Effects Of Proprotein Convertase Subtilisin/kexin Type 9 Inhibitors Research Articles

Early Use of PCSK9 Inhibitors in the Prognosis of Patients with Acute Coronary Syndrome by Protecting Vascular Endothelial Function.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has a protective effect on acute coronary syndrome (ACS). However, most studies have shown that this protective effect is based on a decrease in low-density lipoprotein cholesterol, while other mechanisms remain limited. This study aimed to determine whether PCSK9i can improve the prognosis of ACS patients by protecting endothelial function. A total of 113 ACS patients were enrolled and randomly assigned to PCSK9i group (PCSK9i combined with statins) and control group (statins only). Blood lipids and endothelial function indicators were measured and analyzed 6 weeks before and after treatment. The effect of PCSK9i on the expression and secretion of endothelial function indicators in vascular endothelial cells were studied by cell experiments. After 6 weeks of treatment, endothelial function indicators such as nitric oxide (NO), thrombomodulin, intercellular cell adhesion molecule-1, endothelin-1, and flow-mediated vasodilation were significantly improved in PCSK9i group compared with control group. Only the changes of NO and von Willebrand factor were associated with blood lipid levels, whereas the changes of other endothelial function indicators were not significantly associated with blood lipid levels. PCSK9i reduced the incidence of major adverse cardiovascular events in patients with ACS compared to those in the control group. In cell experiments, PCSK9i treatment significantly ameliorated LPS induced endothelial injury in HUVECs. PCSK9i can protect vascular endothelial function partly independently of its lipid-lowering effect and ameliorate the prognosis of patients with ACS within 6 weeks. This mechanism may involve heat shock transcription factor 1/heat shock proteins -related signaling pathways. Early use of PCSK9i in patients with ACS should be strongly considered in clinical practice.

Association of genetic variants related to combined lipid-lowering and antihypertensive therapies with risk of cardiovascular disease: 2 × 2 factorial Mendelian randomization analyses.

Lipid-lowering drugs and antihypertensive drugs are commonly combined for cardiovascular disease (CVD). However, the relationship of combined medications with CVD remains controversial. We aimed to explore the associations of genetically proxied medications of lipid-lowering and antihypertensive drugs, either alone or both, with risk of CVD, other clinical and safety outcomes. We divided 423,821 individuals in the UK Biobank into 4 groups via median genetic scores for targets of lipid-lowering drugs and antihypertensive drugs: lower low-density lipoprotein cholesterol (LDL-C) mediated by targets of statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lower systolic blood pressure (SBP) mediated by targets of β-blockers (BBs) or calcium channel blockers (CCBs), combined genetically lower LDL-C and SBP, and reference (genetically both higher LDL-C and SBP). Associations with risk of CVD and other clinical outcomes were explored among each group in factorial Mendelian randomization. Independent and additive effects were observed between genetically proxied medications of lipid-lowering and antihypertensive drugs with CVD (including coronary artery disease, stroke, and peripheral artery diseases) and other clinical outcomes (ischemic stroke, hemorrhagic stroke, heart failure, diabetes mellitus, chronic kidney disease, and dementia) (P > 0.05 for interaction in all outcomes). Take the effect of PCSK9 inhibitors and BBs on CVD for instance: compared with the reference, PCSK9 group had a 4% lower risk of CVD (odds ratio [OR], 0.96; 95%CI, 0.94-0.99), and a 3% lower risk was observed in BBs group (OR, 0.97; 95%CI, 0.94-0.99), while combined both were associated with a 6% additively lower risk (OR, 0.94; 95%CI, 0.92-0.97; P = 0.87 for interaction). Genetically proxied medications of combined lipid-lowering and antihypertensive drugs have an independent and additive effects on CVD, other clinical and safety outcomes, with implications for CVD clinical practice, subsequent trials as well as drug development of polypills.

