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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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Mitochondrial bioenergetics and redox dysfunctions in hypercholesterolemia and atherosclerosis.
Oliveira, HCF, Vercesi, AE
Molecular aspects of medicine. 2020;:100840
Abstract
In the first part of this review, we summarize basic mitochondrial bioenergetics concepts showing that mitochondria are critical regulators of cell life and death. Until a few decades ago, mitochondria were considered to play essential roles only in respiration, ATP formation, non-shivering thermogenesis and a variety of metabolic pathways. However, the concept presented by Peter Mitchell regarding coupling between electron flow and ATP synthesis through the intermediary of a H+ electrochemical potential leads to the recognition that the proton-motive force also regulates a series of relevant cell signalling processes, such as superoxide generation, redox balance and Ca2+ handling. Alterations in these processes lead to cell death and disease states. In the second part of this review, we discuss the role of mitochondrial dysfunctions in the specific context of hypercholesterolemia-induced atherosclerosis. We provide a literature analysis that indicates a decisive role of mitochondrial redox dysfunction in the development of atherosclerosis and discuss the underlying molecular mechanisms. Finally, we highlight the potential mitochondrial-targeted therapeutic strategies that are relevant for atherosclerosis.
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A Review of the Efficacy and Tolerability of Bempedoic Acid in the Treatment of Hypercholesterolemia.
Niman, S, Rana, K, Reid, J, Sheikh-Ali, M, Lewis, T, Choksi, RR, Goldfaden, RF
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(6):535-548
Abstract
Despite the widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease (ASCVD), many patients do not achieve adequate LDL-C lowering as per the recommended American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and demonstrate residual cardiovascular risk. The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in 2015 was a promising addition to hypercholesterolemia therapies, but their cost and subcutaneous administration has limited their use, and therefore, new affordable and patient friendly treatment strategies are crucial to help reduce ASCVD risk. Bempedoic acid, a drug currently under investigation, is a small molecule that has been shown to upregulate LDL receptors, decrease LDL-C, and reduce atherosclerotic plaque formation in hypercholesterolemic patients. Furthermore, bempedoic acid is a prodrug that becomes activated by an enzyme expressed primarily in the liver, allowing it to avoid the potential myotoxicity associated with statin therapy. The purpose of this review is to summarize the major clinical studies evaluating bempedoic acid and describe its potential addition to currently approved lipid-lowering therapies.
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Treatment of hypercholesterolaemia in older adults calls for a patient-centred approach.
Kleipool, EE, Dorresteijn, JA, Smulders, YM, Visseren, FL, Peters, MJ, Muller, M
Heart (British Cardiac Society). 2020;(4):261-266
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Abstract
Due to an increasing number of older adults with (risk factors for) cardiovascular disease (CVD), the sum of older adults eligible for lipid-lowering drugs will increase. This has risen questions about benefits and harms of lipid-lowering therapy in older adults with a varying number of (cardiovascular) comorbidities and functional status. The heterogeneity in physical and functional health increases with age, leading to a much wider variety in cardiovascular risk and life expectancy than in younger adults. We suggest treatment decisions on hypercholesterolaemia in adults aged ≥75 years should shift from a strictly 10-year cardiovascular risk-driven approach to a patient-centred and lifetime benefit-based approach. With this, estimated 10-year risk of CVD should be placed into the perspective of life expectancy. Moreover, frailty and safety concerns must be taken into account for a risk-benefit discussion between clinician and patient. Based on the Dutch addendum 'Cardiovascular Risk Management in (frail) older adults', our approach offers more detailed information on when not to initiate or deprescribe therapy than standard guidelines. Instead of using traditional risk estimating tools which tend to overestimate risk of CVD in older adults, use a competing risk adjusted, older adults-specific risk score (available at https://u-prevent.com). By filling in a patient's (cardiovascular) health profile (eg, cholesterol, renal function), the tool estimates risk of CVD and models the effect of medication in terms of absolute risk reduction for an individual patient. Using this tool can guide doctors and patients in making shared decisions on initiating, continuing or deprescribing lipid-lowering therapy.
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Bempedoic acid, an inhibitor of ATP citrate lyase for the treatment of hypercholesterolemia: early indications and potential.
Brandts, J, Ray, KK
Expert opinion on investigational drugs. 2020;(8):763-770
Abstract
INTRODUCTION The lowering of low-density lipoprotein cholesterol (LDL-C), regardless of the method used, results in a reduction of cardiovascular events. Bempedoic acid is a new and until now, the only approved adenosine triphosphate citrate lyase inhibitor that works through the cholesterol-synthesis pathway (similar to statins) that leads to a safe and effective reduction in LDL-C. AREAS COVERED We review clinical phase 2 and 3 studies on bempedoic acid's lipid-lowering effect and approved indications. EXPERT OPINION In the United States, bempedoic acid is currently approved for use in secondary prevention. In primary prevention, its approval is limited to individuals with heterozygous familial hypercholesterolemia (FH). However, its tolerability and safety profile may warrant its use in primary prevention besides FH. Even though its efficacy appears weaker than high-intensity statins, it may be a useful adjunct in individuals who achieve less than desirable LDL-C reductions with statins or who cannot tolerate statins, where bempedoic acid alone or in combination with ezetimibe may be useful alternatives.
