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Om P Ganda, Joanna Mitri
Despite major advances, many patients with diabetes are currently achieving suboptimal control of lipids and blood pressure. The new cholesterol guidelines by the ACC/AHA have reignited the emphasis on more intensive treatment with statins in the population at high risk of CVD, including those with diabetes. While these guidelines do not include specific lipid goals, several other guidelines have retained previously defined risk-based LDL-C and non-HDL-C goals. More recent data indicate potential benefits in CVD outcomes with non-statin therapy added to statin therapy...
November 2016: Current Cardiology Reports
AnneMarie Gagnon, Teik C Ooi, Marion Cousins, Colette Favreau, Kathy Henry, Anne Landry, Alexander Sorisky
OBJECTIVE: To determine the effect of (1) an oral fat load and (2) pro-protein convertase subtilisin/kexin type (PCSK) 9 loss-of-function (LOF) variant status on the ability of peripheral blood mononuclear cells (PBMC) to inhibit human adipogenesis. METHODS: PBMC from subjects with one or more PCSK9 LOF variants versus non-variant controls were compared in the fasting state and after an oral fat load. RESULTS: Fasting triglyceride (TG) levels were lower in the LOF variant versus non-variant group but rose to the same level after the oral fat load...
September 24, 2016: Obesity
Stacey Knight, Arthur T Maness, Sue M Dintelman, Benjamin D Horne
BACKGROUND: Many landmark genetic breakthroughs, including the recent discovery of PCSK-9 inhibitor drugs, were accomplished with substantial contributions from evaluation of pedigrees. Finding and ascertaining high-value pedigrees is not trivial and requires considerable time and cost. Here, we describe the creation of the Intermountain Genealogy Registry for use in studying the genetics of cardiovascular and other diseases. METHODS: Using publicly available pedigree records and probabilistic linkage techniques, we created a genealogy of ≈23 million records that we linked to 3...
July 16, 2016: Human Heredity
Lillian Smith, Juan Mosley, Jarah Yates, Luke Caswell
This review analyzes Proprotein Convertase Subtilisin/Kexin 9 inhibitors (PCSK-9), a new medication class that has arisen in the last year to combat hypercholesterolemia. They are targeted towards patients who are unable to achieve acceptable low density lipoprotein (LDL) levels despite maximum statin therapy, as well as those who are unable to tolerate maximum statin therapy due to side effects such as myopathy or myalgia. Two of these medications have been released in the last year: alirocumab (Praluent) and evolocumab (Repatha)...
2016: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
Cristobal L Miranda, Valerie D Elias, Joshua J Hay, Jaewoo Choi, Ralph L Reed, Jan F Stevens
Xanthohumol (XN) is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The dose-dependent effects of XN on glucose and lipid metabolism in a preclinical model of metabolic syndrome were the focus of our study. Forty-eight male C57BL/6J mice, 9 weeks of age, were randomly divided into three XN dose groups of 16 animals. The mice were fed a high-fat diet (60% kcal as fat) supplemented with XN at dose levels of 0, 30, or 60 mg/kg body weight/day, for 12 weeks. Dietary XN caused a dose-dependent decrease in body weight gain...
June 1, 2016: Archives of Biochemistry and Biophysics
Richard Češka
At the present time there are novel hypolipidemics registered globally (alirocumab was the first drug of this group in the world registered by an American drug agency FDA) and in Europe, which in many ways differ from the medicines administered until now. They are bringing another advancement in the treatment of disorders of lipid metabolism and in preventive cardiology. Alirocumab is a fully human monoclonal antibody to PCSK-9 enzyme (proprotein convertase subtilisin kexin-9). PCSK-9 enzyme plays an important role in the metabolism of LDL-cholesterol through affecting the breakdown and eventually the amount and activity of LDL-receptors...
November 2015: Vnitr̆ní Lékar̆ství
Rene Rodriguez-Gutierrez, Nilay D Shah, Victor M Montori
No abstract text is available yet for this article.