The effect of antibody-mediated PCSK9 inhibitor on bare-metal stent implantation outcome

Abstract Introduction Percutaneous coronary intervention (PCI) is the gold standard for the management of acute coronary syndrome, and has been benefited from advances in pharmacotherapy and device innovation. Nevertheless, in-stent restenosis and stent thrombosis remain serious complications following PCI procedure with stent implantation. Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme known for its role in plasma cholesterol homeostasis. Efficiently reducing plasma cholesterol, PCSK9 inhibition recently became a pivotal treatment strategy for hypercholesterolemia. However, the effect of PCSK9 inhibition on stent implantation outcomes remains uninvestigated. Methods Carotid artery bare-metal stent (BMS) implantation was performed on C57Bl/6 mice, which then a parallel assessment of various inflammatory mediators was performed. To inhibit PCSK9, alirocumab was administered weekly to antiplatelet-treated mice started before stent implantation. Six weeks after the stent implantation procedure, animals were harvested and histomorphometric analysis was performed on stented arteries. In vitro cell migration and cellular senescence were also assessed on alirocumab-treated primary human aortic endothelial (EC) and vascular smooth muscle cells (VSMC). Results Compared to sham intervention, stent implantation was associated with increased expression of several inflammatory mediators, including PCSK9. Interestingly, the increase in PCSK9 level was confirmed in the stented vascular tissue, but not in plasma (Fig 1A). Following alirocumab treatment, PCSK9 inhibition results in an increased intimal hyperplasia in the stented vascular segment of alirocumab-treated animals compared to controls (Fig 1B). In vitro, alirocumab promoted migration and inhibited the onset of senescence in primary human VSMC, while blunted the migration and increased the senescence of EC. Conclusion The results of this study demonstrated that antibody-based PCSK9 inhibition worsen bare-metal stent implantation outcome in mice. This observed effect is mediated, in part, by the differential effect on VSMC and EC senescence, thus promoting in-stent intimal hyperplasia while blunting vascular healing. The herein-reported data warrant additional investigations concerning the use of PCSK9 inhibitors in patients undergoing PCI with stent implantation.

Effect of PCSK9 inhibitors on early neurological deterioration in patients with branch atheromatous disease

Objective: To investigate the effect of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors on the incidence of early neurological deterioration during the treatment of branch atheromatous disease (BAD). Methods: A retrospective analysis of 297 BAD patients admitted to the Department of Neurology in Zhengzhou People's Hospital from January 2020 to April 2023 was made. According to whether to use PCSK9 inhibitor treatment, they were divided into PCSK9 inhibitor group (81 cases) and control group (216 cases). Propensity score matching (PSM) method was used to eliminate the general situation difference between PCSK9 inhibitor group and control group. Seventy-two cases were successfully matched in each group. The early neurological deterioration (END) and low-density lipoprotein cholesterol (LDL-C) were compared. END was defined as the National Institutes of Health Stroke Scale (NIHSS) score increase≥2 points within 72 hours after stroke. Suspicious influencing factors leading to END were screened for multivariate logistic regression model analysis. Results: After PSM matching, among the 144 patients, 90 were male and 54 were female, aged (61.2±9.6) years. After matching, The hospital stay[M(Q1, Q3)] [9(7, 11)d vs 10(8, 13)d] in PCSK9 and NIHSS score at discharge [2(1, 3) vs 3(1, 4) points] were significantly different from those in the control group (all P<0.05). In addition, the incidence of END was reduced in the PCSK9 inhibitor group [12.5%(9/72) vs 31.9%(23/72),P<0.05]. Multivariate logistic regression analysis found that C-reactive protein (CRP)(OR=1.119,95%CI: 1.010-1.240, P<0.05) and PCSK9 inhibitor (OR=0.298, 95%CI: 0.117-0.755, P<0.05) were factors associated with the development of END. Conclusion: The use of PCSK9 inhibitors in the treatment of patients with BAD can reduce the incidence of END.

