODS: We identified a retrospective cohort of severe HTG patients with a fasting triglyceride level ≥ 1000 mg/dL during January 1, 2007 to June 30, 2013 (index date) in an integrated health care delivery system. Patients were aged ≥18 years on index date and had 12 months of continuous membership and drug eligibility before the index date and during postindex including index date. Baseline patient characteristics, comorbidities, and risk factors were evaluated during 12-month preindex. Outcomes such as development of AP, treatment patterns, adherence to index therapy, and change in triglyceride (TG) laboratory levels were evaluated during postindex. Descriptive statistics were used to identify differences between patients developing AP vs no development of AP. A stepwise multivariate logistic regression and backward elimination method were used to assess statistically significant predictive factors associated with development of AP vs no AP. RESULTS: We identified 5550 patients with severe HTG, and 5.4% of these patients developed AP during postindex. Patients were mostly male (≥70%) in both groups; however, younger in the AP group (45 years ± 10.6) vs no AP group (50 years ± 11.4) with P value < .0001. The AP group had higher baseline Charslon Comorbidity Index score, alcohol abuse history (42.2%), any pancreatitis history (51.5%), diabetes (47%), and hypertension (55%), vs the no AP group (P values < .05). Patients in the AP group had higher baseline mean TG levels (2148, SD ± 1578) vs the no AP group (1559, SD ± 861), P value < .0001. Over 50% of the patients were prescribed their index therapy by a primary care provider. Predictive factors associated with the development of AP included younger age, alcohol use, and prior history of any pancreatitis, hypertension, renal disease stage 4, and other prescriber specialty. From parameters estimates, for each 100 mg/dL unit of increase in the TG level above 1000 mg/dL, there was a 3 percent increase in risk of developing AP. CONCLUSIONS: Patients with severe HTG are at a higher risk of developing AP. A number of comorbidities, risk factors, and baseline TG levels are associated with an increased incidence of AP. Patients with severe HTG are underdiagnosed, undertreated and are nonadherent to their index lipid therapy. There is a need to better define optimal approaches to treating severe HTG so as to reduce the incidence of AP. Economic studies are also needed to evaluate the burden of AP on various health care systems.

18 Article Association of faecal elastase 1 with non-fasting triglycerides in type 2 diabetes. 2016

Rathmann, Wolfgang / Haastert, Burkhard / Oscarsson, Jan / Berglind, Niklas / Lindkvist, Björn / Wareham, Nicholas J. ·Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Auf'm Hennekamp 65, D-40225 Düsseldorf, Germany. Electronic address: rathmann@ddz.uni-duesseldrof.de. · MediStatistica, Neuenrade, Germany. · AstraZeneca R&D, Mölndal, Sweden. · Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. ·Pancreatology · Pubmed #27086060.

ABSTRACT: AIMS: Intestinal absorption of esterified fatty acids depends on exocrine pancreatic function and influences plasma triglycerides levels. The aim was to investigate the association of reduced exocrine pancreatic function (low fecal elastase-1; FE1) with plasma triglycerides in type 2 diabetes and controls without diabetes. METHODS: FE1 (μg/g stool) and non-fasting plasma triglyceride measurements were undertaken in 544 type 2 diabetes patients (age: 63 ± 8 years) randomly selected from diabetes registers in Cambridgeshire (UK), and 544 matched controls (age, sex, practice) without diabetes. Linear regression models were fitted using FE1 as dependent and log-triglycerides as independent variable adjusting for sex, age, body mass index, alcohol consumption, serum lipase, HbA1c, and smoking. RESULTS: FE1 concentrations were lower (mean ± SD: 337 ± 204 vs. 437 ± 216 μg/g, p < 0.05) and plasma triglycerides were higher (geometric mean */: standard deviation factor: 2.2*/:1.9 vs. 1.6*/:1.8 mmol/l, p < 0.05) in type 2 diabetes compared to controls, respectively. Within the category of type 2 diabetes and controls separately, a 10% increase in plasma triglycerides was associated with 4.5 μg/g higher FE1 concentrations (p < 0.01) after adjusting for confounders. In contrast, in diabetes patients and controls with pathological FE1 (<100 μg/g), low FE1 levels were associated with high plasma triglycerides (significant only in controls). CONCLUSIONS: Non-fasting triglycerides were positively related to FE1 in both type 2 diabetes and controls suggesting that impairment of exocrine pancreas function is influencing plasma triglycerides. Marked loss of exocrine pancreatic function had the opposite effect, resulting in higher levels of plasma triglycerides.

