PCSK9 Inhibition with alirocumab increases the catabolism of lipoprotein(a) particles in statin-treated patients with elevated lipoprotein(a)

Watts, Gerald F.; Chan, Dick C.; Pang, Jing; Ma, Louis; Ying, Qidi; Aggarwal, Shashi; Marcovina, Santica M.; Barrett, P. Hugh R.

doi:10.1016/j.metabol.2020.154221

Cited by 51 publications

(42 citation statements)

References 42 publications

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“…Kinetic studies indicate that in statin-treated patients with elevated lipoprotein(a) levels, alirocumab reduces those levels by increasing clearance. 16 …”

Section: Discussionmentioning

confidence: 99%

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial

Szarek

Bittner

Aylward

et al. 2020

European Heart Journal

138

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Aims Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events. Methods and results Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median −5.0 [−13.6, 0] mg/dL) and corrected LDL-C (median −51.3 [−67.1, −34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events. Conclusion Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.

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“…Kinetic studies indicate that in statin-treated patients with elevated lipoprotein(a) levels, alirocumab reduces those levels by increasing clearance. 16 …”

Section: Discussionmentioning

confidence: 99%

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial

Szarek

Bittner

Aylward

et al. 2020

European Heart Journal

138

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“…Familial hypercholesterolemia patients are most often treated with statins, a class of drugs highly effective in lowering LDL-C levels, especially when combined with ezetimibe ( Gagné et al, 2002 ). A breakthrough in the treatment of FH came with the discovery of PCSK9 inhibitors shown to decrease LDL-C by ≥50% ( Watts et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part I: Genetics and Biochemical Parameters

et al. 2022

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Introduction: The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/kexin type 9. Identification and treatment of patients with FH improves their prognosis. Our data represent retrospective analysis of 50 years of specialised care in our center.Patients and Methods: A group of 1236 FH patients (841 women, 395 men; 993 study subjects and 243 relatives; mean age 44.8 ± 16.7 years) included 154 FDB patients followed at the Lipid Clinic of the General University Hospital in Prague since the mid-1960s to the present. Clinical diagnosis was based on the Dutch Lipid Clinic Network Criteria. Genetic analysis was performed using PCR-RFLP to detect FDB and apolipoprotein E (APOE) polymorphism. Biochemical data were collected and statistically analysed.Results: At baseline, mean LDL-C and total cholesterol (TC) levels of all FH patients combined were 6.49 ± 1.92 mmol/L and 8.95 ± 1.95 mmol/L, respectively. Their LDL-C levels decreased to 3.26 ± 1.57 mmol/L and TC levels to 5.43 ± 1.69 mmol/L during follow-up. In the subgroup of LDL receptor-mediated FH (non-FDB) patients, baseline LDL-C and TC levels of 6.61 ± 1.95 mmol/L and 9.09 ± 1.97 mmol/L declined to 3.21 ± 1.60 mmol/L and 5.39 ± 1.72 mmol/L, respectively, during follow-up. In the FDB subgroup of patients, baseline levels of LDL-C and TC were 5.57 ± 1.46 mmol/L and 7.88 ± 1.58 mmol/L decreasing to 3.45 ± 0.24 mmol/L and 5.58 ± 1.37 mmol/L, respectively, during follow-up. Differences were also found in the effects of various APOE isoforms on lipid lowering. A significant decrease in lipid parameters was observed with the E2E2 isoform whereas a minimal decrease was seen with the E4E4 and E3E3 isoforms.Conclusion: Whereas, overall, non-FDB patients had higher baseline lipid levels, these levels declined more appreciably compared with FDB patients during follow-up. Our retrospective analysis also found different effects of APOE isoforms on the decrease in lipid levels.

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“…Furin is an enzyme that converts various inactive protein precursors into their active forms. In lipid metabolism, furin-cleaved PCSK9 increases the LDL receptor, leading to a decrease in LDL-C [ 11 , 19 ]. On the other hand, ANGPTL 3 and 4, which are also cleaved by furin, can mediate endothelial lipase and lipoprotein lipase inactivation [ 9 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

The association between plasma furin and cardiovascular events after acute myocardial infarction

Liu

Ma²,

Liu³

et al. 2021

BMC Cardiovasc Disord

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Background Furin is the key enzyme involved in the cleavage of pro-BNP and plays a critical role in the cardiovascular system through its involvement in lipid metabolism, blood pressure regulation and the formation of atheromatous plaques. NT-proBNP and recently, corin, also a key enzyme in the cleavage of pro-BNP, have been accepted as predictors of prognosis after acute myocardial infarction (AMI). This cohort study was conducted to investigate the relationship between plasma furin and the prognostic outcomes of AMI patients. Methods In total, 1100 AMI patients were enrolled in the study and their plasma furin concentrations were measured. The primary endpoint was major adverse cardiac events (MACE), a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI) and non-fatal stroke. The associations between plasma furin concentration and AMI outcomes were explored using Kaplan–Meier curves and multivariate Cox regression analysis. Results The results showed a slight increase in mean cTNT in patients with higher furin concentrations (P = 0.016). Over a median follow-up of 31 months, multivariate Cox regression analysis indicated that plasma furin was not significantly associated with MACE (HR 1.01; 95% CI 0.93–1.06; P = 0.807) after adjustment for potential conventional risk factors. However, plasma furin was associated with non-fatal MI (HR 1.09; 95% CI 1.01–1.17; P = 0.022) in the fully adjusted model. Subgroup analyses indicated no relationship between plasma furin and MACE in different subgroups. Conclusions This study found no association between plasma furin and risk of MACE. Thus, plasma furin may not be a useful predictor of poor prognosis after AMI. However, higher levels of plasma furin may be associated with a higher risk of recurrent non-fatal MI.

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PCSK9 Inhibition with alirocumab increases the catabolism of lipoprotein(a) particles in statin-treated patients with elevated lipoprotein(a)

Cited by 51 publications

References 42 publications

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part I: Genetics and Biochemical Parameters

The association between plasma furin and cardiovascular events after acute myocardial infarction

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