scholarly journals Alirocumab as add-on therapy to statins: current evidence and clinical potential

2018 ◽  
Vol 12 (7) ◽  
pp. 191-202
Author(s):  
Johann Auer ◽  
Robert Berent
Keyword(s):  
High Risk ◽  
Statin Therapy ◽  
Lifestyle Modification ◽  
Current Knowledge ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Current Evidence ◽  
Pcsk9 Inhibition ◽  
Clinical Potential ◽  
Very High

Atherosclerotic cardiovascular diseases (ASCVDs) are associated with a substantial mortality, physical morbidity, and mental disability. Elevated plasma low-density lipoprotein cholesterol (LDL-C) levels play a major role in the pathophysiology of ASCVDs. Statins have been shown to reduce ASCVD risk and associated events and are recommended as first-line therapy for treatment of hypercholesterolemia by current international guidelines. The key issue is to attain guideline-recommended LDL-C levels (below 70 mg/dl) for patients at very high cardiovascular risk. However, many high-risk and very-high-risk patients on statin therapy remain beyond treatment goals despite lifestyle modification and statins, and are exposed to a high risk of future cardiovascular events including myocardial infarction (MI), stroke, revascularization procedures, and death. This clearly emphasizes the urgent need for additional LDL-C reduction with new therapeutic strategies to target these highly atherogenic particles and to further reduce the burden of ASCVDs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role as a key regulator of the hepatic LDL receptor recycling process. Developments over the past 15 years have demonstrated PCSK9 inhibition to be a novel therapeutic strategy to manage increased LDL-C levels. A number of clinical studies using humanized monoclonal antibody technology against PCSK9 have shown profound reductions of LDL-C levels when used either alone or in combination with statin therapy. Recently, the first cardiovascular outcome study demonstrated a significant reduction of ASCV events when evolocumab was added to a statin therapy. This review will discuss current knowledge about antibody-mediated PCSK9 inhibition as add-on therapy to statin and the clinical potential that may be expected.

P5327Are we being able to meet current guidelines LDL-cholesterol goals in very high risk patients? How many of them could benefit of PSCK9 inhibition by the FOURIER/ODYSSEY and NICE criteria?

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T El Andere ◽  
J A T Soto ◽  
I S Moreira ◽  
M N Wamser ◽  
H C Freitas ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
High Risk ◽  
Statin Therapy ◽  
Ldl Cholesterol ◽  
Target Range ◽  
Pcsk9 Inhibitors ◽  
High Risk Patients ◽  
Risk Patients ◽  
Pcsk9 Inhibition ◽  
Very High

Abstract Background/Introduction With increasing evidence of LDL-cholesterol (LDL-c) lowering and a subsequent reduction in cardiovascular events, guidelines of different parts of the world aim for lower LDL-c goals by risk stratification. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has been able to reduce up to 60% LDL-c levels, with further reduction in cardiovascular outcomes. Purpose Our aim was to evaluate the proportion of very high risk patients in a tertiary cardiology center that met LDL-c goal of less than 50mg/dL proposed by the Brazilian Society of Cardiology (BSC) guidelines. Furthermore, we assessed the number of patients that were receiving adequate statin intensity therapy and could benefit from PCSK9 inhibition by the FOURIER/ODYSSEY and by the National Institute for Health and Care Excellence (NICE) criteria. Methods We screened 2180 consecutive patients from March, 2018 to February, 2019 for cardiovascular risk factors, cholesterol and glycemic levels, and current medical therapy at use. Patients were stratified by level of risk, and compliance to recommended statin therapy was evaluated. We then analyzed how many of the very high risk patients, that were in use of high intensity statin therapy, met the inclusion LDL-c levels of the FOURIER/ODYSSEY trials (≥70mg/dL) and the NICE recommendations (≥140mg/dL) for the introduction of PCSK9 inhibitors. Results Of the 2180 patients enrolled to our study, 1225 (56.2%) patients were at very high cardiovascular risk level. Of these patients, 136 (11.1%) met LDL-c BSC guideline levels. Using the LDL-c target of 70mg/dL, an additional 320 (26.1%) patients were below target range. When analyzing statin therapy at use, 913 (74,5%) were receiving adequate statin therapy. Of the very high risk patients in adequate statin treatment, 617 (65.9%) by the FOURIER/ODYSSEY criteria and 88 (9.4%) patients by the NICE criteria would benefit from PCSK9 inhibitors. Conclusions With lower LDL-c goals, achievement of optimal LDL-c levels is now a challenge for current clinical practice. Even though many patients are receiving adequate guideline-based statin therapy, difficulty remains in achieving optimal treatment, especially in the higher risk stratum. These patients would benefit from PCSK9 inhibition, being the NICE criteria, a more cost-effective strategy, still applicable in a substantial portion of our patients.

