PCSK9 inhibition for LDL lowering and beyond – implications                     for patients with peripheral artery disease

Abstract. Low-density lipoprotein cholesterol (LDL-C) has been proven to be a causal factor of atherosclerosis and, along with other triggers like inflammation, the most frequent reason for peripheral arterial disease. Moreover, a linear correlation between LDL-C concentration and cardiovascular outcome in high-risk patients could be established during the past century. After the development of statins, numerous randomized trials have shown the superiority for LDL-C reduction and hence the decrease in cardiovascular outcomes including mortality. Over the past decades it became evident that more intense LDL-C lowering, by either the use of highly potent statin supplements or by additional cholesterol absorption inhibitor application, accounted for an even more profound cardiovascular risk reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serin protease with effect on the LDL receptor cycle leading to its degradation and therefore preventing continuing LDL-C clearance from the blood, is the target of a newly developed monoclonal antibody facilitating astounding LDL-C reduction far below to what has been set as target level by recent ESC/EAS guidelines in management of dyslipidaemias. Large randomized outcome trials including subjects with PAD so far have been able to prove significant and even more intense cardiovascular risk reduction via further LDL-C debasement on top of high-intensity statin medication. Another approach for LDL-C reduction is a silencing interfering RNA muting the translation of PCSK9 intracellularly. Moreover, PCSK9 concentrations are elevated in cells involved in plaque composition, so the potency of intracellular PCSK9 inhibition and therefore prevention or reversal of plaques may provide this mechanism of action on PCSK9 with additional beneficial effects on cells involved in plaque formation. Thus, simultaneous application of statins and PCSK9 inhibitors promise to reduce cardiovascular event burden by both LDL-C reduction and pleiotropic effects of both agents.

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Language Concordance as a Determinant of Patient Outcomes in a Pharmacist-Managed Cardiovascular Risk Reduction Clinic

Journal of Pharmacy Practice ◽

10.1177/0897190014544790 ◽

2014 ◽

Vol 29 (2) ◽

pp. 103-105 ◽

Cited By ~ 4

Author(s):

Jasmine D. Gonzalvo ◽

Nora H. Sharaya

Keyword(s):

Cardiovascular Risk ◽

Risk Reduction ◽

Clinical Outcomes ◽

Health Care Disparities ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Retrospective Chart Review ◽

Cardiovascular Risk Reduction ◽

Language Concordance ◽

English Speaking

Background: Published literature reveals that health care disparities exist due to race, gender, and language, although this has not been confirmed in a pharmacist-managed patient population. Objective: The objective of this study is to examine the association of language concordance and clinical outcomes in a comparison of English-speaking (ES) and Spanish-speaking (SS) patients in a pharmacist-managed cardiovascular risk reduction clinic (CVRRC). Methods: A retrospective chart review was undertaken to collect hemoglobin A1C, blood pressure, and low-density lipoprotein cholesterol (LDL-C) for patients enrolled in the CVRRC from July 2010 and August 2012. A 2-sample t-test was utilized to compare these outcomes between ES and SS patients. Results: A total of 9 SS patients and 62 ES patients were included. No statistically significant differences were found between ES and SS patients in this language-concordant, pharmacist-managed clinic setting. Conclusions: These results suggest that similar clinical outcomes between ES and SS patients may be achieved with the ability of pharmacists to speak the same language as their patients.

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PCSK9 and inflammation: a review of experimental and clinical evidence

European Heart Journal - Cardiovascular Pharmacotherapy ◽

10.1093/ehjcvp/pvz022 ◽

2019 ◽

Vol 5 (4) ◽

pp. 237-245 ◽

Cited By ~ 16

Author(s):

Amir Abbas Momtazi-Borojeni ◽

Sarvenaz Sabouri-Rad ◽

Antonio M Gotto ◽

Matteo Pirro ◽

Maciej Banach ◽

...

Keyword(s):

Atherosclerotic Plaque ◽

Vascular Inflammation ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Atherosclerotic Lesion ◽

Density Lipoprotein ◽

Pcsk9 Inhibitors ◽

Protein Levels ◽

Major Player ◽

Pcsk9 Inhibition

AbstractProprotein convertase subtilisin/kexin Type 9 (PCSK9) is now identified as an important and major player in hypercholesterolaemia and atherosclerosis pathophysiology. PCSK9, through promoting lysosomal degradation of hepatic low-density lipoprotein (LDL) receptor, can decrease the clearance of plasma LDLs, leading to hypercholesterolaemia and consequent atherosclerotic plaque formation. Hypercholesterolaemia has been found to promote systemic and vascular inflammation, which can cause atherosclerotic lesion formation and progression and subsequent incidence of cardiovascular disease. Recent studies have shown the involvement of PCSK9 in the inflammatory pathway of atherosclerosis. Although trials with PCSK9 inhibitors have not shown any alteration in plasma C-reactive protein levels, there is accumulating evidence showing lessened inflammatory response in the arterial wall that could attenuate atherosclerotic plaque development beyond the established LDL-lowering effect of PCSK9 inhibition. In this review, we represent mounting evidence indicating that PCSK9 can locally increase vascular inflammation and contribute to atherosclerotic plaque progression in patients with hypercholesterolaemia.

