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An overview of rosuvastatin/ezetimibe association for the treatment of hypercholesterolemia and mixed dyslipidemia.
Strilchuk, L, Tocci, G, Fogacci, F, Cicero, AFG
Expert opinion on pharmacotherapy. 2020;(5):531-539
Abstract
Introduction: Although statin therapy is a powerful lipid-lowering strategy, only one-fifth of statin users currently reach their lipid goals. In addition, statin treatment alone has relatively low efficacy in reducing other lipid fractions than low-density lipoprotein-cholesterol (LDL-C). In such cases, most guidelines recommend adding the cholesterol absorption inhibitor ezetimibe.Areas covered: This paper summarizes the main pharmacological characteristics of rosuvastatin and ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic effects, with particular attention to the clinical effects of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as the ones affected by diabetes mellitus and Acquired Immune Deficiency Syndrome (AIDS)).Expert opinion: The additive effect of rosuvastatin and ezetimibe helps to reach lipid goals in a large number of high-risk patients, while avoiding some safety issues related to high dosages of intensive statin therapy. Patients with diabetes receive additional benefits from ezetimibe as they seem to absorb cholesterol more effectively than non-diabetic ones, because of increased NPC1L1 gene expression. Ezetimibe augments rosuvastatin triglyceride-lowering and anti-inflammatory effects, as well. Taking into account its excellent safety profile and lack of clinically relevant drug-drug interactions, the rosuvastatin/ezetimibe association is a valuable alternative to statin dose uptitration.
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Lipidome Abnormalities and Cardiovascular Disease Risk in HIV Infection.
Bowman, E, Funderburg, NT
Current HIV/AIDS reports. 2019;(3):214-223
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Abstract
PURPOSE OF REVIEW Human immunodeficiency virus (HIV) infection and its treatment with antiretroviral therapy (ART) are associated with lipid abnormalities that may enhance cardiovascular disease risk (CVD). RECENT FINDINGS Chronic inflammation persists in HIV+ individuals, and complex relationships exist among lipids and inflammation, as immune activation may be both a cause and a consequence of lipid abnormalities in HIV infection. Advances in mass spectrometry-based techniques now allow for detailed measurements of individual lipid species; improved lipid measurement might better evaluate CVD risk compared with the prognostic value of traditional assessments. Lipidomic analyses have begun to characterize dynamic changes in lipid composition during HIV infection and following treatment with ART, and further investigation may identify novel lipid biomarkers predictive of adverse outcomes. Developing strategies to improve management of comorbidities in the HIV+ population is important, and statin therapy and lifestyle modifications, including diet and exercise, may help to improve lipid levels and mitigate CVD risk.
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Serum IL-10, IL-17 and IL-23 levels as "bioumoral bridges" between dyslipidemia and atopy.
Manti, S, Leonardi, S, Panasiti, I, Arrigo, T, Salpietro, C, Cuppari, C
Cytokine. 2017;:43-49
Abstract
BACKGROUND Although several studies suggest a possible link between dyslipidemia and atopy, literature findings are still unclear. OBJECTIVE The aim of the study was to investigate the relationship between dyslipidemia and atopy in a pediatric population affected by dyslipidemia or dyslipidemia/atopic predisposition. MATERIALS AND METHODS Children with dyslipidemia, dyslipidemia and atopy as well as healthy children were recruited. Serum total IgE, IL-10, IL-17, and IL-23 levels as well as fasting lipid values (total cholesterol, LDL, HDL and triglycerides) were performed on all enrolled children. RESULTS The present study evaluated 23 patients affected by dyslipidemia, 26 patients affected by atopy and dyslipidemia and, 22healthy children. Serum total IgE levels significantly related also with serum cholesterol levels: positively with total cholesterol (p<0.05), LDL (p<0.05), and tryglicerides (p<0.001), but negatively with HDL (p<0.05). Serum levels of IL-10 were lower in children with atopy and dyslipidemia than patients with dyslipidemia (p<0.001). Serum IL-10 levels significantly related also with serum cholesterol levels: negatively with total cholesterol (p<0.001), LDL (p<0.05), and triglycerides (p<0.05), but positively with HDL (p<0.05). Serum IL-17 and IL-23 levels showed the same trend. They were significantly higher in children with atopy and dyslipidemia than patients with dyslipidemia (p<0.001). In particular, serum IL-17 and IL-23 values positively correlated with serum total IgE levels (p<0.05); serum total cholesterol levels (p<0.001); serum LDL levels (p<0.001); serum triglycerides levels (p<0.05). Although not statistically significant, an inverse correlation has been noted between serum IL-17, IL-23 and HDL levels. CONCLUSIONS These findings support the notion that dyslipidemia and atopic predisposition share the same immune pathways as well as they offer new insights in the complex crosstalk between hyperlipidemia and atopy.
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PCSK9 as a therapeutic target of dyslipidemia.
