Experience with proprotein convertase subtilisin/kexine type 9 inhibitors (PCSK9i) in patients undergoing lipoprotein apheresis.

We analyzed efficacy and safety of PCSK9i in patients undergoing lipoprotein apheresis (LA) and in patients treated at our outpatient department for metabolic disorders. The medical records of 40 LA patients, taking PCSK9i were reviewed with respect to LDL-cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) lowering as well as occurrence of adverse events. Furthermore, we analyzed the data of 152 patients of our outpatient department, undergoing PCSK9i therapy. Mean pre-apheresis LDL-C value was reduced by PCSK9i from 3.71 ± 1.19 to 1.78 ± 0.84 mmol/l (53 ± 12%). The relative lowering of the pre-apheresis Lp(a) was 20 ± 12% (from 191 ± 63.5 to 152 ± 51.9 nmol/l). 25% of LA patients could stop LA after reaching LDL-C target after initiation of PCSK9i. 75% of the patients are continuing the regular LA therapy, showing an insufficient LDL-C lowering following PCSK9i injections or/and additionally elevated Lp(a) or/and adverse effects of PCSK9i, leading to the discontinuation of injections. The number of LA patients has grown from 112 in 2016 to 128 nowadays due to an increasing percentage of patients with elevated Lp(a) (79% and 89% respectively). The mean reduction rate of LDL-C under PCSK9i therapy in outpatients was 53.03%. In 34% of patients the target value could not be reached. 43% of persons suffered from adverse effects. 3/4 of LA patients could not stop extracorporeal treatment after PCSK9i administration. In hypercholesterolemic patients with coexisting elevated Lp(a) and progressive cardiovascular disease the combination of LA and PCSK9i could be beneficial. The total patients' number in LA units increases due to persons with Lp(a)-hyperlipoproteinemia.

Tselmin S ，Julius U ，Weinert N ，Bornstein SR ，Schatz U ... -  《-》

Lipoprotein Apheresis and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Patients With Heterozygous Familial Hypercholesterolemia: A One Center Study.

Kolovou V ，Katsiki N ，Makrygiannis S ，Mavrogieni S ，Karampetsou N ，Manolis A ，Melidonis A ，Mikhailidis DP ，Kolovou GD ... -  《-》

NMR-based lipoprotein analysis for patients with severe hypercholesterolemia undergoing lipoprotein apheresis or PCSK9-inhibitor therapy (NAPALI-Study).

Taking into account the discordance between low-density lipoprotein cholesterol (LDL-C) and LDL particle (LDL-P) number, cardiovascular risk more closely correlates with LDL-P in patients. The aim of our study was to evaluate the number of lipid particles in patients with severe hypercholesterolemia treated with different lipid-lowering regimens. Four groups of patients differing with respect to lipid-lowering therapy were recruited from hypercholesterolemic outpatients and lipoprotein apheresis (LA) facilities, and were treated with statins alone (group A), with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) (group B), with statins and LA (group C), or with statins, PCSK9i, and LA (group D). Cholesterol, triglycerides, LDL-C, high-density lipoprotein cholesterol (HDL-C), LDL-P number and size, HDL-P number and size were determined using nuclear magnetic resonance spectroscopy. The lowest LDL-P number was achieved at the end of LA sessions in combination with statins or in combination with statins and a monoclonal PCSK9i (median; 25th and 75th percentile) (group C: 244 nmoL/L: 237, 244, P < 0.05; group D: 244 nmoL/L: 99, 307, P < 0.05). Comparing LDL-P number at the start of LA (group C: 978 nmoL/L: 728, 1404; group D: 954 nmoL/L: 677, 1521) to the other patient groups (groups A and B), the lowest LDL-P number was measured in patients treated with PCSK9i and a statin (group B): LDL-P (762 nmoL/L: 604, 1043, P < 0.05), large LDL-P (472 nmoL/L: 296, 574, P < 0.05), and small LDL-P (342 nmoL/L: 152, 494, P < 0.05). Very low-density lipoprotein and HDL particle sizes remained approximately the same in all groups. LA in combination with statins or in combination with statins and PCSK9i most reduced LDL-P numbers in hypercholesterolemic patients.

