scholarly journals Changes in circulating pro-protein convertase subtilisin/kexin type 9 levels – experimental and clinical approaches with lipid-lowering agents

2019 ◽  
Vol 26 (9) ◽  
pp. 930-949 ◽  
Author(s):  
C Macchi ◽  
M Banach ◽  
A Corsini ◽  
CR Sirtori ◽  
N Ferri ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Cardiovascular Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cardiovascular Outcomes ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Coronary Syndrome

Regulation of pro-protein convertase subtilisin/kexin type 9 (PCSK9) by drugs has led to the development of a still small number of agents with powerful activity on low-density lipoprotein cholesterol levels, associated with a significant reduction of cardiovascular events in patients in secondary prevention. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) studies, with the two available PCSK9 antagonists, i.e. evolocumab and alirocumab, both reported a 15% reduction in major adverse cardiovascular events. Regulation of PCSK9 expression is dependent upon a number of factors, partly genetic and partly associated to a complex transcriptional system, mainly controlled by sterol regulatory element binding proteins. PCSK9 is further regulated by concomitant drug treatments, particularly by statins, enhancing PCSK9 secretion but decreasing its stimulatory phosphorylated form (S688). These complex transcriptional mechanisms lead to variable circulating levels making clinical measurements of plasma PCSK9 for cardiovascular risk assessment a debated matter. Determination of total PCSK9 levels may provide a diagnostic tool for explaining an apparent resistance to PCSK9 inhibitors, thus indicating the need for other approaches. Newer agents targeting PCSK9 are in clinical development with a major interest in those with a longer duration of action, e.g. RNA silencing, allowing optimal patient compliance. Interest has been expanded to areas not only limited to low-density lipoprotein cholesterol reduction but also investigating other non-lipid pathways raising cardiovascular risk, in particular inflammation associated to raised high-sensitivity C-reactive protein levels, not significantly affected by the present PCSK9 antagonists.

Cardiovascular event rates increase after each recurrence and associate with poor statin adherence

2020 ◽  
pp. 204748732090433 ◽  
Author(s):  
Mariann I Lassenius ◽  
Iiro Toppila ◽  
Susanne Bergius ◽  
Julia Perttilä ◽  
KE Juhani Airaksinen ◽  
...  
Keyword(s):  
Cardiovascular Event ◽  
Cardiovascular Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Increased Risk ◽  
Event Rates

Aims The study evaluated the quality of cardiovascular prevention in real-world clinical practice. The recurrence of up to five cardiovascular events was assessed, as data on recurrence beyond the first event and interindividual variations in event rates past the second event have been sparse. Low-density lipoprotein cholesterol concentrations and lipid-lowering therapy use were investigated. Methods This retrospective register-based study included adult patients with an incident cardiovascular event between 2004 and 2016 treated in the hospital district of southwest Finland. Patients were followed for consecutive cardiovascular events or cardiovascular death, low-density lipoprotein cholesterol and statin purchases. The timing of event recurrence was evaluated, and predictive factors were assessed. Results A wide interindividual variation in cardiovascular event recurrence was observed, each additional event caused an increased risk, the median time of recurrence decreased from 7 to one year for the second and fifth event. Event rates increased correspondingly from 12 to 43/100 patient-years and were most pronounced in the first years following the previous event. The low-density lipoprotein cholesterol goal (<1.8 mmol/l) was reached by 18% in the year after the event and statin underuse was associated with an increased risk of recurrence. Six months after the index event high intensity statins were used by only 22% of the cohort. Conclusion The study provides new perspectives on individual risk assessment showing that event rates are not stable for all patients but increase 1.2–1.9-fold per consecutive event. The underuse of statins and poor adherence support the identification of these patients for intensified multifactorial preventive measures.

scholarly journals Influence of lipid-lowering drugs on inflammation: what is yet to be done?

