الملخص
Lipoprotein(a) (Lp(a)) is a complex circulating lipoprotein, and increasing evidence has demonstrated its role as a risk factor for atherosclerotic cardiovascular disease and as a possible therapeutic target. Proprotein converting enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor significantly decreases the circulating level of Lp(a) and reduces the risk of cardiovascular events. Based on the research results in recent years, this review will systematically summarize the relevant mechanisms of PCSK9 inhibitor reducing Lp(a) synthesis and promoting its degradation. The mechanisms are influenced by whether statins used in combination and baseline levels of Lp(a). PCSK9 inhibitors decrease Lp(a) levels mainly by reducing Lp(a) synthesis. However, the importance of low-density lipoprotein receptor (LDLR) mediated enhancing Lp(a) degradation gradually increases when the LDL level decreases. Meanwhile, many other receptor pathways may also exist, including very low-density lipoprotein (VLDL) receptor, LDL receptor-related protein 1, CD36, toll-like receptor 2, scavenger receptor B1 and plasminogen receptor. At present, further studies are still needed to explore the mechanisms by which PCSK9 inhibitors reduce Lp(a) level, such as inhibition of Lp(a) synthesis and intracellular assembly, and LDLR-mediated Lp(a) degradation. In addition, whether the reduction of Lp(a) level by PCSK9 inhibitor is related to age, gender and race and whether the dose-effect relationship of reducing Lp(a) is influenced by background lipid level, all of which require in-depth exploration. In short, the cellular and molecular mechanisms underlying the regulation of Lp(a) synthesis and degradation is not completely clear. It is worth carrying out relevant research to provide a theoretical basis for better clinical application of such drugs.
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Obiective Alzheimer’s disease (AD) is a degenerative disease of the central nervous system (CNS) caused by a variety of risk factors. There are various pathological changes, but apoptosis of the neurological meridian cells is one of the most important pathological bases. Hyperlipidemia is a high-risk factor for the development of AD, which can lead to increased levels of oxidized low-density lipoprotein (ox-LDL) in brain tissues. PCSK9 is a protease closely related to lipid metabolism, but studies have shown that it may be related to the development of AD. LRP1 is abundantly expressed in neuronal cells, and it is an important transporter for the clearance of Aβ. There is now a large amount of literature confirming that PCSK9 can induce the degradation of LRP1. PI3K/AKT is an important signaling pathway in vivo, which plays an important role in apoptosis, and there is now a large amount of literature confirming that LRP1 activates the PI3K/AKT pathway, which has an anti-apoptotic effect. So can PCSK9 affect the PI3K/AKT pathway through LRP1 and thus regulate neuronal apoptosis? This deserves further investigation.The aim of this study was to explore the role of PCSK9 in mediating ox-LDL pro-apoptotic neuronal cell death and its mechanism, and then further elaborate the mechanism of hyperlipidemia leading to neurodegenerative diseases such as AD. MethodsFirstly, PC12 cells were treated with different concentrations of ox-LDL (0, 25, 50, 75 and 100 mg/L) for 24 h. Oil red O staining was used to detect lipid accumulation in PC12 cells, Hoechst33258 staining and flow cytometry to detect apoptosis in PC12 cells, ELISA to detect the content of Aβ secreted by PC12, Western blot to detect expression of SREBP2, PCSK9 and LRP1. Then PC12 cells were treated with 75 mg/L ox-LDL for different times (0, 6, 12, 24, 48 h), and Western blot were performed to detect the expression of SREBP2, PCSK9 and LRP1. Finally, after transfecting 100 nmol/L PCSK9 siRNA into PC12 cells for 48 h, PC12 cells were treated with 75 mg/L ox-LDL for 24 h, Hoechst33258 staining and flow cytometry to detect apoptosis rate of PC12 cells, and Western blot to detect PCSK9, LRP1, PI3K, AKT, P-PI3K , P-AKT, NF-κB, Bcl-2, Bax, Caspase-9 and Caspase-3 expression, and ELISA detected Aβ content secreted by PC12 cells. Resultsox-LDL increased lipid accumulation and promoted apoptosis and Aβ secretion in PC12 cells, as well as increasing the expression of SREBP2 and PCSK9 and decreasing the expression of LRP1 in PC12 cells. pCsk9 siRNA could be inhibited through the PI3K/AKT pathway and the NF-κB-Bcl-2/Bax-Caspase-9/3 pathway to inhibit ox-LDL-induced apoptosis in PC12 cells while increasing Aβ secretion in PC12 cells. Conclusionox-LDL plays a bidirectional regulatory role in ox-LDL-induced apoptosis of PC12 cells by inducing an increase in PCSK9 expression and a decrease in LRP1 expression in PC12 cells, which in turn affects different signaling pathways downstream.