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

VASA ◽  
2018 ◽  
Vol 47 (3) ◽  
pp. 165-176 ◽  
Author(s):  
Katrin Gebauer ◽  
Holger Reinecke
Keyword(s):  
Cardiovascular Risk ◽  
Risk Reduction ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Past Century ◽  
Pcsk9 Inhibitors ◽  
Cardiovascular Risk Reduction ◽  
Simultaneous Application ◽  
The Past ◽  
Pcsk9 Inhibition

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.

scholarly journals High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 574
Author(s):  
Maria Pia Adorni ◽  
Nicoletta Ronda ◽  
Franco Bernini ◽  
Francesca Zimetti
Keyword(s):  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Current Knowledge ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
High Density ◽  
Current Evidence ◽  
Endocrine Disorders ◽  
Lifestyle Modifications ◽  
Cholesterol Efflux Capacity

Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches.

scholarly journals Increased Circulating Malondialdehyde-Modified Low-Density Lipoprotein Level Is Associated with High-Risk Plaque in Coronary Computed Tomography Angiography in Patients Receiving Statin Therapy

2021 ◽  
Vol 10 (7) ◽  
pp. 1480
Author(s):  
Keishi Ichikawa ◽  
Toru Miyoshi ◽  
Kazuhiro Osawa ◽  
Takashi Miki ◽  
Hiroshi Ito
Keyword(s):  
Computed Tomography ◽  
High Risk ◽  
Statin Therapy ◽  
Computed Tomography Angiography ◽  
Coronary Computed Tomography Angiography ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Coronary Cta ◽  
Coronary Computed Tomography

Objective: To evaluate the association of serum malondialdehyde low-density lipoprotein (MDA-LDL), an oxidatively modified LDL, with the prevalence of high-risk plaques (HRP) determined with coronary computed tomography angiography (CTA) in statin-treated patients. Methods: This study was a single-center retrospective cohort comprising 268 patients (mean age 67 years, 58% men) with statin therapy and who underwent coronary CTA for suspected stable coronary artery disease. Patients were classified into two groups according to median MDA-LDL level or median LDL-C level. Coronary CTA-verified HRP was defined when two or more characteristics, including positive remodeling, low-density plaques, and spotty calcification, were present. Results: Patients with HRP had higher MDA-LDL (p = 0.011), but not LDL-C (p = 0.867) than those without HRP. High MDA-LDL was independently associated with HRP (odds ratio 1.883, 95% confidential interval 1.082–3.279) after adjustment for traditional risk factors. Regarding incremental value of MDA-LDL for predicting CTA-verified HRP, addition of serum MDA-LDL levels to the baseline model significantly increased global chi-square score from 26.1 to 32.8 (p = 0.010). Conclusions: A high serum MDA-LDL level is an independent predictor of CTA-verified HRP, which can lead to cardiovascular events in statin-treated patients.

Statin dose titration patterns and subsequent major cardiovascular events in very high-risk patients: estimates from Swedish population-based registry data

2020 ◽  
Vol 6 (4) ◽  
pp. 323-331
Author(s):  
Jonas Banefelt ◽  
Maria Lindh ◽  
Maria K Svensson ◽  
Björn Eliasson ◽  
Ming-Hui Tai
Keyword(s):  
High Risk ◽  
Statin Therapy ◽  
High Intensity ◽  
Lower Risk ◽  
Cardiovascular Events ◽  
Population Based ◽  
Moderate Intensity ◽  
Risk Patients ◽  
Population Based Registry ◽  
Very High

Abstract Aims Clinical studies have demonstrated the efficacy of intensive statin therapy in lowering low-density lipoprotein cholesterol and cardiovascular (CV) events. Our objective was to examine statin titration patterns and the association between titration patterns and subsequent CV events in very high-risk patients. Methods and results Using Swedish national population-based registry data, we identified 192 435 patients with very high risk of atherosclerotic CV disease initiated on moderate-intensity statin therapy between 2006 and 2013. Outcomes of interest were titration to high-intensity therapy and the major adverse cardiovascular events (MACE) composite (myocardial infarction, ischaemic stroke, and CV death) outcome. Cumulative incidence of MACE was assessed by titration status 1-year post-treatment initiation in patients adherent to treatment during the first year, using a 12-week cut-off from initiation to define early, delayed and no up-titration to high-intensity statins. Cox regression analysis was used to estimate adjusted hazard ratios (HRs). In 144 498 eligible patients, early titration was associated with significantly lower risk of MACE in the subsequent 2 years compared to no up-titration (HR 0.76, P < 0.01]. Delayed up-titration was associated with a smaller reduction (HR 0.88, P = 0.08). The majority of patients did not up-titrate. Conclusion Early up-titration to high-intensity statins was independently associated with lower risk of subsequent CV events compared to no up-titration. Delayed up-titration was not associated with the same benefit. Despite the higher risk associated with no up-titration, few patients at very high CV risk who started treatment on moderate-intensity up-titrated to high intensity, indicating a potential need for more aggressive lipid management of these patients in clinical practice.