2021 ◽  
Author(s):  
Sabina Ugovšek ◽  
Janja Zupan ◽  
Andreja Rehberger Likozar ◽  
Miran Sebestjen
Keyword(s):  
Cardiovascular Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Low Density ◽  
C Reactive Protein ◽  
Low Density Lipoprotein Cholesterol ◽  
Reactive Protein ◽  
Lipid Lowering Drugs

Atherosclerosis is a chronic inflammatory disease that is associated with risk of cardiovascular events. The best-characterised and well-standardised clinical indicator of inflammation is C-reactive protein. Current evidence-based drug therapies for prevention and treatment of cardiovascular diseases are mainly focused on reduction of low-density lipoprotein cholesterol. However, these drugs do not provide sufficient protection against recurrent cardiovascular events. One of the possible mechanisms behind this recurrence might be the persistence of residual inflammation. For the most commonly used lipid-lowering drugs, the statins, their reduction of cardiovascular events goes beyond lowering of low-density lipoprotein cholesterol. Here, we review the effects of these lipid-lowering drugs on inflammation, in terms of statins, ezetimibe, fibrates, niacin, proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, ethyl eicosapentaenoic acid and antisense oligonucleotides. We focus in particular on C-reactive protein, and discuss how the effects of the statins might be related to reduced rates of cardiovascular events.

Low-density lipoprotein cholesterol target attainment in patients with stable or acute coronary heart disease in the Asia-Pacific region: results from the Dyslipidemia International Study II

2018 ◽  
Vol 25 (18) ◽  
pp. 1950-1963 ◽  
Author(s):  
Kian-Keong Poh ◽  
Baishali Ambegaonkar ◽  
Carl A Baxter ◽  
Philippe Brudi ◽  
Wacin Buddhari ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Acute Coronary Syndrome ◽  
Heart Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Coronary Syndrome

Background As mortality due to cardiovascular disease increases throughout the world, accurate data on risk factors such as hyperlipidemia are required. This is lacking in the Asia-Pacific region. Design The observational Dyslipidemia International Study (DYSIS) II was established to quantify the extent of hyperlipidemia in adults with acute and stable coronary heart disease globally. Methods Patients with stable coronary heart disease or hospitalised with an acute coronary syndrome were enrolled across nine Asia-Pacific countries from July 2013 to October 2014. Lipid-lowering therapy and low-density lipoprotein cholesterol target attainment (<70 mg/dL) were assessed. The acute coronary syndrome cohort was followed up 4 months post-discharge. Results Of the 4592 patients enrolled, 2794 had stable coronary heart disease and 1798 were admitted with an acute coronary syndrome. In the coronary heart disease cohort, the mean low-density lipoprotein cholesterol level was 86.9 mg/dL, with 91.7% using lipid-lowering therapy and 31% achieving low-density lipoprotein cholesterol of less than 70 mg/dL. In the acute coronary syndrome cohort at admission, the corresponding values were 103.2 mg/dL, 63.4% and 23.0%, respectively. Target attainment was significantly higher in lipid-lowering therapy-treated than non-treated patients in each cohort (32.6% vs. 12.9% and 31.1% vs. 9.0%, respectively). Mean atorvastatin-equivalent dosages were low (20 ± 15 and 22 ± 18 mg/day, respectively), with little use of non-statin adjuvants (13.0% and 6.8%, respectively). Low-density lipoprotein cholesterol target attainment had improved by follow-up for the acute coronary syndrome patients, but remained low (41.7%). Conclusions Many patients in Asia at very high risk of recurrent cardiovascular events had a low-density lipoprotein cholesterol level above the recommended target. Although lipid-lowering therapy was common, it was not used to its full potential.

scholarly journals Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment

2018 ◽  
Vol 40 (33) ◽  
pp. 2775-2781 ◽  
Author(s):  
Lotte C A Stiekema ◽  
Erik S G Stroes ◽  
Simone L Verweij ◽  
Helina Kassahun ◽  
Lisa Chen ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Arterial Wall ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Controlled Study ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Lipoprotein A

AbstractAimsSubjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a).Methods and resultsIn this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0–67.0] years, Lp(a) 200.0 [155.5–301.5] nmol/L [80.0 (62.5–121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8–55.5] and Lp(a) by 13.9% (95% CI 19.3–8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0–268.0) nmol/L [75.2 (56.0–107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (−8.3%) vs. placebo (−5.3%) [treatment difference −3.0% (95% CI −7.4% to 1.4%); P = 0.18].ConclusionEvolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation.

