RETRACTED: Plasma PCSK9 Levels and Clinical Outcomes in the TNT (Treating to New Targets) Trial

Huijgen, Roeland; Boekholdt, S. Matthijs; Arsenault, Benoît J.; Bao, Weihang; Davaine, Jean-Michel; Tabet, Fatiha; Petrides, Francine; Rye, Kerry‐Anne; DeMicco, David A.; Barter, Philip J.; Kastelein, John J.P.; Lambert, Gilles

doi:10.1016/j.jacc.2011.12.043

Cited by 52 publications

(35 citation statements)

References 31 publications

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“…In this study, administration with 10 mg rosuvastatin daily for 14 days sufficiently raises circulating PCSK9 concentrations to a plateau, leaving little room for incremental PCSK9 promotion from further LDL-C lowering. This plateau effect has also been confirmed by many other investigators when compared between different doses of statins (16). Besides the mechanism mentioned above, statins may upregulate PCSK9 concentrations by peroxisome proliferator-activated receptor (PPAR) related pathway (21,22) or sterol regulatory element binding protein-2 (SREBP-2) associated mechanism (7,(23)(24)(25).…”

Section: Discussionsupporting

confidence: 56%

“…It combines with epidermal growth factor A (EGF-A) on LDL-R, forming PCSK9-EGF-A complexes which increase the degradation of the LDL-R by downregulating its utilization, thus increasing the blood LDL-C concentrations (5,(13)(14)(15). PCSK9 concentrations have been regarded to be associated with hypercholesterolaemia, major CVD events or even mortalities and morbidities (6,16,17). According to previous investigations, statins could upregulate the levels of LDL-R LDL-C percent reductions were divided into three intervals:…”

Section: Discussionmentioning

confidence: 99%

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The effects of additional ezetimibe treatment to baseline rosuvastatin on circulating PCSK9 among patients with stable angina

Zhang

Long

2017

J. Thorac. Dis.

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Background: Blood lipid management is one of the effective strategies for coronary heart disease, and statins are the first-line lipid-lowering drugs. Low density lipoprotein cholesterol (LDL-C) drop brings about cardioprotective effects. Proprotein convertase subtilisin kexin type 9 (PCSK9) is known to increase LDL-C, thus hazarding LDL-C reduction-induced benefits. To date, how PCSK9 responds to various lipidlowering strategies has not been fully clarified. Methods:This study involves patients with stable angina and aims to explore and clarify the short-term impacts of rosuvastatin and ezetimibe, alone or in combination, on circulating PCSK9. A total of 68 patients with stable angina were enrolled and 60 eligible patients were randomly assigned into 3 groups (20 subjects in each). Patients in different groups were treated for a period of 14 days with rosuvastatin 10 mg/d, ezetimibe 10 mg/d, and rosuvastatin 10 mg/d plus ezetimibe 10 mg/d, respectively. Concentrations of blood LDL-C and PCSK9 levels were measured at baseline and at the 14 th day after treatment. Results: Both rosuvastatin and ezetimibe could reduce the LDL-C levels, and rosuvastatin displayed a stronger cholesterol-lowering effect than ezetimibe. Moreover, when combined, they yielded even greater efficacy in lowering LDL-C, as compared with either rosuvastatin or ezetimibe mono-treatment (P<0.05).Rosuvastatin therapy (alone or combined with ezetimibe) caused significant rise in circulating PCSK9.Nevertheless, no significant growth of PCSK9 levels (P=0.558) was observed during ezetimibe treatment.At the 14 th day, no difference in PCKS9 levels was observed between the rosuvastatin group and the combination-therapy group (P=0.906).Conclusions: Rosuvastatin plus ezetimibe therapy is more effective in reducing LDL-C levels as compared with either rosuvastatin or ezetimibe mono-medication. Meanwhile, such combination strategy does not further increase the levels of circulating PCSK9 compared to rosuvastatin mono-intervention, thus maintaining maximal clinical benefits from lipid-lowering.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

The effects of additional ezetimibe treatment to baseline rosuvastatin on circulating PCSK9 among patients with stable angina

Zhang

Long

2017

J. Thorac. Dis.

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“…Furthermore, a retracted paper that reported PCSK9 and CVD outcomes was also excluded. 19 Seven studies were ultimately included in the present meta-analysis (Figure 1). Table 1 lists the characteristics of the 7 prospective studies including 6 cohort 20-25 and 1 nested case-control study.…”

Section: Study Selectionmentioning

confidence: 99%

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events　― Systematic Review and Meta-Analysis of Prospective Studies ―

Xiao

Peng

Huang

et al. 2017

Circ J

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Background: Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and the risk of cardiovascular events. The aim of this meta-analysis was to evaluate this association in prospective studies. Methods and Results:A systematic search of prospective studies published through October 2016 was carried out in order to identify studies that met pre-specified inclusion criteria. After independent data extraction, summary relative risks were calculated using random-effects models. On meta-analysis of 6 cohort and 1 nested case-control study, circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events (overall RR, 1.12; 95% CI: 0.98-1.29; P=0.09), with significant heterogeneity (I 2 =55.1%, Pheterogeneity=0.038). The highest but not middle categories of circulating PCSK9 was significantly associated with the risk of cardiovascular events. On subgroup analysis of study design, mean age at baseline, sample size, follow-up time, and pre-existing disease, there was no significant association between PCSK9 and cardiovascular events. Sensitivity analysis with various exclusion and inclusion criteria did not materially change the results. Conclusions:Circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events. More well-designed studies are needed to clarify the role of PCSK9 in cardiovascular risk.

