PCSK9 inhibition: drug development for low-density lipoprotein lowering

2013 ◽  
pp. 42-57
Author(s):  
Geetha Mukerji ◽  
Rawand M Abdin ◽  
Dominic S Ng
Keyword(s):  
Drug Development ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Pcsk9 Inhibition

Abstract 13200: Relationship Between Baseline Low-Density Lipoprotein Cholesterol and Percent Low-Density Lipoprotein Cholesterol Reduction With Evolocumab in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) Trial

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dan P Marcusa ◽  
Robert P Giugliano ◽  
Jeong-Gun Park ◽  
Peter Sever ◽  
Huei Wang ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Study Drug ◽  
Lipoprotein Cholesterol ◽  
Moderate Intensity ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitor ◽  
Lower Baseline ◽  
Pcsk9 Inhibition

Introduction: The FOURIER trial demonstrated that the PCSK9 inhibitor evolocumab robustly reduced LDL-C amongst patients on moderate or high intensity statins. We investigated whether the magnitude of the percentage LDL-C reduction is consistent across baseline LDL-C levels. Methods: FOURIER enrolled 27,564 patients with ASCVD and an LDL-C ≥70 mg/dl or a non-HDL-C ≥100 mg/dl on optimized statin therapy at the time of enrollment. The % LDL-C reduction from baseline to 12 wks was examined in patients on study drug through 12 wks (N=25,847) using a quadratic regression model including terms for treatment (evolocumab vs. placebo), baseline LDL-C and [LDL-C] 2 , and interaction terms. Stratified analyses were done for patients on high vs. moderate intensity statin. Results: Overall, compared with placebo, evolocumab reduced LDL-C by 61% (95% CI 61-62%). Patients with lower baseline LDL-C had significantly greater % LDL-C reductions (Figure top; P<0.001 for interaction between baseline LDL-C and % LDL-C reduction with evolocumab). Among patients with a baseline LDL-C of 70 mg/dL, LDL-C reduction was 68% (95% CI 67-69%) vs. 54% (95% CI 53-55%) in patients with a baseline LDL-C of 130 mg/dl. When stratified by concomitant statin intensity, similar relationships were observed (Figure middle & bottom). Conclusions: The magnitude of % LDL-C reduction with evolocumab is greater in patients with lower baseline LDL-C levels. These data are encouraging for the use of PCSK9 inhibition even for patients at the lower end of LDL-C.

scholarly journals Relationship Between Low‐Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab

2019 ◽  
Vol 8 (4) ◽  
Author(s):  
Michael D. Shapiro ◽  
Jessica Minnier ◽  
Hagai Tavori ◽  
Helina Kassahun ◽  
Andrea Flower ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Lipoprotein A ◽  
Link Type ◽  
Pcsk9 Inhibition

See Editorial by Nestel

scholarly journals Profile of Surrounding MicroRNAs in Low Density Lipoprotein Uptake

2017 ◽  
Author(s):  
Maria Elisabete Silva Santos ◽  
Ricardo Sousa De Oliveira Paraense ◽  
Eric Artur Cortinhas-Alves ◽  
Danilo Leôncio Aguiar Pereira
Keyword(s):  
Cardiovascular Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Ldl Receptors ◽  
Lipid Metabolism Disorders ◽  
Lipoprotein Uptake ◽  
Ldl Uptake ◽  
Pcsk9 Inhibition ◽  
Potential Biomarkers

The atherosclerosis, a chronic and inflammatory disease that occurs when there are high levels of low-density lipoprotein (LDL) on plasma. This important risk factor for development of cardiovascular disease (CVD) is the main cause of death worldwide. MicroRNAs have recently emerged as potential biomarkers and therapeutic target for lipid metabolism disorders. In this review, we will provide profile of surrounding miRNAs that have demonstrated being regulators of PCSK9, LDLR and APOB100 genes. Recent work has identified the mir-148, mir-128, mir-27a/b, mir-185, mir-301, mir-130 as important regulators of this pathway because they decrease supply of LDL receptors through interaction with PCSK9. Inhibition of LDLR expression cause elevation of plasma LDL levels which induces atherosclerosis. While mir-30c, mir-122, mir-34 decrease MTTP, which promotes degradation of APOB100 preventing assembly and secretion of VLDL. We conclude that, when overexpressed, mir-148a, mir128 and mir-27a/b, mir-122 and mir-34 are related to decrease in LDLR, facilitating occurrence of atherosclerosis. While mir-30 has been linked to decreased atherosclerosis. Detection of miRNAs profile could be used in the future as a biomarker for disturbs linked to c-LDL uptake and in future anti-miRNAs therapies may be used in the treatment of atherosclerosis.

scholarly journals The consequences of PCSK9 inhibition in selected tissues

2021 ◽  
Vol 75 ◽  
pp. 385-397
Author(s):  
Mateusz Maligłówka ◽  
Łukasz Bułdak ◽  
Bogusław Okopień ◽  
Aleksandra Bołdys
Keyword(s):  
Bacterial Infections ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Low Density ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibition

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of nine members of the proprotein convertase family. These serine proteases play a pivotal role in the post-translational modification of proteins and the activation of hormones, enzymes, transcription factors and growth factors. As a result, they participate in many physiological processes like embryogenesis, activity of central nervous system and lipid metabolism. Scientific studies show that the family of convertases is also involved in the pathogenesis of viral and bacterial infections, osteoporosis, hyperglycaemia, cardiovascular diseases, neurodegenerative disorders and cancer. The inhibition of PCSK9 by two currently approved for use monoclonal antibodies (alirocumab, evolocumab) slows down the degradation of low-density lipoprotein cholesterol receptors (LDLRs). This leads to increased density of LDLRs on the surface of hepatocytes, resulting in decreased level of low-density lipoprotein cholesterol (LDL-C) in the bloodstream, which is connected with the reduction of cardiovascular risk. PCSK9 inhibitors (PCSK9i) were created for the patients who could not achieve appropriate level of LDL-C using current statin and ezetimibe therapy. It seems that high therapeutic efficacy of PCSK9i will make them more common in the clinical use. The pleiotropic effects of previously mentioned lipid-lowering therapies were the reasons for literature review of possible positive and negative effects of PCSK9 inhibition beyond cholesterol metabolism.

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