PCSK9 in cholesterol metabolism: from bench to bedside

2018 ◽  
Vol 132 (11) ◽  
pp. 1135-1153 ◽  
Author(s):  
Allison B. Reiss ◽  
Neal Shah ◽  
Dalia Muhieddine ◽  
Juan Zhen ◽  
Jennifer Yudkevich ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cholesterol Metabolism ◽  
Treatment Options ◽  
Low Density Lipoprotein ◽  
Regulatory Protein ◽  
Density Lipoprotein ◽  
Atherosclerotic Cardiovascular Disease ◽  
Pcsk9 Inhibitors ◽  
Adequate Treatment ◽  
First Line Therapy

Dyslipidemia, and specifically elevated low-density lipoprotein (LDL) cholesterol, is one of the most important cardiovascular risk factors. Statins are considered first line therapy for the primary and secondary prevention of cardiovascular disease. However, statins may not be adequate treatment for elevated circulating LDL levels and are ineffective in certain familial hypercholesterolemias. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulatory protein that affects LDL receptors, offers a new alternative for these patients. Moreover, gain-of-function PCSK9 mutations were discovered to be the root cause of familial autosomal dominant hypercholesterolemia. Inhibition of PSCK9 reduces plasma LDL levels, even in patients for whom statins are ineffective or not tolerated. Alirocumab and evolocumab, human monoclonal antibodies that inhibit PCSK9, have been approved to lower LDL levels. While there are drawbacks to these treatments, including adverse events, administration by subcutaneous injection, and high cost, these drugs are indicated for the treatment of atherosclerotic cardiovascular disease and familial hypercholesterolemia as adjunct to diet and maximally tolerated statin therapy. PCSK9 inhibitors may work synergistically with statins to lower LDL. Novel approaches to PCSK9 inhibition are currently in development with the aim of providing safe and effective treatment options to decrease cardiovascular event burden, ideally at lower cost and with oral bioavailability.

scholarly journals Real-world use of PCSK9 inhibitors: A single-center experience

2018 ◽  
Vol 47 (1) ◽  
pp. 265-270 ◽  
Author(s):  
Sinan Sarsam ◽  
Abeer Berry ◽  
George Degheim ◽  
Robby Singh ◽  
Marcel Zughaib
Keyword(s):  
Cardiovascular Disease ◽  
Lipid Profile ◽  
Real World ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Pcsk9 Inhibitors ◽  
Pcsk9 Inhibitor ◽  
The Impact

Objective Hyperlipidemia is an important risk factor for atherosclerotic cardiovascular disease. Many patients are intolerant to or have limited benefit from statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been approved for treating hyperlipidemia in these patients. We sought to investigate the impact of these medications in a real-world cardiology practice. Methods This was a retrospective study of 17 patients with either heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) levels above the treatment target despite maximally tolerated statins. Baseline lipid profile was compared with a repeat lipid profile obtained 4 to 6 weeks after initiating treatment with a PCSK9 inhibitor. Results The average duration of PCSK9 inhibitor treatment was 10.7 months. Lipid profile comparison showed that total cholesterol decreased from 243 ± 72 to 148 ± 39 (mg/dL) (39% reduction), triglycerides decreased from 185 ± 86 to 149 ± 62 (mg/dL) (19.5% reduction), high-density lipoprotein cholesterol increased from 56 ± 20 to 62 ± 26 (mg/dL) (10.7% increase), and LDL-C decreased from 154 ± 30 to 57 ± 32 (mg/dL) (63% reduction) from baseline. Conclusions PCSK9 inhibitors as add-on therapy to maximally tolerated statins resulted in an approximately 63% reduction in LDL-C.

PCSK9 Inhibitors and Ezetimibe Monotherapy in Patients Not Receiving Statins: A Meta-Analysis of Randomized Trials

2020 ◽  
Vol 18 ◽  
Author(s):  
Benjamin Benhuri ◽  
Hiroki Ueyama ◽  
Hisato Takagi ◽  
Alexandros Briasoulis ◽  
Toshiki Kuno
Keyword(s):  
Randomized Trials ◽  
Primary Outcome ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Treatment Options ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors

Background: Statins are the mainstay of treatment for low-density lipoprotein cholesterol (LDL-C) lowering, however, some patients cannot tolerate statins because of adverse effects. Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are alternative treatment options. The purpose of this meta-analysis is to compare LDL-C reduction with ezetimibe vs PCSK9i in patients not on statins. Methods: PubMed and EMBASE were searched until 14 March 2020 for randomized clinical trials (RCTs) assessing the efficacy of ezetimibe vs PCSK9i in patients not on statins. The primary outcome was reduction in LDL-C levels. A subgroup analysis of statin intolerant patients was also performed. Results: We identified 8 RCTs that enrolled a total of 1602 patients comparing the two pharmacotherapies. PCSK9i lowered LDL-C levels significantly more than ezetimibe (mean difference (MD): -36.5; 95% confidence interval (CI) [-38.3, -34.7, p<0.00001, I2=4%]. In the statin intolerant subgroup, PCSK9i showed significantly greater reduction in LDL-C levels compared with ezetimibe (MD: -36.1; 95% CI [-39.2, -33.1, p<0.00001, I2=21%]. There were no significant differences in LDL-C reduction between different PCSK9i dosages (140 mg once every 2 weeks vs 420 mg once every 4 weeks) (MD: - 1.87; 95% CI [-4.45, 0.71, p<0.16, I2=0]. Conclusions: Among patients who are statin intolerant or not receiving statins, PCSK9i use is associated with significantly lower LDL-C levels than after treatment with ezetimibe. PCSK9i might be useful in the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) in this subset of patients.

