Lipoprotein apheresis affects lipoprotein particle subclasses more efficiently compared to the PCSK9 inhibitor evolocumab, a pilot study

Lappegård, Knut Tore; Kjellmo, Christian Abendstein; Ljunggren, Stefan; Cederbrant, Karin; Marcusson-Ståhl, Maritha; Mathisen, M.; Karlsson, Helén; Hovland, Anders

doi:10.1016/j.transci.2018.01.002

Cited by 18 publications

(17 citation statements)

References 52 publications

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“…Long‐term treatment with LA is associated with stabilization of progressive ASCVD and prevention of ASCVD events in patients with severe hypercholesterolemia, and in patients with concomitant or isolated Lp(a)‐HLP . Whether the intermittent, very low values of LDL seen after LA with a rebound before the next treatment is preferential to a more constant, moderate reduction seen with PCKS9 inhibition is a matter of debate . The immediate effect of LA is pulsed physical extracorporeal elimination of atherogenic apoB‐containing lipoproteins from plasma, including Lp(a) with its load of oxidized phospholipids, leading to subsequent replacement by endogenous nascent LDL particles without oxidative changes.…”

Section: Discussionmentioning

confidence: 99%

“…24,29,30 Whether the intermittent, very low values of LDL seen after LA with a rebound before the next treatment is preferential to a more constant, moderate reduction seen with PCKS9 inhibition is a matter of debate. 31 The immediate effect of LA is pulsed physical extracorporeal elimination of atherogenic apoB-containing lipoproteins from plasma, including Lp(a) with its load of oxidized phospholipids, leading to subsequent replacement by endogenous nascent LDL particles without oxidative changes. At the tissue level, improving plaque morphology could be another mechanism of preventing clinical events by LA, quantitatively reducing the number of vulnerable plaques, and qualitatively limiting the propensity of plaques to rupture.…”

Section: Discussionmentioning

confidence: 99%

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Real‐world study: Escalating targeted lipid‐lowering treatment with PCSK9‐inhibitors and lipoprotein apheresis

Spitthöver

Röseler²,

Julius

et al. 2019

J of Clinical Apheresis

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Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition with monoclonal antibodies has complemented the armamentarium of lipid‐lowering therapy (LLT) before the final step of commencing chronic lipoprotein apheresis (LA). Data are scarce on patients who, after escalation of LLT with PCSK9 antibodies, have commenced chronic LA or PCSK9 antibody treatment during ongoing long‐term LA. Patients and Methods In this study, a cohort of 110 patients with established atherosclerotic cardiovascular disease (ASCVD) due to hypercholesterolemia or concomitant lipoprotein(a)‐hyperlipoproteinemia, who received PCSK9 antibodies for the first time during routine care, were consecutively identified. Results Mean LDL‐C concentration prior to initiation of LA or PCSK9 antibody treatment was 5.3 ± 2.6 mmol/L (205 ± 102 mg/dL). Due to established ASCVD, the risk‐adjusted LDL‐C target value was <1.8 mmol/L (<70 mg/dL) in all patients. Use of PCSK9 antibodies increased the proportion of patients attaining the LDL‐C target concentration by 41.8% overall. Treatment emergent adverse events (TEAE) associated with PCSK9 antibody medication were reported in 35 patients (31.8%). Discontinuation of PCSK9 antibody therapy due to TEAEs occurred in 25 patients (22.7%). Conclusion Finally, 55.5% of patients received a combination of PCSK9 antibody therapy and LA at individually optimized treatment frequencies resulting in an increase of target attainment in 54.1% of patients. About 18.1% of chronic LA patients terminated LA treatment in this real‐world study. The termination of long‐term LA therapy, which has hitherto prevented the progression of ASCVD, requires careful individual risk assessment and cannot be recommended by the general criteria of LDL‐C reduction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Real‐world study: Escalating targeted lipid‐lowering treatment with PCSK9‐inhibitors and lipoprotein apheresis

Spitthöver

Röseler²,

Julius

et al. 2019

J of Clinical Apheresis

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“…In these patients, plasma apheresis is considered the last treatment option, particularly when treatment targets are not met ( 21 ). Recently, lipoprotein apheresis has been shown to affect lipoprotein-particle subclasses more efficiently compared with the PCSK-9 inhibitor evolocumab ( 22 ). Considering apoE mimetics have been shown to enhance paraoxonase-1 activity, reduce plasma lipid hydroperoxides, exert potent anti-oxidant properties, and dramatically reduce plasma cholesterol, the new potent apoE mimetics described in this study may provide an alternative to plasma apheresis, a procedure not well tolerated in all patients.…”

