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https://www.readbyqxmd.com/read/29231064/pharmacokinetics-pharmacodynamics-and-clinical-efficacy-of-non-statin-treatments-for-hypercholesterolemia
#1
Arrigo F G Cicero, Marilisa Bove, Claudio Borghi
Hypercholesterolemia is the main modifiable risk factor for atherosclerosis progression and cardiovascular disease (CVD) development. Its pharmacological management is usually based on the prescription of statins, that in some cases are not however fully effective to reach the desired Low-Density-Lipoproteins cholesterol (LDL-C) target, or are not tolerated by patients due to side effects. Areas covered: This manuscript summarizes the basic properties of the emerging new classes of lipid-lowering drugs such as ezetimibe, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, and Microsomal Triglyceride Transfer Protein (MTP) inhibitors, also citing new drugs in development...
December 13, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29219151/familial-hypercholesterolaemia
#2
REVIEW
Joep C Defesche, Samuel S Gidding, Mariko Harada-Shiba, Robert A Hegele, Raul D Santos, Anthony S Wierzbicki
Familial hypercholesterolaemia is a common inherited disorder characterized by abnormally elevated serum levels of low-density lipoprotein (LDL) cholesterol from birth, which in time can lead to cardiovascular disease (CVD). Most cases are caused by autosomal dominant mutations in LDLR, which encodes the LDL receptor, although mutations in other genes coding for proteins involved in cholesterol metabolism or LDLR function and processing, such as APOB and PCSK9, can also be causative, although less frequently...
December 7, 2017: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/29212965/effects-of-ezetimibe-statin-combination-therapy-on-coronary-atherosclerosis-in-acute-coronary-syndrome
#3
Kiyoshi Hibi, Shinjo Sonoda, Masanori Kawasaki, Yutaka Otsuji, Toyoaki Murohara, Hideki Ishii, Katsuhiko Sato, Ryoji Koshida, Yukio Ozaki, Masataka Sata, Yoshihiro Morino, Tadashi Miyamoto, Tetsuya Amano, Satoshi Morita, Ken Kozuma, Kazuo Kimura, Hisayoshi Fujiwara
BACKGROUND: The results of previous clinical trials on the effects of ezetimibe-statin combination therapy on atherosclerosis are inconsistent, and the anti-atherosclerotic effect of ezetimibe remains controversial.Methods and Results:We conducted a prospective, randomized open-label study at 10 centers. One hundred and twenty-eight statin-naïve patients with acute coronary syndrome (ACS) undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were randomized to receive either 2 mg/day pitavastatin plus 10 mg/day ezetimibe, or 2 mg/day pitavastatin...
December 7, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/29201198/comparison-of-the-effect-of-rosuvastatin-versus-rosuvastatin-ezetimibe-on-markers-of-inflammation-in-patients-with-acute-myocardial-infarction
#4
Yizhi Ren, Hao Zhu, Zhongguo Fan, Yali Gao, Nailiang Tian
Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP), and the addition of ezetimibe to statins further reduces LDL-C and hsCRP. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a potentially important pathogenic factor participating in the progression of atherosclerosis. The aim of current study was to investigate how the addition of ezetimibe to rosuvastatin treatment affects reductions in LDL-C, hsCRP and Lp-PLA2 in patients with acute myocardial infarction (AMI)...
November 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29200765/simvastatin-ezetimibe-therapy-for-recalcitrant-alopecia-areata-an-open-prospective-study-of-14-patients
#5
Joong-Woon Choi, Dong-Woo Suh, Bark-Lynn Lew, Woo-Young Sim
Background: Simvastatin belongs to the statin family, whose members have immunomodulatory activities. Ezetimibe have synergetic effects when co-administered with simvastatin. In several case reports, alopecia totalis and alopecia universalis were successfully treated with simvastatin/ezetimibe, suggesting that this combination could be a new efficient therapy for recalcitrant alopecia areata (AA). Objective: To verify the efficacy of the simvastatin/ezetimibe combination therapy for recalcitrant AA and investigate the relationship between various treatment responses and prognostic factors...