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OBJECTIVE To systematically review the pharmacoeconomic evaluation literature about proprotein convertase subtilisin/kexin type 9 （PCSK9） inhibitors for the prevention of cardiovascular disease in patients with hypercholesterolemia， and to provide a reference for clinical treatment， health decision-making and future follow-up research. METHODS Retrieved from English and Chinese databases such as PubMed and CNKI， the pharmacoeconomic literature about PCSK9 inhibitors （evolocumab and alirocumab） for the prevention of cardiovascular disease in patients with hypercholesterolemia was collected from the establishment of the database to October 8， 2023. The quality of the included literature was assessed with Consolidated Health Economic Evaluation Reporting Standards 2022 （CHEERS 2022） scale. The descriptive analysis was performed for basic information， model structure， related parameters， sensitivity analysis and the results of included studies. RESULTS & CONCLUSIONS A total of 29 literature were included， with overall good quality. The evaluation mainly adopted the Markov model from the healthcare system， payer and societal perspective. The effectiveness and utility data mainly came from the previous studies； the direct cost was mainly considered with a discount rate of 1.5%-5.0% per year， while the willingness-to-pay threshold was often set at 1-3 times the gross domestic product per capita. Most health output indicators were measured in life years and quality-adjusted life years. The sensitivity analysis of most studies demonstrated the robustness and the main influential factor was the drug cost. Most Chinese studies showed that PCSK9 inhibitor was not cost-effective for the prevention of cardiovascular disease in patients with acute coronary syndrome， myocardial infarction and atherosclerotic cardiovascular disease. It was cost-effective to use PCSK9 inhibitors for the prevention of cardiovascular disease only in specific groups， such as patients with triple vessel disease， patients with newly diagnosed acute coronary syndrome and low-density lipoprotein cholesterol≥100 mg/dL. Future research should refer to the CHEERS 2022 scale to improve the design， and strive to select large-scale， high-quality data to enhance the quality of reports and the transparency of health decisions， so as to more accurately assess the cost-effectiveness of PCSK9 inhibitors.
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RESUMEN Introducción: el modelo SMART-REACH predice el riesgo de eventos cardiovasculares recurrentes. Objetivos: los objetivos de este estudio fueron: a) evaluar el riesgo residual en una población en prevención secundaria y niveles de colesterol asociado a lipoproteínas de baja densidad (C-LDL) fuera de meta; b) mediante un modelo de simulación, determinar el impacto de optimizar las terapias hipolipemiantes en términos de reducción del riesgo residual. Material y métodos: estudio transversal, descriptivo y multicéntrico. Se incluyeron consecutivamente pacientes con antecedentes cardiovasculares y un C-LDL mayor o igual que 55 mg/dL. El riesgo de eventos recurrentes (infarto agudo de miocardio, accidente cerebrovascular o muerte vascular) a 10 años y a lo largo de la vida se estimó utilizando el modelo SMART-REACH. Mediante una simulación, se optimizó el tratamiento hipolipemiante de cada paciente (utilizando estatinas, ezetimibe o inhibidores de proproteína convertasa subtilisina kexina tipo 9 [iPCSK9]), se estimó el descenso del C-LDL, se verificó el alcance del objetivo lipídico y se calculó la reducción del riesgo cardiovascular y el número necesario a tratar (NNT) correspondiente. Resultados: se incluyeron 187 pacientes (edad media 67,9 ± 9,3 años, 72,7% hombres). Los riesgos residuales calculados a 10 años y a lo largo de la vida fueron 37,1 ± 14,7% y 60,3 ± 10,7%, respectivamente. Globalmente, se pudo optimizar una sola estrategia farmacológica con estatinas, ezetimibe o un iPCSK9 en el 38,5%, el 11,5% y el 5,5% de la población, respectivamente. La optimización basada en dos tratamientos se realizó en el 27,5% (estatinas + ezetimibe), el 7,7% (estatinas + iPCSK9) y el 1,1% (ezetimibe + iPCSK9) de los casos. En 15 pacientes se optimizó el tratamiento considerando los tres fármacos. El 53,9% y el 62,9% de las acciones para optimizar el tratamiento mostraron un NNT menor que 30 para evitar un evento a 10 años o a lo largo de la vida, respectivamente. Conclusión: en este estudio, los pacientes con antecedentes cardiovasculares que no alcanzan la meta de C-LDL mostraron un riesgo residual considerable. La simulación mostró un importante margen para optimizar el tratamiento, con un impacto notable en el riesgo residual.
ABSTRACT Background: The SMART-REACH model predicts the risk or recurrent cardiovascular events. Objectives: The objectives of this study were: a) to evaluate the residual cardiovascular risk in a secondary prevention population with LDL-C levels above the recommended goal, using a simulation model; and b) to determine the impact of optimizing lipid-lowering therapies in terms of residual cardiovascular risk reduction. Methods: We conducted a cross-sectional, descriptive and multicenter study. Patient with a history of cardiovascular disease and a LDL-C ≥55 mg/dL were consecutively included. The 10-year and lifetime risk of recurrent events (myocardial infarction, stroke, or vascular death) were estimated using the SMART-REACH model. By means of a simulation, lipid-lowering treatment was optimized for each patient [using statins, ezetimibe and/or PCSK9 (PCSK9) inhibitors], with estimation of LDL-C reduction, checking if lipid-lowering goal was achieved and calculating the reduction in cardiovascular risk and the corresponding number needed to treat (NNT). Results: The cohort was made up of 187 patients; mean age was 67.9 ± 9.3 years and 72.7% were men. The calculated 10-year and lifetime residual risks were 37.1 ± 14.7% and 60.3 ± 10.7%, respectively. Overall, treatment was optimized with a single pharmacological strategy with statins, ezetimibe or PCSK9 inhibitor in 38.5%, 11.5% and 5.5% of the population, respectively. Optimization based on two treatments was performed in 27.5% (statins + ezetimibe), 7.7% (statins + PCSK9 inhibitor) and 1.1% (ezetimibe + PCSK9 inhibitor) of the cases. In 15 patients, treatment was optimized when the three drugs (statins + ezetimibe + PCSK9 inhibitor) were considered. Overall, 53.9% and 62.9% of the actions implemented to optimize treatment showed a 10-year or lifetime NNT < 30 to prevent an event, respectively. Conclusion: In this study, patients with a history of cardiovascular disease who do not reach LDL-C goal showed significant residual cardiovascular risk. The simulation model showed a significant margin for optimizing treatment, with a marked reduction in residual cardiovascular risk.