19 Article A VOYAGER Meta-Analysis of the Impact of Statin Therapy on Low-Density Lipoprotein Cholesterol and Triglyceride Levels in Patients With Hypertriglyceridemia. 2016

Karlson, Björn W / Palmer, Michael K / Nicholls, Stephen J / Lundman, Pia / Barter, Philip J. ·AstraZeneca, Gothenburg, Mölndal, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: Bjorn.W.Karlson@astrazeneca.com. · School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom. · South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia. · Department of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden. · Centre for Vascular Research, University of New South Wales, Sydney, Australia. ·Am J Cardiol · Pubmed #26969416.

ABSTRACT: Elevated triglyceride (TG) levels are associated with increased cardiovascular disease risk. In patients with mild-to-moderate hypertriglyceridemia, defined by the European Atherosclerosis Society Consensus Panel as a TG level of 177 to 885 mg/dl (2.0 to 10.0 mmol/L), low-density lipoprotein cholesterol (LDL-C) reduction remains the primary treatment goal. Using data from the indiVidual patient meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin (VOYAGER) meta-analysis, we analyzed LDL-C and TG reductions in patients with baseline TG ≥177 mg/dl (≥2.0 mmol/L). Least squares mean percentage change from baseline in LDL-C and TG was compared using 15,800 patient exposures to rosuvastatin 5 to 40 mg, atorvastatin 10 to 80 mg, and simvastatin 10 to 80 mg in patients with baseline TG ≥177 mg/dl (≥2.0 mmol/L). Comparisons were made using mixed-effects models with data only from studies directly comparing treatments by randomized design. Mean LDL-C reductions ranged from -26.9% to -55.5%. Rosuvastatin 10 to 40 mg resulted in significantly greater LDL-C reductions than equal or double doses of atorvastatin and simvastatin (p <0.05). Mean TG reductions ranged from -15.1% to -31.3%. Rosuvastatin 10 mg resulted in significantly greater TG reductions than atorvastatin 10 mg (p <0.05). Rosuvastatin 20 and 40 mg resulted in TG reductions similar to those with equal doses of atorvastatin. Rosuvastatin 10 to 40 mg resulted in significantly greater TG reductions than equal or double doses of simvastatin (p <0.05). In conclusion, in patients with hypertriglyceridemia, LDL-C reduction was substantial and dependent on the choice and dose of statin. TG reduction was numerically less than for LDL-C, and additional TG-lowering therapy may be considered to further reduce residual cardiovascular risk.

20 Article PROMETHEUS: an observational, cross-sectional, retrospective study of hypertriglyceridemia in Russia. 2015

Karpov, Yuri / Khomitskaya, Yunona. ·Russian Cardiology Research and Production Complex, Moscow, Russian Federation. yuri_karpov@inbox.ru. · AstraZeneca, Moscow, Russian Federation. Yunona.Khomitskaya@astrazeneca.com. ·Cardiovasc Diabetol · Pubmed #26303403.