Lipid-Lowering Therapy and Low-Density Lipoprotein Cholesterol (LDL-C) Goal Achievement in High-Cardiovascular-Risk Patients in Fuzhou, China

2020 ◽  
Vol 25 (4) ◽  
pp. 307-315 ◽  
Author(s):  
Xing Wang ◽  
Yan He ◽  
Tao Wang ◽  
Chunming Li ◽  
Zihui Ma ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
High Intensity ◽  
Index Date ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

Purpose: This study aims to analyze the treatment patterns and goal attainment of low-density lipoprotein cholesterol (LDL-C) among patients with atherosclerotic cardiovascular disease (ASCVD) and diabetes mellitus (DM) in the real-world setting in Fuzhou, China. Methods: Patients aged ≥20 years with a valid LDL-C measurement (index date) in 2016 were selected from National Healthcare Big Data in Fuzhou, China. Patients were stratified into mutually exclusive cardiovascular risk categories: ASCVD (including recent acute coronary syndrome [ACS], chronic coronary heart disease [CHD], stroke, and peripheral arterial disease [PAD]), and DM alone (without ASCVD). Lipid-modifying medication and LDL-C attainment at the index date were assessed. Results: A total of 21 989 patients met the inclusion criteria, including 17 320 (78.8%) with ASCVD and 4669 (21.2%) with DM alone; 47.7% of patients received current statin therapy in the overall cohort (53.5% in ASCVD, 26.5% for DM); 20.5% ASCVD population achieved LDL-C target with the highest in patients with recent ACS (33.8%), followed by chronic CHD (21.2%), PAD (20.9%), and ischemic stroke (17.3%); 49.0% of patients with DM achieved LDL-C target. Higher LDL-C attainment was observed in high-intensity statin and a combination of statin and nonstatin groups. Atorvastatin was the most commonly used statin with the highest LDL-C attainment, followed by rosuvastatin. Conclusion: Compared with previous studies in China, our study found a relatively low statin use and LDL-C target attainment, but higher than similar studies in Europe. Guidelines should be well complied and more prescription of high-intensity statin or statin and nonstatin combination should be advocated.

scholarly journals Intensification of lipid-lowering therapy in patients with acute coronary syndrome

2020 ◽  
Vol 8 (4S) ◽  
pp. 121-129
Author(s):  
N. V. Fedorova ◽  
D. Yu. Sedykh ◽  
V. V. Kashtalap ◽  
L. Yu. Chesnokova ◽  
O. V. Gruzdeva ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Cardiovascular Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Coronary Syndrome ◽  
Lowering Therapy

Lipid metabolism disorders play a key role in determining cardiovascular risk. The level of low-density lipoprotein cholesterol is a significant factor in the pathophysiology of atherosclerosis and an indicator, the assessment of which reduces the risk of cardiovascular events. The prevalence of acute coronary syndrome in Russia remains at a high level. To date, the successful implementation and implementation of standards for the management of acute coronary syndrome has significantly reduced hospital mortality rates, however, secondary prevention issues remain relevant. Despite a wide range of lipid-lowering drugs, the use of which at maximum doses in acute coronary syndrome does not allow reaching the target levels of the lipid spectrum, the risk of developing repeated cardiovascular events remains high. Recently, a promising direction is the use of type 9 subtilisin/ kexin proprotein convertase inhibitors for the intensification of lipid-lowering therapy in patients with acute coronary syndrome. This article presents the clinical case of the successful use of one of the inhibitors of the proprotein convertase of subtilisin/kexin type 9, alirocoumab, in lowering low-density lipoprotein cholesterol and thereby reducing the risk of repeated cardiovascular events in a patient with acute coronary syndrome.

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