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1.
Role of Bempedoic Acid in Clinical Practice.
Ballantyne, CM, Bays, H, Catapano, AL, Goldberg, A, Ray, KK, Saseen, JJ
Cardiovascular drugs and therapy. 2021;(4):853-864
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Abstract
Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.
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Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges.
Packard, C, Chapman, MJ, Sibartie, M, Laufs, U, Masana, L
Heart (British Cardiac Society). 2021;(17):1369-1375
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Abstract
Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of 'lower is better'. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5-7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.
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Familial Hypercholesterolemia: A Narrative Review on Diagnosis and Management Strategies for Children and Adolescents.
Tada, H, Takamura, M, Kawashiri, MA
Vascular health and risk management. 2021;:59-67
Abstract
Familial hypercholesterolemia (FH) is a relatively common inherited disorder caused by deleterious mutation(s) in the low-density lipoprotein (LDL) receptor or its associated genes. Given its nature as a heritable disease, any useful screening scheme, including universal, and cascade screening, allows for the early identification of patients with FH. Another important aspect to note is that early diagnosis associated with appropriate treatment can promote better prognosis. However, most clinical diagnostic criteria for adults have adopted clinical elements, such as physical xanthomas and family history, both of which are usually obscure and/or difficult to obtain in children and adolescents. Moreover, LDL cholesterol levels fluctuating considerably during adolescence, hindering the timely diagnosis of FH. In addition, recent advancements in human genetics have revealed several types of FH, including conventional monogenic FH, polygenic FH caused by common single nucleotide variations (SNV) accumulation associated with elevated LDL cholesterol, and oligogenic FH with multiple deleterious genetic variations leading to substantially elevated LDL cholesterol. The aforementioned findings collectively suggest the need for amassing information related to genetics and imaging, in addition to classical clinical elements, for the accurate diagnosis of FH in this era of personalized medicine. The current narrative review summarizes the current status of the clinical and genetic diagnosis of FH in children and adolescents, as well as provide useful management strategies for FH in children and adolescents based on currently available clinical evidence.
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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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Why patients with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels.
Bianconi, V, Banach, M, Pirro, M, ,
Trends in cardiovascular medicine. 2021;(4):205-215
Abstract
Familial hypercholesterolemia (FH) is a common genetic cause of elevated low-density lipoprotein cholesterol (LDL-C) due to defective clearance of circulating LDL particles. All FH patients are at high risk for premature cardiovascular disease (CVD) events due to their genetically determined lifelong exposure to high LDL-C levels. However, different rates of CVD events have been reported in FH patients, even among those with the same genetic mutations and comparable LDL-C levels. Hence, additional CVD risk modifiers, beyond LDL-C, may contribute to increase CVD risk in the FH population. In this review, we discuss the overall CVD risk burden of the FH population. Additionally, we revise the prognostic impact of several traditional and emerging predictors of CVD risk and we provide an overview of the role of specific tools to stratify CVD risk in FH patients in order to ensure them a more personalized treatment approach.
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Prevalence of plasma lipid disorders with an emphasis on LDL cholesterol in selected countries in the Asia-Pacific region.
Lee, ZV, Llanes, EJ, Sukmawan, R, Thongtang, N, Ho, HQT, Barter, P, ,
Lipids in health and disease. 2021;(1):33
Abstract
Cardiovascular disease (CVD) is a major cause of mortality and morbidity within the Asia-Pacific region, with the prevalence of CVD risk factors such as plasma lipid disorders increasing in many Asian countries. As members of the Cardiovascular RISk Prevention (CRISP) in Asia network, the authors have focused on plasma lipid disorders in the six countries within which they have clinical experience: Indonesia, Malaysia, Philippines, Thailand, Vietnam, and Australia. Based on country-specific national surveys, the prevalence of abnormal levels of total cholesterol, low- and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), and triglycerides (TG) are reported. An important caveat is that countries have used different thresholds to define plasma lipid disorders, making direct comparisons difficult. The prevalence of abnormal lipid levels was as follows: high total cholesterol (30.2-47.7%, thresholds: 190-213 mg/dL); high LDL-C (33.2-47.5%; thresholds: 130-135 mg/dL); low/abnormal HDL-C (22.9-72.0%; thresholds: 39-50 mg/dL); and high/abnormal TG (13.9-38.7%; thresholds: 150-177 mg/dL). Similarities and differences between country-specific guidelines for the management of plasma lipid disorders are highlighted. Based on the authors' clinical experience, some of the possible reasons for suboptimal management of plasma lipid disorders in each country are described. Issues common to several countries include physician reluctance to prescribe high-dose and/or high-intensity statins and poor understanding of disease, treatments, and side effects among patients. Treatment costs and geographical constraints have also hampered disease management in Indonesia and the Philippines. Understanding the factors governing the prevalence of plasma lipid disorders helps enhance strategies to reduce the burden of CVD in the Asia-Pacific region.
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Role of Lipid-Lowering Therapy in Low-Density Lipoprotein Cholesterol Goal Attainment: Focus on Patients With Acute Coronary Syndrome.