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@#Objective To develop quality control methods for the key quality properties of recombinant monoclonal antibodies against proprotein convertase subtilisin/Kexin 9(PCSK9). Methods According to the corresponding requirements of Chinese Pharmacopoeia(Volume Ⅲ,2020 edition)and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH),the PCSK9 monoclonal antibody was identified for the identity by reducing trypsin peptide fingerprint mapping analysis,identified for the specificity by ELISA,determined for the charge heterogeneity by imaging capillary isoelectric focusing electrophoresis(icIEF),detected for the variant purity by reducing/non-reducing capillary electrophoresis-sodium dodecyl sulfonate(CE-SDS),measured for the content of monomers,high molecular weight substances and low molecular weight substances by size-exclusion chromatography high performance liquid chromatography(SEC-HPLC),analyzed for the glycotype with N-glycan labeled with 2AB after carbohydrate cutting by Waters ACQUITY UPLC system with fluorescence detector,determined for the biological potency with HepG2 cell line and low-density lipoprotein(LDL),and detected for the content of polysorbate 20 by the liquid phase detection system(CAD detector). Results PCSK9 monoclonal antibody sample had characteristic peptide segments,and the peptide fingerprint was consistent with that of reference substance. The sample contained specific antibodies;The relative area percentages of main peak,acid peak and alkaline peak of the sample were(49. 27 ± 0. 38)%,(46. 44 ± 0. 35)% and(4. 28 ± 0. 04)%,respectively. The relative area percentages of“heavy chain + light chain”peak,non-glycosyl main peak and low molecular weight substance peak were(94. 16 ± 0. 82)%,(4. 11 ± 0. 76)% and(0. 85 ± 0. 20)%,respectively. The relative area percentages of main peak,nonglycosyl main peak and low molecular weight substance peak were(94. 27 ± 0. 22)%,(2. 85 ± 0. 08)% and(2. 88 ± 0. 15)%,respectively. The relative area percentages of monomer,high molecular weight substance and low molecular weight substance were(98. 30 ± 0. 03)%,(0. 75 ± 0. 01)% and(0. 96 ± 0. 02)%,respectively. The relative percentages of G0F,G1F,G2F and non-fucosylated(G0 + G1 + G2 + Man5)were(39. 31 ± 0. 54)%,(34. 69 ± 0. 41)%,(9. 09 ± 0. 14)% and(12. 61 ± 0. 50)%,respectively. The relative biological potency was(101. 64 ± 3. 61)% of the reference. The content of polysorbate 20 was(0. 012 ± 0. 000 3)%. Conclusion According to the key quality attribute of monoclonal antibody against PCSK9,the corresponding key quality control methods have been established,which can ensure the safety,effectiveness and quality controllability of the product.
الملخص
Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitor has become a new drug for the treatment of hypercholesterolemia and atherosclerotic cardiovascular disease. Recent studies have shown that the mechanism of PCSK9 in atherosclerotic cardiovascular disease is very complex, which is closely related to the increase of plasma low-density lipoprotein cholesterol level, apoptosis, autophagy, inflammation, foam cell formation and vascular smooth muscle cell calcification, which will help us better understand the " multiple effects" of PCSK9 inhibitors. This review aims to analyze the research status of PCSK9 in molecular structure, cell function and cardiovascular disease treatment, which will further consolidate the success of new treatment strategies for atherosclerosis.
الملخص
@#Dyslipidemia is a causal risk factor of atherosclerotic cardiovascular disease(ASCVD),and lipid-lowering therapies play a major role in preventing and managing ASCVD. Proprotein convertase subtilisin/kexin type 9(PCSK9)promotes atherosclerosis by increasing low-density lipoprotein cholesterol(LDL-C)and inflammatory response,while PCSK9 inhibitors can target to reduce PCSK9 levels and have high lipid lowering efficiency. Especially on the basis of statin or ezetimibe treatment,it can also bring more clinical benefits. With the in-depth study,PCSK9 inhibitor has become the research focus in recent years. This paper reviewed the development progress of PCSK9 inhibitors,in order to provide references for the clinical application of this class of drugs.
