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Kwang-Youn Kim, Hyun-Jun Jang, Yong Ryul Yang, Kwang-Il Park, JeongKon Seo, Il-Woo Shin, Tae-Il Jeon, Soon-Cheol Ahn, Pann-Ghill Suh, Timothy F Osborne, Young-Kyo Seo
Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride...
October 21, 2016: Scientific Reports
Michiyo Deushi, Mizuko Osaka, Kaku Nakano, Kyoichi Osada, Kensuke Egashira, Masayuki Yoshida
Oxidized cholesterol (oxysterols) plays an important and multifaceted role in lipid metabolism. Here we examined whether dietary oxysterols accelerate hepatic lipid accumulation and inflammation in nonhuman primates. We also examined the effect of the Niemann-Pick C1-like1 inhibitor, ezetimibe (Ez). Macaca fascicularis (5-year-old males) were fed either regular cholesterol + high-fat diet (control-HFD) or oxysterols + high-fat diet (ox-HFD; with 0.015% of oxysterols cholesterol) for 24 weeks. Compared with control-HFD, ox-HFD did not affect plasma lipid levels, but it did affect hepatic lipid levels [total cholesterol, 40...
October 2016: FEBS Open Bio
Peter P Toth, Alberico L Catapano, Michel Farnier, Joanne Foody, Joanne E Tomassini, Erin Jensen, Adam B Polis, Mary E Hanson, Thomas A Musliner, Andrew M Tershakovec
Statin therapy is associated with a slightly increased risk of developing diabetes mellitus and insulin resistance in patients without diabetes. Ezetimibe combined with statins may be considered for high-risk patients who do not achieve optimal low-density lipoprotein cholesterol lowering on statin monotherapy or who are statin intolerant. Changes in fasting serum glucose (FSG) levels during ezetimibe, ezetimibe/statin, and statin treatments were assessed using data pooled from clinical trials in hypercholesterolemic and heterozygous familial hypercholesterolemic patients, who were or were not receiving statin therapy...
September 13, 2016: American Journal of Cardiology
Michel Farnier
PURPOSE OF REVIEW: After the approval of alirocumab and evolocumab, the first two monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin kexin type 9 (PCSK9), this review provides an update on recent PCSK9 inhibitors data and describes recommendations for the use before the results of the ongoing cardiovascular endpoint trials. RECENT FINDINGS: New studies and complementary analysis of phase III trials have consistently shown that alirocumab and evolocumab are highly effective in reducing LDL-cholesterol and to some extent lipoprotein (a)...
October 17, 2016: Current Opinion in Lipidology
V V Muthusamy
Cardiovascular disease burden is increasing all over the world. The diagnosis of hypertension is considered when a person has persistently elevated BP (Systolic BP more than 140 mmHg and/or Diastolic BP more than 90 mmHg). Dyslipidemia denotes abnormal levels of lipids in the blood (Total Cholesterol >200 mg%, Low density lipoprotein (LDL) >100 mg%, Triglycerides (TGL) >150 mg% and High density lipoprotein (HDL) <40 mg in men and < 50 mg in women. Hypertension and Dyslipidemia constitute the important components of metabolic syndrome as per the definition of NCEP Guidelines-Adult Treatment Panel III (ATP III)...
September 2016: Journal of Hypertension
Christoph H Saely, Heinz Drexel
Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) plays an important role in the regulation of blood cholesterol levels, and inhibition of PCSK9 with monoclonal antibodies reduces LDL cholesterol by more than 50% over and above what can be achieved with statins or ezetimibe alone. Diet and exercise influence PCSK9 levels; however data on this issue are scarce. Regarding diet, a high oleic canola/docosahexaenoic acid oil blend, marine n-3 polyunsaturated fatty acids, vegetable n-6 polyunsaturated fatty acids, a Mediterranean style diet and acute fasting, but not necessarily weight reduction are associated with low PCSK9 concentrations, whereas a high fructose diet is associated with high PCSK9 concentrations...
October 13, 2016: Vascular Pharmacology
John J P Kastelein, Dean J Kereiakes, Christopher P Cannon, Harold E Bays, Pascal Minini, L Veronica Lee, Jaman Maroni, Michel Farnier
OBJECTIVES: The objective of this study is to report the dose response in ODYSSEY phase 3 clinical trials of proprotein convertase subtilisin kexin type 9 inhibition with alirocumab in patients not at prespecified lipid goals who received a per-protocol dose increase from 75 every 2 weeks (Q2W) to 150 mg Q2W. METHODS: Patients (n=2181) receiving statins were enrolled in six phase 3 randomized, double-blind, double-dummy trials (24-104 weeks): alirocumab versus placebo or ezetimibe 10 mg/day...