Wang, Q, Liang, C
Journal of cardiovascular pharmacology. 2020;(6):658-670
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Abstract
Dyslipidemia is a major risk factor for cardiovascular (CV) disease, which is the leading cause of death globally. Acute coronary syndrome (ACS) is a common cause of death, accounting for nearly half of the global burden of CV mortality. Epidemiologic studies have identified low-density lipoprotein cholesterol (LDL-C) as an independent CV risk factor, and this is now the primary target for initiating and adjusting lipid-lowering therapies in most current guidelines. Evidence from pivotal studies supports the use of high-intensity statin therapy and a lower level for optimal LDL-C in secondary prevention of atherosclerotic CV disease, especially in patients with ACS undergoing percutaneous coronary intervention. However, current research has identified a gap between the target LDL-C goal attainment and target LDL-C levels recommended by the guidelines. Statins have proven benefits in the management of CV disease and are the cornerstone of lipid-lowering management in patients with ACS. Recent randomized controlled trials have also demonstrated the benefits of cholesterol absorption inhibitors and proprotein convertase subtilisin/kexin type 9 inhibitors. This review summarizes the current evidence for LDL-lowering therapy in patients with ACS, with an emphasis on the importance of LDL-C goal attainment, rapid LDL-C lowering, and duration of LDL-C-lowering therapy.
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The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia.
Penson, PE, Banach, M
Current atherosclerosis reports. 2020;(11):67
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Abstract
PURPOSE OF REVIEW We aimed to summarize recent guidelines, position papers, and high-quality clinical research relating the use of nutraceuticals in the management of individuals at high risk of atherosclerotic cardiovascular disease. RECENT FINDINGS It is essential that individuals at high risk of cardiovascular disease receive guideline-directed evidence-based therapies to reduce their risk of morbidity and mortality from cardiovascular events. Compared with conventional therapeutics, nutraceuticals have undergone relatively little investigation in randomized controlled trials. Thus, recommendations for nutraceuticals in international guidelines are rare, and nutraceuticals should not be used preferentially in place of statins. Nevertheless, recent position papers from the International Lipid Expert Panel and clinical evidence from studies of triglyceride reduction by polyunsaturated fatty acid administration demonstrate that nutraceuticals do have an important role in optimizing therapy in individuals at high risk of cardiovascular disease. Roles for nutraceuticals include as follows: (1) managing residual risk associated with lipids other than low-density lipoprotein cholesterol (LDL-C); (2) managing non-lipid-mediated residual risk; (3) optimizing LDL-C treatment in statin intolerance; (4) optimizing LCL-C treatment when add-on therapies for statins are not available; (5) as adjuncts to lifestyle for individuals at high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The strength of evidence for each of these applications is variable. In addition to guideline-directed therapeutics, nutraceuticals may have roles in optimizing preventative therapy and targeting residual risk in individuals at high risk of ASCVD. Application of Good Manufacturing Practice and randomized controlled trials when producing and evaluating nutraceuticals will expand the armoury of evidence-based agents for the prevention of ASCVD.
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An expert opinion paper on statin adherence and implementation of new lipid-lowering medications by the ESC Working Group on Cardiovascular Pharmacotherapy: Barriers to be overcome.
Drexel, H, Coats, AJS, Spoletini, I, Bilato, C, Mollace, V, Perrone Filardi, P, Rosano, GMC
European heart journal. Cardiovascular pharmacotherapy. 2020;(2):115-121
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Abstract
Benefits and safety on statins have been well-established over 20 years of research. Despite this, the vast majority of patients are not adequately treated and do not achieve the low-density lipoprotein cholesterol target levels. This is mainly due to poor adherence, which is associated with dangerous and sometimes fatal outcomes. To increase adherence and prevent worse outcomes, a combination therapy with lower dosage of statins and new lipid-lowering drugs may be used. However, the implementation of new lipid-lowering drugs in European countries is still at the beginning. For these reasons, the aim of this position paper is to give an up-to-date indication from the ESC Working Group on Cardiovascular Pharmacotherapy in order to discuss the barriers towards statins adherence and new lipid-lowering drugs implementation in Europe.
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Highlights of Studies in Cardiovascular Disease Prevention Presented at the 2020 American College of Cardiology Annual Scientific Session.
Jia, X, Al Rifai, M, Liu, J, Agarwala, A, Gulati, M, Virani, SS
Current atherosclerosis reports. 2020;(8):32
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PURPOSE OF REVIEW The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the American College of Cardiology 2020 Virtual Scientific Session (ACC.20)/World Cardiology Congress (WCC). RECENT FINDINGS The studies reviewed include clinical trials on the efficacy and safety of alirocumab (Study in Participants with Homozygous Familial Hypercholesterolemia [ODYSSEY HoFH]) and evinacumab in the treatment of homozygous familial hypercholesterolemia (HoFH); Evaluating the Efficacy of E-cigarettes for Smoking Cessation (E3); the use of renal denervation in the treatment of hypertension (SPYRAL HTN-OFF MED PIVOTAL); and the assessment of vericiguat in the treatment of heart failure (A Study of Vericiguat in Participants with Heart Failure with Reduce Ejection Fraction [VICTORIA]). In addition, results from the pooled analysis of phase III trials on inclisiran and secondary analysis examining eicosapentaenoic acid levels and cardiovascular outcomes from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) were included. Finally, we discuss studies examining the use of polygenic risk score with low density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) on lifetime cardiovascular risk. The studies presented at the ACC.20/WCC represent notable contributions in the field of CVD prevention.