ABSTRACT: BACKGROUND: Data regarding the prevalence of hypertriglyceridemia in the Russian population are lacking, despite triglyceride (TG)-mediated pathways being causal in cardiovascular disease. The prevalence of mixed dyslipidemia and severe hypertriglyceridemia in the Russian population (PROMETHEUS) was undertaken to address this gap. METHODS: This was an observational, cross-sectional retrospective study. Data from adults with a full/partial lipoprotein record who had blood analyses done at an INVITRO laboratory in Russia between January 1, 2011 and December 31, 2013 were analyzed. The primary endpoint was the prevalence of hypertriglyceridemia (TG ≥ 1.7 mmol/L); secondary endpoints included prevalence of borderline high, high, and very high TG and severe hypertriglyceridemia, defined as a TG level of 1.7 to <2.3, 2.3 to <5.6, ≥5.6, and ≥10.0 mmol/L, respectively. Statistical analyses involved the Wilcoxon and the Chi square tests. Correlations between log-transformed TG and low- and high-density lipoprotein cholesterol (LDL-C and HDL-C) and total cholesterol (TC) were assessed. The correlation between glycated hemoglobin (HbA1c) and TG levels in a nested sample of subjects with HbA1c and TG data was also assessed using a log-linear model. RESULTS: The full dataset and nested sample comprised 357,072 and 54,602 individuals, respectively. Prevalence of hypertriglyceridemia, borderline high TG, high TG, very high TG, and severe hypertriglyceridemia in the full dataset was 29.2, 16.2, 12.9, 0.11, and 0.011%, respectively; corresponding rates in the nested sample were 19.0, 17.2, 0.25, and 0.016%, respectively. TG levels were 16.4% higher in males versus females; males had a greater risk of hypertriglyceridemia (risk ratio 1.25; 95% CI 1.24, 1.26; P < 0.0001). Prevalence of hypertriglyceridemia increased with age, peaking at 40-49 years in males (42.8%) and 60-69 years in females (34.4%); a 0.61% increase in TG levels for each year of life was predicted. Hypertriglyceridemia prevalence increased over time. Correlations between TG and LDL-C, HDL-C, TC, and HbA1c (nested sample only) were observed. CONCLUSIONS: Almost one-third of Russians have hypertriglyceridemia, but severe disease (TG ≥ 10.0 mmol/L) is rare. Although the risk of hypertriglyceridemia was greater in males versus females, its prevalence increased with age, regardless of sex. TG was associated with HbA1c, LDL-C, HDL-C, and TC.

21 Article Effect of TAK-085 on Low-density Lipoprotein Particle Size in Patients with Hypertriglyceridemia: A Double-blind Randomized Clinical Study. 2015

Tatsuno, Ichiro / Kudou, Kentarou / Kagawa, Tomoya. ·Center of Diabetes, Endocrine and Metabolism, School of Medicine, Sakura Hospital, Toho University, Chiba, Japan. · Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan. ·Cardiovasc Ther · Pubmed #26222126.

ABSTRACT: BACKGROUND: Low-density lipoproteins (LDLs) comprise a heterogeneous group of particles with various size and density. A shift to larger LDL particle size is mainly the result of a decrease in small dense LDL (sd-LDL) levels and an increase in large buoyant LDL (lb-LDL) levels. METHODS: In a randomized, double-blind study of TAK-085 (containing docosahexaenoic and eicosapentaenoic acid-ethyl esters [EPA-E]) and an EPA-E product in Japanese patients with hypertriglyceridemia, exploratory evaluations of the effects of the LDL particle size were performed on the basis of LDL-cholesterol/apolipoprotein B ratios and LDL subfractions, which were analyzed with a polyacrylamide gel electrophoresis system. RESULTS: Patients were randomized to 12-week treatment with TAK-085 4 g/day (N = 210), TAK-085 2 g/day (N = 205), or EPA-E 1.8 g/day (N = 195). Treatment with TAK-085 4 g/day, TAK-085 2 g/day, and EPA-E 1.8 g/day caused an increase in the LDL cholesterol/apolipoprotein B ratios (3.99%, 3.35%, and 0.66%, respectively), the mean diameter of LDL particles (1.12%, 0.84%, and 0.67%, respectively), and the level of lb-LDL at the end of the study (16.37%, 9.51%, and 7.31%, respectively). The increases in the LDL cholesterol/apolipoprotein B ratios and the mean diameter of LDL particles from baseline to the end of the study were greater with TAK-085 4 g/day than EPA-E 1.8 g/day. TAK-085 4 g/day and TAK-085 2 g/day caused a decrease in the sd-LDL levels (-16.21% and -6.96%, respectively). CONCLUSION: TAK-085 produced a favorable shift in the LDL particle size in Japanese patients with hypertriglyceridemia. JAPIC Clinical Trials Information: Japic CTI-090937.

22 Article Effects of Extended-Release Nicotinic Acid on Apolipoprotein (a) Kinetics in Hypertriglyceridemic Patients. 2015

