Discordant response of low-density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9

Edmiston, Jonathan; Brooks, Nathan; Tavori, Hagai; Minnier, Jessica; Duell, Bart; Purnell, Jonathan Q.; Kaufman, Tina M.; Wojcik, Cezary; Vörös, Szilárd; Fazio, Sergio; Shapiro, Michael D.

doi:10.1016/j.jacl.2017.03.001

Cited by 39 publications

(25 citation statements)

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“…We previously defined PCSK9 inhibitor-induced discordance as expected LDL-C reduction without significant Lp(a) reduction (LDL-C reduction >35% and Lp(a) reduction 10%), and recently published an analysis of four Phase 3 clinical trials to determine the prevalence of discordance with evolocumab therapy. 22,23 Overall, the prevalence of expected LDL-C reduction in the absence of significant Lp(a) reduction (discordance) after evolocumab therapy was 18.4%. Furthermore, the prevalence of discordance was influenced by baseline Lp(a), being more common in patients with higher baseline Lp(a).…”

Section: Introductionmentioning

confidence: 98%

“…Though Lp(a) may be cleared partly through the LDLR, several lines of evidence point toward alternative mechanisms. [22][23][24][25] If Lp(a) clearance was fully accounted for by the LDLR pathway, one would anticipate PCSK9 inhibitor therapy to consistently reduce LDL-C and Lp(a) in a 2:1 ratio (a concordant reduction) in the same individual. We previously defined PCSK9 inhibitor-induced discordance as expected LDL-C reduction without significant Lp(a) reduction (LDL-C reduction >35% and Lp(a) reduction 10%), and recently published an analysis of four Phase 3 clinical trials to determine the prevalence of discordance with evolocumab therapy.…”

Section: Introductionmentioning

confidence: 99%

“…Given potential differences between the two therapeutic PCSK9 monoclonal antibodies, we sought to determine the prevalence of discordance in response to treatment with alirocumab using the same definitions of concordance/discordance. 22,23 Furthermore, we used a database including a significant proportion of patients with familial hypercholesterolemia, since it is important to determine whether discordant PCSK9 inhibitor response between these two lipoproteins is diminished or accentuated by a defective LDLR pathway.…”

Section: Introductionmentioning

confidence: 99%

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Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies

Mahmood

Minnier

Ito

et al. 2020

European Journal of Preventive Cardiology

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Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors consistently reduce low-density lipoprotein cholesterol (LDL-C) by 50–60% and lipoprotein(a) (Lp(a)) by 20–30%, but the mechanism of Lp(a) lowering remains unclear. If Lp(a) is cleared by the LDL receptor, similar to LDL-C, then one would expect PCSK9 inhibition to induce a concordant LDL-C/Lp(a) response in an approximately 2:1 ratio. We aim to determine the prevalence of discordant plasma LDL-C/Lp(a) response to the PCSK9 inhibitor alirocumab. Methods This is a post hoc, pooled analysis of 10 randomized controlled trials from the ODYSSEY Phase 3 clinical trial program for alirocumab. Patients enrolled in the trials were high cardiovascular risk and/or with heterozygous familial hypercholesterolemia. The primary end point was prevalence of discordant LDL-C/Lp(a) response to alirocumab at 24 weeks. Discordant response was defined as LDL-C reduction >35% and Lp(a) reduction ≤10%, or LDL-C reduction ≤35% and Lp(a) reduction >10%. Results Of the 1709 patients in the pooled study cohort, 62.4% were male, and the mean age was 59.2 (SD: 11.0) years. Baseline mean LDL-C was 126.5 (SD: 46.3) mg/dL and baseline median Lp(a) was 46.9 (interquartile range: 21.8-89.0) mg/dL. Total prevalence of discordant LDL-C/Lp(a) response was 21.5% (12.6% with LDL-C >35% reduction and Lp(a) ≤10% reduction; 8.9% with LDL-C ≤35% reduction and Lp(a) >10% reduction). Baseline Lp(a) and familial hypercholesterolemia status did not affect discordance. Conclusion A high prevalence of discordant LDL-C/Lp(a) response was observed with alirocumab, further suggesting that PCSK9 inhibitor therapy with alirocumab reduces plasma Lp(a) through alternative pathways to LDL receptor clearance.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies

Mahmood

Minnier

Ito

et al. 2020

European Journal of Preventive Cardiology

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“…The association of PCSK9 with LDL particles lowers the ability of PCSK9 to bind to cell surface LDLRs thereby blunting PCSK9-mediated LDLR degradation [8]. In addition, PCSK9 also binds to Lp(a) [9], an effect that could partially explain the reduction of plasma Lp(a) levels observed in hypercholesterolemic patients treated with monoclonal antibodies against PCSK9 [10,11], for which the molecular mechanism is still unknown, although pathways beyond the LDLR appears to be involved [12]. More controversial is the binding of PCSK9 to HDL [13].…”

Section: Introductionmentioning

confidence: 99%

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

Ruscica

Simonelli

Botta

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.

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confidence: 99%

Elusive Therapeutic Effect of PCSK9 Inhibitors on Lipoprotein(a) Levels

Sbrana¹,

Bigazzi²,

Pino³

et al. 2018

Ther Apher Dial

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Discordant response of low-density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9

Cited by 39 publications

References 25 publications

Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies

Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

Elusive Therapeutic Effect of PCSK9 Inhibitors on Lipoprotein(a) Levels

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