- Atherosclerotic Cardiovascular Disease and Chronic Kidney Disease: An Emerging Role for Evolocumab? [Editorial]
- JACCJ Am Coll Cardiol 2019 Jun 18; 73(23):2971-2975
- Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial. [Journal Article]
- JACCJ Am Coll Cardiol 2019 Jun 18; 73(23):2961-2970
- CONCLUSIONS: LDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633).
- Discontinuation of LDL apheresis with evolocumab in an FH patient with a duplication of exon 2-6 in the LDLR gene. [Case Reports]
- JCJ Cardiol Cases 2019; 19(2):55-58
- We report here a familial hypercholesterolemia (FH) patient with a rare mutation, exon 2-6 duplication in the low-density lipoprotein (LDL) receptor gene, who had received LDL apheresis with drug tre…
We report here a familial hypercholesterolemia (FH) patient with a rare mutation, exon 2-6 duplication in the low-density lipoprotein (LDL) receptor gene, who had received LDL apheresis with drug treatment for 15 years. We added evolocumab (proprotein convertase subtilisin/kexin type 9 inhibitor) 140 mg bi-weekly to the treatment, and checked lipid profiles [LDL cholesterol, lipoprotein(a), malondialdehyde-modified LDL, etc.] for 34 weeks. Evolocumab enabled the patient to discontinue LDL apheresis and decrease the dose of statin. We demonstrate that evolocumab contributed to the management of atherogenic lipoproteins in an FH patient with exon 2-6 duplication as an alternative to LDL apheresis. <Learning objective: LDL apheresis has been the last therapeutic tool for FH patients, however, the treatment is invasive and time consuming. FH patients show various clinical presentations and different responses to medication depending on their genetic mutations. In this severe heterozygous FH patient which seemed to be homozygous FH, we explored various lipid profiles and assessed the treatment when altering the treatment from LDL apheresis to evolocumab, moreover decreasing the dose of statin.>.
- Proprotein convertase subtilisin/kexin type 9 in kidney disease. [Journal Article]
- NDNephrol Dial Transplant 2019 Jun 13
- Chronic kidney disease (CKD) is associated with a substantially increased risk for the development of atherosclerotic cardiovascular (CV) disease. Accordingly, CV mortality is increased even in the e…
Chronic kidney disease (CKD) is associated with a substantially increased risk for the development of atherosclerotic cardiovascular (CV) disease. Accordingly, CV mortality is increased even in the earliest stages of CKD. In the general population and in CKD patients, high plasma levels of low-density lipoprotein cholesterol (LDL-C) are crucially involved in the initiation and progression of atherosclerotic vascular lesions. Lowering LDL-C by use of statins and/or ezetimibe represents the gold standard of lipid-lowering therapy, with a great body of evidence from several large clinical trials. Statin therapy reduces CV events in patients with normal and impaired kidney function alike, while the evidence for patients on maintenance haemodialysis is weaker. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease represents a novel lipid-lowering tool. Currently the monoclonal antibodies evolocumab and alirocumab are the approved PCSK9 inhibitors. Despite maximum-tolerated statin therapy, they efficiently further reduce LDL-C plasma levels without any major adverse effects. Moreover, in large clinical outcome trials, both antibodies have been proven to lower CV events. Notably, the LDL-lowering capacity was independent of baseline kidney function and also efficient in patients with moderate CKD. However, patients with severely impaired kidney function, that is, the population at the highest CV risk, have been excluded from those trials. The relevance of the LDL-independent effects of PCSK9 inhibitors, such as lowering lipoprotein(a) or ameliorating dyslipidaemia in patients with nephrotic syndrome, has to be determined. Therefore further specific studies assessing the effects and outcomes of PCSK9-inhibiting treatment in CKD patients are warranted.
- Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer's Disease. [Journal Article]
- FAFront Aging Neurosci 2019; 11:120
- Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of pla…
Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of plasma low-density lipoprotein cholesterol, was first identified in the brain with a potential involvement in brain development and apoptosis. However, its role in the central nervous system (CNS) and in AD pathogenesis is still far from being understood. While in vitro and in vivo evidence led to controversial results, genetic studies apparently did not find an association between PCSK9 loss of function mutations and AD risk or prevalence. In addition, a potential impairment of cognitive performances by the treatment with the PCSK9 inhibitors, alirocumab and evolocumab, have been excluded, although ongoing studies with longer follow-up will provide further insights. PCSK9 is able to affect the expression of neuronal receptors involved in cholesterol homeostasis and neuroinflammation, and higher PCSK9 concentrations have been found in the cerebrospinal fluid (CSF) of AD patients. In this review article, we critically examined the science of PCSK9 with respect to its modulatory role of the mechanisms underlying the pathogenesis of AD. In addition, based on literature data, we made the hypothesis to consider brain PCSK9 as a negative modulator of brain cholesterol homeostasis and neuroinflammation and a potential pharmacological target for treatment.