Croyal, Mikaël / Ouguerram, Khadija / Passard, Maxime / Ferchaud-Roucher, Véronique / Chétiveaux, Maud / Billon-Crossouard, Stéphanie / de Gouville, Anne-Charlotte / Lambert, Gilles / Krempf, Michel / Nobécourt, Estelle. ·From the CRNH, West Human Nutrition Research Center, Nantes, France (M.C., K.O., M.P., V.F.-R., S.B.-C., G.L., M.K., E.N.) · UMR 1280 PhAN Laboratory, National Institute of Agronomic Research, INRA, CHU Hôtel Dieu, HNB1, Nantes, France (M.C., K.O., M.P., V.F.-R., S.B.-C., G.L., M.K.) · University of Nantes and Medical School, Nantes, France (M.C., K.O., M.P., M.C., S.B.-C., G.L., M.K., E.N.) · GlaxoSmithKline, Les Ulis, France (A.-C.d.G.) · and Endocrinology and Nutrition Department, G and R Laennec Hospital, Bd Jacques Monod, Nantes, France (M.K., E.N.). ·Arterioscler Thromb Vasc Biol · Pubmed #26160958.

ABSTRACT: OBJECTIVE: To determine the mechanisms by which extended-release nicotinic acid reduces circulating lipoprotein (a) concentrations in hypertriglyceridemic patients. APPROACH AND RESULTS: Eight nondiabetic, obese male subjects (aged 48±12 years; body mass index, 31.2±1.8 kg/m(2)) with hypertriglyceridemia (triglycerides, 226±78 mg/dL) were enrolled in an 8 week, double blind, placebo-controlled cross-over study. At the end of each treatment phase, fasted subjects received a 10 µmol/L per kg bolus injection of [5,5,5-(2)H3]-l-Leucine immediately followed by constant infusion of [5,5,5-(2)H3]-l-Leucine (10 µmol L(-1) kg(-1) h(-1)) for 14 hours, and blood samples were collected. A liquid chromatography-tandem mass spectrometry method was used to study apolipoprotein (a) (Apo(a)) kinetics. The fractional catabolic rate of Apo(a) was calculated with a single compartmental model using the apolipoprotein B100 (ApoB100) containing very low density lipoprotein tracer enrichment as a precursor pool. Extended-release nicotinic acid decreased plasma triglycerides (-46%; P=0.023), raised high-density lipoprotein cholesterol (+20%; P=0.008), and decreased Apo(a) plasma concentrations (-20%; P=0.008). Extended-release nicotinic acid also decreased ApoB100 (22%; P=0.008) and proprotein convertase subtilisin/kexin type 9 (PCSK9, -29%; P=0.008) plasma concentrations. Apo(a) fractional catabolic rate and production rates were decreased by 37% (0.58±0.28 versus 0.36±0.19 pool/d; P=0.008) and 50% (1.4±0.8 versus 0.7±0.4 nmol/kg per day; P=0.008), respectively. CONCLUSIONS: Extended-release nicotinic acid treatment decreased Apo(a) plasma concentrations by 20%, production rates by 50%, and catabolism by 37%. ApoB100 and PCSK9 concentrations were also decreased by treatment, but no correlation was found with Apo(a) kinetic parameters.

23 Article Randomized trial showing efficacy and safety of twice-daily remogliflozin etabonate for the treatment of type 2 diabetes. 2015

Sykes, A P / O'Connor-Semmes, R / Dobbins, R / Dorey, D J / Lorimer, J D / Walker, S / Wilkison, W O / Kler, L. ·Metabolic Pathways and Cardiovascular, GlaxoSmithKline, Uxbridge, UK. ·Diabetes Obes Metab · Pubmed #25223369.

ABSTRACT: We compared the efficacy of twice-daily doses of remogliflozin etabonate (RE) and once-daily pioglitazone with placebo for reduction in glycated haemoglobin (HbA1c) concentration. In this 12-week, double-blind, randomized, active- and placebo-controlled trial, 336 treatment-naïve subjects with type 2 diabetes and an HbA1c of 7.0-9.5% (53-80 mmol/mol) were randomized to RE (50, 100, 250, 500 or 1000 mg twice daily), matching placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c from baseline. Other endpoints included changes in body weight, lipid levels, safety and tolerability. RE produced a decreasing dose response in HbA1c at week 12 (p < 0.001), with reductions in HbA1c versus placebo ranging from 0.64 to 1.07% (p < 0.001). Statistically significant reductions in body weight for RE compared with placebo were also observed. Twice-daily RE resulted in a dose-ordered improvement in glycaemic control and was generally well tolerated.