scholarly journals Trends in PCSK9 Inhibitor Prescriptions before and after the Price Reduction in Patients with Atherosclerotic Cardiovascular Disease

2021 ◽  
Vol 10 (17) ◽  
pp. 3828
Author(s):  
Alex Smith ◽  
Drew Johnson ◽  
Joshua Banks ◽  
Scott W. Keith ◽  
Dean G. Karalis
Keyword(s):  
Cardiovascular Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Prescribing Patterns ◽  
Price Reduction ◽  
High Price ◽  
Atherosclerotic Cardiovascular Disease ◽  
Pcsk9 Inhibitors ◽  
Pcsk9 Inhibitor ◽  
Before And After

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein (LDL) cholesterol and cardiovascular event rates, yet due to their high price remain underutilized and difficult to prescribe in clinical practice. In March 2018, their price was significantly reduced. We evaluated whether the price reduction would improve prescribing patterns of PCSK9 inhibitors in eligible patients with atherosclerotic cardiovascular disease (ASCVD). Methods: We identified the number of eligible ASCVD patients and those prescribed a PCSK9 inhibitor for each year between July 2015 and December 2019. Patient demographics and clinical characteristics for those prescribed a PCSK9 inhibitor were extracted from their electronic health record. Results: In total 1059 patients of eligible patients received a new prescription for a PCSK9 inhibitor. From 2015 to 2019, the rate of new prescriptions among eligible patients increased from 0.5 to 3.3% (p < 0.001) and continuation rates increased from 18 to 60% (p < 0.001). Following the price reduction, patients who were prescribed a PCSK9 inhibitor were younger and more likely to be female, but less likely to have Medicare insurance. Conclusions: Despite the reduction in the cost of PCSK9 inhibitors, most eligible patients are not prescribed one. The reduction in cost has improved adherence, primarily in patients with commercial insurance. Older patients and those on Medicare still face significant barriers in accessing a PCSK9 inhibitor. Further reductions in the price of the PCSK9 inhibitors are needed as is further study of the barriers that exist in prescribing one.

scholarly journals Inclisiran—Silencing the Cholesterol, Speaking up the Prognosis

2021 ◽  
Vol 10 (11) ◽  
pp. 2467
Author(s):  
Sylwester Rogula ◽  
Ewelina Błażejowska ◽  
Aleksandra Gąsecka ◽  
Łukasz Szarpak ◽  
Milosz J. Jaguszewski ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
General Information ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiovascular Risk Reduction ◽  
Speaking Up ◽  
Pcsk9 Inhibitor

The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%–20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.

scholarly journals Emerging Non-statin Treatment Options for Lowering Low-Density Lipoprotein Cholesterol

2021 ◽  
Vol 8 ◽  
Author(s):  
Chandni Bardolia ◽  
Nishita Shah Amin ◽  
Jacques Turgeon
Keyword(s):  
Cardiovascular Disease ◽  
Adverse Drug Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
New Drugs ◽  
Lipoprotein Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors

Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for the development of atherosclerotic cardiovascular disease. Statins have been the gold standard for managing cholesterol levels and reducing the risks associated with atherosclerotic cardiovascular disease; however, many patients do not achieve their cholesterol goals or are unable to tolerate this drug class due to adverse drug events. Recent studies of non-statin cholesterol lowering drugs (i.e., ezetimibe, PCSK9 inhibitors) have demonstrated cardiovascular benefits; and new drugs [i.e., bempedoic acid (BDA), inclisiran] have produced promising results in pre-clinical and clinical outcome trials. This narrative review aims to discuss the place in therapy of ezetimibe, PCSK9 inhibitors, BDA, and inclisiran and describe their relative pharmacokinetic (PK) profiles, efficacy and safety as monotherapy and combination therapy, and cardiovascular benefit(s) when used for hypercholesterolemia.

Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

2021 ◽  
pp. 107424842110236
Author(s):  
Ruihai Zhou ◽  
George A. Stouffer ◽  
Sidney C. Smith
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Outcomes ◽  
Mechanism Of Action ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Blood Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Pcsk9 Inhibitors ◽  
Cholesterol Lowering ◽  
Cholesterol Levels

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as “bad” cholesterol and high-density lipoprotein cholesterol (HDL-C) as “good” cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.