October 12, 2016: Coronary Artery Disease
Kazuhiko Kotani, Michiaki Miyamoto, Hitoshi Ando
Rheumatoid arthritis (RA) is a chronic inflammatory disease with a potential cardiovascular (CV) risk. Flow-mediated vasodilation (FMD) is an ultrasonic method to evaluate endothelial function. RA is a contributor to endothelial dysfunction, a CV risk. Relevant insights on the improvement of the CV outcomes in RA patients may be obtained by a systematic review of trials that investigated the effects of RA treatment on FMD in RA patients. This review found that treatments with antirheumatic drugs and some non-antirheumatic drugs could improve the FMD in RA patients...
October 13, 2016: Current Vascular Pharmacology
Terry McCormack, Ricardo Dent, Mark Blagden
BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in Europe and increased low-density lipoprotein cholesterol (LDL-C) is a major contributor to CVD risk. Extensive evidence from clinical studies of statins has demonstrated a linear relationship between LDL-C levels and CVD risk. It has been proposed that lower LDL-C levels than those currently recommended may provide additional clinical benefit to patients. AIM: This review summarises the genetic and clinical evidence on the efficacy and safety of achieving very low LDL-C levels...
October 14, 2016: International Journal of Clinical Practice
Scott M Grundy
An ongoing dispute in the nutrition field is whether dietary cholesterol contributes significantly to elevated serum cholesterol and to atherosclerotic disease. Carefully controlled metabolic studies have shown that high-cholesterol intakes cause moderate increases in serum cholesterol levels. It is been difficult to verify this in population studies because of confounding factors. Nonetheless, meta-analysis of controlled studies documents a cholesterol-raising action of dietary cholesterol. Most of this effect occurs in low-density lipoproteins (LDLs), but the cholesterol content of other lipoproteins can be increased as well...
November 2016: Current Atherosclerosis Reports
Peter H Jones, Harold E Bays, Umesh Chaudhari, Robert Pordy, Christelle Lorenzato, Kathryn Miller, Jennifer G Robinson
Previous individual trials of alirocumab (a PCSK9 monoclonal antibody) showed significant low-density lipoprotein cholesterol reductions with overall treatment-emergent adverse event (TEAE) rates comparable with controls. This analysis evaluated safety data from 14 trials (4 phase 2 and 10 phase 3, 8 to 104 weeks; n = 5,234), in 2 pools according to control (placebo/ezetimibe). Overall, 3,340 patients received alirocumab (4,029 patient-years' exposure), 1,276 received placebo, and 618 received ezetimibe. Incidence of deaths, serious TEAEs, discontinuations because of TEAEs, and overall TEAEs were similar between alirocumab and control groups...
September 14, 2016: American Journal of Cardiology
María Beatriz Araujo, María Sol Pacce
BACKGROUND: Current pediatric guidelines for heterozygous familial hypercholesterolemia (HeFH) propose pharmacotherapy (PT) with statins from age 8 to 10 years; however, schemes with absorption inhibitors combined with statins, could be started earlier. The aim of the study was to show the 10-year results of a combined treatment protocol. METHODS: Prospective, descriptive and analytical study. Pediatric patients (n=70; mean age at PT initiation 9.3 years [range, 2-17...
October 8, 2016: Journal of Pediatric Endocrinology & Metabolism: JPEM
Tracey G Simon, Kathleen E Corey, Raymond T Chung, Robert Giugliano
Nonalcoholic fatty liver disease (NAFLD) is widely considered to be the hepatic manifestation of the metabolic syndrome and is closely linked to dyslipidemia, obesity, and insulin resistance. Patients with NAFLD have increased mortality when compared to the general population, primarily related to cardiovascular disease or malignancy. The biologic mechanisms that link NAFLD to cardiovascular disease include expansion of visceral adipose tissue, atherogenic dyslipidemia, impaired insulin signaling, systemic inflammation, and endothelial dysfunction...
October 6, 2016: Digestive Diseases and Sciences
Ping Luo, Lixia Wang, Haohui Zhu, Song Du, Guanggong Wang, Shoukun Ding
BACKGROUND: This study aimed to investigate the impact of atorvastatin (Ato) combined with ezetimibe (Eze) for the treatment of carotid atherosclerosis in patients with coronary heart disease (CHD). METHODS: One hundred and forty-eight CHD patients with carotid atherosclerosis were divided into the control (Ato alone) and combination (Ato and Eze) groups. The treatment course was 12 months; patient blood lipids, carotid intima-media thickness (CIMT), and carotid plaque area were measured before and after treatment...
