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.

scholarly journals Real-world data on metabolic effects of PCSK9 inhibitors in a tertiary care center in patients with and without diabetes mellitus

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Laurenz T. Fischer ◽  
Daniel A. Hochfellner ◽  
Lisa Knoll ◽  
Tina Pöttler ◽  
Julia K. Mader ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Real World ◽  
Cardiovascular Events ◽  
Care Center ◽  
Tertiary Care ◽  
Lipid Lowering ◽  
Tertiary Care Center ◽  
Pcsk9 Inhibitors ◽  
Real World Data ◽  
Pcsk9 Inhibitor

Abstract Background The lipid-lowering and positive cardiovascular effect of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors was shown in several studies, hence, they are more widely used in the lipid-lowering management of individuals with high cardiovascular risk. As real-world data are still scarce, specifically in patients with type 2 diabetes (T2D), the aim of this retrospective analysis was to investigate the efficacy of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol (LDL-C) in an outpatient clinic of a tertiary care center in routine care. Methods A retrospective analysis of data extracted from the electronic patient record was performed. Patients who were routinely prescribed with PCSK9 inhibitor therapy (alirocumab or evolocumab) during the years 2016 and 2019 were included in the analysis. Characteristics of the patient population, the effects on LDL-C and HbA1c levels as well as subsequent cardiovascular events were assessed over an observation period of 18 months. Results We identified 237 patients treated with PCSK9 inhibitors between January 2016 and September 2019. Almost all patients (97.5%) received PCSK9 inhibitors for secondary prevention. 26.2% of the population had a concomitant diabetes diagnosis. Intolerance to statins (83.1%), ezetimibe (44.7%) or both agents (42.6%) was reported frequently. Three months after initiation of PCSK9 inhibitor therapy, 61.2% of the patients achieved LDL-C levels < 70 mg/dl, and 44.1% LDL-C levels < 55 mg/dl. The median LDL-C was lowered from 141 mg/dl at baseline, to 60 mg/dl after 3 months and 66 mg/dl after 12 months indicating a reduction of LDL-C as follows: 57.5% after 3 months and 53.6% after 12 months. After 3 months of observation, target achievement of LDL-C was higher in patients with T2D compared to non-diabetes patients; < 55 mg/dl: 51% vs. 41.5%; < 70 mg/dl 69.4 vs. 58.5%. After 12 months even more pronounced target LDL achievement in T2D was demonstrated < 55 mg/dl: 58.8% vs. 30.1%; < 70 mg/dl 70.6 vs. 49.6%. Patients with insufficiently controlled T2D (HbA1c > 54 mmol/mol) had a higher reduction in LDL-C but still were more likely to subsequent cardiovascular events. Conclusions Significant reductions in LDL-C and a high percentage of patients achieving recommended treatment targets were observed. The percentage of patients with T2D meeting recommended LDL-C targets was higher than in those without T2D. Still some patients did not achieve LDL-C levels as recommended in current guidelines. Special attention to the characteristics of these patients is required in the future to enable achievement of treatment goals and avoid adverse cardiovascular outcomes.

scholarly journals The history of proprotein convertase subtilisin kexin-9 inhibitors and their role in the treatment of cardiovascular disease

2020 ◽  
Vol 11 ◽  
pp. 204062232092456
Author(s):  
Eun Ji Kim ◽  
Anthony S. Wierzbicki
Keyword(s):  
Cardiovascular Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Epidemiological Studies ◽  
Lipid Lowering ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Activating Mutations ◽  
History Of ◽  
New Guidelines

A consensus has formed based on epidemiological studies and clinical trials that intervention to reduce low density lipoprotein cholesterol (LDL-C) will reduce cardiovascular disease (CVD) events. This has progressively reduced the thresholds for intervention and targets for treatment. Whist statins are sufficient for many people in primary prevention, they only partially achieve the newer targets of secondary prevention for established CVD. Increasing use of statins has highlighted that 1–2% cannot tolerate these drugs. Other cholesterol-lowering drugs such as ezetimibe add to the benefits of statins but have limited efficacy. The discovery of activating mutations in proprotein convertase subtilisin kexin-9 (PCSK9) as a cause of familial hypercholesterolaemia while inactivating mutations lower LDL-C led to the idea to develop PCSK9 inhibitors as drugs. This article reviews the history of lipid-lowering therapies, the discovery of PCSK9 and the development of PCSK9 inhibitors. It reviews the key trials of the current antibody-based drugs and how these have influenced new guidelines. It also reviews the controversy caused by their cost and the increasing application of health economics to determine the optimum strategy for implementation of novel therapeutic pathways and surveys other options for targeting PCSK9 as well as other LDL-C lowering compounds in late development.

scholarly journals Exposure to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the association with neurocognitive side effects: a meta-analysis and meta-regression

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
B Hirsh-Raccah ◽  
A Yanovsky ◽  
V Rotshild ◽  
H Danenberg ◽  
R Eliaz ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Effects ◽  
Meta Analysis ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Lowering Therapy ◽  
Meta Regression ◽  
Meta Analyses