December 2017: Annals of Dermatology
https://www.readbyqxmd.com/read/29194462/new-strategies-for-the-development-of-lipid-lowering-therapies-to-reduce-cardiovascular-risk
#6
Ian Graham, Chuck Shear, Pieter De Graeff, Caroline Boulton, Alberico L Catapano, Wendy Gattis Stough, Stefan C Carlsson, Guy De Backer, Joseph Emmerich, Scott Greenfeder, Albert M Kim, Dominik Lautsch, Tu Nguyen, Steven E Nissen, Krishna Prasad, Kausik Ray, Jennifer G Robinson, William J Sasiela, Karsten Bruins Slot, Erik Stroes, Tom Thuren, Bart Van der Schueren, Maja Velkovski-Rouyer, Scott M Wasserman, Olov Wiklund, Emmanouil Zouridakis
The very high occurrence of cardiovascular events presents a major public health issue because treatment remains suboptimal. Lowering low-density lipoprotein cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals, could benefit from additional LDL-C lowering therapy, or experience side effects of statins...
November 28, 2017: European Heart Journal. Cardiovascular Pharmacotherapy
https://www.readbyqxmd.com/read/29189433/transintestinal-cholesterol-excretion-in-humans
#7
Laurens F Reeskamp, Emma C E Meessen, Albert K Groen
PURPOSE OF REVIEW: To discuss recent insights into the measurement and cellular basis of transintestinal cholesterol excretion (TICE) in humans and to explore TICE as a therapeutic target for increasing reverse cholesterol transport. RECENT FINDINGS: TICE is the net effect of cholesterol excretion by the enterocyte into the intestinal lumen and is the balance between input and output fluxes through the enterocytes. These fluxes are: cholesterol excretion into the intestinal lumen mainly via ATP-binding cassette (ABC) G5/8, cholesterol absorption from the intestine by Niemann-Pick C1 like protein 1, the uptake of plasma lipoproteins by enterocytes at the basolateral membrane, and the excretion of cholesterol in chylomicrons into the lymph...
November 16, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/29186684/pancreatic-adenocarcinoma-therapeutic-targets-revealed-by-tumor-stroma-cross-talk-analyses-in-patient-derived-xenografts
#8
Rémy Nicolle, Yuna Blum, Laetitia Marisa, Celine Loncle, Odile Gayet, Vincent Moutardier, Olivier Turrini, Marc Giovannini, Benjamin Bian, Martin Bigonnet, Marion Rubis, Nabila Elarouci, Lucile Armenoult, Mira Ayadi, Pauline Duconseil, Mohamed Gasmi, Mehdi Ouaissi, Aurélie Maignan, Gwen Lomberk, Jean-Marie Boher, Jacques Ewald, Erwan Bories, Jonathan Garnier, Anthony Goncalves, Flora Poizat, Jean-Luc Raoul, Veronique Secq, Stephane Garcia, Philippe Grandval, Marine Barraud-Blanc, Emmanuelle Norguet, Marine Gilabert, Jean-Robert Delpero, Julie Roques, Ezequiel Calvo, Fabienne Guillaumond, Sophie Vasseur, Raul Urrutia, Aurélien de Reyniès, Nelson Dusetti, Juan Iovanna
Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk...
November 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/29186504/no-evidence-of-neurocognitive-adverse-events-associated-with-alirocumab-treatment-in-3340-patients-from-14-randomized-phase-2-and-3-controlled-trials-a-meta-analysis-of-individual-patient-data
#9
Philip D Harvey, Marwan N Sabbagh, John E Harrison, Henry N Ginsberg, M John Chapman, Garen Manvelian, Angele Moryusef, Jonas Mandel, Michel Farnier
Aims: Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab. Methods and results: Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618)...
November 27, 2017: European Heart Journal
https://www.readbyqxmd.com/read/29181773/budget-impact-analysis-of-pcsk9-inhibitors-for-the-management-of-adult-patients-with-heterozygous-familial-hypercholesterolemia-or-clinical-atherosclerotic-cardiovascular-disease
#10
Usha G Mallya, Susan H Boklage, Andrew Koren, Thomas E Delea, C Daniel Mullins
OBJECTIVE: The aim of this study was to assess the budget impact of introducing the proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) alirocumab and evolocumab to market for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular (CV) disease requiring additional lowering of low-density lipoprotein cholesterol (LDL-C). METHODS: A 3-year model estimated the costs of lipid-modifying therapy (LMT) and CV events to a hypothetical US health plan of 1 million members, comparing two scenarios-with and without the availability of PCSK9i as add-on therapy to statins...