الملخص
Objective:To explore the mechanism of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the inflammatory response induced by Helicobacter pylori ( H. pylori) infection. Methods:From May 1, 2020 to January 31, 2021, 60 patients with gastritis (30 H. pylori positive and 30 H. pylori negative)and 30 healthy individuals, who initially visited the Department of Gastroenterology, Shiyan Taihe Hospital were collected, and their serum PCSK9 levels were detected. Normal gastric epithelial cell line GES-1 and macrophages induced from THP-1 cells, and GES-1 infected with H. pylori were selected to prepare different supernatant media. Phosphate buffer saline empty medium (negative control group), normal GES-1 cell supernatant medium ( H. pylori-uninfected GES-1 group), H. pylori infected GES-1 cell supernatant medium ( H. pylori infected GES-1 group), H. pylori infected GES-1 cell supernatant + PCSK9 neutralizing antibody medium (anti PCSK9 group), H. pylori infected GES-1 cell supernatant+ human immunoglobulin G medium (isotype control group) were established. The differences between H. pylori infected GES-1 group and H. pylori-uninfected GES-1 group, negative control group, anti PCSK9 group and isotype control group in number of migrated macrophages, relative expression level of CC chemokine receptor ( CCR2), the levels of released interleukin(IL)-6 and cell necrosis factor (TNF)- α, level of CD8 + T cell membrane phosphorylation, and the number of macrophage colonies were determined by Transwell assay, real time fluorescence quantitative polymerase chain reaction, plate colony assay, H. pylori and phagocytosis lysosome co-localization assay. The regulating mechanism of PCSK9 in H. pylori infection induced inflammation was analyzed. Independent sample t test was used for statistical analysis. Results:The serum level of PCSK9 of patients with H. pylori positive gastritis was higher than that of patients with H. pylori negative gastritis and healthy individuals ((384.00±57.57) g/L vs. (208.80±48.89) and (176.10±47.14) g/L), and the differences were statistically significant ( t=12.71 and 15.31; both P<0.001). Compared with negative control group, H. pylori standard strain and 4 isolated H. pylori strains could stimulate GES-1 to secrete PCSK9 ((1 267.00±287.50) g/L vs.(2 717.00±199.20), (4 858.00±302.40), (3 167.00±334.20), (6 075.00±597.30), (4 283.00±331.20) g/L), and the differences were statistically significant( t=10.15, 21.09, 10.56, 17.77, 16.85, all P<0.001). The number of migrated macrophages, CCR2 mRNA expression level in macrophage, expression levels of IL-6 and TNF-α, and the number of macrophage colonies of H. pylori-infected GES-1 group were all higher than those of H. pylori-uninfected GES-1 group and negative control group (132.20±5.67 vs.84.83±4.62, 39.83±4.12; 8.66±0.94 vs. 6.52±0.47 and 1.00±0.09, (281.00±8.56) ng/L vs. (115.00±7.72) and (64.00±5.44) ng/L, (619.80±18.47) ng/L vs.(373.30±12.85)and (225.70±6.44) ng/L, (357.00±16.31) colony forming unit (CFU) vs. (134.80±8.64) and (74.17±9.68) CFU), and the differences were statistically significant ( t=15.85, 32.27; 4.96, 19.79; 35.28, 52.43; 26.84, 49.37; 29.49, 36.53; all P<0.001). The percentage of co-localization of H. pylori and phagocytosis lysosome, and the expression of cell membrane CD3ζ Tyr142, granzyme B and perforin in CD8 + T cell of H. pylori-infected GES-1 group were lower than that of H. pylori-uninfected GES-1 group ((15.33±1.86)% vs. (34.50±3.72)% and (65.67±3.56)%, 464.20±120.80 vs. 1 924.00±262.10 and 2 390.00±484.10; (6.41±0.42)% vs.(17.37±0.73)% and (26.60±1.57)%; (6.84±1.37)% vs.(14.53±0.48)% and (26.22±1.21)%), and the differences were statistically significant( t=11.27 and 30.70, 12.39 and 9.45, 30.50 and 31.90, 25.96 and 13.00; all P<0.001). The number of migrated macrophages, the relative expression level of CCR2 mRNA, the expression levels of IL-6 and TNF-α, and the number of macrophage colonies of anti-PCSK9 group were all lower than those of isotype control group (72.50±4.97 vs. 128.30±6.74, 0.82±0.06 vs. 1.00±0.08, (85.50±4.37) ng/L vs. (277.70±8.98) ng/L, (291.80±13.69) ng/L vs. (615.30±12.65) ng/L, (111.50±10.21) CFU vs. (346.20±18.04) CFU), and the differences were statistically significant ( t=16.33, 4.40, 47.13, 42.50 and 27.73, all P<0.001). The percentage of co-localization of H. pylori and phagocytosis lysosome, the expression levels of CD3ζ Tyr142, granzyme B and perforin of anti-PCSK9 group were all higher than those of isotype control group ((51.05±3.03)% vs. (16.71±1.91)%, 2 948.00±384.00 vs. 1 156.00±178.60, (53.88±3.86)% vs. (5.88±0.93)%, (32.80±2.07)% vs. (6.83±0.54)%), and the differences were statistically significant ( t=23.49, 10.36, 29.60 and 29.76, all P<0.001). Conclusions:H. pylori can inhibit CD8 + T activation and cytotoxicity by inducing the release of PCSK9 from gastric epithelial cells, and can also recruit macrophages, activate nuclear factor-κB signal axis to up-regulate the level of released inflammatory factors from macrophages, inhibit the phagocytosis and killing effects of macrophages, so as to regulate the inflammatory response.
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@#To observe whether PCSK9 inhibitor combined with statin therapy can bring additional benefits on near-term clinical prognosis in patients with acute cerebral infarction，in order to provide clinical data on the effects of PCSK9 inhibitors in the early treatment of patients with cerebral infarction. Methods124 patients with acute cerebral infarction admitted to the neurology ward of our hospital from December 2020 to July 2021 were included as study subjects. A 90-day clinical follow-up was used to compare the differences in hematological indices，clinical neurological function scores，documentation of recurrent cerebral infarction and other thrombotic events during the follow-up period and differenses in the time to recurrence between the PCSK9 inhibitor combined with statin treatment and standard statin treatment groups. ResultsThe levels of hs-CRP，IL-6，Lp-PLA2，HCY，TC and LDL-C，NIHSS score and mRS score in the PCSK9 inhibitor combined with statin treatment group and the standard statin treatment group were all decreased before and after treatment（P<0.05），and there was a statistically significant difference in the combined treatment group（P<0.05），and lowered TG（P<0.05），while the level of HDL-C was improved（P<0.05）. There was no statistical significance in fasting plasma glucose of both groups before and after treatment（P>0.05）. Compared with the combined treatment group，the recurrence rate of cerebral infarction in the standard treatment group was obviously high（χ2=7.694，P=0.006），while the time to cerebral infarction recurrence was significantly longer in the combined treatment group（P<0.05）. ConclusionPCSK9 inhibitors can effectively reduce peripheral inflammatory response，promote neurological function recovery，significantly reduce stroke recurrence rate，and significantly prolong the recurrence time.