Seidah, NG
Expert opinion on therapeutic targets. 2009;(1):19-28
Abstract
BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes degradation of hepatic low density lipoprotein receptor (LDLR), has a role in plasma cholesterol metabolism. Its gene is associated with the development of familial hypercholesterolemia. mRNA silencing or inhibition of PCSK9-induced degradation of LDLR may be used to treat this disease. OBJECTIVE/METHODS To summarize approaches proposed to reduce the levels of PCSK9 and/or its activity. RESULTS/CONCLUSIONS mRNA knockdown approaches include the use of antisense oligonucleotides either as soluble phosphorothioates or locked nucleic acids and lipidoid nanoparticles embedded with small interfering RNAs. Passive immunization is also an option. Other strategies include inhibition of the zymogen activation of proPCSK9, or the interaction of PCSK9 with the EGF-A domain of the LDLR. The N-terminal prosegment and the C-terminal Cys-His rich domain (CHRD), are alternative targets. Annexin A2 specifically binds the CHRD and inhibits PCSK9 function, and Annexin A2 peptide mimics could pave the way for the development of novel PCSK9-inhibitory compounds.
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Mechanism of action of niacin.
Kamanna, VS, Kashyap, ML
The American journal of cardiology. 2008;(8A):20B-26B
Abstract
Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B-containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I-containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B-containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI-mediated cholesterol esters. Decreased HDL-apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of beta-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-I. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The niacin flush results from the stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells via the G protein-coupled receptor 109A niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin.
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[LDL: from metabolic syndrome to instability of the atherosclerotic plaque].
Siqueira, AF, Abdalla, DS, Ferreira, SR
Arquivos brasileiros de endocrinologia e metabologia. 2006;(2):334-43
Abstract
The dyslipidemia of the metabolic syndrome (MS) confers an elevated cardiovascular risk and is characterized by increased concentrations of triglycerides, decreased HDL-cholesterol and qualitative alterations in LDL which renders it more atherogenic, like the small dense LDL. Modified forms of LDL (mLDL) have been detected in vivo in the plasma and atherosclerotic plaques. A minor fraction of the total LDL has an electronegative charge and is represented by a heterogenic subpopulation of particles [LDL(-)], with higher potential to induce endothelial injury. It could be derived from oxidation, glication or other processes that alter its chemical composition and is increased in diabetic, hypercholesterolemic subjects, and in those with established coronary artery disease. mLDL are internalized by macrophages through scavenger receptors, originating foam cells and inducing an immune-inflammatory reaction. In the atherosclerotic process, the action of mLDL continues until plaque rupture and thrombogenesis, when it promotes apoptosis in endothelial and smooth muscle cells, and activates matrix metalloproteinases, weaken the fibrous cap, and further enhance the inflammatory process that ends in the thrombus formation. Development of new laboratory methods is necessary to enhance the clinical applicability of mLDL and the predictive power of the conventional lipid profile and other cardiovascular risk factors of the MS.
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Long-term statin use does not act on the temporal trend of CD4 cell count in patients on virologically effective HAART.
Manfredi, R, Calza, L, Chiodo, F
AIDS (London, England). 2006;(3):455-7
Abstract
Pleiotropic features are attributed to statins and fibrates, and effects on laboratory markers of HIV disease progression have been claimed. To assess whether statins/fibrates have long-term effects on the immune recovery of patients on virologically effective HAART, a prospective, comparative study was conducted on 267 dyslipidemic patients treated with either statins, fibrates, or on a dietary exercise programme only. Quarterly assessment of CD4 cell counts showed no differences between groups, thus excluding in-vivo negative immunological effects during effective HAART.
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[Lipid disorders in patients with HIV-induced diseases].
Chanu, B, Valensi, P
Presse medicale (Paris, France : 1983). 2005;(15):1087-94
Abstract
Before the availability of protease inhibitors, elevated triglyceride levels were frequently observed in patients with advanced-stage HIV infection. Since the addition of protease inhibitors to combination treatments, metabolic side effects (alterations in distribution of adipose tissue and metabolic disorders combining dyslipidemia, insulin-resistance and glucose intolerance) have been observed in HIV-positive patients receiving these treatments. Reverse transcriptase nucleoside inhibitors also provoke metabolic disorders. Dyslipidemia is defined by an increase in triglyceride levels of varying and sometimes major intensity, either isolated or combined with a more moderate increase in LDL-cholesterol, while HDL-cholesterol levels may decrease or remain unchanged. These metabolic alterations are potentially atherogenic and may explain these patients' increased risk of cardiovascular disorders. Their mechanism is complex and not yet clearly elucidated. The infection, the improvement in patients' general health and immune status, and individual predisposing factors are probably involved. Treatment probably plays a major role, since the different drugs in these two classes show effects of clearly different intensity. In vitro and ex vivo studies suggest that protease inhibitors alter adipocyte differentiation and induce insulin resistance. Reverse transcriptase nucleoside inhibitors modify adipocyte metabolism too, promoting tissue atrophy. Endocrine factors (cortisol and growth hormones) are also likely to have a role in this hypertrophy of adipose, especially visceral, tissue. These metabolic abnormalities result mainly from the effects of the antiretroviral drugs, notably protease inhibitors, on the hepatic lipid metabolism and on tissue sensitivity to insulin. Lipodystrophy contributes to these abnormalities, as does the reduction in cytokine secretion by adipose tissue. Management of these metabolic disorders is based primarily on a change in the drug regimen (administration of the least deleterious combinations), followed by standard dietary measures and, when necessary, lipid-lowering agents.