Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia

Santos, Raúl D.; Ruzza, Andrea; Hovingh, G. Kees; Wiegman, Albert; Mach, François; Kurtz, Christopher; Hamer, Andrew; Bridges, Ian; Bartuli, Andrea; Bergeron, Jean; Szamosi, T; Santra, Saikat; Stefanutti, Claudia; Descamps, Olivier; Greber‐Platzer, Susanne; Luirink, Ilse K.; Kastelein, John J.P.; Gaudet, Daniel

doi:10.1056/nejmoa2019910

Cited by 122 publications

(100 citation statements)

References 22 publications

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“…The considerable progress in developing newer drugs and strategies for the management of hyperlipidemias will probably lead to considerable improvement in the clinical practice in the near future. New agents are now taking optimal care of FH, even of the homozygous phenotype both in adults and pediatric individuals [115,116]. In this context, the enigmatic activity of evinacumab, an antagonist of ANGPTL3, to ameliorate LDL-C in HoFH patients may become of interest if statins, cholesterol-absorption inhibitors, or PCSK9 inhibitors would not be able to lower LDL-C to a sufficient degree or have unacceptable side effects.…”

Section: Resultsmentioning

confidence: 99%

Lipid Lowering Drugs: Present Status and Future Developments

Ruscica

Ferri

Santos

et al. 2021

Curr Atheroscler Rep

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Purpose of review Based on the recent data of the DA VINCI study, it is clear that, besides utilization of statins, there is a need to increase non-statin lipid lowering approaches to reduce the cardiovascular burden in patients at highest risk. Recent findings For hypercholesterolemia, the small synthetic molecule bempedoic acid has the added benefit of selective liver activation, whereas inclisiran, a hepatic inhibitor of the PCSK9 synthesis, has comparable effects with PCSK9 monoclonal antibodies. For hypertriglyceridemia, cardiovascular benefit has been achieved by the use of icosapent ethyl, whereas results with pemafibrate, a selective agonist of PPAR-α, are eagerly awaited. In the era of RNA-based therapies, new options are offered to dramatically reduce levels of lipoprotein(a) (APO(a)LRX) and of triglycerides (ANGPTL3LRX and APOCIII-LRx). Summary Despite the demonstrated benefits of statins, a large number of patients still remain at significant risk because of inadequate LDL-C reduction or elevated blood triglyceride-rich lipoproteins or lipoprotein(a). The area of lipid modulating agents is still ripe with ideas and major novelties are to be awaited in the next few years.

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Section: Resultsmentioning

confidence: 99%

Lipid Lowering Drugs: Present Status and Future Developments

Ruscica

Ferri

Santos

et al. 2021

Curr Atheroscler Rep

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“…Furthermore, levels of steroid hormones, fat-soluble vitamins (vitamins A, D, E, and K), glucose, and HbA1c were similar in the two groups at week 24. 61 Thus, the above evidence indicates that therapeutic PCSK9 inhibition does not seem to cause any clinically meaningful adverse effects with respect to changes in levels of fat-soluble vitamins. In addition, treatment with PCSK9 inhibitors does not adversely affect normalized and tissue vitamin E levels, nor does it affect steroid hormone synthesis.…”

Section: Effect Of Pcsk9 Inhibitor Therapy On Vitamin E and Other Fatmentioning

confidence: 87%

<p>Safety and Tolerability of PCSK9 Inhibitors: Current Insights</p>

Kosmas¹,

Skavdis²,

Sourlas³

et al. 2020

CPAA

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The current era of preventive cardiology continues to emphasize on low-density lipoprotein cholesterol (LDL-C) reduction to alleviate the burden of atherosclerotic cardiovascular disease (ASCVD). In this regard, the pharmacological inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme via monoclonal antibodies has emerged as a novel lipid-lowering therapy, leading to a marked reduction in circulating LDL-C levels and subsequent improvement of cardiovascular outcomes. As these agents are increasingly used in current clinical practice, mounting scientific and clinical evidence supports that PCSK9 inhibitors offer an excellent safety and tolerability profile with a low incidence of adverse events. Notably, the most frequently reported side effects are injection-site reactions. In contrast to statins, PCSK9 inhibitors do not appear to exert a detrimental effect on glycemic control or to increase the incidence of new-onset diabetes mellitus. Accumulating evidence also indicates that PCSK9 inhibitors are a safe, well-tolerated and effective therapeutic strategy for patients with statin intolerance. On the other hand, as PCSK9 inhibitors reduce LDL-C to unprecedented low levels, a large body of current research has examined the effects of their long-term administration on neurocognition and on levels of vitamin E and other fat-soluble vitamins, providing encouraging results. This review aims to present and discuss the current clinical and scientific evidence pertaining to the safety and tolerability of PCSK9 inhibitors.

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“…protein (LDL) Disorders (HAUSER-RCT), 157 pediatric patients aged 10 to 17 years with HeFH diagnosed by genetic testing or clinical diagnostic criteria with LDL-C ≥130 mg/dL (3.4 mmol/L) on stable lipid-lowering treatment for at least 4 weeks were treated with evolocumab 420 mg or placebo QM for 24 weeks [60]. The mean±SD age of the patients was 13.7±2.4 years and the placebo-corrected reduction in LDL-C at 24 weeks was 38.3%, or 68.6 mg/dL (1.8 mmol/L) in absolute terms.…”

Section: Article In Pressmentioning

confidence: 99%

Role of PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia

2021

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Patients with familial hypercholesterolemia (FH) are at high or very high risk for cardiovascular disease. Those with heterozygous FH (HeFH) often do not reach low-density lipoprotein cholesterol (LDL-C) targets with statin and ezetimibe therapy, and those with homozygous FH (HoFH) usually require additional lipid-modifying therapies. Drugs that inhibit proprotein convertase subtilisin/ kexin type 9 (PCSK9) offer a novel approach to reduce LDL-C. The monoclonal antibodies, alirocumab and evolocumab, given by subcutaneous injection every 2 or 4 weeks produce reductions in LDL-C of 50% to 60% in patients with HeFH, allowing many of them to achieve their LDL-C goals. Patients with HoFH show a reduced and more variable LDL-C response, which appears to depend on residual LDL receptor activity, and those with receptor-negative mutations may show no response. Inclisiran is a long-acting small interfering RNA therapeutic agent that inhibits the synthesis of PCSK9. Subcutaneous doses of 300 mg can reduce LDL-C by more than 50% for at least 6 months and the responses in HeFH and HoFH patients are similar to those achieved with monoclonal antibodies. These PCSK9 inhibitors are generally well tolerated and they provide a new opportunity for effective treatment for the majority of patients with FH.

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Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia

Cited by 122 publications

References 22 publications

Lipid Lowering Drugs: Present Status and Future Developments

Lipid Lowering Drugs: Present Status and Future Developments

<p>Safety and Tolerability of PCSK9 Inhibitors: Current Insights</p>

Role of PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia

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