Major cardiovascular events increase in long-term proprotein convertase subtilisin/kexin type 9 inhibitors therapy: the Tuscany cost-effective study.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a breakthrough in the treatment of hypercholesterolemia. The aim of this study was to perform a multicentre prospective analysis on the effects of PCSK9i since their distribution in Italy. During the study period (July 2017 to February 2022) 246 patients (mean age 61 ± 11 years, male 73%) who were evolocumab (142/246) or alirocumab (104/246) new users were enrolled in the CERTI (Costo Efficacia Regione Toscana Inibitori PCSK9) study. Lipid value, adverse events (AEs), major cardiovascular events (MACEs) and intima-media thickness were analysed. PCSK9i therapy allowed a significant improvement in patients' lipid profile [total cholesterol -35%, P < 0.001; triglycerides -9%, P < 0.05; low-density lipoprotein (LDL) cholesterol -51%, P < 0.001; Lp(a) levels -4%, P < 0.05], maintained during the follow-up. No significant variations in intima-media thickness were observed. In the subgroup of patients with more than 1 year of PCSK9i therapy (165/246 patients) we highlighted: a 66% reduction in MACEs compared with the year before recruitment; a progressive increase in MACEs during the follow-up (MACEs event/rate at first year 0.08 vs. MACEs event/rate at year 5: 0.47); a patients cluster with late MACEs older, with higher prevalence of hypertension, smoking habit and peripheral vascular disease. During the follow-up, we recorded AEs in 31% of patients, which mainly resulted in reduction/discontinuation of lipid-lowering therapy for 50 patients or in discontinuation/shift of PCSK9i (respectively 8 and 6 cases). Our data agree with the large evidence on the effectiveness/tolerability of PCSK9i therapy; however, although PCSK9i represents a good cholesterol-lowering therapeutic option, our study shows a progressive increase in MACEs during the late follow-up that deserve further research.

Blocking cholesterol formation and turnover improves cellular and mitochondria function in murine heart microvascular endothelial cells and cardiomyocytes.

Background: Statins and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are cornerstones of therapy to prevent cardiovascular disease, acting by lowering lipid concentrations and only partially identified pleiotropic effects. This study aimed to analyze impacts of atorvastatin and synthetic peptide PCSK9i on bioenergetics and function of microvascular endothelial cells and cardiomyocytes. Methods: Mitochondrial function and abundance as well as intracellular nucleotides, membrane potential, cytoskeleton structure, and cell proliferation rate were evaluated in mouse heart microvascular endothelial cells (H5V) and cardiomyocytes (HL-1) under normal and hypoxia-mimicking conditions (CoCl2 exposure). Results: In normal conditions PCSK9i, unlike atorvastatin, enhanced mitochondrial respiratory parameters, increased nucleotide levels, prevented actin cytoskeleton disturbances and stimulated endothelial cell proliferation. Under hypoxia-mimicking conditions both atorvastatin and PCSK9i improved the mitochondrial respiration and membrane potential in both cell types. Conclusion: This study demonstrated that both treatments benefited the endothelial cell and cardiomyocyte bioenergetics, but the effects of PCSK9i were superior.

How Genetic Variants in Children with Familial Hypercholesterolemia Not Only Guide Detection, but Also Treatment

Familial hypercholesterolemia (FH) is a hereditary disorder that causes severely elevated low-density lipoprotein (LDL-C) levels, which leads to an increased risk for premature cardiovascular disease. A variety of genetic variants can cause FH, namely variants in the genes for the LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and/or LDL-receptor adaptor protein 1 (LDLRAP1). Variants can exist in a heterozygous form (HeFH) or the more severe homozygous form (HoFH). If affected individuals are diagnosed early (through screening), they benefit tremendously from early initiation of lipid-lowering therapy, such as statins, and cardiovascular imaging to detect possible atherosclerosis. Over the last years, due to intensive research on the genetic basis of LDL-C metabolism, novel, promising therapies have been developed to reduce LDL-C levels and subsequently reduce cardiovascular risk. Results from studies on therapies focused on inhibiting PCSK9, a protein responsible for degradation of the LDLR, are impressive. As the effect of PCSK9 inhibitors (PCSK9-i) is dependent of residual LDLR activity, this medication is less potent in patients without functional LDLR (e.g., null/null variant). Novel therapies that are expected to become available in the near future focused on inhibition of another major regulatory protein in lipid metabolism (angiopoietin-like 3 (ANGPTL3)) might dramatically reduce the frequency of apheresis in children with HoFH, independently of their residual LDLR. At present, another independent risk factor for premature cardiovascular disease, elevated levels of lipoprotein(a) (Lp(a)), cannot be effectively treated with medication. Further understanding of the genetic basis of Lp(a) metabolism, however, offers a possibility for the development of novel therapies.