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PCSK9 inhibition-based therapeutic approaches: an immunotherapy perspective

Current Medicinal Chemistry ◽

10.2174/0929867328666211027125245 ◽

2021 ◽

Vol 28 ◽

Author(s):

Amir Abbas Momtazi-Borojeni ◽

Matteo Pirro ◽

Suowen Xu ◽

Amirhossein Sahebkar

Keyword(s):

Clinical Studies ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Cost Effective ◽

Atherosclerotic Cardiovascular Disease ◽

Therapeutic Approaches ◽

Pcsk9 Inhibitors ◽

Therapeutic Tools ◽

Pcsk9 Inhibition

: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9-I) are novel therapeutic tools to decrease cardiovascular risk. These agents work by lowering the low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients who are statin resistant/intolerant. Current clinically approved and investigational PCSK9-I act generally by blocking PCSK9 activity in the plasma or suppressing its expression or secretion by hepatocytes. The most widely investigated method is the disruption of PCSK9/LDL receptor (LDLR) interaction by fully-humanized monoclonal antibodies (mAbs), evolocumab and alirocumab, which have been approved for the therapy of hypercholesterolemia and atherosclerotic cardiovascular disease (CVD). Besides, a small interfering RNA called inclisiran, which specifically suppresses PCSK9 expression in hepatocytes, is as effective as mAbs but with administration twice a year. Because of the high costs of such therapeutic approaches, several other PCSK9-I have been surveyed, including peptide-based anti-PCSK9 vaccines and small oral anti-PCSK9 molecules, which are under investigation in preclinical and phase I clinical studies. Interestingly, anti-PCSK9 vaccination has been found to serve as a more widely feasible and more cost-effective therapeutic tool over mAb PCSK9-I for managing hypercholesterolemia. The present review will discuss LDL-lowering and cardioprotective effects of PCSK9-I, mainly immunotherapy-based inhibitors including mAbs and vaccines, in preclinical and clinical studies.

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A lipid lover’s guide to novel therapeutics for lipid and cardiovascular risk reduction

Future Cardiology ◽

10.2217/fca-2020-0216 ◽

2021 ◽

Vol 17 (3) ◽

pp. 507-520

Author(s):

Rama Hritani ◽

Aliza Hussain ◽

Anum Saeed ◽

Anandita Agarwala

Keyword(s):

Cardiovascular Risk ◽

Risk Reduction ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

High Sensitivity ◽

Cardiovascular Risk Reduction ◽

Apolipoprotein C3 ◽

Novel Therapeutics ◽

Reactive Protein ◽

Lipids And Lipoproteins

Lipids and lipoproteins are the target of many novel therapeutics and are an area with great potential for the prevention and treatment of cardiovascular disease (CVD). Reduction of low-density lipoprotein cholesterol has been the mainstay of reducing the burden of CVD, however, several other atherogenic particles have more recently come into the spotlight as potential avenues for primary and/or secondary prevention of CVD. These include triglycerides, high sensitivity C-reactive protein, apolipoprotein A, apolipoprotein C3 and lipoprotein(a). In this review, we showcase novel therapeutics to target lipid and cardiovascular risk reduction that are either in development or that have recently been approved for use. We discuss the mechanisms of action, data from clinical trials and expected effects of each therapy based on the current body of literature.

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Low-Density Lipoprotein Cholesterol and Cardiovascular Risk Reduction

JAMA Cardiology ◽

10.1001/jamacardio.2018.2273 ◽

2018 ◽

Vol 3 (9) ◽

pp. 802 ◽

Cited By ~ 1

Author(s):

Antonio M. Gotto

Keyword(s):

Cardiovascular Risk ◽

Risk Reduction ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Cardiovascular Risk Reduction

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Changes in C-reactive protein in response to anti-inflammatory therapy as a predictor of cardiovascular outcomes: A systematic review and meta-analysis

JRSM Cardiovascular Disease ◽

10.1177/2048004020929235 ◽

2020 ◽

Vol 9 ◽

pp. 204800402092923

Author(s):

Annie Berkley ◽

Albert Ferro

Keyword(s):

Cardiovascular Risk ◽

Risk Reduction ◽

Cardiovascular Events ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipid Levels ◽

C Reactive Protein ◽

Cardiovascular Risk Reduction ◽

Reactive Protein ◽

Protein Reduction

Background Despite the availability of aggressive lipid-lowering strategies, many patients remain at risk of cardiovascular events. C-reactive protein is a marker of inflammation elevated in patients at high risk of cardiovascular events. C-reactive protein has demonstrated value as a predictor of cardiovascular risk; however, it is unclear whether targeting C-reactive protein levels improves outcomes. This systematic review aimed to characterise the relationship between C-reactive protein and cardiovascular outcomes and to assess whether the magnitude of C-reactive protein reduction correlates to the extent of cardiovascular risk reduction. Methods A systematic review was conducted to identify randomised controlled trials that measured C-reactive protein before and after administration of therapies for cardiovascular disease and measured incidence of cardiovascular events. A meta-analysis of placebo-controlled studies assessed the relationship between extent of C-reactive protein reduction and cardiovascular risk reduction. Placebo-controlled studies where low-density lipoprotein and triglyceride data were available were also included in a meta-regression to assess the influence of these established risk factors on the efficacy of treatment when compared to C-reactive protein. Results Fifteen studies met the criteria for inclusion in this review, of which six were active comparator studies and nine were placebo controlled. Six placebo-controlled studies had data available for meta-regression. Eight studies demonstrated a reduction in events that could be explained by changes in lipid levels, whereas the results of five studies suggested that the association between C-reactive protein reduction and event rates cannot be explained by changes in lipid levels alone. No correlation was found between magnitude of C-reactive protein reduction and cardiovascular risk reduction. A strong correlation was found between C-reactive protein and low-density lipoprotein reduction (adjusted r2 = 0.8). Conclusions Targeting C-reactive protein does not offer additional benefit over targeting low-density lipoprotein across the general population in terms of cardiovascular risk reduction. However, there is value in targeting C-reactive protein in patients at high residual inflammatory risk despite non-elevated lipid levels or use of lipid-lowering therapy.

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