Association Between Circulating Baseline Proprotein Convertase Subtilisin Kexin Type 9 Levels and Efficacy of Evolocumab

Desai, Nihar R.; Giugliano, Robert P.; Wasserman, Scott M.; Gibbs, John P.; Liu, Thomas T.; Scott, Rob; Sabatine, Marc S.

doi:10.1001/jamacardio.2016.5395

Cited by 24 publications

(21 citation statements)

References 18 publications

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“…Additional research is needed to determine the relationship between PCSK9 and inflammation and to determine whether circulating PCSK9 levels influence atherogenesis in HIV. A recent study in the general population showed that PCSK9 levels do not predict LDL-c response to PCSK9 inhibitors [ 36 ], suggesting that PCSK9 levels should not be used to influence PCSK9 inhibitor treatment decisions. Studies in the general population have also shown that PCSK9 inhibition reduces plaque burden [ 37 ] and major adverse cardiovascular events [ 38 ] among high-risk patients on statins; however, it is unclear the extent to which these effects are driven by LDL lowering.…”

Section: Discussionmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV

Zanni

Stone

Toribio

et al. 2017

Open Forum Infectious Diseases

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BackgroundProprotein convertase subtilisin/kexin 9 (PCSK9) is known to mediate homeostasis of low-density lipoprotein cholesterol (LDL-c), but it may also participate in immune reactivity and atherogenesis.MethodsWe compared circulating PCSK9 levels among asymptomatic individuals with and without HIV. Further, within each group, we assessed the relationship between PCSK9 levels, traditional cardiovascular disease risk factors, immune activation, and subclinical coronary atherosclerotic plaque.ResultsPCSK9 levels were higher among HIV-infected (n = 149) vs matched non-HIV-infected subjects (n = 69; 332 [272, 412] ng/mL vs 304 [257, 375] ng/mL; P = .047). Among HIV-infected subjects, significant albeit modest positive associations were noted between PCSK9 levels and markers of systemic monocyte activation including sCD14 (rho = 0.22; P = .009) and sCD163 (rho = 0.23; P = .006). In this group, PCSK9 levels related weakly to LDL-c (rho = 0.16; P = .05) and also to Framingham Point Score but did not relate to subclinical coronary atherosclerotic plaque parameters.ConclusionsAmong HIV-infected individuals, circulating PCSK9 levels are elevated and related to systemic markers of monocyte activation but not to coronary plaque parameters. Additional studies are needed to determine the effects of PCSK9 on immune activation and atherogenesis in HIV and to assess whether PCSK9 inhibition reduces immune activation and coronary atherosclerotic plaque burden.Clinical Trial RegistrationNCT00455793.

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Section: Discussionmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV

Zanni

Stone

Toribio

et al. 2017

Open Forum Infectious Diseases

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“…The effect of baseline PCSK9 on reductions in LDL-C were evaluated using pooled data from four phase III randomized clinical studies [ 47 ]. Across all quartiles of baseline PCSK9 concentrations, evolocumab 140 mg Q2W and 420 mg QM suppressed circulating PCSK9 levels by 90–100% within 1 week of administration.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor

et al. 2018

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11–17 days. The pharmacodynamic effects of evolocumab on PCSK9 are rapid, with maximum suppression within 4 h. At steady state, peak reduction of LDL-C occurs approximately 1 week after a subcutaneous dose of 140 mg every 2 weeks (Q2W) and 2 weeks after a subcutaneous dose 420 mg once monthly (QM), and returns towards baseline over the dosing interval. In several clinical studies, these doses of evolocumab reduced LDL-C by approximately 55–75% compared with placebo. Evolocumab also reduced lipoprotein(a) [Lp(a)] levels and improved those of other lipids in clinical studies. No clinically meaningful differences in pharmacodynamic effects on LDL-C were observed in adult subjects regardless of mild/moderate hepatic impairment, renal impairment or renal failure, body weight, race, sex, or age. No clinically meaningful differences were observed for the pharmacodynamic effects of evolocumab on LDL-C between patients who received evolocumab alone or in combination with a statin, resulting in additional lowering of LDL-C when evolocumab was combined with a statin. No dose adjustment is necessary based on patient-specific factors or concomitant medication use.Electronic supplementary materialThe online version of this article (10.1007/s40262-017-0620-7) contains supplementary material, which is available to authorized users.

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“…The effects of PCSK9 antibodies are independent from the circulating PCSK9 concentration [38]. Apart from the therapeutic use of IgG antibodies, smaller molecular scaffolds targeting circulating PCSK9 are in development.…”

Section: Approaches To Reduce Pcsk9 Synthesis And/or Pcsk9/ldlr Intermentioning

confidence: 99%

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

et al. 2017

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Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Two humanized antibodies directed against the LDLR-binding site in PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics are climbing up the phases of clinical trials. The first outcome data of the PCSK9 inhibitor evolocumab reported a significant reduction in the composite endpoint (cardiovascular death, myocardial infarction, or stroke) and further outcome data are awaited. Meanwhile, it became evident that PCSK9 has (patho)physiological roles in several cardiovascular cells. In this review, we summarize and discuss the recent biological and clinical data on PCSK9, the regulation of PCSK9, its extra-hepatic activities focusing on cardiovascular cells, molecular concepts to target PCSK9, and finally briefly summarize the data of recent clinical studies.

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Association Between Circulating Baseline Proprotein Convertase Subtilisin Kexin Type 9 Levels and Efficacy of Evolocumab

Abstract: Regardless of baseline PCSK9 levels, the doses of evolocumab being studied in a large cardiovascular outcomes trial suppress PCSK9 levels and consistently and substantially reduce LDL-C levels.

Cited by 24 publications

References 18 publications

Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV

Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV

Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

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