PCSK9 Inhibitors: Novel Therapeutic Strategies for Lowering LDLCholesterol

2018 ◽  
Vol 19 (2) ◽  
pp. 165-176 ◽  
Author(s):  
Yan Wang ◽  
Zhao-Peng Liu
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Maximum Tolerated Dose ◽  
Therapeutic Strategies ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Cvd Risk ◽  
Safety Issues ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-offunction mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues.

scholarly journals The Protective Role of Adiponectin for Lipoproteins in End-Stage Renal Disease Patients: Relationship with Diabetes and Body Mass Index

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Susana Coimbra ◽  
Flávio Reis ◽  
Sara Nunes ◽  
Sofia Viana ◽  
Maria João Valente ◽  
...  
Keyword(s):  
End Stage Renal Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Obese Patients ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Cardiovascular disease (CVD) events are the main causes of death in end-stage renal disease (ESRD) patients on dialysis. The number and severity of CVD events remain inappropriate and difficult to explain by considering only the classic CVD risk factors. Our aim was to clarify the changes and the relationship of lipoprotein subfractions with other CVD risk factors, namely, body mass index (BMI) and adipokines, inflammation and low-density lipoprotein (LDL) oxidation, and the burden of the most prevalent comorbidities, diabetes mellitus (DM) and hypertension (HT). We studied 194 ESRD patients on dialysis and 22 controls; lipid profile, including lipoprotein subpopulations and oxidized LDL (oxLDL), C-reactive protein (CRP), adiponectin, leptin, and paraoxonase 1 activity were evaluated. Compared to controls, patients presented significantly lower levels of cholesterol, high-density lipoprotein cholesterol (HDLc), LDLc, oxLDL, and intermediate and small HDL and higher triglycerides, CRP, adiponectin, large HDL, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein- (IDL) B. Adiponectin levels correlated positively with large HDL and negatively with intermediate and small HDL, oxLDL/LDLc, and BMI; patients with DM (n=17) and with DM+HT (n=70), as compared to patients without DM or HT (n=69) or only with HT (n=38), presented significantly higher oxLDL, oxLDL/LDLc, and leptin and lower adiponectin. Obese patients (n=45), as compared to normoponderal patients (n=81), showed lower HDLc, adiponectin, and large HDL and significantly higher leptin, VLDL, and intermediate and small HDL. In ESRD, the higher adiponectin seems to favor atheroprotective HDL modifications and protect LDL particles from oxidative atherogenic changes. However, in diabetic and obese patients, adiponectin presents the lowest values, oxLDL/LDLc present the highest ones, and the HDL profile is the more atherogenic. Our data suggest that the coexistence of DM and adiposity in ESRD patients on dialysis contributes to a higher CVD risk, as showed by their lipid and adipokine profiles.

scholarly journals Sex Differences in Primary and Secondary Prevention of Cardiovascular Disease in China

Circulation ◽  
2020 ◽  
Vol 141 (7) ◽  
pp. 530-539 ◽  
Author(s):  
Shijun Xia ◽  
Xin Du ◽  
Lizhu Guo ◽  
Jing Du ◽  
Clare Arnott ◽  
...  
Keyword(s):  
Sex Differences ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Education Level ◽  
Lipid Lowering ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Primary And Secondary Prevention ◽  
Cvd Risk ◽  
Cvd Prevention

