-
European Heart Journal Apr 2022
Topics: Anticholesteremic Agents; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Humans
PubMed: 34999786
DOI: 10.1093/eurheartj/ehab889 -
Kardiologia Polska 2023Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) metabolism. Pharmacological PCSK9 inhibitors have been... (Review)
Review
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) metabolism. Pharmacological PCSK9 inhibitors have been developed as a novel approach to treating dyslipidemia. This article reviews the spectrum of evidence implicating the role of PCSK9 in lipid metabolism and the clinical impact of PCSK9 inhibitors on lipid parameters and cardiovascular risk. Biochemical and genomic studies have established the role that PCSK9 plays in lipid metabolism and potential protection from cardiovascular disease observed in the setting of PCSK9 deficiency. This led to the development of inhibitory monoclonal antibodies (evolocumab, alirocumab) that produce dose-dependent lowering of LDL cholesterol up to 60%, with evidence of regression and stabilization of coronary atherosclerosis (GLAGOV, HUYGENS, PACMAN-AMI) and reduction in cardiovascular risk in large clinical outcomes trials (FOURIER, ODYSSEY Outcomes). More recent developments have witnessed alternative approaches to PCSK9 inhibition such as RNA interference (inclisiran), vaccines, and gene editing, which are currently undergoing clinical evaluation. PCSK9 inhibition has emerged as an important component of treatment approaches to lowering LDL cholesterol and plays an increasing role in preventive strategies.
Topics: Humans; PCSK9 Inhibitors; Cholesterol, LDL; Proprotein Convertase 9; Cardiovascular Diseases; Anticholesteremic Agents
PubMed: 36739653
DOI: 10.33963/KP.a2023.0030 -
Science (New York, N.Y.) May 2001HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition...
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.
Topics: Acyl Coenzyme A; Anticholesteremic Agents; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Humans; Hydrogen Bonding; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Models, Molecular; Pliability; Protein Binding; Protein Structure, Secondary
PubMed: 11349148
DOI: 10.1126/science.1059344 -
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 -
MMW Fortschritte Der Medizin May 2024
Topics: Humans; PCSK9 Inhibitors; Proprotein Convertase 9; Anticholesteremic Agents; Cholesterol, LDL
PubMed: 38693368
DOI: 10.1007/s15006-024-3912-5 -
Drugs Nov 2023Tafolecimab (SINTBILO), a subcutaneously administered anti-proprotein convertase subtilisin/kexin type 9 enzyme (PCSK9) monoclonal antibody, is being developed by... (Review)
Review
Tafolecimab (SINTBILO), a subcutaneously administered anti-proprotein convertase subtilisin/kexin type 9 enzyme (PCSK9) monoclonal antibody, is being developed by Innovent for the treatment of hypercholesterolemia and mixed hyperlipidemia. Tafolecimab was approved in August 2023 in China as an adjunct to diet, in combination with a statin or statin with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, for the treatment of adults with primary hyperlipidemia [including heterozygous familial hypercholesterolemia (HeFH) and non-familial hypercholesterolemia (non-FH)] and mixed dyslipidemia who have failed to achieve LDL-C goals despite moderate or higher doses of statins, to reduce LDL-C, total cholesterol (TC), and apolipoprotein B (ApoB) levels. This article summarizes the milestones in the development of tafolecimab leading to this first approval for the treatment of adults with primary hyperlipidemia and mixed dyslipidemia.
Topics: Adult; Humans; Proprotein Convertase 9; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Antibodies, Monoclonal; Hypercholesterolemia; Dyslipidemias; Anticholesteremic Agents
PubMed: 37847461
DOI: 10.1007/s40265-023-01952-y -
Vnitrni Lekarstvi 2020PCSK9 inhibitors (inhibitors of proprotein convertase subtilisin/kexin type 9) offer a promising treatment strategy decreasing the concentrations of both atherogenic low...
PCSK9 inhibitors (inhibitors of proprotein convertase subtilisin/kexin type 9) offer a promising treatment strategy decreasing the concentrations of both atherogenic low density lipoprotein (LDL) and cholesterol contained within LDL. Alirocumab is one of two PCSK9 inhibitors that entered clinical practice so far. Alirocumab is a specific antibody against PCSK9, manufactured using recombinant technique. When the antibody binds to the PCSK9 isoenzyme, no complex encompassing PCSK9 and LDL receptor can be formed, thus enabling further recirculation of the LDL receptor. Increasing the amount of LDL receptors available on the cell membranes leads to higher internalization of LDL within cells and to lowering of LDL cholesterol concentration. It has been shown that alirocumab exerts favorable effect on atherogenic lipoproteins (i.e. decrease of concentrations of LDL cholesterol by more than 50%) both in monotherapy and in combination with statins or other hypolipidemics. Odyssey Outcomes study brought new information into light and changed the guidelines of treating the patients with cardivascular diseases. Alirokumab added to intensive statin therapy reduced significantly the risk of cardiovascular diseases and the post hoc analysis confirmed also the reduction of total death rate. The positive effect of alirocumab is higher in patients with higher initial LDL-C. The therapy with alirokumab is safe, with minimum adverse events.
Topics: Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Proprotein Convertase 9
PubMed: 32942879
DOI: No ID Found -
Current Opinion in Lipidology Apr 2016
Topics: Anticholesteremic Agents; Atorvastatin; Cardiovascular Diseases; Cholesterol; Humans; Intestinal Absorption
PubMed: 26959709
DOI: 10.1097/MOL.0000000000000283 -
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 -
Expert Review of Clinical Pharmacology Jun 2017Prescription of statins for low-density lipoprotein cholesterol (LDL-C) reduction is the standard of care in primary and secondary prevention of cardiovascular disease;... (Review)
Review
Prescription of statins for low-density lipoprotein cholesterol (LDL-C) reduction is the standard of care in primary and secondary prevention of cardiovascular disease; nevertheless, a large number of patients treated with statins are unable to reach the recommended LDL-C targets. Therefore, there is need for safe and effective novel therapies for the pharmacological management of hypercholesterolaemia, in addition or as alternative to lipid-lowering therapies (LLT) currently in use. Areas covered: In 2015, the Food and Drug Administration and the European Medicines Agency approved alirocumab (Praluent®; Sanofi), a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), for the treatment of hypercholesterolaemic patients unable to meet LDL-C targets, as an adjunct to diet in addition/alternative to LLT. The authors review the pharmacological features, clinical efficacy, and safety of alirocumab in lowering LDL-C, and discuss its therapeutic perspectives based on the most recent clinical trials. Expert commentary: Alirocumab causes a marked reduction in LDL-C, presents good safety and tolerability, and represents a promising approach for LDL-C lowering, particularly in patients with intolerance to statin or elevated LDL-C despite maximal statin therapy; nevertheless, further long-term data on safety and efficacy are necessary, such as data on the improvement of cardiovascular outcomes.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; PCSK9 Inhibitors
PubMed: 28395555
DOI: 10.1080/17512433.2017.1318063