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Herz Jun 2022Patients with atherosclerotic cardiovascular disease have a high risk for subsequent cardiovascular events despite optimal drug treatment including statins and... (Review)
Review
Patients with atherosclerotic cardiovascular disease have a high risk for subsequent cardiovascular events despite optimal drug treatment including statins and ezetimibe. Dyslipidemia represents a central and direct cause of this, with a frequent failure to achieve the target values recommended in the guidelines. New lipid-lowering substances are increasingly becoming available for treatment of this residual risk. Due to their high cost, cost-effectiveness analyses are required in order to justify their use. Important variables when considering the cost-effectiveness of a drug are quality adjusted life years (QALY) and the incremental cost-effectiveness ratio (ICER). The lower bounds of the ICER determining the cost-effectiveness of a treatment vary between healthcare systems. The proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab are deemed to be cost-effective particularly in patients with high levels of low-density lipoprotein cholesterol (LDL-C) prior to treatment or with a high cardiovascular risk as determined by the presence of defined risk criteria. Similar considerations apply to the PCSK9 small interfering RNA (siRNA) inclisiran. Administration of bempedoic acid is deemed cost-effective especially in patients with statin intolerance. Eicosapentaenoic acid is deemed cost-effective overall, although the data with respect to the exact placebo-controlled efficacy are still inconclusive.
Topics: Antibodies, Monoclonal; Anticholesteremic Agents; Cholesterol, LDL; Cost-Benefit Analysis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PCSK9 Inhibitors; Proprotein Convertase 9
PubMed: 35467096
DOI: 10.1007/s00059-022-05116-8 -
Cellular and Molecular Biology... Jan 2021Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global... (Review)
Review
Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global mortality. It is initiated by the accumulation of cholesterol-laden macrophages in the artery wall, thereby forming the foam-cells, the hallmark of AS. Increased influx of oxidized LDL and decreased efflux of free cholesterol from macrophages constitute major factors that mediate the progression of AS. Natural compounds treatment and prevention of AS being an effective approach for a long time. Currently, as interests in medicinally important natural products increased that including medicinal herbs, numerous studies on natural compounds effective forAS have been reported. In the current review, we shed light on the available plant-based natural compounds as AS modulators with underlying mechanisms that may lead to potential therapeutic implications.
Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol; Foam Cells; Humans; Lipoproteins, LDL; Molecular Structure; Phytochemicals; Phytotherapy; Plant Extracts; Plants, Medicinal
PubMed: 34817349
DOI: 10.14715/cmb/2021.67.1.27 -
Aging Dec 2019
Topics: Aged; Anticholesteremic Agents; Atherosclerosis; Biomarkers; Humans; PCSK9 Inhibitors
PubMed: 31829977
DOI: 10.18632/aging.102621 -
Medicina (Kaunas, Lithuania) Apr 2023Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of... (Review)
Review
Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of coronary artery disease and peripheral vascular disease, including stroke. Recent guidelines recommend considering low-density lipoprotein cholesterol (LDL-C)-lowering therapies, such as statins (preferably), ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to prevent the occurrence or recurrence of stroke, adhering to the "lower is better" approach. In this review, we examined the evidence supporting lipid-lowering medications like statins, ezetimibe, and PCSK9 inhibitors for secondary stroke prevention and dyslipidemia management in different stroke subtypes. Stroke guidelines advocate for administering the maximum tolerable dose of statins as the primary treatment and as soon as possible despite the potential for new-onset diabetes mellitus and possible muscle and liver toxicity due to their demonstrated benefits in secondary prevention of cardiovascular diseases and mortality reduction. When statin use is insufficient for LDL lowering, ezetimibe and PCSK9 inhibitors are recommended as complementary therapies. It is essential to establish lipid-lowering therapy goals based on the stroke subtype and the presence of comorbidities.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Proprotein Convertase 9; PCSK9 Inhibitors; Ezetimibe; Cardiovascular Diseases; Dyslipidemias; Cholesterol, LDL; Stroke; Secondary Prevention
PubMed: 37109734
DOI: 10.3390/medicina59040776 -
Expert Opinion on Drug Metabolism &... May 2020: Reduction of low-density-lipoprotein cholesterol (LDL-C) and other apolipoprotein B (apoB)-containing lipoproteins reduces cardiovascular (CV) events and greater... (Review)
Review
: Reduction of low-density-lipoprotein cholesterol (LDL-C) and other apolipoprotein B (apoB)-containing lipoproteins reduces cardiovascular (CV) events and greater reductions have greater benefits. Current lipid treatments cannot always achieve desirable LDL-C targets and additional or alternative treatments are often needed.: In this article, we review the pharmacokinetics of the available and emerging treatments for hypercholesterolemia and focus on recently approved drugs and those at a late stage of development.: Statin pharmacokinetics are well known and appropriate drugs and doses can usually be chosen for individual patients to achieve LDL-C targets and avoid adverse effects and drug-drug interactions. Ezetimibe, icosapent ethyl and the monoclonal antibodies evolocumab and alirocumab have established efficacy and safety. Newer oral agents including pemafibrate and bempedoic acid have generally favorable pharmacokinetics supporting use in a wide range of patients. RNA-based therapies with antisense oligonucleotides are highly specific for their targets and those inhibiting apoB, apoCIII, angiopoietin-like protein 3 and lipoprotein(a) have shown promising results. The small-interfering RNA inclisiran has the notable advantage that a single subcutaneous administration may be effective for up to 6 months. The CV outcome trial results and long term safety data are eagerly awaited for these new agents.