Effects of PCSK9 inhibitors on metabolic-associated fatty liver disease: a short review.

Metabolic-associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease, is a significant epidemiological problem and a well-known cardiovascular risk factor. The increasing number of cases creates the need for new therapeutic methods aimed at improving patient outcomes. Recent studies have highlighted the relationship between MAFLD and proprotein convertase subtilisin/kexin type 9 (PCSK9). Based on the available data, PCSK9 inhibitors appear to have beneficial effects in patients with MAFLD, and they may be a treatment option in the future. Further research is necessary to better evaluate the efficiency of PCSK9 inhibitors in MAFLD treatment.

Effects of PCSK9 Inhibition on Coronary Atherosclerosis Regression of Nontarget Lesions after Primary Percutaneous Coronary Intervention in Acute Coronary Syndrome Patients.

To evaluate the regression of coronary atherosclerosis with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in acute coronary syndrome (ACS) patients following primary percutaneous coronary intervention (PPCI). Methods and Result. We examined 40 nontarget lesions in 17 ACS patients who underwent PPCI and were treated with PCSK9 inhibitors. At 1 year, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and atherogenic index (AI) decreased significantly by 2.5 mmol/L, 2.01 mmol/L, and 1.86, respectively. On quantitative coronary angiography, treatment with PCSK9 inhibitors reduced significantly the atherosclerotic area stenosis in nontarget lesions (61.18 ± 14.55 at baseline vs. 52.85 ± 15.51 at 1 year, P < 0.001). After 1 year of PCSK9 inhibition treatment for ACS patients, the area stenosis of non-TLR was considerably reduced.

Modulation of vascular endothelial inflammatory response by proprotein convertase subtilisin-kexin type 9

Background and AimsEndotoxins carried within LDL are cleared from the circulation via hepatic LDL receptor (LDLR)-mediated endocytosis. Proprotein convertase subtilisin-kexin type 9 (PCSK9) reduces this clearance by down-regulating LDLR density on hepatocytes. In addition to hepatocytes, vascular endothelial cells also express receptor targets of PCSK9, including LDLR. Therefore, we hypothesized that PCSK9 may regulate vascular endothelial cell uptake of lipopolysaccharide (LPS) and alter the vascular endothelial cell inflammatory response. Methods and resultsWe found that LPS is internalized by human umbilical vein vascular endothelial cells (HUVECs) and LPS uptake dose-dependently increased with increasing LDL concentration. Intracellular LPS co-localized with LDL. PCSK9 and, separately, blocking antibodies against LDLR, dose-dependently decreased the vascular endothelial cell uptake of LPS and, furthermore, inhibition of endocytosis using Dynasore blocked LPS uptake. In contrast, blocking antibodies against TLR4 did not alter LPS uptake. PCSK9 decreased the LPS-induced proinflammatory response (IL-6 and IL-8 gene expression and protein secretion, and VCAM-1/ICAM-1 expression) in vascular endothelial cells. In addition, a decrease in PCSK9 and increase in LDLR, mediated by triciribine or siPCSK9, increased LPS uptake and the LPS-induced proinflammatory response. Similar results were also found in aortic vascular tissue from Pcsk9−/− mice after LPS injection. ConclusionsOur data suggest that, similar to PCSK9 treatment in hepatocytes, PCSK9 reduces vascular endothelial cell uptake of LPS via LDLR-mediated endocytosis. Consequently, PCSK9 decreases the LPS-induced proinflammatory response in vascular endothelial cells. These results raise the possibility that PCSK9 inhibition may have additional effects on vascular endothelial inflammation via this alternative pathway, beyond the known effects of PCSK9 inhibition on LDL lowering and hepatic endotoxin clearance.