scholarly journals Cardiovascular risk management in antiphospholipid syndrome: trends over time and comparison with rheumatoid arthritis and diabetes mellitus

2021 ◽  
Vol 8 (1) ◽  
pp. e000579
Author(s):  
Eleana Bolla ◽  
Nikolas Tentolouris ◽  
Petros P Sfikakis ◽  
Maria G Tektonidou
Keyword(s):  
Rheumatoid Arthritis ◽  
Diabetes Mellitus ◽  
Cardiovascular Risk ◽  
High Risk ◽  
Density Lipoprotein ◽  
Risk Patients ◽  
Esc Guidelines ◽  
Trends Over Time ◽  
Very High ◽  
Over Time

ObjectiveAntiphospholipid syndrome (APS) is characterised by increased cardiovascular morbidity and mortality, related to thrombo-inflammatory and atherogenic mechanisms. We examined the achievement of traditional cardiovascular risk factor (CVRF) therapeutic goals in APS versus other high cardiovascular risk disorders such as rheumatoid arthritis (RA) and diabetes mellitus (DM), and trends over time.Methods122 patients with APS (74 primary APS, female 68%, mean age 44.5±11.3) were classified according to their first visit (2011–2015 and 2016–2020 APS subgroups, 61 patients in each subgroup) and matched 1:1 for age/sex with patients with RA and DM. Cardiovascular risk was estimated by the Systemic Coronary Risk Evaluation, and the CVRF therapeutic targets were defined according to the European Society of Cardiology (ESC) guidelines. Individual and multiple CVRF control was compared between APS subgroups, and in APS versus RA and DM.ResultsWe found a comparable or higher prevalence of CVRFs between APS and age-matched/sex-matched patients with RA and DM but low CVRF target attainment in APS according to the ESC guidelines. Despite improving trends between 2011–2015 and 2016–2020, CVRF control in high/very high-risk patients with APS was 12%, 18%, 24% and 35% for low-density lipoprotein, waist circumference, exercise and body mass index, respectively, and 59%–65% for triglycerides, high-density lipoprotein (HDL) and blood pressure, in 2016–2020 subgroup. CVRF control was worse in APS versus RA for smoking (p=0.014), HDL (p<0.001), waist circumference (p=0.042) and five CVRFs (p=0.030), and versus DM for exercise (p=0.077). Similar results were found in the sensitivity analysis.ConclusionsComparable prevalence of modifiable CVRFs to RA and DM but suboptimal CVRF target achievement was observed in APS, especially in high/very high-risk patients, highlighting the need for CVRF management strategies.

scholarly journals Statins for primary prevention of cardiovascular disease: modelling guidelines and patient preferences based on an Irish cohort

2019 ◽  
Vol 69 (683) ◽  
pp. e373-e380 ◽  
Author(s):  
Paula Byrne ◽  
John Cullinan ◽  
Paddy Gillespie ◽  
Rafael Perera ◽  
Susan M Smith
Keyword(s):  
Cardiovascular Disease ◽  
Primary Prevention ◽  
High Risk ◽  
Statin Therapy ◽  
Clinical Guidelines ◽  
Baseline Risk ◽  
Recommended Treatment ◽  
Risk Patients ◽  
Very High ◽  
Prevention Of Cardiovascular Disease

BackgroundChanges in clinical guidelines for primary prevention of cardiovascular disease (CVD) have widened eligibility for statin therapy.AimTo illustrate the potential impacts of changes in clinical guidelines.Design and settingModelling the impacts of seven consecutive European guidelines based on a cohort of people aged ≥50 years from the Irish Longitudinal Study on Ageing.MethodThe eligibility for statin therapy of a sample of people without a history of CVD was established, according to changing guideline recommendations and modelled associated potential costs. The authors calculated the numbers needed to treat (NNT) to prevent one major vascular event in patients at the lowest baseline risk for which each of the seven guidelines recommended treatment, and for those at low, medium, high, and very-high risk according to 2016 guidelines. These were compared with the NNT that patients reported as required to justify taking a daily medicine.ResultsThe proportion of patients eligible for statins increased from approximately 8% in 1987 to 61% in 2016; associated costs rose from €13.9 million to €107.1 million per annum. The NNT for those at the lowest risk for which each guideline recommended treatment rose from 40 to 400. By 2016, the NNT for low-risk patients was 400 compared to ≤25 very-high risk patients. The proportion of patients eligible for statins achieving NNT levels that patients regarded as justified to taking a daily medicine fell as guidelines changed over time.ConclusionIncreased eligibility for statin therapy impacts large proportions of the present population and healthcare budgets. Decisions to take and reimburse statins should be considered on the basis of expected cost-effectiveness and acceptability to patients.

scholarly journals PCSK9 and inflammation: a review of experimental and clinical evidence

2019 ◽  
Vol 5 (4) ◽  
pp. 237-245 ◽  
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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