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AIM: To observe the effect of PCSK9 inhibitors on blood lipid levels and common inflammatory factors in patients with coronary heart disease. METHODS: The clinical data of 201 patients with coronary heart disease who were admitted to the Department of Cardiology of Shanghai East Hospital from April 2020 to June 2021 were retrospectively analyzed. The patients were divided into PCSK9 inhibitor treatment group (101 cases: statin + PCSK9 inhibitor) and control group (100 cases: statin treatment only) according to their medication status. Blood lipids, blood routine, CRP and FIB were re-examined after 1 month of treatment. The changes of blood lipids and inflammatory factors before and after treatment were compared. RESULTS: Before treatment, there was no significant difference in blood lipids, blood routine, CRP and FIB between the two groups (P> 0.05). The levels of sdLDL and Lp(a) were significantly decreased (P< 0.05); the levels of WBC, CRP, N and FIB were significantly decreased (P< 0.05). Compared with the control group, the levels of TC, HDL, LDL-C, CRP and FIB in the PCSK9 inhibitor group were significantly changed (P< 0.05), and the results were statistically significant. CONCLUSION: PCSK9 inhibitors can not only reduce LDL-C levels, but also reduce Lp(a) levels. PCSK9 inhibitors can reduce CRP and FIB levels, suggesting that it can partially improve inflammation in peripheral blood in patients with coronary heart disease.
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Objective:To observe the expression of hepatocyte nuclear factor 1<italic>α</italic> （HNF1<italic>α</italic>）， proprotein convertase subtilisin/kexin type 9 （PCSK9） and low-density lipoprotein cholesterol （LDLR） in hypercholesterolemia rat liver， and investigate the mechanism of Shuangyu Tiaozhi Decoction regulating cholesterol metabolism and attenuating hypercholesterolemia. Method:After providing a high-fat diet for 4 weeks， 40 SD rats were selected， 8 of which were randomly selected as normal group and fed a normal diet， and the remaining 32 rats were fed a high-fat diet. The rats successfully established as hypercholesterolemic model， were randomized into 4 groups： model group， low dose of Shuangyu Tiaozhi decoction group （7.8 g·kg<sup>-1</sup>）， high dose of Shuangyu Tiaozhi decoction group （15.6 g·kg<sup>-1</sup>）， and simvastatin group （4 mg·kg<sup>-1</sup>）， with 8 rats in each group. The drugs were continuously given for 8 weeks. Serum total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C） were measured. The pathomorphological changes in liver were observed by hematoxylin and eosin （HE） staining. The immunohistochemistry was used to detect PCSK9 and LDLR expression in liver. The mRNA and protein expression levels of HNF1<italic>α</italic>， PCSK9 and LDLR were determined by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot. Result:Compared with normal group， the TC， TG， LDL-C levels in model group were significantly increased （<italic>P</italic><0.01）， the morphology showed obvious liver steatosis. The mRNA and protein expression of HNF1<italic>α</italic> and PCSK9 were increased （<italic>P</italic><0.05）， the mRNA and protein expression of LDLR was decreased （<italic>P</italic><0.05）. Compared with model group， the serum TC， TG， LDL-C levels were significantly lowered in the Shuangyu Tiaozhi decoction high-dose group （<italic>P</italic><0.01）， the serum TC， LDL-C levels were significantly lowered in the Shuangyu Tiaozhi decoction low-dose group and simvastatin group （<italic>P</italic><0.05，<italic>P</italic><0.01）， while no significant effect was observed on the serum HDL-C levels in each treatment group. The liver steatosis decreased in each treatment group. The mRNA and protein expression of HNF1<italic>α</italic> was obviously decreased in each treatment group （<italic>P</italic><0.05，<italic>P</italic><0.01）， the mRNA and protein expression of PCSK9 was obviously decreased in Shuangyu Tiaozhi decoction low and high-dose groups （<italic>P</italic><0.05，<italic>P</italic><0.01）， the mRNA expression of PCSK9 was significantly increased in the simvastatin group （<italic>P</italic><0.01）， while the protein expression showed a downward trend. The LDLR mRNA levels were significantly increased in each treatment group （<italic>P</italic><0.01）， the LDLR protein expression was significantly increased in Shuangyu Tiaozhi high-dose group （<italic>P</italic><0.01）， and showed an upward trend in Shuangyu Tiaozhi low-dose group and simvastatin group. Results of immunohistochemistry showed PCSK9 expression was weakly positive， the expression of LDLR was strongly positive in each treatment group. The therapeutic effect of Shuangyu Tiaozhi decoction high-dose group was more remarkable than simvastatin group， while there was no obvious difference between the Shuangyu Tiaozhi decoction low-dose group and simvastatin group. Conclusion:Shuangyu Tiaozhi decoction may reduce the blood lipid levels through HNF1<italic>α</italic>/PCSK9/LDLR signaling pathway， play an active role on regulating cholesterol metabolism and alleviating high-fat diet-induced hypercholesterolemia.
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Metabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for cholesterol, plays a pivotal role in regulating CD8
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@#In order to explore the therapeutic effects and preliminary mechanism of gypenosides (GP) on hypercholesterolemia, as well as the protective effect on liver injury induced by high-dose simvastatin and high cholesterol diet (HCD), the hypercholesterolemia model of golden hamster was established by high cholesterol diet. The experimental animals were divided into blank group, model group, GP low and high dose groups (60 mg/kg, 120 mg/kg), simvastatin group (10 mg/kg), and GP high dose combined with simvastatin group (120 mg/kg + 10 mg/kg).The efficacy was investigated through dynamic monitoring serum cholesterol and liver function related indexes after drug treatment of 14 and 23 days. The results showed that GP could significantly reduce the levels of serum low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), increase the level of serum high density lipoprotein cholesterol (HDL-C), and reduce the secretion of PCSK9. It is suggested that GP has a good therapeutic effect on HCD diet-induced hypercholesterolemia hamsters, which may be related to its inhibition of PCSK9 secretion. In addition, GP can significantly ameliorate liver damage caused by HCD diet and high-dose simvastatin. These findings provide a scientific basis and useful reference for the combination of GP and statins to reduce toxicity and increase efficacy.
