Proprotein convertase subtilisin/kexin type 9 inhibition in cardiovascular disease: current status and future perspectives

Cho, Kyung Hoon; Hong, Young Joon

doi:10.3904/kjim.2020.140

Cited by 9 publications

(11 citation statements)

References 88 publications

(129 reference statements)

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“…49 Proprotein convertase subtilisin‐kexin type 9 inhibitors are now available and are an effective option, but these agents do not affect inflammation 45 and are associated with a high cost and the burden of self‐injection. 50 As the role of inflammation in atherosclerosis has been revealed, anti‐inflammatory therapies have become a major focus of research, with mixed results to date in reducing the risk of MACE. 6 , 51 Anti‐LOX‐1 therapy may offer an additional line of defense against atherosclerosis, alongside lipid‐lowering therapies and emerging anti‐inflammatory therapies.…”

Section: Discussionmentioning

confidence: 99%

Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results

Vavere

Sinsakul

Yang

et al. 2023

JAHA

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Background Blockade of the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high‐affinity monoclonal blocking antibody to LOX‐1. Methods and Results This phase 1, first‐in‐human, placebo‐controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX‐1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half‐life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target‐mediated drug disposition. Dose‐dependent reductions in mean soluble LOX‐1 levels from baseline were observed (>66% at 4 weeks and 71.61–82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (−13.45 mm 3 versus −8.25 mm 3 ). Conclusions MEDI6570 was well tolerated and demonstrated dose‐dependent soluble LOX‐1 suppression and a pharmacokinetic profile consistent with once‐monthly dosing. Registration URL: https://clinicaltrials.gov/ ; Unique identifier: NCT03654313.

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Section: Discussionmentioning

confidence: 99%

Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results

Vavere

Sinsakul

Yang

et al. 2023

JAHA

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“…These drugs are intended exclusively for injection, are present on the market, and are approved by the US Food and Drug Administration and the European Medicines Agency. As an addition to statin therapy, they lower LDL cholesterol levels by 61% and can also significantly lower CVD event frequency [12]. Nevertheless, quite a large number of lipid-lowering drugs have a key role in the treatment of atherosclerosis, since it is impossible to ignore the fact that this disease is inflammatory.…”

Section: Atherosclerosismentioning

confidence: 99%

Modulating mTOR Signaling as a Promising Therapeutic Strategy for Atherosclerosis

Poznyak

Sukhorukov

Zhuravlev

et al. 2022

IJMS

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For more than a decade, atherosclerosis has been one of the leading causes of death in developed countries. The issue of treatment and prevention of the disease is especially acute. Despite the huge amount of basic and clinical research, a significant number of gaps remain in our understanding of the pathogenesis of atherosclerosis, and only their closure will bring us closer to understanding the causes of the disease at the cellular and molecular levels and, accordingly, to the development of an effective treatment. One of the seemingly well-studied elements of atherogenesis is the mTOR signaling pathway. However, more and more new details are still being clarified. Therapeutic strategies associated with rapamycin have worked well in a number of different diseases, and there is every reason to believe that targeting components of the mTOR pathway may pay off in atherosclerosis as well.

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“…PCSK9 is a ligand for LDL receptors and the identification of its function in metabolizing lipids has led to efforts for the development of novel therapies that could either reduce its levels in the body or inhibit it through protein synthesis or by binding with LDL receptors [ 21 ]. Free circulating PCSK9 results in a reduction of hepatic surface LDL receptors, causing an increase in LDL-C levels due to low clearance on account of lysosomal degradation of the receptors [ 13 ].…”

Section: Reviewmentioning

confidence: 99%

“…Besides injection-site reactions, very few instances of adverse effects were noticed in the trials for both the agents. LDL-C metabolism is also associated with vitamin E transport and an absolute reduction in vitamin E levels was seen in a randomized trial of 901 patients, where it decreased by 16% from baseline to week 52 in patients treated with evolocumab but showed a 19% increase under normal cholesterol levels [ 21 ].…”

Section: Reviewmentioning

confidence: 99%

The Use of Monoclonal Antibody-Based Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9) Inhibitors in the Treatment of Hypercholesterolemia

Parikh¹,

Breve²,

Magnusson³

et al. 2022

Cureus

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In this review, we evaluated several studies in the literature to analyze the benefits and deleterious effects of the use of monoclonal antibodies (MABs)-based proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in patients with hypercholesterolemia. Increased low-density lipoprotein cholesterol (LDL-C) levels lead to an increase in the risk of cardiovascular (CV) disease. Statins are the cornerstones of hypercholesterolemia treatment, but the patient response may often vary, and additional therapies may be needed to control the increased LDL-C levels. MABs bind to PCSK9 receptors, causing a reduction in LDL-C levels. MAB-based PCSK9 inhibitors such as alirocumab and evolocumab have been approved for use in hypercholesterolemia in combination with statins. Studies have suggested that both alirocumab and evolocumab are effective in lowering LDL-C levels, have favorable side effect profiles, and can be administered at convenient dosing intervals; however, further double-blind, randomized trials evaluating the long-term safety and efficacy of both the agents could assist with clinical decision-making.

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Proprotein convertase subtilisin/kexin type 9 inhibition in cardiovascular disease: current status and future perspectives

Cited by 9 publications

References 88 publications

Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results

Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results

Modulating mTOR Signaling as a Promising Therapeutic Strategy for Atherosclerosis

The Use of Monoclonal Antibody-Based Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9) Inhibitors in the Treatment of Hypercholesterolemia

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