scholarly journals Current Treatment of Familial Hypercholesterolaemia

2014 ◽  
Vol 9 (2) ◽  
pp. 76 ◽  
Author(s):  
Cameron T Lambert ◽  
Pratik Sandesara ◽  
Ijeoma Isiadinso ◽  
Maria Carolina Gongora ◽  
Danny Eapen ◽  
...  
Keyword(s):  
Familial Hypercholesterolaemia ◽  
Lifestyle Modification ◽  
Receptor Gene ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors ◽  
Autosomal Dominant Disorder

Familial hypercholesterolaemia is an autosomal-dominant disorder associated with mutations in the LDL receptor gene resulting in markedly elevated plasma low-density lipoprotein cholesterol levels. FH is significantly underrecognised with as many as 1 in 300 having the heterozygous form and 1 in 1 million having the homozygous form of the disease. Early diagnosis and treatment of FH is paramount to reduce the risk of premature atherosclerotic cardiovascular disease and death. The goal of treatment is to reduce LDL-C by 50 % from baseline levels with lifestyle modification, pharmacologic lipid-lowering therapy, LDL apheresis and in rare cases, liver transplantation. Pharmacologic treatment ranges from statin medications to newer agents such as lomitapide, mipomersin and PCSK9 inhibitors. Combination therapy is frequently required to achieve goal lipoprotein level reductions and prevent complications.

scholarly journals Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1073
Author(s):  
Alessandro Di Minno ◽  
Roberta Clara Orsini ◽  
Mattia Chiesa ◽  
Viviana Cavalca ◽  
Ilenia Calcaterra ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Platelet Activating Factor ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Pleiotropic Effect ◽  
Untargeted Metabolomics ◽  
Lipid Lowering ◽  
P Value ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors

Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. Methods: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. Results: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, p < 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (p-value = 0.041), indole (p-value = 0.045), and indoleacrylic acid (p-value= 0.045) concentrations. Conversely, significant decreases in choline (p-value = 0.045) and phosphatidylcholine (p-value < 0.01) together with a reduction in platelet activating factor (p-value = 0.041) were observed. Conclusions: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i.

Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

2019 ◽  
Vol 20 (10) ◽  
pp. 1029-1040 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Novel Target ◽  
New Treatments ◽  
And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

scholarly journals Lower is better: ezetimibe and PCSK9 inhibition join the mainstream of lipid‑lowering therapy

2016 ◽  
Vol 7 (1) ◽  
pp. 17-25
Author(s):  
Cezary Wójcik
Keyword(s):  
Statin Therapy ◽  
Heart Association ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors ◽  
Level Of Evidence ◽  
Cholesterol Guidelines ◽  
Pcsk9 Inhibition ◽  
Current Guidelines

The focus of 2013 cholesterol guidelines to prevent atherosclerotic cardiovascular disease (ASCVD) released by American College of Cardiology (ACC) and American Heart Association (AHA) is the administration of high intensity statin therapy to specific four groups of patients, which were found to benefit the most from such therapy. They no longer promote achieving specific LDL-C goals with a combination therapy involving statins and other drugs, as advocated by the former ATP-III guidelines as well as current guidelines of European Atherosclerosis Society, International Atherosclerosis Society or National Lipid Association. Such approach has been dictated by the strict reliance on randomized controlled trials as the only acceptable level of evidence. However, since publication of the 2013 ACC/AHA guidelines, cardiovascular benefits of ezetimibe added to statin therapy have been established. Moreover, the advent of PCSK9 inhibitors, providing a powerful supplement and/or alternative to statin therapy, further complicates the therapeutic horizon in dyslipdiemias. It is very likely that a new set of ACC/AHA guidelines will be published in 2016, with a return of specific LDL-C and Non-HDL-C goals of therapy as well as integration of drugs other than statins. As the treatment of dyslipidemias becomes more complex, the need for the subspecialty of clinical lipidology to be officially recognized becomes more evident.

scholarly journals Application of the 2019 ESC/EAS dyslipidaemia guidelines to nationwide data of patients with a recent myocardial infarction: a simulation study

2020 ◽  
Vol 41 (40) ◽  
pp. 3900-3909 ◽  
Author(s):  
Ali Allahyari ◽  
Tomas Jernberg ◽  
Emil Hagström ◽  
Margrét Leosdottir ◽  
Pia Lundman ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
High Intensity ◽  
Low Density Lipoprotein ◽  
Monte Carlo Model ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors ◽  
Recent Myocardial Infarction ◽  
Lowering Therapy

Abstract Aims To estimate the proportion of patients with a recent myocardial infarction (MI) who would be eligible for additional lipid-lowering therapy according to the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidaemias, and to simulate the effects of expanded lipid-lowering therapy on attainment of the low-density lipoprotein cholesterol (LDL-C) target as recommended by the guidelines. Methods and results Using the nationwide SWEDEHEART register, we included 25 466 patients who had attended a follow-up visit 6–10 weeks after an MI event, 2013–17. While most patients (86.6%) were receiving high-intensity statins, 82.9% of the patients would be eligible for expanded lipid-lowering therapy, as they had not attained the target of an LDL-C level of &lt;1.4 mmol and a ≥50% LDL-C level reduction. When maximized use of high-intensity statins followed by add-on therapy with ezetimibe was simulated using a Monte Carlo model, the LDL-C target was reached in 19.9% using high-intensity statin monotherapy and in another 28.5% with high-intensity statins and ezetimibe, while 50.7% would still be eligible for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. When use of alirocumab or evolocumab was simulated in those who were eligible for PCSK9 inhibitors, around 90% of all patients attained the LDL-C target. Conclusion  Our study suggests that, even with maximized use of high-intensity statins and ezetimibe, around half of patients with MI would be eligible for treatment with PCSK9 inhibitors according to the 2019 ESC/EAS guidelines. Considering the current cost of PCSK9 inhibitors, the financial implications of the new guidelines may be substantial.

