New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B

Nurmohamed, Nick S.; Návar, Ann Marie; Kastelein, John J.P.

doi:10.1016/j.jacc.2020.11.079

Cited by 65 publications

(40 citation statements)

References 94 publications

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“…Statins are lipid-lowering drugs which inhibit the activity of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme in the cholesterol synthesis pathway [ 1 , 2 ]. They have been widely used for the prevention and treatment of coronary artery disease (CAD) in hypercholesterolemic patients during almost the past four decades [ 3 ] and despite the introduction of newer agents [ 4 , 5 , 6 , 7 ]. Beyond their lipid-lowering activity, statins can modulate multiple metabolic pathways in different tissues and organs by which they achieve beneficial therapeutic effects in different diseases [ 8 ] Pravastatin (PRA), pitavastatin (PTV), rosuvastatin (RSV), lovastatin (LOV), simvastatin (SIM), atorvastatin (ATV), and fluvastatin (FLV) are different types of statins [ 9 ] that have not only low density lipoproteins cholesterol (LDL-C) lowering effects but many other pleiotropic beneficial effects such as anti-inflammatory, antioxidant, anti-apoptotic, and immunomodulatory [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases

Mansouri

Reiner

Ruscica

et al. 2022

JCM

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Statins are competitive inhibitors of hydroxymethylglutaryl-CoA (HMG-CoA) reductase and have been used to treat elevated low-density lipoprotein cholesterol (LDL-C) for almost four decades. Antioxidant and anti-inflammatory properties which are independent of the lipid-lowering effects of statins, i.e., their pleiotropic effects, might be beneficial in the prevention or treatment of many diseases. This review discusses the antioxidant effects of statins achieved by modulating the nuclear factor erythroid 2 related factor 2/ heme oxygenase-1 (Nrf2/HO-1) pathway in different organs and diseases. Nrf2 and other proteins involved in the Nrf2/HO-1 signaling pathway have a crucial role in cellular responses to oxidative stress, which is a risk factor for ASCVD. Statins can significantly increase the DNA-binding activity of Nrf2 and induce the expression of its target genes, such as HO-1 and glutathione peroxidase) GPx, (thus protecting the cells against oxidative stress. Antioxidant and anti-inflammatory properties of statins, which are independent of their lipid-lowering effects, could be partly explained by the modulation of the Nrf2/HO-1 pathway.

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Section: Introductionmentioning

confidence: 99%

Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases

Mansouri

Reiner

Ruscica

et al. 2022

JCM

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“…Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are broadly used as lipid-lowering drugs in patients with cardiovascular diseases (CVDs) [1,2]. Although several classes of newer agents have been introduced in recent decades, statins still remain as the cornerstone of management of dyslipidemias [3][4][5][6]. Statins interfere with cholesterol synthesis in the liver cells and, therefore, decrease the levels of total cholesterol and lowdensity lipoprotein cholesterol (LDL-C) in serum [7].…”

Section: Introductionmentioning

confidence: 99%

Effect of Statins on Serum level of hs-CRP and CRP in Patients with Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Kandelouei

Abbasifard

Imani

et al. 2022

Mediators of Inflammation

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Background. Several studies have reported that statins have anti-inflammatory effects. Nevertheless, results of clinical trials concerning the effect of statins on the levels of C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) have been inconsistent. Therefore, we performed a systematic review and meta-analysis of randomized clinical trials (RCTs) evaluating the effect of statins on CRP and hs-CRP levels in patients with cardiovascular diseases (CVDs). Methods. Literature search of the major databases was performed to find eligible RCTs assessing the effect of statins on serum levels of CRP and hs-CRP from the inception until the last week of April 2021. The effect sizes were determined for weighted mean difference (WMD) and 95% confidence intervals (CI). Results. 26 studies were identified (3010 patients and 2968 controls) for hs-CRP and 20 studies (3026 patients and 2968 controls) for CRP. Statins reduced the serum levels of hs-CRP ( WMD = − 0.97 mg / L ; 95% CI: -1.26 to -0.68 mg/L; P < 0.001 ) and CRP ( WMD = − 3.05 mg / L ; 95% CI: -4.86 to -1.25 mg/L; P < 0.001 ) in patients with CVDs. Statins decreased the serum levels of hs-CRP in patients receiving both high-intensity and moderate/low-intensity treatments with these drugs. In addition, the duration of treatment longer than 10 weeks decreased hs-CRP levels. Only high-intensity statin treatment could marginally decrease serum levels of CRP in CVDs patients. Conclusions. This meta-analysis showed the efficacy of statins to reduce the concentrations of CRP and hs-CRP in patients with different types of CVDs.

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“…Recently, two studies reported that evolocumab (a PCSK9 monoclonal antibody) was well tolerated and effective at reducing LDL‐C levels by 30% in patients with HoFH 13,14 . Mipomersen (an antisense oligonucleotide targeting hepatic apolipoprotein B100 mRNA) and lomitapide (a selectively inhibiting microsomal triglyceride transfer protein) are approved by the US Food and Drug Administration (FDA) for HoFH patients 15,16 . Still, some safety concerns, including elevation of liver enzymes and gastrointestinal side effects, have limited their implementation 15 .…”

Section: Introductionmentioning

confidence: 99%

“…13,14 Mipomersen (an antisense oligonucleotide targeting hepatic apolipoprotein B100 mRNA) and lomitapide (a selectively inhibiting microsomal triglyceride transfer protein) are approved by the US Food and Drug Administration (FDA) for HoFH patients. 15,16 Still, some safety concerns, including elevation of liver enzymes and gastrointestinal side effects, have limited their implementation. 15 New lipid-lowering drugs are urgently needed for the treatment of this patient population.…”

mentioning

confidence: 99%

“…15,16 Still, some safety concerns, including elevation of liver enzymes and gastrointestinal side effects, have limited their implementation. 15 New lipid-lowering drugs are urgently needed for the treatment of this patient population. Thus, researchers are searching for additional pharmacological and therapeutic targets to further reduce residual cardiovascular risk.…”

mentioning

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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New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B

Cited by 65 publications

References 94 publications

Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases

Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases

Effect of Statins on Serum level of hs-CRP and CRP in Patients with Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

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

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