Background: Despite improvements in diagnostic and therapeutic interventions to combat cardiovascular disease (CVD) in recent decades, there are significant ongoing access gaps and sex disparities in prevention that have not been adequately quantified in China. Methods: A representative, cross-sectional, community-based survey of adults (aged ≥45 years) was conducted in 7 geographic regions of China between 2014 and 2016. Logistic regression models were used to determine sex differences in primary and secondary CVD prevention, and any interaction by age, education level, and area of residence. Data are presented as adjusted odds ratios (ORs) and 95% CIs. Results: Of 47 841 participants (61.3% women), 5454 (57.2% women) had established CVD and 9532 (70.5% women) had a high estimated 10-year CVD risk (≥10%). Only 48.5% and 48.6% of women and 39.3% and 59.8% of men were on any kind of blood pressure (BP)–lowering medication, lipid-lowering medication, or antiplatelet therapy for primary and secondary prevention, respectively. Women with established CVD were significantly less likely than men to receive BP-lowering medications (OR, 0.79 [95% CI, 0.65–0.95]), lipid-lowering medications (OR, 0.69 [95% CI, 0.56–0.84]), antiplatelets (OR, 0.53 [95% CI, 0.45–0.62]), or any CVD prevention medication (OR, 0.62 [95% CI, 0.52–0.73]). Women with established CVD, however, had better BP control (OR, 1.31 [95% CI, 1.14–1.50]) but less well-controlled low-density lipoprotein cholesterol (OR, 0.66 [95% CI, 0.57–0.76]), and were less likely to smoke (OR, 13.89 [95% CI, 11.24–17.15]) and achieve physical activity targets (OR, 1.92 [95% CI, 1.61–2.29]). Conversely, women with high CVD risk were less likely than men to have their BP, low-density lipoprotein cholesterol, and bodyweight controlled (OR, 0.46 [95% CI, 0.38–0.55]; OR, 0.60 [95% CI, 0.52–0.69]; OR, 0.55 [95% CI, 0.48–0.63], respectively), despite a higher use of BP-lowering medications (OR, 1.21 [95% CI, 1.01–1.45]). Younger patients (<65 years) with established CVD were less likely to be taking CVD preventive medications, but there were no sex differences by area of residence or education level. Conclusions: Large and variable gaps in primary and secondary CVD prevention exist in China, particularly for women. Effective CVD prevention requires an improved overall nationwide strategy and a special emphasis on women with established CVD, who have the greatest disparity and the most to benefit.

Should we Consider Lipoprotein (a) in Cardiovascular Disease Risk Assessment in Patients with Familial Hypercholesterolaemia?

2019 ◽  
Vol 24 (31) ◽  
pp. 3665-3671 ◽  
Author(s):  
Panagiotis Anagnostis ◽  
Pavlos Siolos ◽  
Dimitrios Krikidis ◽  
Dimitrios G. Goulis ◽  
John C. Stevenson
Keyword(s):  
Cardiovascular Disease ◽  
Familial Hypercholesterolaemia ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Cvd Risk ◽  
Lipoprotein A ◽  
Increased Risk

Background: Familial hypercholesterolaemia (FH) is a genetically determined lipid disorder, affecting 1 per 200-500 individuals in the general population. It is significantly and independently associated with an increased risk of Cardiovascular Disease (CVD), although it remains still an underrecognized and undertreated disease. Lipoprotein (a) [Lp(a)] is a low-density-lipoprotein (LDL)-like molecule, containing an additional protein, apolipoprotein (a). Objective: This review aims to present and discuss available data on the role of Lp(a) in patients with FH, in terms of its potential augmentation of CVD risk. Methods: A comprehensive search of the literature was performed to identify studies evaluating the CV effects of Lp(a) in patients with FH. Results: Lp(a) has been recognised as an independent risk factor for CVD, mainly coronary artery disease (CAD). Most, but not all, studies show increased Lp(a) concentrations in adults and children with FH. There is also evidence of an independent association between Lp(a) and CVD (mainly CAD) risk in these patients. Conclusion: Some therapeutic modalities, such as niacin, oestrogens, tibolone and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors may effectively reduce Lp(a) concentrations by 25-30%, although their clinical benefit of this effect remains to be established.

scholarly journals The Role of PCSK9 Inhibitors in the Improvement of Outcomes in Patients after Acute Coronary Syndrome: Results of ODYSSEY OUTCOMES Trial

2019 ◽  
Vol 14 (6) ◽  
pp. 922-934 ◽  
Author(s):  
Yu. A. Karpov
Keyword(s):  
Acute Coronary Syndrome ◽  
Statin Therapy ◽  
High Intensity ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors ◽  
Coronary Syndrome

