Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9

2015 ◽  
Vol 129 (1) ◽  
pp. 63-79 ◽  
Author(s):  
Michael M. Page ◽  
Claudia Stefanutti ◽  
Allan Sniderman ◽  
Gerald F. Watts
Keyword(s):  
Genetic Testing ◽  
Familial Hypercholesterolaemia ◽  
Lipoprotein Metabolism ◽  
New Drugs ◽  
High Density Lipoproteins ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Statin Intolerance ◽  
Cascade Screening ◽  
Recent Advances

Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder that markedly raises plasma low-density lipoprotein-cholesterol (LDL-C) concentration, causing premature atherosclerotic coronary artery disease (CAD). FH has recently come under intense focus and, although there is general consensus in recent international guidelines regarding diagnosis and treatment, there is debate about the value of genetic studies. Genetic testing can be cost-effective as part of cascade screening in dedicated centres, but the full mutation spectrum responsible for FH has not been established in many populations, and its use in primary care is not at present logistically feasible. Whether using genetic testing or not, cholesterol screening of family members of index patients with an abnormally raised LDL-C must be used to determine the need for early treatment to prevent the development of CAD. The metabolic defects in FH extend beyond LDL, and may affect triacylglycerol-rich and high-density lipoproteins, lipoprotein(a) and oxidative stress. Achievement of the recommended targets for LDL-C with current treatments is difficult, but this may be resolved by new drug therapies. Lipoprotein apheresis remains an effective treatment for severe FH and, although expensive, it costs less than the two recently introduced orphan drugs (lomitapide and mipomersen) for homozygous FH. Recent advances in understanding of the biology of proprotein convertase subtilisin/kexin type 9 (PCSK9) have further elucidated the regulation of lipoprotein metabolism and led to new drugs for effectively treating hypercholesterolaemia in FH and related conditions, as well as for treating many patients with statin intolerance. The mechanisms of action of PCSK9 inhibitors on lipoprotein metabolism and atherosclerosis, as well as their impact on cardiovascular outcomes and cost-effectiveness, remain to be established.

2981Treatment of Hypercholesterolaemia with PCSK9 Inhibitors in Denmark. Assessment of real-life data; Extent and Efficacy after the first years of clinical use

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Mulverstedt ◽  
I C Klausen ◽  
H Kanstrup ◽  
J Knold ◽  
L J Andersen ◽  
...  
Keyword(s):  
Familial Hypercholesterolaemia ◽  
Plasma Lipids ◽  
Coronary Revascularization ◽  
Real Life ◽  
Atherosclerotic Cardiovascular Disease ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Statin Intolerance ◽  
Treatment Target ◽  
Number Of Patients

Abstract Introduction Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 I) are a new group of drugs for treatment of hypercholesterolaemia. At present there are two available drugs evolocumab and alirocumab, which lowers low-density lipoprotein cholesterol (LDL-C) by inhibiting the enzyme proprotein convertase subtilisin/kexin type 9. Both evolocumab and alirocumab outcome data (FOURIER and ODYSSEY OUTCOMES respectively) have shown a reduced risk of myocardial infarction, stroke, and coronary revascularization without adverse effects. Patients included in these trials had existing atherosclerotic cardiovascular disease and all patients received maximum-tolerated statin. In the FOURIER trail 100% of the patients received statin and 69% high intensity statin, in the ODYSSEY trial is was 98% and 89%, respectively Purpose In collaboration with lipid clinics in Denmark we aimed to describe the clinical characteristics of patients treated, along with the efficacy of LDL-C reduction of such treatment in a real-life population. Methods We contacted lipid and cardiological clinics throughout Denmark and obtained clinical data on the majority of patients treated with PCSK9 I in Denmark between October 1st, 2015 and May 1st, 2018. A database containing information on medical history, medications used prior to PCSK9 I initiation, adverse events and plasma lipids including LDL-C was created. Records of baseline LDL-C and at follow up visits were analysed. Results From October 1st 2015 to may 1st2018, 383 patients were enrolled; an estimated 90% of all patients in Denmark. The distribution of clinical indications for PCSK9 I initiation is shown in figure 1. A total 243 of these patients (63.4%) were characterised as statin intolerant and 225 (58.7%) had familial hypercholesterolaemia. More than two thirds (69.5%) of the patients were given PCSK9 Inhibitors as secondary prophylaxis. Overall LDL was significantly reduced from 5.11 mmol/L (CI [4.95; 5.28]) to 2.46 mmol/L (CI [2.33–2.68]) after the first month of treatment, corresponding to a 48.9% decrease in LDL-C, which persisted without significant changes throughout the two years of observation. Even with this reduction, only about half of the population of both primary and secondary prevention reached their treatment target. This remained unchanged in patients with familial hypercholesterolaemia an those with statin intolerance (Table 1). A subgroup analysis showed a significantly lower LDL in the first 12 months when PCSK9 I were combined with statins versus PCSK9 I as monotherapy (p<0.05) (results not shown). Conclusion Patients treated with PCSK9 I in this real-life do not resemble the populations in the major endpoint studies, as the majority in this real-life population are statin intolerant. Nevertheless, we see an overall reduction of LDL of approx. 50%, even though the number of patients reaching their treatment target remains low (approx. 50% at best).