Section: Discussionmentioning

confidence: 99%

Novel fatty acyl apoE mimetic peptides have increased potency to reduce plasma cholesterol in mice and macaques

Anantharamaiah

Garber

Goldberg³

et al. 2018

Journal of Lipid Research

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Ac-hE18A-NH2 is a dual-domain apoE mimetic peptide that possesses the putative receptor binding domain from apoE (LRKLRKRLLR, denoted hE; residues 141–150) covalently attached to lipid-associating peptide 18A. Like apoE, Ac-hE18A-NH2 reduces plasma cholesterol in animal models and exhibits anti-inflammatory properties independent of its cholesterol-reducing effect. Ac-hE18A-NH2 has already undergone phase I clinical trials as a lipid-lowering agent. To explore the therapeutic potential more, we designed and synthesized new analogues by linking ɑ-aminohexanoic acid, octanoic acid, or myristic acid to LRRLRRRLLR-18A-NH2 ([R]hE18A-NH2) and examined the cholesterol-lowering potency in animals. The modified peptides effectively reduced plasma cholesterol in apoE-null mice fed standard chow or a Western diet; the myristyl analogue was the most effective. A single administration of the myristyl analogue reduced plasma total and LDL cholesterol in a dose-dependent manner in hypercholesterolemic cynomolgus macaques for up to 1 week despite the continuation of a cholesterol-supplemented diet. The myristyl peptide (7.4 mg/kg) reduced total and LDL cholesterol at 24 h by 64% and 74%, respectively; plasma HDL levels were modestly reduced and returned to baseline by day 7. These new analogues should exhibit enhanced potency at lower doses than Ac-hE18A-NH2, which may make them attractive therapeutic candidates for clinical trials.

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“…Two smaller studies on the PCSK9 inhibitors, alirocumab and evolocumab, also reported a proportionally larger reduction in the large LDL particles compared to the small LDL particles, but significant reductions nonetheless [ 54 , 55 ]. In a pilot study of three patients with FH, who converted from lipid apheresis to evolocumab, our group reported reductions of all LDL subfractions [ 56 ]. For comparison, studies evaluating the effects of statins on LDL subfractions are more discordant, with no changes [ 57 , 58 ], significant decreases [ 59 , 60 , 61 , 62 ], and also slight increases [ 63 ] of LDL subfraction metrics being reported.…”

Section: Ldl Subfractions and Pcsk9 Inhibitorsmentioning

confidence: 99%

CVD Risk Stratification in the PCSK9 Era: Is There a Role for LDL Subfractions?

2018

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce the risk of cardiovascular events and all-cause mortality in patients at high risk of cardiovascular disease (CVD). Due to high costs and unknown long-term adverse effects, critical evaluation of patients considered for PCSK9 inhibitors is important. It has been proposed that measuring low-density lipoprotein (LDL) subfractions, or LDL particle numbers (LDL-P), could be of value in CVD risk assessment and may identify patients at high risk of CVD. This review evaluates the evidence for the use of LDL subfractions, or LDL-P, when assessing CVD risk in patients for whom PCSK9 inhibitors are considered as a lipid-lowering therapy. Numerous methods for measuring LDL subfractions and LDL-P are available, but several factors limit their availability. A lack of standardization makes comparison between the different methods challenging. Longitudinal population-based studies have found an independent association between different LDL subfractions, LDL-P, and an increased risk of cardiovascular events, but definitive evidence that these measurements add predictive value to the standard risk markers is lacking. No studies have proven that these measurements improve clinical outcomes. PCSK9 inhibitors seem to be effective at lowering all LDL subfractions and LDL-P, but any evidence that measuring LDL subfractions and LDL-P yield clinically useful information is lacking. Such analyses are currently not recommended when considering whether to initiate PCKS9 inhibitors in patients at risk of CVD.

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Lipoprotein apheresis affects lipoprotein particle subclasses more efficiently compared to the PCSK9 inhibitor evolocumab, a pilot study

Cited by 18 publications

References 52 publications

Real‐world study: Escalating targeted lipid‐lowering treatment with PCSK9‐inhibitors and lipoprotein apheresis

Real‐world study: Escalating targeted lipid‐lowering treatment with PCSK9‐inhibitors and lipoprotein apheresis

Novel fatty acyl apoE mimetic peptides have increased potency to reduce plasma cholesterol in mice and macaques

CVD Risk Stratification in the PCSK9 Era: Is There a Role for LDL Subfractions?

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