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Medicinal plants and bioactive natural compounds as inhibitors of HMG-CoA reductase: A literature review.
Mahdavi, A, Bagherniya, M, Fakheran, O, Reiner, Ž, Xu, S, Sahebkar, A
BioFactors (Oxford, England). 2020;(6):906-926
Abstract
Cardiovascular diseases (CVDs) are one of the most important causes for mortality worldwide. Elevated levels of total cholesterol, and particularly LDL-cholesterol (LDL-C) are the main risk factor for acute myocardial infarction (AMI) and ischemic heart disease. The risk of CVDs could be reduced by decreasing the elevated cholesterol levels. β-hydroxy β-methylglutaryl-CoA reductase (HMGCoAR) is the primary and rate-limiting enzyme in the cholesterol biosynthesis pathway. Recently, the crucial role of nutraceuticals in maintaining normal physiological function was established. Nutraceuticals play an important role in preventing several non-communicable diseases such as obesity, CVDs, cancer, diabetes, and reducing hyperlipidemia. Although the effect of nutraceuticals and herbal medicine on CVDs and dyslipidemia was previously investigated thoroughly, the effect of these natural products on HMGCoAR as one of the important enzymes involved in CVDs etiopathogenesis has not yet been investigated. Therefore, the major aim of this paper was to review the effects of nutraceuticals and medicinal plants on HMGCoAR. Results indicate that different types of natural foods, isolated nutrients, herbal products, and dietary supplements as nutraceuticals decrease the expression and activity of HMGCoAR. This review shows that medicinal plants and nutraceuticals could be used to decrease HMGCoAR activity as accessible and convenient and economical natural compounds to prevent dyslipidemia and CVDs.
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PCSK9 inhibitors for treating hypercholesterolemia.
Pasta, A, Cremonini, AL, Pisciotta, L, Buscaglia, A, Porto, I, Barra, F, Ferrero, S, Brunelli, C, Rosa, GM
Expert opinion on pharmacotherapy. 2020;(3):353-363
Abstract
Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.
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Current pharmacotherapeutic options for primary dyslipidemia in adults.
Cicero, AFG, Landolfo, M, Ventura, F, Borghi, C
Expert opinion on pharmacotherapy. 2019;(10):1277-1288
Abstract
INTRODUCTION Atherosclerotic cardiovascular disease (ASCVD) and its clinical manifestations, remain a leading cause of death and disability worldwide. One of the major risk factors of ASCVD is dyslipidemia and all the available guidelines suggest the importance of strategies for lipid control in a remarkable proportion of the general population. AREAS COVERED This review focuses on the therapeutic options available for the management of lipid disorders in adults. EXPERT OPINION A large body of evidence supports that statins are still the first-line option for the management of hypercholesterolemia in a large percentage of patients. Statins should be given at the appropriate dose and considering the differences in lipid-lowering potency across the different medications. The main current challenge in the treatment of lipid disorders is the need of improving patient adherence and persistence to lipid-lowering treatments beyond the drug choice and the target lipid component. To achieve this goal, the best strategy would be to treat the patients by using the appropriate drugs given at adequate doses to reach the treatment target. We should also avoid drug interactions, monitor possible untoward side effects and promote adherence to treatment by tailoring treatment strategies to each patient.
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The role of red yeast rice (RYR) supplementation in plasma cholesterol control: A review and expert opinion.
Banach, M, Bruckert, E, Descamps, OS, Ellegård, L, Ezhov, M, Föger, B, Fras, Z, Kovanen, PT, Latkovskis, G, März, W, et al
Atherosclerosis. Supplements. 2019;:e1-e8
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Current Role of Lipoprotein Apheresis.
Thompson, G, Parhofer, KG
Current atherosclerosis reports. 2019;(7):26
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Abstract
PURPOSE OF REVIEW Lipoprotein apheresis is a very efficient but time-consuming and expensive method of lowering levels of low-density lipoprotein cholesterol, lipoprotein(a)) and other apoB containing lipoproteins, including triglyceride-rich lipoproteins. First introduced almost 45 years ago, it has long been a therapy of "last resort" for dyslipidaemias that cannot otherwise be managed. In recent years new, very potent lipid-lowering drugs have been developed and the purpose of this review is to define the role of lipoprotein apheresis in the current setting. RECENT FINDINGS Lipoprotein apheresis still plays an important role in managing patients with homozygous FH and some patients with other forms of hypercholesterolaemia and cardiovascular disease. In particular, patients not achieving treatment goals despite modern lipid-lowering drugs, either because these are not tolerated or the response is insufficient. Recently, lipoprotein(a) has emerged as an important cardiovascular risk factor and lipoprotein apheresis has been used to decrease lipoprotein(a) concentrations in patients with marked elevations and cardiovascular disease. However, there is considerable heterogeneity concerning the recommendations by scientific bodies as to which patient groups should be treated with lipoprotein apheresis. Lipoprotein apheresis remains an important tool for the management of patients with severe drug-resistant dyslipidaemias, especially those with homozygous FH.