Effect of PCSK9 Inhibitors on Hemostasis in Patients with Isolated Hypercholesterolemia.

Background: In addition to reducing plasma lipids, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may produce numerous nonlipid-related pleiotropic effects. The purpose of this trial was to determine the efficacy of PCSK9 inhibitors alone in patients with isolated hypercholesterolemia. Methods: The trial enrolled 21 individuals with isolated hypercholesterolemia and atherosclerosis who received alirocumab for 90 days (150 mg every two weeks). Lipids, glucose homeostasis factors, and hemostatic markers were measured in the plasma at baseline and after treatment. Results: The PCSK9 inhibitor administered to these patients reduced plasma levels/activity of fibrinogen (from 3.6 ± 0.5 to 2.9 ± 0.4 g/L, p < 0.01), factor VII (from 143.8 ± 16.7 to 114.5 ± 14.1%, p < 0.01) and plasminogen activator inhibitor-1 (PAI-1) (from 74.9 ± 13.9 to 52.8 ± 9.1 ng/mL, p < 0.001) without a significant reduction in von Willebrand factor levels, and it tended to prolong the partial thromboplastin and prothrombin times. Conclusion: Our findings indicate that treatment with PCSK9 inhibitors has a multipotential effect on fibrinolysis and coagulation in patients with isolated hypercholesterolemia and that this medication may have some future benefits in patients who are statin-intolerant or contraindicated to statin use.

PCSK9 Plasma Levels Are Associated with Mechanical Vascular Impairment in Familial Hypercholesterolemia Subjects without a History of Atherosclerotic Cardiovascular Disease: Results of Six-Month Add-On PCSK9 Inhibitor Therapy.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) metabolism involved in the degradation of the low-density lipoprotein receptor (LDLR) through complex mechanisms. The PCSK9 plasma levels change according to lipid lowering therapy (LLT). Few data exist regarding the role of PCSK9 in vascular damage. We aimed to evaluate the impact of PCSK9 plasma levels on pulse wave velocity (PWV) and the effect of PCSK9 inhibitors (PCSK9-i) on circulating PCSK9 and PWV in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. In a previous step, HeFH patients were enrolled and LLT was prescribed according to guidelines. Biochemical analyses and PWV assessment were performed at baseline (T0), after 6 months of high-efficacy statin plus ezetimibe (T1) and after 6 months of PCSK9-i (T2). The PCSK9 levels were evaluated in 26 selected HeFH subjects at the three time points and 26 healthy subjects served as controls for the reference value for PCSK9 plasma levels. The PWV values decreased at each time point in HeFH subjects after LLT starting (8.61 ± 2.4 m/s, −8.7%; p < 0.001 vs. baseline at T1, and 7.9 ± 2.1 m/s, −9.3%; p < 0.001 vs. both T1 and baseline) and it was correlated to PCSK9 (r = 0.411, p = 0.03). The PCSK9 levels increased on statin/EZE therapy (+42.8% at T1) while it decreased after PCSK9-i was started (−34.4% at T2). We noted a significant relationship between PCSK9 levels and PWV changes at T1 and T2. In conclusion, PCSK9 levels were associated with baseline PWV values in HeFH subjects; moreover, we found that PCSK9 level variations seemed to be correlated with PWV changes on LLT. A longer observation time and wider sample size are needed to assess the potential role of PCSK9 plasma levels on the vascular function and remodelling, and to clarify the effects of PCSK9-i in these pathways.

