New and emerging lipid-modifying drugs to lower LDL cholesterol

Kosmas, Constantine E.; Pantou, Dafni; Sourlas, Andreas; Papakonstantinou, Evangelia; Uceta, Rogers Echavarria; Guzman, Eliscer

doi:10.7573/dic.2021-8-3

Cited by 22 publications

(27 citation statements)

References 85 publications

(94 reference statements)

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“…Thence, the reduction of intrahepatic cholesterol synthesis leads to upregulation of LDLR, consequently leading to increased cholesterol uptake by the hepatocytes and lower plasma LDL-C levels. 9 Ezetimibe is a second-line agent, reducing the absorption of cholesterol by the gastrointestinal tract via inhibition of the Niemann-Pick C1-like 1 (NPC1L1) protein. 10 PCSK9 inhibitors is a new class of agents that is also a valuable addition to lipid-lowering therapy, blocking the lysosomal degradation of LDLR.…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia

Kosmas¹,

Bousvarou²,

Sourlas³

et al. 2022

CPAA

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Cardiovascular disease (CVD) is the most common cause of death in a global scale and significantly depends on the elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and the subsequent formation of atherosclerotic plaques. While physicians have several LDL-C-lowering agents with diverse mechanisms of action, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inclisiran, angiopoietin-like protein 3 (ANGPTL3) inhibitors have recently emerged as a powerful addition in the armamentarium of lipid-lowering strategies, especially for patients with refractory hypercholesterolemia, as in the case of patients with homozygous familial hypercholesterolemia (HoFH). ANGPTL3 protein is a glycoprotein secreted by liver cells that is implicated in the metabolism of lipids along with other ANGPTL proteins. These proteins inhibit lipoprotein lipase (LPL) and endothelial lipase (EL) in tissues. Loss-of-function mutations affecting the gene encoding ANGPTL3 are linked with lower total cholesterol, LDL-C, and triglyceride (TG) levels. Evinacumab is a monoclonal antibody that targets, binds to, and pharmacologically inhibits ANGPTL3, which was recently approved by the United States Food and Drug Administration (FDA) as a complementary agent to other LDL-C lowering regimens for patients aged 12 or older with HoFH, based on clinical trial evidence that confirmed its safety and efficacy in those patients. Antisense oligonucleotides (ASOs) also represent an interesting class of agents that target and inhibit the mRNA derived from the transcription of ANGPTL3 gene. This review aims to present and discuss the current clinical and scientific data pertaining to the role of ANGPTL3 inhibitors, a novel lipid-modifying class of agents capable of reducing LDL-C levels via a mechanism independent of LDL receptors.

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Section: Introductionmentioning

confidence: 99%

Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia

Kosmas¹,

Bousvarou²,

Sourlas³

et al. 2022

CPAA

Self Cite

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“…The model is flexible enough to allow the introduction of other novel medications for cholesterol lowering, and this is now happening following the recent incorporation of bempedoic acid and inclisiran into the clinical pathway. These new agents have been shown to significantly reduce LDL-C, 32 but outcomes data have not yet been reported.…”

Section: Discussionmentioning

confidence: 99%

Innovative, centralised, multidisciplinary medicines optimisation clinic for PCSK9 inhibitors

et al. 2022

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BackgroundProprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) are an important but underutilised option to help optimise lipid management. We developed a new service to improve patient access to these medicines in line with National Institute for Health and Care Excellence recommendations. This paper describes the model and provides lipid-lowering results and feedback from the first 100 referred patients.MethodsThe service is based on a centralised multidisciplinary clinic that is the sole prescriber of PCSK9i therapy in the area. Referred patients are assessed for eligibility and given tailored, person-centred support, education and monitoring to promote treatment adherence and lipids optimisation. The clinic also supports referred patients that do not meet PCSK9i eligibility criteria.ResultsAmong the first 100 patients referred (n=62 male; mean age: 62.9±10.5 years), 48 were initiated on PCSK9i therapy. Mean total cholesterol decreased from 7.7±1.6 mmol/L at baseline to 4.5±1.4 mmol/L at 3 months (41% reduction), while mean low-density lipoprotein-cholesterol (LDL-C) fell from 5.0±1.6 mmol/L to 2.1±1.3 mmol/L (58% reduction; p<0.0001) and median LDL-C decreased from 4.8 mmol/L to 1.6 mmol/L (67% reduction) over the same period. These decreases were maintained at 12 months (45%, 65% and 67% reductions, respectively; p<0.0001 for the decrease in mean LDL-C from baseline). Patient feedback on the clinic was positive and overall satisfaction was high.ConclusionsThis innovative, person-centred, multidisciplinary service successfully initiated PCSK9i therapy for eligible patients and drove long-term monitoring, adherence and cholesterol lowering. It also provided medicines optimisation and adherence assistance to PCSK9i-ineligible patients. The model could be used in other areas to support better uptake and optimisation of PCSK9i therapy.

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“…Because a significant number of CV events persist despite maximal therapy, it has been necessary to combine different therapeutic approaches and test several new drugs to reduce the burden of CVD [ 3 ]. Research has therefore focused on the development of alternative therapies that, alone or in combination with statins, effectively and durably reduce LDL-C levels, while being well tolerated and having a rather harmless side effect profile [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Current Options and Future Perspectives in the Treatment of Dyslipidemia

Muscoli

Ifrim

Russo

et al. 2022

JCM

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Low-density lipoprotein cholesterol (LDL-C) plays a crucial role in the development of atherosclerosis. Statin therapy is the standard treatment for lowering LDL-C in primary and secondary prevention. However, some patients do not reach optimal LDL-C target levels or do not tolerate statins, especially when taking high doses long-term. Combining statins with different therapeutic approaches and testing other new drugs is the future key to reducing the burden of cardiovascular disease (CVD). Recently, several new cholesterol-lowering drugs have been developed and approved; others are promising results, enriching the pharmacological armamentarium beyond statins. Triglycerides also play an important role in the development of CVD; new therapeutic approaches are also very promising for their treatment. Familial hypercholesterolemia (FH) can lead to CVD early in life. These patients respond poorly to conventional therapies. Recently, however, new and promising pharmacological strategies have become available. This narrative review provides an overview of the new drugs for the treatment of dyslipidemia, their current status, ongoing clinical or preclinical trials, and their prospects. We also discuss the new alternative therapies for the treatment of dyslipidemia and their relevance to practice.

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New and emerging lipid-modifying drugs to lower LDL cholesterol

Cited by 22 publications

References 85 publications

Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia

Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia

Innovative, centralised, multidisciplinary medicines optimisation clinic for PCSK9 inhibitors

Current Options and Future Perspectives in the Treatment of Dyslipidemia

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