Abstract Background Lipid lowering therapy may be associated with impaired cognitive function. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse effects remains unclear. Purpose To assess the neurocognitive safety of PCSK9 inhibitors using meta-analysis and meta-regression of randomized controlled trials (RCTs). Methods PubMed (MEDLINE), Embase and Cochrane library were searched. RCTs that reported assessments of neurocognitive outcomes of participants using PCSK9 inhibitors, with a duration of follow up of at least six months were included. The results of the search were screened by two independent reviewers. Any disagreements were resolved by consensus. The research was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for meta-analyses. Results were pooled using random-effects models. The primary safety outcome of this analysis was defined as the reported incidence of neurocognitive adverse effects. Results Results of 21 trials were included in the analysis. Among 59,733 patients, 31,611 were treated with PCSK9 inhibitors. No significant difference in the incidence of neurocognitive side effects between the treatment and control groups was identified (RR=1.01, 95% CI: 0.86–1.19, I2=3%). Same results were seen in separate analysis for each of the medicines (Alirocumab- RR=0.88, 95% CI: 0.72–1.08, I2=0%, Evolocumab- RR=1.42, 95% CI: 0.74–2.73, I2=55%). In a meta-regression analysis there was no statistically significant association between the assessed and the risk for neurocognitive side effects. Conclusions Pooled results of our meta-analysis and meta-regression clearly show that the exposure to PCSK9 inhibitors is not associated with an increased risk of neurocognitive adverse events. Due to the increasing proportion of patients using lipid-lowering therapy these results are positively reassuring. However, more data from long-term outcomes studies is needed to further evaluate the effect of longer exposure to PCSK9 inhibitors Funding Acknowledgement Type of funding source: None

Proprotein convertase subtilisin/kexin type 9 in kidney disease

2019 ◽  
Vol 34 (8) ◽  
pp. 1266-1271 ◽  
Author(s):  
David Schmit ◽  
Danilo Fliser ◽  
Thimoteus Speer
Keyword(s):  
Kidney Disease ◽  
Statin Therapy ◽  
Kidney Function ◽  
Plasma Levels ◽  
Vascular Lesions ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Increased Risk

Abstract 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.

scholarly journals The impact of the revised ESC Dyslipidaemia Guidelines on lipid-lowering therapy: simulating the need for PCSK9 inhibition in a contemporary ASCVD cohort

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Blaum ◽  
F.J Brunner ◽  
F Kroeger ◽  
J Braetz ◽  
B Bay ◽  
...  
Keyword(s):  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors ◽  
Treatment Target ◽  
Pcsk9 Inhibitor ◽  
Lowering Therapy ◽  
Artery Disease ◽  
Pcsk9 Inhibition ◽  
The Impact

Abstract Introduction The recently updated ESC guidelines on the management of dyslipidaemias recommend a more intense LDL-cholesterol (LDL-C) reduction. For patients with atherosclerotic cardiovascular disease (ASCVD) the LDL-C goal has been revised to ≤55 mg/dl with a concomitant class IA upgrade for cost intensive PCSK9 inhibitors. Purpose We aim to quantify the need for PCSK9 inhibitors to achieve the revised LDL-C target compared to former ESC recommendations in ASCVD patients Methods We included all patients with ASCVD (angiographically documented coronary artery disease, history of peripheral artery disease or stroke) from an observational cohort study ongoing since 2015. A simulation treatment algorithm adding sequentially a high intensity statin, ezetimibe and a PCSK9 inhibitor in case of a missed treatment target was applied with consideration of both partial and total statin intolerance. The need for PCSK9 inhibitors was calculated for 3 recommendations: 1. LDL-C treatment target ≤55 mg/dl (ESC 2019 Guidelines), 2. LDL-C treatment target ≤70 mg/dl (ESC 2016 Guidelines) and 3. risk-based use of PCSK9 inhibitors restricted to patients with a residual LDL-C &gt;140 mg/dl or &gt;100 mg/dl with clinical/angiographic risk factors (ESC consensus update 2017). Results We included 1936 patients (mean age 69 years, 74% male). Median LDL-C at inclusion was 86 mg/dl, with 60% of patients taking lipid lowering medication (55% statin only, 4% statin + ezetimibe, 1% ezetimibe only). Table 1 shows the distribution of medications required to meet recommendations 1–3. After simulated stepwise intensification of lipid lowering therapy 99% of patients achieved the revised LDL-C target of ≤55 mg/dl, with a need of 23.5% for a PCSK9 inhibitor. For the former LDL-C target of ≤70 mg/dl the need for PCSK9 inhibitors was 10.5%. Restricting the use of PCSK9 inhibitors to the highest risk patients according to the ESC 2017 consensus statement reduced the need for PCSK9 inhibition to only 1.4% with slightly fewer patients achieving their LDL-C target (78% for ≤55 mg/dl and 91% for ≤70 mg/dl respectively). Conclusion The revised LDL-C treatment goals substantially increase the projected need for PCSK9 inhibitors with an unclear health economic impact. Identification of ASCVD patients with a reasonable benefit/cost-ratio of PCSK9 inhibition remains to be investigated urgently. Funding Acknowledgement Type of funding source: None

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.