The Trajectory of Lipoprotein(a) During the Peri- and Early Postinfarction Period and the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition

Lipoprotein(a), or Lp(a), levels and the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on Lp(a) during the peri-infarction and early postinfarction period are not well characterized. This study aimed to describe the trajectory of Lp(a), as well as the effect of PCSK9 inhibition on that trajectory during the peri-infarction and early postinfarction period. Lp(a) levels were obtained within 24hours of hospital admission as well as within 24hours of hospital discharge and at 30days from 74 participants who presented with a NSTEMI (troponin I >5ng/ml) or with a STEMI and were enrolled in 2 randomized, double-blind trials of evolocumab and placebo (Evolocumab in Acute Coronary Syndrome [EVACS I]; ClinicalTrials.gov, NCT03515304 and Evolocumab in Patients With STEMI [EVACS II]; ClinicalTrials.gov Identifier: NCT04082442). There was a significant increase from the pretreatment level in the placebo-treated patients, from 64 (41,187) nmol/L to 80 (47, 172) nmol/L at hospital discharge and to 82 (37, 265) at 30days. This was primarily driven by the results from participants with high Lp(a) at hospital admission (>75nmol/L) in whom the median increase was 28% as compared with a 10% increase in those with pretreatment Lp(a) of <75nmol/L. In contrast, there was no significant change from the pretreatment level in the evolocumab-treated patients regardless of pretreatment Lp(a) levels. In conclusion, Lp(a) rises during the peri-infarction and early postinfarction period in patients with acute myocardial infarction. The increase was prevented by a single dose of subcutaneous evolocumab given within 24hours of hospital admission.

An Untargeted Lipidomic Analysis Reveals Depletion of Several Phospholipid Classes in Patients with Familial Hypercholesterolemia on Treatment with Evolocumab

Rationale: Familial hypercholesterolemia (FH) is caused by mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism, including those for pro-protein convertase subtilisin/kexin type 9 (PCSK-9). The effect of PCSK-9 inhibition on the plasma lipidome has been poorly explored. Objective: Using an ultra-high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry method, the plasma lipidome of FH subjects before and at different time intervals during treatment with the PCSK-9 inhibitor Evolocumab was explored. Methods and Results: In 25 FH subjects, heterozygotes or compound heterozygotes for different LDL receptor mutations, untargeted lipidomic revealed significant reductions in 26 lipid classes belonging to phosphatidylcholine (PC), sphingomyelin (SM), ceramide (CER), cholesteryl ester (CE), triacylglycerol (TG) and phosphatidylinositol (PI). Lipid changes were graded between baseline and 4- and 12-week treatment. At 12-week treatment, five polyunsaturated diacyl PC, accounting for 38.6 to 49.2% of total PC at baseline; two ether/vinyl ether forms; seven SM; five CER and glucosyl/galactosyl-ceramide (HEX-CER) were reduced, as was the unsaturation index of HEX-CER and lactosyl—CER (LAC-CER). Although non quantitative modifications were observed in phosphatidylethanolamine (PE) during treatment with Evolocumab, shorter and more saturated fatty acyl chains were documented. Conclusions: Depletion of several phospholipid classes occurs in plasma of FH patients during treatment with the PCSK-9 inhibitor Evolocumab. The mechanism underlying these changes likely involves the de novo synthesis of SM and CER through the activation of the key enzyme sphingomyelin synthase by oxidized LDL and argues for a multifaceted system leading to vascular improvement in users of PCSK-9 inhibitors.

New Insights Into the Regulation of Lipoprotein Metabolism by PCSK9: Lessons From Stable Isotope Tracer Studies in Human Subjects.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation.