Abstract 129: Effects of a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor, Alirocumab, on Lipid and Lipoprotein Metabolism in Normal Subjects

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Gissette Reyes-Soffer ◽  
Marianna Pavlyha ◽  
Colleen Ngai ◽  
Paul Ippolito ◽  
Stephen Holleran ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Phase 1 ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Normal Subjects ◽  
New Drugs ◽  
Low Density ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors

Background: Proprotein convertase subtilisin/kexin type (PCSK9) inhibitors are promising new drugs for the treatment of hypercholesterolemia. They inhibit the binding of PCSK9 to the low density lipoprotein (LDL) receptor that, in turn, decreases lysosomal degradation of LDL receptors and increases their numbers on the cell surface. In Phase 2/3 studies, alirocumab significantly lowered plasma levels of LDL-cholesterol (C) and apolipoprotein B (apoB). The mechanism underlying the LDL-C lowering effects of PCSK9 inhibition has not been reported. Method: We enrolled 10 healthy volunteers (4 male, 6 female), into a Phase 1, placebo-controlled, single-blind, single-sequence study to examine the effects of alirocumab, 150 mg administered subcutaneously every two weeks, on lipid and lipoproteins levels and the metabolism of apoB in very low density (VLDL), intermediate density (IDL) and LDL. Subjects received 2 doses of placebo followed by 5 doses of alirocumab. At the end of each treatment period, fasting lipids and lipoprotein levels were measured, and stable isotope studies of the apoB turnover in VLDL, IDL and LDL were performed. Results: Alirocumab significantly reduced plasma levels of total-C by 37% (178.4±34 to 112.7±29 mg/dL), LDL-C by 59% (110.2±25 to 45.5±26 mg/dL), and apoB by 51% (93.6±25 to 45.5±13 mg/dL) compared to placebo. Plasma triglycerides (TG) and HDL-C did not change. Levels of LDL-C, LDL-TG, and LDL-apoB fell by 55.8±10%, 33.9±13%, and 56.0±11%, respectively (all p<0.0001), on alirocumab. The reductions in LDL apoB were explained by a dramatic increase in the fractional clearance rate (FCR) of LDL apoB from 0.50±0.18 on placebo to 1.02±0.35 pools/day on alirocumab (p<0.001) and a trend toward lower LDL apoB production rates on alirocumab (15.1±4.6 vs 12.9±3.3 mg/kg/day; p=0.10). Levels of IDL-C, IDL-TG and IDL-apoB were also reduced significantly and there was a trend toward an increase in IDL apoB FCR on alirocumab (placebo: 9.2±4 vs alirocumab: 10.8±3 pools/day; p=0.06). Additional kinetic parameters will be presented at the meeting. Summary: Alirocumab treatment significantly reduced the levels of IDL and LDL, and these changes were due to increases in the FCRs of these lipoproteins, particularly LDL.

scholarly journals Management of Lipid Abnormalities in Patients with Diabetes

2019 ◽  
Vol 21 (11) ◽  
Author(s):  
Anne Sillars ◽  
Naveed Sattar
Keyword(s):  
Evidence Base ◽  
New Drugs ◽  
Lipid Lowering ◽  
Pcsk9 Inhibitors ◽  
Statin Intolerance ◽  
Younger Patients ◽  
Lipid Management ◽  
Life Years ◽  
Patients With Diabetes ◽  
Lipid Abnormalities

Abstract Purpose of Review To describe lipid abnormalities in diabetes, when they occur and the evidence base for lipid management with established and new drugs to prevent diabetes complications. We also discuss how to manage statin intolerance. Recent Findings Statins remain first-line therapy in patients with diabetes, though newer therapies to reduce LDL-C have emerged, including ezetimibe as an add-on therapy to statins, and injectable PCSK9 inhibitors, both of which are safe and effective in diabetes. Emerging evidence suggests a need to consider lipid-lowering therapies more often in younger patients with both type 1 and type 2 diabetes. Summary Statins remain the cornerstone of lipid management in diabetes but other options are increasing. There is also now evidence for better managing apparent statin intolerance. Notably, younger patients lose the most life years from their diabetes, an observation that future guidelines need to consider.

