ANGPTL3, PCSK9, and statin therapy drive remarkable reductions in hyperlipidemia and atherosclerosis in a mouse model

Hurt-Camejo, Eva

doi:10.1194/jlr.c120000650

Cited by 7 publications

(6 citation statements)

References 13 publications

(11 reference statements)

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“…As for pre‐existing atherosclerosis in the thoracic aorta, triple therapy blocked the progression of atherosclerosis by 86% and blocked the development of the existing lesions by 50% compared with baseline. This study showed that PCSK9 mAbs and ANGPTL3 mAbs in combination with atorvastatin could block further progression of atherosclerosis and potentially ameliorate ASCVD 97,98 …”

Section: Angptl3‐targeted Therapies In Ascvdmentioning

confidence: 80%

“…Consistent with these results, another study showed that evinacumab and atorvastatin in combination blocked the progression of atherosclerosis. It was also shown that inhibition of ANGPTL3 might decrease local inflammatory responses in the artery wall by augmenting the activity of EL and LPL, which was one of the mechanisms whereby ANGPTL3 inhibitors decrease the progression of atherosclerosis 97 . Recently, one study explored the additive efficacy of combination treatments with two drugs, a PCSK9 monoclonal antibody (alirocumab) and an ANGPTL3 monoclonal antibody (evinacumab), each combined with atorvastatin.…”

Section: Angptl3‐targeted Therapies In Ascvdmentioning

confidence: 99%

“…This study showed that PCSK9 mAbs and ANGPTL3 mAbs in combination with atorvastatin could block further progression of atherosclerosis and potentially ameliorate ASCVD. 97,98 As to the vital issue of patient safety, it was reported that the safety of evinacumab was comparable with placebo and that no serious treatment-emergent adverse events occurred. 3,11,61,62 Influenzalike illness (11%), headache (11%) and urinary tract infection (11%)…”

Section: Monoclonal Antibodies Against Angptl3mentioning

confidence: 99%

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Targeting angiopoietin‐like 3 in atherosclerosis: From bench to bedside

Ling

Zheng

Luo

et al. 2021

Diabetes Obesity Metabolism

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Atherosclerotic cardiovascular disease (ASCVD) is the largest cause of morbidity and mortality worldwide. Lipid‐lowering therapies are the current major cornerstone of ASCVD management. Statins, ezetimibe, fibrates and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively reduce the plasma low‐density lipoprotein cholesterol (LDL‐C) level in most individuals at risk of atherosclerosis. Still, some patients (such as those with homozygous familial hypercholesterolaemia), who do not respond to standard therapies, and other patients who cannot take these agents, remain at a high risk of ASCVD. In recent years there has been tremendous progress in understanding the mechanism and efficacy of lipid‐lowering strategies. Apart from the recently approved PCSK9 and ATP citrate lyase inhibitors, angiopoietin‐like 3 (ANGPTL3) is another potential target for the treatment of dyslipidaemia and its clinical sequalae of atherosclerosis. ANGPTL3 is a pivotal modulator of plasma triglycerides (TG), LDL‐C and high‐density lipoprotein cholesterol (HDL‐C) levels, achieved by inhibiting the activities of lipoprotein lipase and endothelial lipase. Familial combined hypolipidaemia is derived from the Angptl3 loss‐of‐function mutations, which leads to low levels of LDL‐C, HDL‐C and TG, and has a 34% decreased risk of ASCVD compared with non‐carriers. To date, monoclonal antibodies (evinacumab) and antisense oligonucleotides against ANGPTL3 have been investigated in clinical trials for dyslipidaemia therapy. Herein, we review the biology and function of ANGPTL3, as well as the latest developments of ANGPTL3‐targeted therapies. We also summarize evidence from basic research to clinical trials, with the aim of providing novel insights into the biological functions of ANGPTL3 and related targeted therapies.

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Section: Angptl3‐targeted Therapies In Ascvdmentioning

confidence: 80%

Section: Angptl3‐targeted Therapies In Ascvdmentioning

confidence: 99%

Section: Monoclonal Antibodies Against Angptl3mentioning

confidence: 99%

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Targeting angiopoietin‐like 3 in atherosclerosis: From bench to bedside

Ling

Zheng

Luo

et al. 2021

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

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“…The ob/ob mice, vaccinated with a peptide targeting ANGPTL3, also exhibited a marked decrease in diet-induced obesity and hepatic steatosis [ 111 ], suggestive of the metabolic impact of ANGPTL3 on NAFLD. In addition, the treatment with evinacumab alone or in combination with other lipid-lowering medications, such as statins and PCSK9 inhibitors, showed promising results for ameliorating hyperlipidemia in comparison to general lipid-lowering drugs alone in a phase 3 clinical trial, as well as in rodent models [ 112 , 113 , 114 , 115 ]. These findings indicate that hepatokine ANGPTL3 acts as an important regulator of lipoprotein metabolism and has great potential for the treatment of atherosclerosis [ 28 ].…”

Section: Hepatokines and Nafldmentioning

confidence: 99%

Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism

2021

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The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.

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“…Mice lacking ANGPTL3 have increased LPL activity and reduced circulating levels of triglycerides and free fatty acids (FFA) [ [53] , [54] , [55] ], a phenotype that has been reproduced pharmacologically in monkeys and humans [ 56 ]. Recent findings from a phase 3 clinical trial and findings in rodents suggest that combinatorial treatment of ANGPTL3 inhibitor evinacumab with other lipid-lowering therapies, including statins and PCSK9 inhibitors, result in significant reductions in hyperlipidemia compared to lipid-lowering therapies alone [ 57 , 58 ]. These data support the possibility that inhibiting ANGPTL3 represents a therapeutic strategy for the treatment of obesity-related metabolic dysfunction.…”

Section: Introductionmentioning

confidence: 99%