Skutki hamowania funkcji PCSK9 w obrębie wybranych tkanek*

Streszczenie Konwertazy probiałkowe (PCs, proprotein convertases) to rodzina 9 proteaz serynowych (PC1/3, PC2, furyna, PC4, PC5/6, PACE4, PC7, SKI-1), której przedstawicielem jest również konwertaza probiałkowa typu 9 o aktywności subtylizyny/keksyny (PCSK9). Poszczególni członkowie tej rodziny, są głównym elementem w potranslacyjnej obróbce białek prekursorowych, prowadzącej do powstania biologicznie czynnych cząsteczek, takich jak hormony, enzymy, czynniki transkrypcyjne oraz czynniki wzrostu. W związku ze zdolnością aktywacji dużej liczby substratów, PCs odgrywają znaczącą rolę w przebiegu procesów fizjologicznych, takich jak embriogeneza, aktywność ośrodkowego układu nerwowego, metabolizm lipidów, a także w stanach patofizjologicznych m.in. infekcjach wirusowych i bakteryjnych, osteoporozie, hiperglikemii, chorobach sercowo-naczyniowych, neurodegeneracyjnych oraz nowotworowych. Zahamowanie funkcji konwertazy proproteiny typu 9 o aktywności subtylizyny/keksyny (PCSK9, proprotein convertase subtilisin/kexin 9) przez przeciwciała, takie jak alirokumab czy ewolokumab zmniejsza tempo degradacji receptora LDL (lipoproteina o małej gęstości). Wiąże się to z redukcją stężenia cholesterolu LDL w osoczu, którego normalizacja jest jednym z głównych celów służących ograniczeniu ryzyka sercowo-naczyniowego. Inhibitory PCSK9 (alirokumab, ewolokumab, bococizumab) zostały stworzone m.in. z myślą o pacjentach, u których mimo stosowania optymalnych dawek dostępnych leków hipolipemizujących (statyn, ezetymibu) nie udało się uzyskać pożądanych wartości stężeń cholesterolu LDL we krwi. Wydaje się, że ze względu na dużą skuteczność, przyszłe zastosowanie inhibitorów PCSK9 (PCSK9i) w codziennej praktyce klinicznej będzie bardziej powszechne. Uwzględniając działania plejotropowe substancji dotychczas stosowanych w hiperlipidemii, takich jak statyny, omówiono piśmiennictwo pod kątem innych, poza hipolipemizującymi, możliwych skutków działania inhibitorów PCSK9 oraz oceniono ich potencjalne zalety lub wady.

Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Plasma Ceramide Levels

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that provide striking lowering of low-density lipoprotein cholesterol (LDL-C) when added to maximum tolerated therapy in patients with hypercholesterolemia. Ceramides, novel cardiac risk markers, have been associated with increased cardiovascular mortality, independent of traditional cardiovascular risk factors. The Ceramide Risk Score (CRS) predicts the likelihood of adverse cardiovascular events within 1 to 3 years in patients with coronary artery disease. The effect of PCSK9 inhibition on plasma ceramides is not well known. The study examines the effect of PCSK9 inhibitors on plasma ceramides and CRS in patients with clinical indication for this therapy. Retrospective chart review of consecutive patients with hypercholesterolemia on PCSK9 inhibitors was conducted (n = 24; Mayo Clinic 2015 to 2018). Plasma ceramides were measured before the initiation of PCSK9 inhibitors and 2 to 12 months after treatment. CRS was calculated before and after therapy based on individual plasma concentrations of 4 ceramides. Treatment with PCSK9 inhibitors was associated with significant reduction in mean CRS and individual ceramides levels (p <0.0001). CRS significantly improved with PCSK9 therapy. PCSK9 inhibitors significantly decreased LDL-C levels by 63% (p <0.0001). The absolute reduction in CRS did not correlate with the absolute reduction in LDL-C (r = 0.31; confidence interval -0.10 to 0.64), indicating that CRS may evaluate a different pathway for risk reduction beyond LDL-C lowering. In conclusion, treatment with PCSK9 inhibitors is associated with significant reduction in CRS and distinct ceramide levels.