24 Article Cholesterol screening in US adults and awareness of high cholesterol among individuals with severe hypertriglyceridemia: National Health and Nutrition Examination Surveys 2001-2008. 2015

Christian, Jennifer Briley / Bourgeois, Nancy Ellen / Lowe, Kimberly Anne. ·Jennifer Briley Christian, PharmD, MPH, PhD Senior Director, GlaxoSmithKline, Durham, North Carolina. Nancy Ellen Bourgeois, BS Data Analyst, GlaxoSmithKline, Durham, North Carolina. Kimberly Anne Lowe, PhD Managing Epidemiologist, Exponent Health Sciences, Bellevue, Washington. ·J Cardiovasc Nurs · Pubmed #24434825.

ABSTRACT: BACKGROUND: Cholesterol screening is an effective method for identifying individuals with elevated triglyceride levels. Individuals with severe hypertriglyceridemia (SHTG; ≥500 mg/dL) have a substantially higher risk for developing coronary heart disease and acute pancreatitis than individuals with lower triglyceride levels. OBJECTIVE: The aims of this study were to estimate the proportion of US adults who reported having their cholesterol checked, to evaluate the characteristics associated with having cholesterol checked, and to assess factors that are associated with awareness of having high cholesterol among adults with SHTG. METHODS: The sample included 7988 adults who participated in the National Health and Nutrition Examination Surveys 2001-2008. Polytomous logistic regression models were used to identify factors that were associated with time since the last cholesterol screening, categorized as never screened, screened less than 2 years ago, and screened 2 or more years ago. RESULTS: Approximately 71% of the US adults reported ever having their cholesterol checked. Only 56% of the individuals with SHTG were aware of having high cholesterol. Factors associated with awareness of high cholesterol among those with SHTG included obesity, education, having insurance, having diabetes, and having a history of cardiovascular events. CONCLUSIONS: Most adults in the United States have had their cholesterol checked; however, only half of those with SHTG were aware of having high cholesterol. Awareness is the first step in implementing strategies to attenuate the health risks associated with dyslipidemia.

25 Article Clinical and economic outcomes in a real-world population of patients with elevated triglyceride levels. 2014

Toth, Peter P / Grabner, Michael / Ramey, Nadia / Higuchi, Keiko. ·CGH Medical Center, Sterling, IL, USA; Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: Peter.Toth@cghmc.com. · HealthCore, Inc., Wilmington, DE, USA. Electronic address: mgrabner@healthcore.com. · Rutgers University, School of Health Related Professions, Newark, NJ, USA; ESAC Inc., Rockville, MD, USA. Electronic address: nadia.ramey@gmail.com. · Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Electronic address: keiko.higuchi@novartis.com. ·Atherosclerosis · Pubmed #25463122.

ABSTRACT: OBJECTIVE: This study investigated real-world treatment patterns, healthcare utilization, and costs of hypertriglyceridemia in a large commercially insured United States population. METHODS: This observational claims study was conducted among adult patients with TG > 500 mg/dL between 01/01/2007 and 04/30/2013. Patients were stratified into mutually exclusive cohorts based on their first available TG measurement (index date): TG ≥ 1500 (Cohort A); 750 ≤ TG < 1500 (Cohort B), and 500 < TG < 750 (Cohort C). Study inclusion required ≥ 12 months of eligibility pre- (baseline) and post-index date (follow-up). Patient characteristics and outcomes were assessed descriptively. Costs associated with acute pancreatitis episodes were estimated using a Generalized Linear Model regression. RESULTS: We identified a total of 1964 patients in Cohort A, 7432 in Cohort B, and 17,500 in Cohort C. Patients were young (mean age 46-48) and mostly male (75%-80%). Treatment switching and augmentation occurred rarely, and almost 50% of patients discontinued their initial treatment. At baseline, healthcare utilization and costs were highest in Cohort A (mean all-cause medical and pharmacy costs, $8850). At follow-up, the number of patients with dyslipidemia-related office and pharmacy claims and related costs almost doubled across the cohorts. Mean all-cause costs/patient in Cohort A at follow-up were $12,642, of which $3730 were dyslipidemia-related. Acute pancreatitis episodes were associated with >300% increase in total all-cause costs in Cohort A. CONCLUSIONS: These results suggest that severe hypertriglyceridemia is undertreated and healthcare utilization and costs scale with magnitude of TG elevation. Patients with more severe hypertriglyceridemia received greater medical and pharmacy services. Managing severe hypertriglyceridemia more aggressively and preventing acute pancreatitis may generate cost savings.

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