Genetics in familial hypercholesterolaemia – from genetic research to new guidelines

2019 ◽  
Vol 88 (3) ◽  
pp. 192-194
Author(s):  
Edyta Kinga Prokop ◽  
Paweł Piotr Jagodziński ◽  
Stefan Grajek
Keyword(s):  
Familial Hypercholesterolaemia ◽  
Disease Risk ◽  
Genetic Disorder ◽  
Cardiovascular Disease Risk ◽  
Genetic Research ◽  
Ldl Receptor ◽  
Early Death ◽  
Atherosclerotic Cardiovascular Disease ◽  
Pcsk9 Inhibitors ◽  
European Society Of Cardiology

Familial Hypercholesterolaemia (FH) is genetic disorder touching up to 1 to 250 people, increasing the risk of atherosclerotic cardiovascular disease risk and early death by 3–13 times. The majority of mutations are autosomal dominant among 3 genes related to cholesterole metabolism: LDL‑receptor (LDLR), apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). It comprises 60% of reported cases, which still is not at satisfactory level. This article summarizes new research in the field of FH and points out new therapeutic methods — PCSK9 inhibitors as advised in new European Society of Cardiology guidelines od dyslipidaemias.

scholarly journals Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia

Cholesterol ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
V. A. Korneva ◽  
T. Yu. Kuznetsova ◽  
T. Yu. Bogoslovskaya ◽  
D. S. Polyakov ◽  
V. B. Vasilyev ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Familial Hypercholesterolaemia ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Gene Mutations ◽  
Density Lipoprotein ◽  
Single Strand Conformation Polymorphism ◽  
Polymorphism Analysis ◽  
Cholesterol Levels

Familial hypercholesterolaemia (FH) is a rare disease that tends to be diagnosed lately. In Russia, the genetic and phenotypic characteristics of the disease are not well defined. We investigated 102 patients with definite FH. In 52 of these patients (50.9%) genetic analysis was performed, revealing pathogenic mutations of the low density lipoprotein (LDL) receptor gene in 22 patients. We report here five mutations of the LDL receptor gene found in the Karelian FH sample for the first time. The detection rate of mutations in definite FH patients was 42.3%. Two groups of patients with a definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria were compared: the first group had putatively functionally important LDL receptor gene mutations, while in the second group LDL receptor gene mutations were excluded by single-strand conformation polymorphism analysis. Total and LDL cholesterol levels were higher in the group with LDL receptor mutations compared to the mutation-free population. The frequency of mutations in patients with LDL cholesterol > 6.5 mmol/L was more than 3 times higher than that in patients with LDL < 6.5 mmol/L. Total and LDL cholesterol levels and the frequency of coronary heart disease and myocardial infarction were higher in the group with definite FH compared to groups with probable and possible FH. Cholesterol figures in FH patients of different age and sex from the Karelian population were comparable.

Importance of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the treatment of dyslipidemia and atherosclerosis

2019 ◽  
pp. 40-52
Author(s):  
Maksim Maksimov ◽  
Anastasia Shikaleva ◽  
Aleksandra Kuchaeva
Keyword(s):  
Clinical Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Lipid Lowering Drugs ◽  
Antibody Preparations

Representatives of different groups of lipid-lowering drugs may have some differences in the nature and severity of the effect on the blood lipid spectrum. A new class of drugs, PCSK9 inhibitors, whose activity is associated with a protein involved in the control of low density lipoprotein receptors, has recently appeared. In clinical practice, this group is represented by monoclonal antibody preparations evolocumab and alirocumab. PCSK9 inhibitors are promising drugs for use in combination lipid-lowering therapy, which so far, given the results of clinical studies, can be recommended in the third place after statins and ezetimibe. In clinical studies, it was shown that alirocoumab and evolocumab alone or in combination with statins and/or other lipid-lowering drugs significantly reduce cholesterol levels in low density lipoproteins – by an average of 60%, depending on the dose.

scholarly journals Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the treatment of dyslipidemia

2021 ◽  
pp. 12-18
Author(s):  
A. A. Shikaleva ◽  
M. L. Maximov ◽  
N. M. Kiseleva
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
Substantial Contribution ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Cholesterol Levels ◽  
Density Lipoprotein Receptor

Dyslipidemia makes a substantial contribution to the mortality as one of the leading pathogenetic factors for cardiovascular diseases. The nature and degree of the effect on the blood lipid spectrum may vary in the lipid-lowering drugs from different groups. Recently, a new class of PCSK9 inhibitors has been developed, which activity is associated with a protein involved in the low-density lipoprotein receptor control. In clinical practice, this group is represented by monoclonal antibody drugs evolocumab and alirocumab. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are promising drugs to be used in the combination lipid-lowering therapy, which, given the results of clinical trials, can be recommended at this point on a third-priority basis after statins and ezetimibe. However, it is vital to indicate that these drugs have a sufficient safety profile, which makes it possible to prescribe these drugs in a triple combination adding it to the two first-line drugs regimen which patients had been given before. It is obvious that further study of PCSK9 will expand the range of their use for the treatment of familial hypercholesterolemia up to indications in cases where statins are limited and a more pronounced lipid-lowering effect is required to achieve target cholesterol levels.

Sign in / Sign up

Export Citation Format

Share Document