Metabolic effects of PCSK9 inhibition with Evolocumab in subjects with elevated Lp(a)

BackgroundEpidemiological studies substantiated that subjects with elevated lipoprotein(a) [Lp(a)] have a markedly increased cardiovascular risk. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers both LDL cholesterol (LDL-C) as well as Lp(a), albeit modestly. Effects of PCSK9 inhibition on circulating metabolites such as lipoprotein subclasses, amino acids and fatty acids remain to be characterized.MethodsWe performed nuclear magnetic resonance (NMR) metabolomics on plasma samples derived from 30 individuals with elevated Lp(a) (> 150 mg/dL). The 30 participants were randomly assigned into two groups, placebo (N = 14) and evolocumab (N = 16). We assessed the effect of 16 weeks of evolocumab 420 mg Q4W treatment on circulating metabolites by running lognormal regression analyses, and compared this to placebo. Subsequently, we assessed the interrelationship between Lp(a) and 14 lipoprotein subclasses in response to treatment with evolocumab, by running multilevel multivariate regression analyses.ResultsOn average, evolocumab treatment for 16 weeks resulted in a 17% (95% credible interval: 8 to 26%, P < 0.001) reduction of circulating Lp(a), coupled with substantial reduction of VLDL, IDL and LDL particles as well as their lipid contents. Interestingly, increasing concentrations of baseline Lp(a) were associated with larger reduction in triglyceride-rich VLDL particles after evolocumab treatment.ConclusionsInhibition of PCSK9 with evolocumab markedly reduced VLDL particle concentrations in addition to lowering LDL-C. The extent of reduction in VLDL particles depended on the baseline level of Lp(a). Our findings suggest a marked effect of evolocumab on VLDL metabolism in subjects with elevated Lp(a).Trial registrationClinical trial registration information is registered at ClinicalTrials.gov on April 14, 2016 with the registration number NCT02729025.

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for the prevention of cardiovascular (CV) events. However, the clinical significance of circulating PCSK9 is unclear in hemodialysis (HD) patients. A total of 353 HD patients were prospectively enrolled from June 2016 to August 2019 in a K-cohort. Plasma PCSK9 level was measured at the time of study enrollment. The primary endpoint was defined as a composite of CV event and death. Plasma PCSK9 level was positively correlated with total cholesterol level in patients with statin treatment. Multivariate linear regression analysis revealed that baseline serum glucose, albumin, total cholesterol, and statin treatment were independent determinants of circulating PCSK9 levels. Cumulative rates of composite and CV events were significantly higher in patients with tertile 3 PCSK9 (p = 0.017 and p = 0.010, respectively). In multivariate Cox-regression analysis, PCSK9 tertile 3 was associated with a 1.97-fold risk of composite events (95% CI, 1.13–3.45), and it was associated with a 2.31-fold risk of CV events (95% CI, 1.17–4.59). In conclusion, a higher circulating PCSK9 level was independently associated with incident CV events and death in HD patients. These results suggest the importance of future studies regarding the effect of PCSK9 inhibition.

Cost-effectiveness analysis of PCSK9 inhibitors in cardiovascular diseases: a systematic review.

To assess the cost-effectiveness of pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in cardiovascular disease. We performed a comprehensive search strategy in electronic databases from January 2015 to January 2019. Out of 475 articles, 16 were entered into the study. Quality-adjusted life year, life years gained (LYG), annual cost, and the incremental cost-effectiveness ratio (ICER) regarding the use of PCSK9 inhibitors were considered as the key outcomes. The cost-effectiveness threshold varied from $45,000 in Spain to $150,000 in the USA. The annual cost of PCSK9 inhibitors for studies undertaken in the USA was in the range of $14,000 to $15,000, while it was about $7000 for other developed countries. The results showed that reduction in the price of PCSK9 inhibitors changed from 20 to 88%. The means of QALY were 0.65 and 0.67 in the Markov and Cardiovascular Disease Policy Modeling (CVDPM) models; also, the ICER means were $197,707 and $625,555 for the Markov and CVDPM model, respectively. According to the current study, the effectiveness of PCSK9 inhibitors is well documented, although all studies pointed out a higher cost of these inhibitors. This study was registered within the International Prospective Register of Systematic Reviews (PROSPERO) database of the University of York (CRD42018088472).