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“…18-20 Moreover, elevated plasma PCSK9 level has been shown to be predictive of recurrent clinical events in patients with stable cardiovascular disease treated with low-dose atorvastatin. 21 PCSK9 expression is regulated primarily by the transcription factor sterol regulatory element-binding protein 2 (SREBP-2), 22,23 which is activated when intracellular free cholesterol levels decline and is inhibited when they increase. Several factors tend to reduce hepatocyte free cholesterol concentration and thereby promote activation of SREBP-2 and upregulation of PCSK9 expression.…”

Section: Association Of Pcsk9 With Hypercholesterolemiamentioning

confidence: 99%

Plasma PCSK9 in Nephrotic Syndrome and in Peritoneal Dialysis: A Cross-sectional Study

Jin

Park

Kim

et al. 2014

American Journal of Kidney Diseases

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Background: Serum total and low-density lipoprotein (LDL) cholesterol levels are elevated in patients with nephrotic syndrome and those with kidney failure treated by peritoneal dialysis (PD), who are characterized by heavy losses of protein in urine and peritoneal dialysate, respectively. Hypercholesterolemia in nephrotic syndrome is associated with and largely due to acquired LDL receptor (LDLR) deficiency. Because PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes degradation of LDLR, we tested the hypothesis that elevation of LDL cholesterol levels in patients with nephrotic syndrome and PD patients may be due to increased PCSK9 levels.Study Design: Cross-sectional study.Setting & Participants: Patients with nephrotic syndrome or treated by PD or hemodialysis and age-and sex-matched healthy Korean individuals (n 5 15 in each group).Predictor: Group and serum total and LDL cholesterol levels.Outcomes: Plasma PCSK9 concentration. Measurements: Concentrations of fasting serum PCSK9, lipids, and albumin, and urine protein excretion.Results: Mean serum total and LDL cholesterol levels in patients with nephrotic syndrome (317.9 6 104.2 [SD] and 205.9 6 91.1 mg/dL) and PD patients (200.0 6 27.6 and 126.7 6 18.5 mg/dL) were significantly (P , 0.05) higher than in hemodialysis patients (140.9 6 22.9 and 79.1 6 19.5 mg/dL) and the control group (166.5 6 26.5 and 95.9 6 25.2 mg/dL). This was associated with significantly (P , 0.05) higher plasma PCSK9 levels in patients with nephrotic syndrome (15.13 6 4.99 ng/mL) and PD patients (13.30 6 1.40 ng/mL) than in the control (9.19 6 0.60 ng/mL) and hemodialysis (7.30 6 0.50 ng/mL) groups. Plasma PCSK9 level was directly related to total and LDL cholesterol concentrations in the study population (r 5 0.559 [P , 0.001] and r 5 0.497 [P , 0.001], respectively).Limitations: Small number of participants may limit generalizability. Conclusions: Nephrotic syndrome and PD are associated with higher plasma PCSK9 concentration, which can contribute to elevation of LDL levels by promoting LDLR deficiency. Am J Kidney Dis. -(-):---. ª 2013 by the National Kidney Foundation, Inc.

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RETRACTED: Plasma PCSK9 Levels and Clinical Outcomes in the TNT (Treating to New Targets) Trial

Abstract: PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

Cited by 52 publications

References 31 publications

The effects of additional ezetimibe treatment to baseline rosuvastatin on circulating PCSK9 among patients with stable angina

The effects of additional ezetimibe treatment to baseline rosuvastatin on circulating PCSK9 among patients with stable angina

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events　― Systematic Review and Meta-Analysis of Prospective Studies ―

Plasma PCSK9 in Nephrotic Syndrome and in Peritoneal Dialysis: A Cross-sectional Study

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RETRACTED: Plasma PCSK9 Levels and Clinical Outcomes in the TNT (Treating to New Targets) Trial

Abstract: PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

Cited by 52 publications

References 31 publications

The effects of additional ezetimibe treatment to baseline rosuvastatin on circulating PCSK9 among patients with stable angina

The effects of additional ezetimibe treatment to baseline rosuvastatin on circulating PCSK9 among patients with stable angina

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events ― Systematic Review and Meta-Analysis of Prospective Studies ―

Plasma PCSK9 in Nephrotic Syndrome and in Peritoneal Dialysis: A Cross-sectional Study

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Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events　― Systematic Review and Meta-Analysis of Prospective Studies ―