November 27, 2017: PharmacoEconomics
https://www.readbyqxmd.com/read/29180457/antihypertensive-treatment-with-%C3%AE-blockade-in-patients-with-asymptomatic-aortic-stenosis-and-association-with-cardiovascular-events
#11
Casper N Bang, Anders M Greve, Anne B Rossebø, Simon Ray, Kenneth Egstrup, Kurt Boman, Christoph Nienaber, Peter M Okin, Richard B Devereux, Kristian Wachtell
BACKGROUND: Patients with aortic stenosis (AS) often have concomitant hypertension. Antihypertensive treatment with a β-blocker (Bbl) is frequently avoided because of fear of depression of left ventricular function. However, it remains unclear whether antihypertensive treatment with a Bbl is associated with increased risk of cardiovascular events in patients with asymptomatic mild to moderate AS. METHODS AND RESULTS: We did a post hoc analysis of 1873 asymptomatic patients with mild to moderate AS and preserved left ventricular ejection fraction in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study...
November 27, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29180351/proprotein-convertase-subtilisin-kexin-type-9-pcsk9-inhibitors-and-incident-type-2-diabetes-mellitus-a-systematic-review-and-meta-analysis-with-over-96-000-patient-years
#12
Luiz Sérgio F de Carvalho, Alessandra M Campos, Andrei C Sposito
OBJECTIVE: Like mutations with loss of function in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, inhibitors of PCSK9 (PCSK9i) may potentially favor the manifestation of diabetes. RESEARCH DESIGN AND METHODS: A meta-analysis of phase 2/3 randomized clinical trials (RCTs) assessed PCSK9i versus placebo in primary hypercholesterolemia setting. Statins and ezetimibe were used in 98.4% of these studies and balanced between PCSK9i and placebo. We calculated relative risks (RRs) and 95% CIs using random- and fixed-effect models...
November 27, 2017: Diabetes Care
https://www.readbyqxmd.com/read/29177335/molecular-actions-of-hypocholesterolaemic-compounds-from-edible-mushrooms
#13
REVIEW
Alicia Gil-Ramírez, Diego Morales, Cristina Soler-Rivas
Cholesterol levels are strictly regulated to maintain its homeostasis; therefore, if it is not absorbed with the diet, the cholesterol biosynthetic pathway is enhanced and vice versa. Nowadays, the commonly prescribed therapeutic treatments for hypocholesterolemic patients are targeted toward the reduction of both cholesterol intestinal absorption and/or its endogenous biosynthesis. But, when hypercholesterolemia is still moderate the consumption of food products with cholesterol-lowering capacities is more desirable than using drugs...
November 27, 2017: Food & Function
https://www.readbyqxmd.com/read/29176657/dyslipidaemia-in-nephrotic-syndrome-mechanisms-and-treatment
#14
REVIEW
Shipra Agrawal, Joshua J Zaritsky, Alessia Fornoni, William E Smoyer
Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9...
November 27, 2017: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/29176407/cholesterol-metabolism-in-humans-a-review-of-methods-and-comparison-of-results
#15
John S Millar, Marina Cuchel
PURPOSE OF REVIEW: Cholesterol metabolism has been the object of intense investigation for decades. This review focuses on classical and novel methods assessing in vivo cholesterol metabolism in humans. Two factors have fueled cholesterol metabolism studies in the last few years: the renewed interest in the study of reverse cholesterol transport (RCT) as an atheroprotective mechanism and the importance of the gut microbiome in affecting cholesterol metabolism. RECENT FINDINGS: Recent applications of these methods have spanned from the assessment of the effect on cholesterol synthesis, absorption or excretion of drugs (such as ezetimibe, PCSK9 inhibitors and plant sterols) and the gut microbiome to the more complex assessment of transintestinal cholesterol excretion (TICE) and RCT...