The aim of this review was to present the recently published results of ODYSSEY OUTCOMES trial and discuss the clinical perspective of these data. Patients with acute coronary syndrome are at very high risk of recurrent ischemic cardiovascular complications, especially during the first year after the event. The use of high-intensity statin therapy in this group of patients does not always lead to the achievement of target levels of atherogenic lipoproteins. PCSK9 inhibitors, administered in addition to statins, can provide additional reduction of low-density lipoprotein cholesterol, which leads to further improvements of outcomes in patients with atherosclerotic cardiovascular disease. According to the latest results from ODYSSEY OUTCOMES trial, among patients with recent acute coronary syndrome, who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who were treated with alirocumab then among those who received placebo. The treatment with alirocumab in patients with recent acute coronary syndrome was associated with reduction in death from any causes. The absolute risk reduction with alirocumab was the most prominent in the subpopulation of patients with low-density lipoprotein cholesterol ≥2,6 mmol/l at baseline. These results have implication for clinical practice and may play an important role for the improvement of outcomes in patients at highest cardiovascular risk after acute cardiovascular syndrome.

scholarly journals PCSK9: from molecular biology to clinical applications

2019 ◽  
Vol 57 (1) ◽  
pp. 7-25 ◽  
Author(s):  
Jonathan Malo ◽  
Arun Parajuli ◽  
Simon W Walker
Keyword(s):  
Molecular Biology ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Clinical Genetics ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
New Era ◽  
Density Lipoprotein Receptor ◽  
Research Findings ◽  
New Generation

Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease with a key role in regulating plasma low-density lipoprotein (LDL) concentration. Since its discovery via parallel molecular biology and clinical genetics studies in 2003, work to characterize PCSK9 has shed new light on the life-cycle of the low-density lipoprotein receptor and the molecular basis of familial hypercholesterolaemia. These discoveries have also led to the advent of the PCSK9 inhibitors, a new generation of low-density lipoprotein cholesterol (LDL-C) lowering drugs. Clinical trials have shown these agents to be both safe and capable of unprecedented reductions in LDL-C, and it is hoped they may herald a new era of cardiovascular disease prevention. As such, the still evolving PCSK9 story serves as a particularly successful example of translational medicine. This review provides a summary of the principal PCSK9 research findings, which underpin our current understanding of its function and clinical relevance.

Importance of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the treatment of dyslipidemia and atherosclerosis

2019 ◽  
pp. 40-52
Author(s):  
Maksim Maksimov ◽  
Anastasia Shikaleva ◽  
Aleksandra Kuchaeva
Keyword(s):  
Clinical Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Lipid Lowering Drugs ◽  
Antibody Preparations

Representatives of different groups of lipid-lowering drugs may have some differences in the nature and severity of the effect on the blood lipid spectrum. A new class of drugs, PCSK9 inhibitors, whose activity is associated with a protein involved in the control of low density lipoprotein receptors, has recently appeared. In clinical practice, this group is represented by monoclonal antibody preparations evolocumab and alirocumab. PCSK9 inhibitors are promising drugs for use in combination lipid-lowering therapy, which so far, given the results of clinical studies, can be recommended in the third place after statins and ezetimibe. In clinical studies, it was shown that alirocoumab and evolocumab alone or in combination with statins and/or other lipid-lowering drugs significantly reduce cholesterol levels in low density lipoproteins – by an average of 60%, depending on the dose.

Sex differences in low-density lipoprotein cholesterol reduction with PCSK9 inhibitors in real world patients

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Alberto Cordero ◽  
Mª Rosa Fernández del Olmo ◽  
Gustavo Aníbal Cortez Quiroga ◽  
Cesar Romero-Menor ◽  
Lorenzo Fácila ◽  
...  
Keyword(s):  
Sex Differences ◽  
Real World ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Cholesterol Reduction ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors
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