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Atherosclerosis is an inflammatory disorder of the vasculature and one of the underlying causes of cardiovasculardiseases. Numerous preventative and therapeutic approaches are being explored to limit the morbidity and mortalityof this disease. Nevertheless, some of the treatments cost greatly and contributed to various side effects; for example,statin therapy is associated with substantial residual cardiovascular risk as well as issues such as tolerability and patientdependent efficacy. Currently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has been attractinginterests in the drug discovery of atherosclerosis treatment, but ezetimibe, a successful PCSK9 inhibitor, is an expensivemonoclonal antibody. Thus, exploring new PCSK9 inhibitors is crucial in overcoming this constraint. In the previouswork, aaptaminoids and methyl benzoate were isolated from marine sponges Aaptos aaptos and Acanthaster planci,respectively. These compounds enhance the transcription of the peroxisome proliferator-activated receptor gamma(PPARγ) in the luciferase assay. PPARγ agonist was hypothesized to inhibit the expression of the PCSK9 gene becausethe former is a transcription factor toward the latter. The synthesis of three aaptaminoids and 11 methyl benzoatederivative was carried out to address its potential as a PCSK9 inhibitor. The structure of the synthesized compound waselucidated using nuclear magnetic resonance spectral and electron impact mass spectral data. The PCSK9 inhibitoryactivities were determined by luciferase assay. Four aaptaminoids, such as aaptamine, N1,N4-bisbenzylaaptamine,N4-[(3,4,5-trimethoxy)benzyl]aaptamine, and N1-[(3,4,5-trimethoxy)benzyl]aaptamine, and one benzamide derivative,N-(2,3-dihydro-1H-inden-2-yl)-2-methoxybenzamide, were found to inhibit the expression of PCSK9 gene.
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Dyslipidemia is an important cause of atherosclerotic cardiovascular disease (ASCVD) worldwide that leads to increased risk of morbidity and mortality; treating dyslipidemia to goal reduces the risks. This article reviews the pharmacological therapy of dyslipidemiawhich is often required in addition to life style intervention to achieve target lipid levels.Currently, there are seven types of approvedlipid modifying drugs which are effective in treating dyslipidemiawhen used singly or in combination. Statins are considered as first line drug and havebeen used extensively in the primary and secondary prevention of ASCVD. Ezetimibe is used as a first line add-on drug for patients already on a statin who have not reached their low density lipoprotein (LDL-C) goals;however,ezetimibe can be used as initial drug in statin intolerant patients. Bile acid sequestrants are a useful alternative to statins or ezetimibe in pregnant women or patients with liver disease. They also lower blood glucose and are useful in diabetes mellitus (DM). The PCSK9 inhibitors are powerful lipid modifying drugs, are expensive, needinjection for delivery, and are used when statin in maximum doses with other drugs cannot lower the LDL-C level to targets in patients with very high CV risk. Fibrates have recently shown to slow the progression of microvascular diseases and are found beneficial for DM with hypertriglyceridemia and microvascular complications. Currently, niacin use is markedly decreased due to development of more effective alternative drugs for managing dyslipidemia andbecause of the adverse effects related to niacin use.Recent trials reveal that, ω-3 fatty acids, when added in pharmacological doses to statin therapy (after controlling LDL-C), are effective in reducing CV events in patientshaving moderate hypertriglyceridemia with high or very high CV risks
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RESUMEN Los inhibidores de la proproteína convertasa subtilisina kexina tipo 9 (iPCSK9) representan un nuevo grupo de fármacos hipolipemiantes, que han generado un cambio sustancial en el manejo clínico de los lípidos. En pocos años, una gran cantidad de estudios han evaluado la eficacia antilipídica y la seguridad de estos fármacos. Más recientemente, grandes ensayos clínicos aleatorizados demostraron que el descenso del C-LDL alcanzado con estos fármacos se asoció con una menor incidencia de eventos cardiovasculares. Dicha evidencia dio lugar a la aprobación y comercialización de los iPCSK9 en muchos países. En consecuencia, diversas sociedades científicas y organismos de referencia en salud incorporaron estos fármacos en el arsenal terapéutico de la dislipidemia, con el objetivo de reducir el riesgo cardiovascular residual. En esta revisión describiremos la eficacia y la seguridad de estos fármacos, analizaremos la evidencia disponible acerca del beneficio cardiovascular y discutiremos en qué población podría ser más efectiva su utilización.
SUMMARY Proprotein convertase subtilisin kexin type 9 (iPCSK9) inhibitors represent a new group of lipid-lowering drugs that have generated a substantial change in lipid management. In a few years, a large number of studies have evaluated the lipid efficacy and safety of these drugs. More recently, large randomized clinical trials showed that the decrease in LDL-C achieved with these drugs was associated with a lower incidence of cardiovascular events. Such evidence resulted in the approval and commercialization of iPCSK9 in many countries. Consequently, various scientific societies and health reference agencies incorporated these drugs into the therapeutic arsenal of dyslipidemia, with the aim of reducing residual cardiovascular risk. In this review, we will describe the efficacy and safety of these drugs, analyze the available evidence about cardiovascular benefit, and discuss in which population their use might be most effective.