November 10, 2015: JAMA: the Journal of the American Medical Association
Jennifer G Robinson, Donald D Heistad, Keith A A Fox
Monoclonal antibodies (mAbs) to proprotein convertase subtilisin/kexin type 9 (PCSK-9) can further lower LDL-C by ≥60% in statin-treated patients. Preliminary data suggest they may reduce cardiovascular (CVD) events. Ongoing PCSK-9 mAb cardiovascular outcomes trials could provide the opportunity to determine whether a "legacy effect" similar to that observed for statins will occur over the post-trial observation period. We hypothesize these trials could demonstrate that (1) very aggressive LDL-C lowering with PCSK-9 mAbs added to background statin therapy will induce extensive atherosclerosis stabilization and regression in the large majority of treated patients, and (2) continued maintenance therapy with high intensity statin therapy (with or without ezetimibe) should then inhibit new plaque formation, with a long-term prevention of CVD events...
December 2015: Atherosclerosis
G P S Shantha, J G Robinson
Statins are established therapies for cardiovascular disease prevention and ezetimibe has recently been shown to modestly reduce cardiovascular events when added to background statin therapy. Yet here remains a clear unmet need for additional therapies aimed at lowering low density lipoprotein cholesterol (LDL-C) to further reduce cardiovascular risk. Multiple strategies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have emerged as effective modalities for LDL-C lowering. PCSK9 monoclonal antibodies are the farthest along in clinical development and alirocumab and evolocumab were approved for clinical use by regulatory agencies in 2015...
January 2016: Clinical Pharmacology and Therapeutics
Juan F Ascaso, Rafael Carmena
The authors present their view on the prevention of cardiovascular diseases, accepting the European ESC/EAS guidelines. They consider that the aim of the lipid control, based on LDL-C goals, is essential for the prevention and treatment of cardiovascular diseases. In subjects with metabolic syndrome (mainly, abdominal obesity, pre-diabetes and diabetes), the primary objective should be apoB or Non-HDL-C, which are better associated with cardiovascular risk. The treatment must be lifestyle changes and control of other risk factors...
November 2015: Clínica e Investigación en Arteriosclerosis
Faheem Maqbool, Malihe Safavi, Haji Bahadar, Mahban Rahimifard, Kamal Niaz, Mohammad Abdollahi
INTRODUCTION: Dyslipidemia is increased fasting level of total cholesterol (TC), LDL cholesterol (LDL-C), and triglycerides (TG), along with decreased levels of HDL cholesterol (HDL-C). Owing to effect on the cardiovascular system and increased chances of metabolic diseases, it is needed to review novel under development drugs and new approaches in drug discovery for dyslipidemia. AREAS COVERED: This article reviews all phases I to IV clinical trials and preclinical trials with results associated with novel treatment of dyslipidemia...
2015: Current Drug Discovery Technologies
LaKenya Williams, Michael Sank, Anjaneya Chimalakonda, Yan Ni, Mark Saewert, Binodh DeSilva, Renuka Pillutla
Bioanalytical data from early human studies conducted in normal volunteers are often used for building pharmacokinetic/pharmacodynamic models that can predict outcomes of future studies in diseased patients. Thus, it is important to develop and validate reliable and accurate bioanalytical assays that instill confidence that the intended therapeutic species (total or free) are being measured. Assays quantifying the free therapeutic species, the partially bound (for multivalent therapeutics) and unbound species, require much more characterization than assays that quantify the total therapeutic species...
April 2015: Journal of Immunological Methods
T A Walton, S Nishtar, P J Lumb, M A Crook, M S Marber, J Gill, A S Wierzbicki
OBJECTIVE: To determine the relationship between proprotein convertase subtilisin kexin 9 (PCSK9) levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. METHODS: A prospective matched case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and PCSK-9 levels...
July 2015: International Journal of Clinical Practice
Xiang Wang, Evan Berry, Samuel Hernandez-Anzaldo, Difei Sun, Ayinuer Adijiang, Liang Li, Dawei Zhang, Carlos Fernandez-Patron
Low-density lipoprotein receptor (LDLR) catalyzes the uptake of LDL-cholesterol by liver and peripheral organs. The function of the LDLR is antagonized by pro-protein convertase subtilisin/kexin type 9 (PCSK9), which binds to LDLR at the plasma membrane inducing LDLR degradation. Here, we report that matrix metalloproteinase-2 (MMP-2) interacts with and cleaves PCSK9, as evidenced by proteomic, chemical cross-linkage, blue native-PAGE and domain-specific antibodies Western blot analyses. Furthermore, MMP-2 overexpression renders Hepa1-c1c7 cells resistant to PCSK9-induced LDLR degradation...