September 2016: Acta Cardiol Sin
Mi Seon Ji, Myung Ho Jeong, Young Keun Ahn, Sang Hyung Kim, Young Jo Kim, Shung Chull Chae, Taek Jong Hong, In Whan Seong, Jei Keon Chae, Chong Jin Kim, Myeong Chan Cho, Seung-Woon Rha, Jang Ho Bae, Ki Bae Seung, Seung Jung Park
BACKGROUND: It is unclear whether simvastatin-ezetimibe could be an alternative therapy to high-intensity statin therapy in high-risk patients. The aim of this study was to compare the clinical outcomes of simvastatin-ezetimibe and high-intensity statin therapy in patients with acute myocardial infarction (AMI), and especially in those with high-risk factor. METHODS: A total of 3520 AMI patients in the KAMIR (Korea Acute Myocardial Infarction Registry) were classified into simvastatin-ezetimibe group (n=1249) and high-intensity statin group (n=2271)...
September 28, 2016: International Journal of Cardiology
Matthew Peach, Ren Xu, Dan Fitzpatrick, Lisa Hamilton, Ransi Somaratne, Rob Scott, Scott M Wasserman, C Stephen Djedjos
The effects of cholesterol-lowering drugs, including those that reduce cholesterol synthesis (statins) and those that reduce cholesterol absorption (ezetimibe), on cholesterol absorption and synthesis are well understood. PCSK9 inhibitors are a novel class of cholesterol-lowering drugs that robustly reduce LDL-C, but little is known about their effects on cholesterol absorption and synthesis. We evaluated how treatment with evolocumab, a fully human monoclonal IgG2 antibody to PCSK9, affects markers of cholesterol synthesis and absorption by measuring these markers in patients from an evolocumab clinical trial...
October 5, 2016: Journal of Lipid Research
Luca A Lotta, Stephen J Sharp, Stephen Burgess, John R B Perry, Isobel D Stewart, Sara M Willems, Jian'an Luan, Eva Ardanaz, Larraitz Arriola, Beverley Balkau, Heiner Boeing, Panos Deloukas, Nita G Forouhi, Paul W Franks, Sara Grioni, Rudolf Kaaks, Timothy J Key, Carmen Navarro, Peter M Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, Jose-Ramón Quirós, Elio Riboli, Olov Rolandsson, Carlotta Sacerdote, Elena Salamanca-Fernandez, Nadia Slimani, Annemieke M W Spijkerman, Anne Tjonneland, Rosario Tumino, Daphne L van der A, Yvonne T van der Schouw, Mark I McCarthy, Inês Barroso, Stephen O'Rahilly, David B Savage, Naveed Sattar, Claudia Langenberg, Robert A Scott, Nicholas J Wareham
Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes...
October 4, 2016: JAMA: the Journal of the American Medical Association
Meghan T Walsh, M Mahmood Hussain
Homozygous familial hypercholesterolemia (HoFH) is a polygenic disease arising from defects in the clearance of plasma low-density lipoprotein (LDL), which results in extremely elevated plasma LDL cholesterol (LDL-C) and increased risk of atherosclerosis, coronary heart disease, and premature death. Conventional lipid-lowering therapies, such as statins and ezetimibe, are ineffective at lowering plasma cholesterol to safe levels in these patients. Other therapeutic options, such as LDL apheresis and liver transplantation, are inconvenient, costly, and not readily available...
October 1, 2016: Critical Reviews in Clinical Laboratory Sciences
Fernando Civeira, Sofia Perez-Calahorra, Rocio Mateo-Gallego
Xanthelasmas are superficial fat deposits around the eyelids commonly present in different hyperlipidemias and associated with increased cardiovascular risk. Statins or other lipid-lowering treatments do not usually modify them. We present the case of a middle-age man with severe high levels of LDL cholesterol from youth due to a genetically defined heterozygous familiar hypercholesterolemia (HeFH). He presented large xanthelasmas of both inner eyelids in spite of long term treatment with statins and ezetimibe that disappeared after treatment with alirocumab75 mg every 2 weeks for 26 months...
September 2016: Journal of Clinical Lipidology
Evan Stein, Harold Bays, Michael Koren, Rebecca Bakker-Arkema, Charles Bisgaier
BACKGROUND: Ezetimibe added to statin therapy further reduces LDL-C and clinical atherosclerotic cardiovascular disease compared to statin alone. However, the number of effective and safe oral agents for patients not at LDL-C goal is limited. In prior clinical trials, gemcabene reduced LDL-C and was generally well-tolerated in nearly 900 patients treated for up to 12 weeks. OBJECTIVE: To evaluate the LDL-C lowering and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients...
September 2016: Journal of Clinical Lipidology
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