scholarly journals The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Atherosclerosis Development

2019 ◽  
Vol 5 (5) ◽  
pp. 112-120 ◽  
Author(s):  
A. Chaulin ◽  
L. Karslyan ◽  
A. Aleksandrov ◽  
A. Mazaev ◽  
E. Grigorieva ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
New Drugs ◽  
Low Density ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Residual Cardiovascular Risk ◽  
Promising Therapeutic Target ◽  
Atherosclerosis Development

Elevated plasma low-density lipoprotein cholesterol (LDL-C) is an important risk factor for cardiovascular diseases. Statins are the most widely used therapy for patients with hyperlipidemia. However, a significant residual cardiovascular risk remains in some patients even after maximally tolerated statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new promising therapeutic target for decreasing LDL-C. PCSK9 reduces LDL intake from circulation by enhancing low-density lipoprotein receptors (LDLR) degradation and preventing LDLR recirculation to the cell surface. In addition to examining the functional role of PCSK9, this review also discusses new drugs for the treatment of hyperlipidemia — PCSK9 inhibitors.

scholarly journals Familial Hypercholesterolaemia: An Updated Overall Management

2020 ◽  
Vol 5 (2) ◽  
pp. 19
Author(s):  
Noor Alicezah Mohd Kasim ◽  
Yung An Chua ◽  
Hapizah Mohd Nawawi
Keyword(s):  
High Risk ◽  
Familial Hypercholesterolaemia ◽  
Density Lipoprotein ◽  
Cost Effective ◽  
Response To Treatment ◽  
Lipid Lowering ◽  
Risk Category ◽  
Premature Coronary Artery Disease ◽  
Statin Intolerance ◽  
Cascade Screening

Familial hypercholesterolaemia (FH), the commonest and serious but potentially treatable form of inherited dyslipidaemias, is characterised by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C) level, which subsequently leads to premature coronary artery disease (pCAD). Effectiveness of FH early detection and treatment is supported by the outcome of several international cohort studies. Optimal FH management relies on prescription of statins either alone or together with other lipid-lowering therapies (LLT). Intensive lifestyle intervention is required in parallel with LLT, which should be commenced at diagnosis in adults and childhood. Treatment with high intensity statin should be started as soon as possible. Combination with ezetimibe and/or bile acid sequestrants is indicated if target LDL-C is not achieved. For FH patients in the very-high risk category, if their LDL-C targets are not achieved, despite being on maximally tolerated statin dose and ezetimibe, proprotein convertase subtilisin/kexin type1 inhibitor (PCSK9i) is recommended. In statin intolerance, ezetimibe alone, or in combination with PCSK9i may be considered. Clinical evaluation of response to treatment and safety are recommended to be done about 4-6 weeks following initiation of treatment. Homozygous FH (HoFH) patients should be treated with maximally tolerated intensive LLT and, when available, with lipoprotein apheresis. This review highlights the overall management, and optimal treatment combinations in FH in adults and children, newer LLT including PCSK9i, microsomal transfer protein inhibitor, allele-specific oligonucleotide to ApoB100 and PCSK9 mRNA. Family cascade screening and/or screening of high-risk individuals, is the most cost-effective way of identifying FH cases and initiating early and adequate LLT.

Tolerance of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) Inhibitors in Patients With Self-Reported Statin Intolerance

2018 ◽  
Vol 33 (3) ◽  
pp. 276-282 ◽  
Author(s):  
Erica R. Davidson ◽  
Melissa J. Snider ◽  
Kelly Bartsch ◽  
Andrea Hirsch ◽  
Junan Li ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Retrospective Chart Review ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Statin Intolerance ◽  
Pcsk9 Inhibitor ◽  
Patient Reported ◽  
Atherogenic Lipid

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to lower atherogenic lipid markers in patients with statin intolerance; however, external validity of these findings is unclear in patients with self-reported statin intolerance. Objective: The objective of this study was to describe the tolerability of evolocumab and alirocumab in patients with self-reported statin intolerance. Secondary objectives were to describe their efficacy and obtainability. Methods: A retrospective chart review was completed and included adult patients with self-reported statin intolerance who were prescribed a PCSK9 inhibitor. Patient-reported side effects, laboratory values, and insurance information were collected for assessment of study objectives. Results: During the study period, 55 patients were prescribed PCSK9 inhibitor, 42 started therapy, and 34 had at least 1 follow-up visit. While myalgias occurred in 14.7% (n = 5) of patients, flu-like symptoms in 11.8% (n = 4), and fatigue in 2.9% (n = 1), only 5.9% (n = 2) of prescriptions for PCSK9 inhibitors were discontinued. Low-density lipoprotein cholesterol (LDL-C) was reduced 48.7% (95% confidence interval [CI]: -1.7%-99.1%), and 20 (58.8%) patients achieved a ≥50% reduction in LDL-C. Regarding obtainability, of the 57 prescriptions written, 77.2% (n = 44) required prior authorization and 5.3% (n = 3) were denied by insurance. Conclusion: PCSK9 inhibitors were well tolerated in patients with self-reported statin intolerance.