February 13, 2015: FEBS Letters
Richard Češka, Michal Vrablík, Tereza Altschmiedová, Martina Prusíková, Zuzana Urbanová, Josef Šobra
Currently, the familial hypercholesterolemia (FH) rises the interest. The reason is that this genetic disorder is targeted by newly emerged and highly effective hypolipidemic agents, PCSK-9 inhibitors, lomitapid and mipomersen. Present paper discusses 2 patient study groups, before 50 years and nowadays. Although direct statistical analysis is impossible some changes in clinical features of FH might be found over the course of the time. In fact, the basic FH characteristic has not changed dramatically. Severe isolated hypercholesterolemia with total cholesterol 9-10 mmol/l, LDL-cholesterol 7-8 mmol/l and normal values of triglycerides dominates in laboratory analysis...
November 2014: Vnitr̆ní Lékar̆ství
Anthony S Wierzbicki, Dilinika Perera, Mfon Ewang-Emukowhate
Hyperlipidaemia is a major risk factor for the development of atherosclerosis and cardiovascular disease. Statins are the mainstay of therapy and new guidelines focus on the use of these agents without specific targets for low-density lipoprotein (LDL)-cholesterol or non high-density lipoprotein (HDL)-cholesterol. However, patients remain at risk of cardiovascular disease despite statin therapy so new drugs are required. This article reviews therapies in development to further lower LDL-cholesterol (Proprotein convertase subtilisin/kexin-9 (PCSK-9) inhibitors), raise HDL-holesterol (cholesterol ester transfer protein inhibitors (CETPIs)) and reduce triglycerides (novel peroxisome proliferator-activated receptor (PPAR)-agonists and omega-3 fatty acid preparations)...
December 2014: Clinical Medicine: Journal of the Royal College of Physicians of London
J I Cuende, C Lahoz, P Armario, J García-Alegría, J Ena, G García de Casasola, J M Mostaza
During 2013 and the first months of 2014, numerous studies have been published in the cardiovascular field. New guidelines have appeared for managing arterial hypertension and reducing cardiovascular risk by lowering cholesterol levels. New data have emerged on the considerable lipid-lowering efficacy of monoclonal antibodies against PCSK-9, in contrast, however, to the clinical trials directed towards raising HDL-cholesterol with nicotinic acid, which have not shown a reduction in the rate of cardiovascular complications...
January 2015: Revista Clínica Española
Raul D Santos
Homozygous familial hypercholesterolaemia (HoFH) is a rare, life-threatening disease characterised by highly elevated low-density lipoprotein cholesterol levels (LDL-C), cutaneous and tendinous xanthomata, severe and precocious atherosclerosis, and aortic and supra aortic valve disease. Although treatment with apheresis and lipid-lowering drugs has improved event-free survival of HoFH patients, the condition is still associated with early onset cardiovascular disease and death due to residual high cholesterol levels...
September 2014: Atherosclerosis. Supplements
Marcin Konarzewski, Marek Szolkiewicz, Elzbieta Sucajtys-Szulc, Joanna Blaszak, Slawomir Lizakowski, Julian Swierczynski, Boleslaw Rutkowski
BACKGROUND: A high level of circulating PCSK9 binds to the LDL receptor, reduces its cell's surface density and leads to hypercholesterolemia. The aim of this study was to examine the circulating PCSK9 level in patients with kidney disease. METHODS: Out of the patients treated in our Departments we selected: (a) 44 patients with CKD stage 3 and 4 (b) 29 patients with CKD stage 5 on maintenance hemodialysis treatment; and (c) 20 patients after successful renal transplantation...
2014: American Journal of Nephrology
De-liang Liu, Li-jun Xu, Hui Dong, Guang Chen, Zhao-yi Huang, Xin Zou, Kai-fu Wang, Yun-huan Luo, Fu-er Lu
OBJECTIVE: To investigate the effect and molecular mechanisms of different doses of 8-hydroxy dihydroberberine (Hdber) for the treatment of hyperlipidemia in rats. METHODS: A rat model of hyperlipidemia was established by feeding rats a high-fat diet for 4 weeks in 70 rats of 80 animals, and 10 rats were randomly selected as control group. The hyperlipidemic rats were then randomly divided into the following groups: a model group (MOD); a berberine group [BBR, 156 mg/(kg day)]; Hdber groups, which were treated with different doses of Hdber [78, 39 and 19...
February 2015: Chinese Journal of Integrative Medicine
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