Schettler VJ ，Muellendorff F ，Schettler E ，Platzer C ，Norkauer S ，Julius U ，Neumann CL ... -  《-》

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

Clinical trials testing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have demonstrated an unanticipated but significant lipoprotein (a) (Lp(a))-lowering effect, on the order of 25% to 30%. Although the 50% to 60% reduction in low-density lipoprotein (LDL)-cholesterol (LDL-C) achieved by PCSK9i is mediated through its effect on LDL receptor (LDLR) preservation, the mechanism for Lp(a) lowering is unknown. We sought to characterize the degree of concordance between LDL-C and Lp(a) lowering because of PCSK9i in a standard of care patient cohort. Participants were selected from our Center for Preventive Cardiology, an outpatient referral center in a tertiary academic medical center. Subjects were included in this study if they had (1) at least 1 measurement of LDL-C and Lp(a) before and after initiation of the PCSK9i; (2) baseline Lp(a) > 10 mg/dL; and (3) continued adherence to PCSK9i therapy. They were excluded if (1) they were undergoing LDL apheresis; (2) pre- or post-PCSK9i LDL-C or Lp(a) laboratory values were censored; or (3) subjects discontinued other lipid-modifying therapies. In total, 103 subjects were identified as taking a PCSK9i and 26 met all inclusion and exclusion criteria. Concordant response to therapy was defined as an LDL-C reduction >35% and an Lp(a) reduction >10%. The cohort consisted of 26 subjects (15 females, 11 males, mean age 63 ± 12 years). Baseline mean LDL-C and median Lp(a) levels were 167.4 ± 72 mg/dL and 81 mg/dL (interquartile range 38-136 mg/dL), respectively. The average percent reductions in LDL-C and Lp(a) were 52.8% (47.0-58.6) and 20.2% (12.2-28.1). The correlation between %LDL and %Lp(a) reduction was moderate, with a Spearman's correlation of 0.56 (P < .01). All subjects except for 1 had a protocol-appropriate LDL-C response to therapy. However, only 16 of the 26 (62%; 95% confidence interval 41%-82%) subjects had a protocol-concordant Lp(a) response. Although some subjects demonstrated negligible Lp(a) reduction associated with PCSK9i, there were some whose Lp(a) decreased as much as 60%. In this standard-of-care setting, we demonstrate moderate correlation but large discordance (∼40%) in these 2 lipid fractions in response to PCSK9i. The results suggest that pathways beyond the LDLR are responsible for Lp(a) lowering and indicate that PCSK9i have the potential to significantly lower Lp(a) in select patients, although confirmation in larger multicenter studies is required.

Edmiston JB ，Brooks N ，Tavori H ，Minnier J ，Duell B ，Purnell JQ ，Kaufman T ，Wojcik C ，Voros S ，Fazio S ，Shapiro MD ... -  《-》

Current insights into the German lipoprotein apheresis standard: PCSK9-inhibitors, lipoprotein apheresis or both?

According to current European guidelines, lipid lowering therapy for progressive cardiovascular disease including cardiovascular events has to be focused on a target level for LDL-C. In contrast for Lp(a) a threshold has to be defined with respect to the method of measurement. However, due to new lipid lowering drug developments like PCSK9-inhibitors (PCSK-9-I) a therapeutic algorithm for patients with severe hypercholesterolemia or isolated Lipoprotein(a)-hyperlipoproteinemia with progressive cardiovascular disease may be necessary to manage the use of PCSK9-I, lipoprotein apheresis (LA) or both. The therapeutic approach for patients with homozygous familial hypercholesterolemia is unambiguous: In addition to LA, in order to improve LDL-C reduction, PCSK9-I could be applied. In patients with heterozygous familial hypercholesterolemia, PCSK9-I is to be applied first. If in addition to a pronounced LDL-C elevation, cardiovascular complications exist or if imaging techniques documented atherosclerotic changes pre-disposing for a cardiovascular event while LDL-C reduction is insufficiently reduced (LDL-C > 100 mg/dl (2.6 mmol/l)), LA treatment should then be applied as last resort. In patients with elevated Lp(a) concentrations (Lp(a) > 60 mg/dl (>120 nmol/l)) and established cardiovascular disease, therapy should rely primarily on LA methods. If in addition to high Lp(a) levels insufficiently treated LDL-C concentrations (LDL-C > 100 mg/dl (2.6 mmol/l)) exist, in rare cases PCSK9-I can supplement the lipid lowering concept.

Schettler VJJ ，Ringel J ，Jacob S ，Julius U ，Klingel R ，Heigl F ，Roeseler E ，Grützmacher P ，German Society of Nephrology (DGfN) and the Foundation of German Centers of Nephrology (DN) ... -  《-》