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OBJECTIVE@#To investigate the triglyceride (TG)-lowering effects of PCSK9 inhibitor in patients with in different baseline triglyceride levels.@*METHODS@#Between February, 2019 and March, 2020, a total of 59 patients were treated with PCSK9 inhibitor (Evolocumab) in 5 hospitals, including Nanfang Hospital, Guangdong Provincial People's Hospital, First Affiliated Hospital of Sun Yat-sen University, Foshan Nanhai District People's Hospital and Yulin First People's Hospital. According to baseline triglyceride levels, the patients were divided into normal TG group (< 1.70 mmol/L, =24), mild hypertriglyceridemia group (1.70-2.29 mmol/L, =11), moderate hypertriglyceridemia group (2.30-5.63 mmol/L, =13), and severe hypertriglyceridemia group (≥5.64 mmol/L, =11), and the changes in TG level after the treatment were compared among the 4 groups.@*RESULTS@#In the groups with normal and mildly elevated baseline TG level, the patients did not show significant changes in TG levels after the treatment. In patients with moderately and severely elevated baseline TG levels, treatment with PCSK9 inhibitor significantly reduced their TG levels ( < 0.005).@*CONCLUSIONS@#PCSK9 inhibitor has a significant TG-lowering effect in patients with moderate to severe hypertriglyceridemia but not in patients with only mildly elevated baseline TG level.
الموضوعات
Humans , Hypertriglyceridemia , Hypolipidemic Agents , Proprotein Convertase 9 , Triglyceridesالملخص
Objective: To compare the efficacy and safety profile of alirocumab (PCSK9 inhibitor) versus ezetimibe on top of maximally tolerated statin dose in high cardiovascular risk Chinese patients with hyperlipidemia. Methods: The ODYSSEY EAST study was a randomized, double-blinded, double dummy, active-control, parallel group, multi-centers clinical trial, the Chinese sub-population included 456 patients with hyperlipidemia and high cardiovascular risk on maximally tolerated statin dose. Patients were randomized (2∶1) to receive the subcutaneous injection of alirocumab (75 mg Q2W; with dose up titration to 150 mg Q2W at week 12 if low-density lipoprotein cholesterol (LDL-C) was ≥1.81 mmol/L at week 8) or the oral administration of ezetimibe (10 mg daily) for 24 weeks. The primary endpoint was percentage change in calculated LDL-C from baseline to week 24. Key secondary efficacy endpoints included percentage change from baseline to week 12 or 24 in LDL-C (week 12) and other lipid parameters, including apolipoprotein (Apo) B, non-high-density lipoprotein cholesterol (non-HDL-C), TC, lipoprotein(a) (Lp(a)), HDL-C, fasting triglycerides (TG), and Apo A1, and the proportion of patients reaching LDL-C<1.81 mmol/L at week 24. Safety profile of therapeutic drugs was also assessed during the treatment period. Results: The mean age of 456 Chinese patients was (59.5±10.9) years, 341(74.8%) patients were male, 303 patients (66.4%) in alirocumab group and 153 patients (33.5%) in ezetimibe group. Demographic characteristics, disease characteristics, and lipid parameters at baseline were similar between the two groups. LDL-C was reduced more from baseline to week 12 and 24 in alirocumab group versus ezetimibe group, the difference of their least-squares mean (standard error) percent change were(-35.2±2.2)% and (-36.9±2.5)% (both P<0.001). At 12 weeks, alirocumab had significant reduction on Lp(a), Apo B, total cholesterol and non HDL-C, the difference of their least-squares mean (standard error) percent change were (-40.3±2.8)%, (-27.7±1.8)%, (-19.6±1.5)% and (-27.7±1.9)%, respectively (all P<0.001). At 24 weeks, the percent of patients who reached LDL-C<1.81 mmol/L and LDL-C<1.42 mmol/L was significantly higher in alirocumab group (85.3% and 70.5%) than in ezetimibe group (42.2% and 17.0%, both P<0.001), and alirocumab use was also associated with significant reduction on Lp(a), Apo B, total cholesterol and non HDL-C, the difference of their least-squares mean (standard error) percent change were (-37.2±2.8)%, (-29.1±2.0)%, (-21.6±1.6)% and (-29.6±2.2)%, respectively (all P<0.001). The incidence of treatment related adverse events was similar between the two treatment groups (223/302 patients (73.8%) in alirocumab group and 109/153 patients (71.2%) in ezetimibe group). Respiratory infection, urinary infection, dizziness and local injection-site reactions were the most frequently reported adverse events. Conclusions: In high cardiovascular risk patients with hyperlipidemia from China on maximally tolerated statin dose, the reduction of LDL-C induced by alirocumab is more significant than that induced by ezetimibe. Both treatments were generally safe during the observation period of study.
الموضوعات
Aged , Humans , Male , Middle Aged , Antibodies, Monoclonal, Humanized , Anticholesteremic Agents/therapeutic use , Cardiovascular Diseases/drug therapy , China , Double-Blind Method , Ezetimibe/therapeutic use , Hypercholesterolemia , Hyperlipidemias , Proprotein Convertase 9 , Risk Factors , Treatment Outcomeالملخص
Resumen: Las estatinas constituyen aún la pieza fundamental para el manejo del riesgo cardiovascular. Utilizadas en dosis de alta intensidad logran reducciones de colesterol asociado a lipoproteínas de baja densidad (C-LDL) de 50%-60%. Sin embargo, en pacientes con hipercolesterolemia severa, las estatinas solas o asociadas a ezetimibe pueden no ser suficientes para alcanzar los objetivos de descenso de C-LDL. Tal es el caso de las dislipemias genéticas como la hipercolesterolemia familiar. Lo mismo ocurre en pacientes con intolerancia total o parcial a estatinas, en los que se requiere de alternativas farmacológicas modernas que permitan reducir el riesgo cardiovascular elevado. En este escenario, los inhibidores de la proproteína convertasa subtilisina kexina tipo 9, se han convertido en una piedra angular para lograr no solo una reducción jamás antes vista del C-LDL, sino también del riesgo cardiovascular. La nueva evidencia posiciona a estos fármacos en un lugar de privilegio, siendo eficaces y bien tolerados, con el costo como principal limitante, a pesar de su marcado descenso en los últimos años.