Low-density lipoprotein cholesterol goal attainment and treatment patterns in a cohort of >143,000 patients with atherosclerotic cardiovascular disease in Ontario, Canada

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Fairbairn ◽  
P Oh ◽  
R Goeree ◽  
R.M Rogoza ◽  
M Packalen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Goal Attainment ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Data Repository ◽  
Funding Source ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

Abstract Background/Introduction Limited real-world data are available on attainment of low-density lipoprotein cholesterol (LDL-C) treatment goals in patients with atherosclerotic cardiovascular disease (ASCVD) in Canada. Purpose A retrospective observational study was conducted to describe types of ASCVD events/procedures, time between events and use of lipid lowering treatment (LLT) in patients who did not achieve LDL-C goal. Methods Patients in Ontario ≥65 years with a primary ASCVD event/procedure between 1 Apr 2005 and 31 Mar 2016, treated with an LLT and with index and follow up LDL-C values were identified from claims data at the Institute for Clinical Evaluative Sciences data repository. Patients were assessed over a 1-year follow up period for LDL-C goal attainment (&lt;2.0 mmol/L or 50% reduction from index LDL-C) and analysed by LLT and by index event type. Results Overall, 28% of 143,302 patients ≥65 years on LLT failed to attain LDL-C goal at follow up (Figure). The proportion of patients failing to achieve LDL-C goal decreased from 35% to 22% over the 11-year study period. Mean time between index and follow up LDL-C (based on lowest score &gt;2 weeks and up to 1 year after index LDL-C) was 203±97 days. When analysed by low-, moderate- or high-intensity statin, 57%, 30%, and 22% of patients failed to achieve LDL-C goal at follow up, respectively. Conclusions In this study, more than 1 in 4 patients with ASCVD in Ontario failed to achieve guideline recommended LDL-C goal despite treatment. In particular, ∼1 in 3 patients with cerebral and peripheral arterial disease were not at goal. An opportunity exists to better manage these high risk ASCVD patients with further statin intensification and additional LLTs This study made use of de-identified data from the ICES Data Repository, which is managed by the Institute for Clinical Evaluative Sciences with support from its funders and partners: Canada's Strategy for Patient-Oriented Research (SPOR), the Ontario SPOR Support Unit, the Canadian Institutes of Health Research and the Government of Ontario. The opinions, results and conclusions reported are those of the authors. No endorsement by ICES or any of its funders or partners is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen Canada Inc.

Eligibility for PCSK9 inhibitors based on the 2019 ESC/EAS and 2018 ACC/AHA guidelines

2020 ◽  
pp. 204748732094010
Author(s):  
Konstantinos C Koskinas ◽  
Baris Gencer ◽  
David Nanchen ◽  
Mattia Branca ◽  
David Carballo ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
High Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Coronary Syndrome ◽  
Coronary Syndromes

Aims The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) lipid guidelines recently updated their recommendations regarding proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i). We assessed the potential eligibility for PCSK9i according to the new guidelines in patients with acute coronary syndromes. Methods and results We analysed a contemporary, prospective Swiss cohort of patients hospitalised for acute coronary syndromes. We modelled a statin intensification effect and an incremental ezetimibe effect on low-density lipoprotein-cholesterol levels among patients who were not on high-intensity statins or ezetimibe. One year after the index acute coronary syndrome event, treatment eligibility for PCSK9i was defined as low-density lipoprotein-cholesterol of 1.4 mmol/l or greater according to ESC/EAS guidelines. For ACC/AHA guidelines, treatment eligibility was defined as low-density lipoprotein-cholesterol of 1.8 mmol/l or greater in the presence of very high-risk atherosclerotic cardiovascular disease, defined by multiple major atherosclerotic cardiovascular disease events and/or high-risk conditions. Of 2521 patients, 93.2% were treated with statins (53% high-intensity statins) and 7.3% with ezetimibe at 1 year, and 54.9% had very high-risk atherosclerotic cardiovascular disease. Low-density lipoprotein-cholesterol levels less than 1.8 mmol/l and less than 1.4 mmol/l at 1 year were observed in 37.5% and 15.7% of patients, respectively. After modelling the statin intensification and ezetimibe effects, these numbers increased to 76.1% and 49%, respectively. The proportion of patients eligible for PCSK9i was 51% according to ESC/EAS criteria versus 14% according to ACC/AHA criteria. Conclusions In this analysis, the 2019 ESC/EAS guidelines rendered half of all post-acute coronary syndrome patients potentially eligible for PCSK9i treatment, as compared to a three-fold lower eligibility rate based on the 2018 ACC/AHA guidelines.

scholarly journals Focus on… Praluent®

2020 ◽  
pp. 175-178
Author(s):  
L Steyn
Keyword(s):  
Cardiovascular Disease ◽  
High Density Lipoprotein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pivotal Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Lipoprotein Receptors

Cholesterol plays a pivotal role in the functioning of healthy cells. Being mostly lipophilic, cholesterol is transported in the blood inside lipophilic particles, e.g. high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). Hypercholesterolaemia refers to elevated low-density lipoprotein cholesterol (LDL-C) levels, and increases the risk for premature atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein receptors (LDL-R) on the surface of hepatocytes, are the primary receptors involved in clearing circulating LDL-C.

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