November 25, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/29174072/acute-myocardial-infarction-in-a-25-year-old-woman-with-sitosterolemia
#16
Ryuki Kawamura, Hitoshi Saiki, Hayato Tada, Akihiro Hata
We report the case of acute myocardial infarction in a 25-year-old woman with sitosterolemia. She was treated using statins, but her low-density lipoprotein cholesterol (LDL-C) levels did not decrease appreciably. Genetic analysis revealed mutations in the ABCG8 gene. Ezetimibe treatment was initiated, and her LDL-C levels decreased substantially. Sitosterolemia must be considered in the differential diagnosis of familial hypercholesterolemia in case of early onset cardiovascular disease patient with high LDL-C...
November 20, 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/29172973/ezetimibe-use-and-ldl-c-goal-achievement-a-retrospective-database-analysis-of-patients-with-clinical-atherosclerotic-cardiovascular-disease-or-probable-heterozygous-familial-hypercholesterolemia
#17
Joseph Menzin, Jyoti Aggarwal, Brian Boatman, Jeffrey Yu, Kevin Stern, David J Harrison, Jeetvan G Patel
BACKGROUND: Ezetimibe is recommended by clinical practice guidelines as a second-line therapy for lowering low-density lipoprotein cholesterol (LDL-C) levels, but little is known about its use and effectiveness in real-world populations. OBJECTIVE: To understand the real-world impact of adding or switching to ezetimibe on LDL-C goal achievement in patients with clinical atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH)...
December 2017: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/29171950/-evolocumab-repatha%C3%A2-a-human-monoclonal-antibody-against-pcsk9-protein-as-potent-cholesterol-lowering-therapy
#18
C Wallemacq
Evolocumab is a fully human monoclonal antibody (mAb) targeting ProProtein Convertase Subtilisin/Kexin 9 (PCSK9). PCSK9 is a circulating enzyme secreted by the liver and plays a key role in the LDL-Receptors (LDL-R) turnover. Binding of PCSK9 on the extracellular part of LDL-R is responsible for its degradation in the lysosome instead of its recycling to the cell surface, thereby producing a reduction in the number of LDL-R on the cell surface, a decreased LDL-C uptake and increased levels of LDL-C. Inhibiting PCSK9 is a new way to markedly reduce LDL-C...
November 2017: Revue Médicale de Liège
https://www.readbyqxmd.com/read/29171769/alirocumab-for-the-treatment-of-hyperlipidemia-in-high-risk-patients-an-updated-review
#19
Michael Farnier
Alirocumab is a fully human immunoglobulin G1 monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) approved for the treatment of hypercholesterolemia in high-risk patients. The objective is to provide an updated review of the recent data published for alirocumab. Areas covered: The efficacy and safety of alirocumab has been initially evaluated in a comprehensive phase 3 program conducted in more than 6 000 patients with primary non-familial and heterozygous familial hypercholesterolemia: alirocumab reduced LDL-cholesterol up to 62% in phase 3 with every 2-week dosing compared with placebo, and up to 36% compared with ezetimibe, with an excellent safety and tolerability profile...
November 24, 2017: Expert Review of Cardiovascular Therapy
https://www.readbyqxmd.com/read/29169939/the-association-between-hypercholesterolemia-and-sitosterolemia-and-report-of-a-sitosterolemia-kindred
#20
Eliot A Brinton, Paul N Hopkins, Robert A Hegele, Andrew S Geller, Eliana Y Polisecki, Margaret R Diffenderfer, Ernst J Schaefer
BACKGROUND: Sitosterolemia is associated with increases in intestinal sterol absorption, low-density lipoprotein cholesterol (LDL-C), and cardiovascular disease risk. OBJECTIVE: We examined the relationship between hypercholesterolemia and sitosterolemia in a large population and report a new sitosterolemia case. METHODS: Plasma sterol concentrations were measured by gas chromatography/mass spectrometry, and LDL-C by direct assay. RESULTS: Of 207,926 subjects tested, 4...
October 27, 2017: Journal of Clinical Lipidology
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