Summary: Statins are still the fundamental piece for cardiovascular risk management. Used in doses of high intensity achieve reductions in cholesterol associated with low density lipoproteins of 50%-60%. However, in patients with severe hypercholesterolemia, statins alone or associated with ezetimibe may not be sufficient to achieve cholesterol associated with low density lipoproteins decrease targets. Such is the case of genetic dyslipidemias as familial hypercholesterolemia. Also in patients with total or partial statin intolerance, a modern pharmacological alternative is required to reduce high cardiovascular risk. In this scenario, proprotein convertase subtilisin kexin type 9 inhibitors have become a cornerstone to achieve not only a reduction never seen before of cholesterol associated with low density lipoproteins levels, but also of cardiovascular risk. These drugs are in a privilege position due to the new evidence, being effective and well tolerated, with cost as its main limitation despite its marked decline in recent years.
Resumo: As estatinas ainda são a peça fundamental da gestão de risco cardiovascular. Utilizada em dose de alta intensidade atinge reduções associadas com colesterol da lipoproteína de baixa densidade de 50%-60%. No entanto em pacientes com hipercolesterolemia grave, estatinas, sozinhas ou associadas a ezetimiba podem não ser suficientes para alcançar os objetivos de redução de colesterol da lipoproteína de baixa densidade. Tal é o caso das dislipidemias genéticas como a hipercolesterolemia familiar. O mesmo ocorre em pacientes com intolerância total ou parcial de estatinas, que exige modernas alternativas farmacológicas que permitem reduzir o risco cardiovascular alto. Neste panorama, os inibidores da pró-proteína convertasa subtilisina kexina tipo 9, se tornaram uma pedra angular para alcançar não apenas uma redução em nunca antes visto colesterol da lipoproteína de baixa densidade, mas de risco cardiovascular. Novas provas colocam essas drogas em um lugar de privilégio, por ser eficaz e bem tolerado, com o custo como sua principal limitante a pesar do seu grande declínio nos últimos anos.
الملخص
La reducción del colesterol-LDL (C-LDL) es un objetivo primordial en prevención cardiovascular. Estudios recientes demostraron beneficio clínico al administrar inhibidores de la proprotein convertase subtilisin/kexin-9 (iPCSK9) a pacientes que no habían logrado la meta de C-LDL con estatinas de alta intensidad y ezetimibe, sin embargo el uso de estos fármacos está limitado por su costo. El American College of Cardiology, la Sociedad Argentina de Cardiología y la European Society of Cardiology recomiendan una meta de C-LDL menor a 70 mg/dl en prevención secundaria, determinando umbrales de C-LDL de 70, 100 o 140 mg/dl respectivamente, para iniciar el tratamiento con iPCSK9. Con el objetivo de evaluar el esquema hipolipemiante prescripto en internados por síndrome coronario agudo o revascularización coronaria y analizar la proporción de elegibles para ser tratados con iPCSK9 en un escenario real y simulado, realizamos un estudio que incluyó 351 pacientes con enfermedad coronaria, tomados de una base de datos electrónica de un hospital universitario. El 48.4% recibió estatinas de elevada intensidad, 11.4% ezetimibe y 54.7% no logró la meta de C-LDL menor a 70 mg/dl. Utilizando un modelo de simulación en el que todos serían medicados con estatinas de elevada intensidad y ezetimibe, la elegibilidad para prescribir iPCSK9 fue de 31.1%, 12.8% y 9.1% según los umbrales de C-LDL determinados por las tres sociedades científicas. Nuestro estudio demostró una brecha entre las recomendaciones de los consensos para reducir el colesterol y la práctica habitual que debería ser minimizada para optimizar la relación costo/efectividad en prevención secundaria.
LDL-cholesterol (LDL-C) lowering is a primary objective in cardiovascular prevention. Recent studies demonstrated clinical benefit when proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i) were added to the treatment in patients who had not achieved the LDL-C goal despite being treated with high intensity statins and ezetimibe, however the use of these drugs is limited by their cost. The American College of Cardiology, the Argentine Society of Cardiology and the European Society of Cardiology recommend an LDL-C goal less than 70 mg/dl in secondary prevention, determining thresholds of LDL-C to start treatment with PCSK9i of 70, 100 or 140 mg/dl respectively. In order to evaluate the lipid-lowering regimen prescribed in patients hospitalized for acute coronary syndrome or coronary revascularization and analyze the proportion of eligible to be treated with PCSK9i in a real and simulated scenario, we conducted a study that included 351 patients with coronary disease collected from an electronic database of a university hospital. The 48.4% received high intensity statins, 11.4% ezetimibe and 54.7% did not achieve the LDL-C goal of less than 70 mg/dL. Using a simulation model in which all would be treated with high intensity statins and ezetimibe, the eligibility to prescribe PCSK9i was 31.1%, 12.8% and 9.1% according to the C- LDL thresholds determined by the three scientific societies. Our study demonstrated a gap between the consensus recommendations for LDL-C lowering and the current practice that should be minimized to optimize the cost/effectiveness ratio in secondary prevention.