Topics: Animals; Anticholesteremic Agents; Cholesterol, LDL; Dose-Response Relationship, Drug; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Oligonucleotides, Antisense
PubMed: 32223657
DOI: 10.1080/17425255.2020.1749261 -
Progress in Cardiovascular Diseases 2019
Topics: Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Cholesterol; Dyslipidemias; Humans; Practice Guidelines as Topic; Protective Factors; Risk Factors; Treatment Outcome
PubMed: 31711789
DOI: 10.1016/j.pcad.2019.11.006 -
Current Atherosclerosis Reports Oct 2022Plasma levels of LDL cholesterol (LDL-C) are causally associated with cardiovascular risk. Reducing LDL-C results in a decreased incidence of cardiovascular events,... (Review)
Review
PURPOSE OF REVIEW
Plasma levels of LDL cholesterol (LDL-C) are causally associated with cardiovascular risk. Reducing LDL-C results in a decreased incidence of cardiovascular events, proportionally to the absolute reduction in LDL-C. The inhibition of proprotein convertase subtilisin kexin 9 (PCSK) is a highly effective and safe approach to reducing LDL-C levels. In this review, we discuss the available data on the efficacy and safety of inclisiran, a siRNA targeting PCSK9 and propose a clinical profile for the patients who can benefit the most from this approach.
RECENT FINDINGS
Inclisiran is a small interfering RNA targeting the mRNA of PCSK9 specifically in the liver, owing to the conjugation with triantennary N-acetylgalactosamine. Randomized clinical trials have shown that inclisiran provides robust and durable reductions of PCSK9 and LDL-C levels, with a dosing schedule of once every 6 months after the initial and 3-month doses. These effects are consistent in different categories of patients, including patients with atherosclerotic cardiovascular disease and/or risk equivalent or patients with heterozygous familial hypercholesterolaemia. Ultimately the administration schedule may improve patients' compliance given also the favourable safety profile of the drug. Completion of ongoing outcome clinical trials will provide information on both the expected clinical benefit and the safety of inclisiran administered for longer.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Humans; PCSK9 Inhibitors; Proprotein Convertase 9; RNA, Small Interfering
PubMed: 35877035
DOI: 10.1007/s11883-022-01056-0 -
BMJ (Clinical Research Ed.) Oct 2021
Topics: Anticholesteremic Agents; Clinical Trials, Phase III as Topic; Heart Disease Risk Factors; Humans; Lipoproteins, LDL; RNA, Small Interfering
PubMed: 34642203
DOI: 10.1136/bmj.n2462 -
Current Opinion in Lipidology Dec 2022We reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable... (Review)
Review
PURPOSE OF REVIEW
We reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable treatment algorithm.
RECENT FINDINGS
Lowering LDL-C levels to normal in patients with HoFH is challenging, but a combination of multiple lipid-lowering therapies (LLT) is key. Patients with (near) absence of LDL receptor expression are most severely affected and frequently require regular lipoprotein apheresis on top of combined pharmacologic LLT. Therapies acting independently of the LDL receptor pathway, such as lomitapide and evinacumab, are considered game changers for many patients with HoFH, and may reduce the need for lipoprotein apheresis in future. Liver transplantation is to be considered a treatment option of last resort. Headway is being made in gene therapy strategies, either aiming to permanently replace or knock out key lipid-related genes, with first translational steps into humans being made. Cardiovascular disease risk management beyond LDL-C, such as residual Lp(a) or inflammatory risk, should be evaluated and addressed accordingly in HoFH.
SUMMARY
Hypercholesterolemia is notoriously difficult to control in most patients with HoFH, but multi-LLT, including newer drugs, allows reduction of LDL-C to levels unimaginable until a few years ago. Cost and availability of these new therapies are important future challenges to be addressed.
Topics: Humans; Hyperlipoproteinemia Type II; Anticholesteremic Agents; Cholesterol, LDL; Homozygous Familial Hypercholesterolemia; Receptors, LDL; Algorithms; Homozygote
PubMed: 36206078
DOI: 10.1097/MOL.0000000000000853 -
Paediatric Drugs Jul 2024Alirocumab (Praluent), a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor that has been co-developed by Regeneron Pharmaceuticals, Inc. and Sanofi... (Review)
Review
Alirocumab (Praluent), a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor that has been co-developed by Regeneron Pharmaceuticals, Inc. and Sanofi (formerly sanofi-aventis), is approved globally for use in adults with established cardiovascular disease, primary hyperlipidemia [including heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH)]. In November 2023, based on clinical data in patients aged 8-17 years, alirocumab received its first pediatric approval in the EU as an adjunct to diet alone, or in combination with a statin and/or other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in pediatric patients aged ≥ 8 years with HeFH. Alirocumab was approved a few months later in the US for use as an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged ≥ 8 years with HeFH to reduce LDL-C. This article summarizes the milestones in the development of alirocumab leading to this first pediatric approval for HeFH.
Topics: Humans; Antibodies, Monoclonal, Humanized; Child; Adolescent; Drug Approval; Hyperlipoproteinemia Type II; Anticholesteremic Agents; PCSK9 Inhibitors; Cholesterol, LDL
PubMed: 38874895
DOI: 10.1007/s40272-024-00637-7