- Updated Cost-effectiveness Analysis of Evolocumab in Patients With Very High-risk Atherosclerotic Cardiovascular Disease. [Journal Article]
- JCJAMA Cardiol 2019 Jun 05
- CONCLUSIONS: At its current list price, the addition of evolocumab to standard background therapy meets accepted cost-effectiveness thresholds across a range of baseline cardiovascular event rates in patients with very high-risk atherosclerotic cardiovascular disease as defined by the 2018 ACC/AHA guideline.
- Protein convertase subtilisin/kexin type 9 biology in nephrotic syndrome: implications for use as therapy. [Journal Article]
- NDNephrol Dial Transplant 2019 Jun 03
- Low-density lipoprotein cholesterol (LDL-C) levels almost constantly increased in patients with nephrotic syndrome (NS). Protein convertase subtilisin/kexin type 9 (PCSK9) [accelerates LDL-receptor (…
Low-density lipoprotein cholesterol (LDL-C) levels almost constantly increased in patients with nephrotic syndrome (NS). Protein convertase subtilisin/kexin type 9 (PCSK9) [accelerates LDL-receptor (LDL-R) degradation] is overexpressed by liver cells in NS. Their levels, correlated inversely to LDL-R expression and directly to LDL-C, seem to play a central role in hypercholesterolaemia in NS. Hypersynthesis resulting from sterol regulatory element-binding protein dysfunction, hyperactivity induced by c-inhibitor of apoptosis protein expressed in response to stimulation by tumour necrosis factor-α produced by damaged podocytes and hypo-clearance are the main possible mechanisms. Increased LDL-C may damage all kidney cell populations (podocytes, mesangial and tubular cells) in a similar manner. Intracellular cholesterol accumulation produces oxidative stress, foam cell formation and apoptosis, all favoured by local inflammation. The cumulative effect of cellular lesions is worsened proteinuria and kidney function loss. Accordingly, NS patients should be considered high risk and treated by lowering LDL-C. However, there is still not enough evidence determining whether lipid-lowering agents are helpful in managing dyslipidaemia in NS. Based on good efficacy and safety proved in the general population, therapeutic modulation of PCSK9 via antibody therapy might be a reasonable solution. This article explores the established and forthcoming evidence implicating PCSK9 in LDL-C dysregulation in NS.
- Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial. [Journal Article]
- JCJAMA Cardiol 2019 May 22
- CONCLUSIONS: The addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes, with significant reductions in total PEP events, driven by decreases in myocardial infarction, stroke, and coronary revascularization. More than double the number of events were prevented with evolocumab vs placebo as compared with the analysis of only first events. These data provide further support for the benefit of continuing aggressive lipid-lowering therapy to prevent recurrent cardiovascular events.
- Status of PCSK9 Monoclonal Antibodies in Australia. [Review]
- HLHeart Lung Circ 2019 May 08
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAb) have progressed from showing marked low density lipoprotein cholesterol lowering in early phase trials through to red…
Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAb) have progressed from showing marked low density lipoprotein cholesterol lowering in early phase trials through to reducing cardiovascular events in large clinical outcome trials. Recently in Australia, the indication for evolocumab has been expanded to include both heterozygous and homozygous familial hypercholesterolaemia under the Pharmaceutical Benefits Scheme (PBS). With prices remaining high currently their use in non-familial hypercholesterolaemia in Australia remains by private prescription only at this stage. This manuscript summarises the major outcomes trials of the PCSK9 mAbs and the secondary analyses that have assessed their benefits in high risk patient groups, and describes the consensus of authors on which patients would most likely benefit from PCSK9 mAb therapy.
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- Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data. [Journal Article]
- EOExpert Opin Drug Saf 2019 May 29; :1-11
- Introduction: Cardiovascular (CV) diseases are the leading cause of death and disability in the developed countries. Lipid-lowering therapy is a cornerstone of the CV risk modification strategy. The …
Introduction: Cardiovascular (CV) diseases are the leading cause of death and disability in the developed countries. Lipid-lowering therapy is a cornerstone of the CV risk modification strategy. The first line treatment for hyperlipidemia is statins, which decrease low-density lipoprotein cholesterol (LDL-C) by 30-50% and proportionally reduce the CV events. However, they are not always enough to achieve LDL-C goals in many patients, and some patients are statin intolerant. For this reason, new powerful injectable lipid-lowering drugs have been developed. Areas covered: The aim of this narrative review was to summarize the more recent clinical data on safety and tolerability of injectable lipid-lowering drugs. After an attentive literature search, the authors resumed here information on proprotein convertase subtilisin/kexin 9 inhibitors (evolocumab and alirocumab), small interfering RNA molecule inclisiran, antisense oligonucleotides (mipomersen, volanesorsen, ISIS 681257), and drugs targeting angiopoietin-like protein 3 (evinacumab, IONIS-ANGPTL3Rx). Expert opinion: Injectable lipid-lowering therapy for patients at high risk for CV disease complications or with severe inherited hypercholesterolemias can be an important element of the available therapeutic armamentarium. Clinical data prove the favorable risk-benefit profile of evolocumab, alirocumab, and inclisiran. Mipomersen, volanesorsen, ISIS 681257, evinacumab, and IONIS-ANGPTL3Rx safety is currently less extensively studied, especially in patients with comorbidities and polypharmacotherapy.