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Clinical development of bempedoic acid: phase 2 and phase 3 clinical trials.
Lekuona, I, Pintó, X
Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis. 2021;:58-64
Abstract
We review all the phase II and III studies carried out with bempedoic acid at the dose of 180mg, alone or in combination with different lipid-lowering drugs and in different subgroups of patients that unequivocally show the efficacy and safety of the drug. We point out some of the potential advantages of its use in clinical practice in patients with statin intolerance and the efficacy in reducing LDL-c when combined with statins, and with statins and ezetimibe, as well as in reducing inflammation markers pending the results of the CV Clear Outcomes trial that will end in 2022.
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New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B: JACC Focus Seminar 1/4.
Nurmohamed, NS, Navar, AM, Kastelein, JJP
Journal of the American College of Cardiology. 2021;(12):1564-1575
Abstract
Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol (LDL-C)-lowering therapies are under development for the prevention of cardiovascular disease. Inclisiran, a small interfering RNA molecule that inhibits PCSK9, only needs to be dosed twice a year and has the potential to help overcome current barriers to persistence and adherence to lipid-lowering therapies. Bempedoic acid, which lowers LDL-C upstream from statins, provides a novel alternative for patients with statin intolerance. Angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering in patients with homozygous familial hypercholesterolemia without major adverse effects as seen with lomitapide and mipomersen, and may reduce the need for apheresis. Finally, CETP inhibitors may yet be effective with the development of obicetrapib. These novel agents provide the clinician the tools to effectively lower LDL-C across the entire range of LDL-C-induced elevation of cardiovascular risk, from primary prevention and secondary prevention to null-null homozygous familial hypercholesterolemia patients.
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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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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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5.
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.
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Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases.
Cabral, CE, Klein, MRST
Arquivos brasileiros de cardiologia. 2017;(5):475-482
Abstract
Phytosterols are bioactive compounds found in foods of plant origin, which can be divided into plant sterols and plant stanols. Clinical studies consistently indicate that the intake of phytosterols (2 g/day) is associated with a significant reduction (8-10%) in levels of low-density lipoprotein cholesterol (LDL-cholesterol). Thus, several guidelines recommend the intake of 2 g/day of plant sterols and/or stanols in order to reduce LDL-cholesterol levels. As the typical western diet contains only about 300 mg/day of phytosterols, foods enriched with phytosterols are usually used to achieve the recommended intake. Although phytosterols decrease LDL-cholesterol levels, there is no evidence that they reduce the risk of cardiovascular diseases; on the contrary, some studies suggest an increased risk of atherosclerosis with increasing serum levels of phytosterols. This review aims to address the evidence available in the literature on the relationship between phytosterols and risk of cardiovascular disease.
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[Evolocumab (Repatha®) : a human monoclonal antibody against PCSK9 protein as potent cholesterol-lowering therapy].
Wallemacq, C
Revue medicale de Liege. 2017;(11):505-512
Abstract
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. The development of mAbs that bind the extracellular PCSK9 and prevent its interaction with LDL-R is the most advanced and tested approach to PCSK9 inhibition to date. The clinical efficacy and safety of evolocumab have been studied in a number of controlled trials versus placebo or versus active comparator (ézétimibe) during 12 to 76 weeks. Added on statin, evolocumab reduced LDL-C up to 50 to 60 % from baseline. Evolocumab also reduced LCL-C in monotherapy in statin-intolerant patients. Evolocumab also significally reduced total cholesterol, non-HDL cholesterol, apoprotein B and lipoprotein(a). Safety and tolerance were good. Evolocumab is commercialized under the trade name Repatha® and administrated subcutaneously at the dose of 140 mg every 2 weeks or 420 mg once per month. Repatha® is approved in Belgium, with conditions, for the treatment of hypercholesterolemia in patients with heterozygous (HFe) and homozygous (HFo) familial hypercholesterolemia.
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[The efficacy and safety of pitavastatin].
Sansoy, V
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2017;(Suppl 3):1-4
Abstract
In short-term, phase III or IV studies in Asian and European patients, pitavastatin 1, 2 and 4 mg once daily reduced LDL-Cholesterol (LDL-C) 34%, 42% and 47%, respectively. Pitavastatin provided sustained LDL-C-lowering efficacy over up to 60 weeks' therapy in extension studies. In comparative studies pitavastatin 4 mg and simvastatin 40 mg reduced LDL-C similarly, reduction in triglycerides and increase in HDL-Cholesterol (HDL-C) was more prominent with pitavastatin. In comparative studies with atorvastatin, pitavastatin 4mg was found to be more effective than 20 mg of atorvastatin, and a little less effective than 40 mg of atorvastatin. The increase in HDL-C demonstrated in short term studies sustained in long term, whereas with atorvastatin the increase in HDL-C was less prominent. Pitavastatin was generally well tolerated in these studies and most treatment emergent adverse events were mild or moderate and their frequency was not different from other statins. Pitavastatin did not appear to adversely affect glucose metabolism parameters (e.g. fasting blood glucose, fasting plasma insulin, glycated hemoglobin) in short- and longer-term prospective and post-marketing surveillance studies in adults. In conclusion, pitavastatin is an effective treatment option in adults with primary hypercholesterolemia and combined (mixed) dyslipidemia, including those at risk of developing type 2 diabetes.
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[Cardiovascular prevention and pitavastatin].
Kayıkçıoğlu, M
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2017;(Suppl 3):8-12
Abstract
HMG-CoA reductase inhibitors (statins) represent the most effective class of LDL lowering drugs with an overall positive safety and tolerability profile. They have also consistent benefit in terms of reduced cardiovascular (CV) events in both primary and secondary prevention. Pitavastatin is a new member of the statin class. This review provides a current overview of pravastatin's role in CV risk reduction. In brief pitatastatin has pleitrophic effects as the other statins. It has been shown that it reduces plaque atheroma volume in acute coranary settings. Also the 'real life' evidence gained with pitavastatin in LIVES study, a longterm postmarketing surveillance study in more than 20,000 patients in Japan, denotes an effective CV risk reduction with this new statin.
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Drugs for hypercholesterolaemia - from statins to pro-protein convertase subtilisin kexin 9 (PCSK9) inhibition.
Wierzbicki, AS, Grant, P
Clinical medicine (London, England). 2016;(4):353-7
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Abstract
Cardiovascular disease (CVD) remains one of the commonest sources of morbidity and mortality in the world. Lipids and especially low density lipoprotein cholesterol (LDL-C) contribute to the risk of CVD events. Statins are the primary therapy for hypercholesterolaemia and recent evidence supports the use of ezetimibe as a second-line agent. Pro-protein convertase subtilisin kexin 9 (PCSK9) is a regulator of LDL receptor expression. Activating mutations in PCSK9 give rise to a form of familial hypercholesterolaemia, while inactivating mutations lead to lower LDL-C levels and fewer CVD events. Therapies to inhibit PCSK9 are in development and two antibody-based therapies - alirocumab and evolocumab - have recently been licensed. This article reviews the actions of PCSK9, the novel therapeutics targeted on this molecule and how they are likely to be used in clinical practice until large scale CVD outcome studies with PCSK9 inhibitors are published.