Recent Advances in Drug Repurposing for Parkinson’s Disease

2019 ◽  
Vol 26 (28) ◽  
pp. 5340-5362 ◽  
Author(s):  
Xin Chen ◽  
Giuseppe Gumina ◽  
Kristopher G. Virga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Discovery ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Cost Effective ◽  
New Drugs ◽  
Recent Advances ◽  
Clinical Drugs

:As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson’s disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson’s disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson’s disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson’s disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson’s disease will be discussed.

Recent Advances in the Synthesis and Development of Nitroaromatics as Anti-Infective Drugs

2020 ◽  
Vol 26 (36) ◽  
pp. 4658-4674 ◽  
Author(s):  
Christina Kannigadu ◽  
David. D. N'Da
Keyword(s):  
Infectious Disease ◽  
Drug Resistance ◽  
Chest Pain ◽  
Muscle Pain ◽  
New Drugs ◽  
Lymph Glands ◽  
Recent Advances ◽  
Personality Changes ◽  
Clinical Drugs ◽  
Antiparasitic Agents

: Infectious diseases commonly occur in tropical and sub-tropical countries. The pathogens of such diseases are able to multiply in human hosts, warranting their continual survival. Infections that are commonplace include malaria, chagas, trypanosomiasis, giardiasis, amoebiasis, toxoplasmosis and leishmaniasis. Malaria is known to cause symptoms, such as high fever, chills, nausea and vomiting, whereas chagas disease causes enlarged lymph glands, muscle pain, swelling and chest pain. People suffering from African trypanosomiasis may experience severe headaches, irritability, extreme fatigue and swollen lymph nodes. As an infectious disease progresses, the human host may also experience personality changes and neurologic problems. If left untreated, most of these diseases can lead to death. : Parasites, microbes and bacteria are increasingly adapting and generating strains that are resistant to current clinical drugs. Drug resistance creates an urgency for the development of new drugs to treat these infections. Nitro containing drugs, such as chloramphenicol, metronidazole, tinidazole and secnidazole had been banned for use as antiparasitic agents due to their toxicity. However, recent discoveries of nitrocontaining anti-tuberculosis drugs, i.e. delamanid and pretonamid, and the repurposing of flexinidazole for use in combination with eflornithine for the treatment of human trypanosomiasis, have ignited interest in nitroaromatic scaffolds as viable sources of potential anti-infective agents. : This review highlights the differences between old and new nitration methodologies. It furthermore offers insights into recent advances in the development of nitroaromatics as anti-infective drugs.

scholarly journals Neurocognitive effects associated with proprotein convertase subtilisin-kexin type 9 inhibitor use: a narrative review

2021 ◽  
Vol 12 ◽  
pp. 204209862095927
Author(s):  
Wei C. Yuet ◽  
Didi Ebert ◽  
Michael Jann
Keyword(s):  
Cognitive Impairment ◽  
Adverse Events ◽  
The United States ◽  
Narrative Review ◽  
Lipid Lowering ◽  
Patient Specific ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Pcsk9 Inhibitor ◽  
Receptor Modulation

Neurocognitive adverse events have been observed with the widespread use of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or “statins,” which reduce low-density lipoprotein cholesterol (LDL-C) levels and subsequently cardiovascular risk. The United States Food and Drug Association directed manufacturers of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to monitor for neurocognitive adverse events due to their potent effects on LDL-C reduction, which is a proposed mechanism for neuronal cell dysfunction. Other proposed mechanisms for PCSK9 inhibitor-associated neurocognitive adverse events include N-methyl-d-aspartate receptor modulation, dysregulation of lipid and glucose metabolism, and patient-specific risk factors for cognitive impairment. The purpose of this narrative review article is to describe the proposed mechanisms, incidence of neurocognitive adverse events from phase II and III trials for PCSK9 inhibitors, neurocognitive assessments utilized in clinical trials, and clinical implications. Given the increasing prevalence of PCSK9 inhibitor use and the neurocognitive adverse events observed with prior lipid-lowering therapies, clinicians should be aware of the risks associated with PCSK9 inhibitors, especially when therapy is indicated for patients at high risk for cardiovascular events. Overall, the incidence of PCSK9 inhibitor-associated neurocognitive appears to be uncommon. However, additional prospective studies evaluating cognitive impairment may be beneficial to determine the long-term safety of these agents.

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