2979The effect of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors on endothelial progenitor cells

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
O Itzhaki Ben Zadok ◽  
A Mager ◽  
D Leshem-Lev ◽  
E Lev ◽  
R Kornowski ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Vascular Repair ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Endothelial Progenitor ◽  
Pcsk9 Inhibitor ◽  
Stable Cad

Abstract Background Endothelial progenitor cells (EPCs) have an important role in the process of vascular repair by promoting re-endothelialization following endothelial injury. We hypothesized that proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, which reduce cardiovascular events, will increase the level of EPCs and thus affect the process of vascular repair. Therefore, we sought to investigate the effect of PCSK9 inhibitors on circulating EPCs. Methods Study population included patients with known stable CAD who were initiated PCSK9 inhibitors. Blood samples were drawn and evaluated for EPCs at baseline and after treatment (1 month). Circulating EPCs were then assessed quantitatively by the expression of VEGFR-2, CD34 and CD133 using flow cytometry, and functionally by the formation of colony forming units (CFUs). Results Our preliminary cohort included 12 patients (median age of 69 years), 31% of whom were female. At baseline, total cholesterol and low density lipoprotein levels were 190 (IQR 180, 227) mg/dL and 123 (IQR 107, 154) mg/dL, respectively. Following 1-month of therapy with a PCSK9 inhibitor and along with a decrease in LDL to a median of 58 (IQR 50, 67) mg/dL, we observed an increase in the expression of CD34(+)/VEGFR-2(+) (1.2% (IQR 0.6, 1.6) to 3.0% (IQR 1.2, 4.5), P=0.07) and CD133(+)/VEGFR-2(+) (0.8% (IQR 0.7, 1.4) to 1.7% (IQR 0.6, 4.0), P=0.5). Proliferation of EPCs was confirmed microscopically (1 CFUs (IQR 1, 1.5) to 1.5 CFUs (IQR 1.5, 2.5), P=0.016) (Figure 1) and by an MTT assay (0.16 (IQR 0.12, 0.19) to 0.19 (IQR 0.17, 0.21), p=0.016). Conclusions These preliminary results in patients with CAD demonstrate that treatment with PCSK9 inhibitors is associated with higher levels of EPCs, thus promote endothelial repair. This finding may represent a novel mechanism of action of PCSK9 inhibitors, which might have important future clinical implications.

The Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition on Sterol Absorption Markers in a Cohort of Real-World Patients

2018 ◽  
Vol 24 (1) ◽  
pp. 54-61 ◽  
Author(s):  
Eric J. Brandt ◽  
Lane B. Benes ◽  
Linda Lee ◽  
Thomas D. Dayspring ◽  
Matthew Sorrentino ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Serum Cholesterol ◽  
Retrospective Cohort ◽  
Cholesterol Absorption ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Pcsk9 Inhibitor ◽  
Before And After ◽  
Pcsk9 Inhibition

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed in multiple tissues, including the small intestine. The effect of PCSK9 inhibition on cholesterol absorption is not known. Objectives: Measure serum cholesterol absorption markers before and after initiation of PCSK9 inhibitors. Methods: Single-center retrospective cohort of patients administered evolocumab and alirocumab between July 2015 and January 2017. Paired t tests were used to compare mean serum cholesterol marker concentrations, and ratios to total cholesterol, before and after PCSK9 inhibitor initiation. Analyses were repeated for those taking and not taking statins and taking or not taking ezetimibe at both initiation and follow-up, for each PCSK9 inhibitor, and based on follow-up time (<60, 60-120, and >120 days). Results: There were 62 possible participants, 34 were excluded for lack of data or unknown PCSK9 inhibitor initiation date. Average follow-up was 92.5 days. Mean campesterol (before 3.14 μg/mL, 95% CI: 2.79-4.38 μg/mL; after 2.09 μg/mL, 95% CI: 1.87-2.31 μg/mL; P < .0001), sitosterol (before 2.46 μg/mL, 95% CI: 2.23-2.70 μg/mL; after 1.62 μg/mL, 95% CI: 1.48-1.75 μg/mL; P < .0001), and cholestanol (before 3.25 μg/mL, 95% CI: 3.04-3.47 μg/mL; after 2.08 μg/mL, 95% CI: 1.96-2.21 μg/mL; P < .0001) all significantly decreased at follow-up. There was no significant change in absorption marker to total cholesterol ratios. Findings were not influenced by statin or ezetimibe use or nonuse, which PCSK9 inhibitor was prescribed, or time to follow-up. Conclusion: Proprotein convertase subtilisin/kexin type 9 inhibition was associated with decreased cholesterol absorption markers.

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