Global Research Trends and Hotspots Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies / 医药导报

Objective To analyze the global research status,hotspots,and frontiers of proprotein convertase subtilisin/Kexin type 9(PCSK9)monoclonal antibodies,and to provide a reference for related scientific research and the rational drug use in clinical practice in China.Methods The research literature related to PCSK9 monoclonal antibody included in the Web of Science database was searched for the period from January 2011 to February 2022,and the literature included in the study was visually analyzed by the CiteSpace software.Results A total of 723 articles were included,and the annual number of publica-tions showed an overall upward trend.The top three countries were the United States,France,and the United Kingdom.Sanofi was the organization with the largest number of articles,and the organization with the highest citation of articles was Brigham and Women's Hospital.The hotspots of research mainly included the use of PCSK9 monoclonal antibody in the treatment of patients with hypercholesterolemia,patients who do not tolerate statins,patients with high cardiovascular risk,and the efficacy and safety of PCSK9 monoclonal antibody in lipid-lowering therapy combined statins;The frontiers of research in recent two years is the appli-cation of PCSK9 monoclonal antibodies in patients with acute coronary syndrome and the clinical benefits after reducing the level of lipoprotein(a).Conclusion A large number of studies have confirmed the efficacy and safety of PCSK9 monoclonal anti-bodies in reducing blood lipids,but there is still a lack of research on its economics and application in special populations,which should be the focus of future research.

Efficacy and safety of evolocumab in elderly patients with high-risk cardiovascular diseases / 中华老年心脑血管病杂志

Objective To explore the efficacy and safety of evolocumab in elderly patients with high-risk cardiovascular diseases.Methods A total of 153 patients with poor lipid control after conventional statin therapy who were hospitalized in the cardiologic departments in the First,Sec-ond,Sixth and Eighth Medical Centers of Chinese PLA General Hospital from November 2019 to November 2022 were included,and divided into non-elderly group(＜60 years old,46 cases),eld-erly group(60-74 years old,66 case)and very elderly group(≥75 years old,41 cases).They were all given evolocumab treatment according to guidelines.Another 50 over-75-year-old patients with high-risk cardiovascular diseases and poor lipid control who were hospitalized in the above cardiologic departments during the same period were treated with a statin drug combined with ezetimibe,and served as conventional treatment group(control group).The baseline clinical data and the blood indicators at 4th and 12th week after drug administration,and the occurrence of ad-verse drug reactions and major adverse cardiovascular events(MACE)within 12 weeks were com-pared among the groups.Results The levels of LDL-C and TC were significantly decreased in the three evolocumab treatment groups at 4 and 12 weeks after medication when compared with the baseline values(P＜0.05,P＜0.01),but there were no obvious differences in the 2 levels among the 3 groups at 12 weeks(P＞0.05).At the time point,no statistical difference was observed in the incidence of adverse events in the three groups(2.2％vs 3.0％vs 2.4％,P＞0.05).The levels of LDL-C and TC were decreased significantly in the very elderly group and the conventional treatment group at the 12th week when compared with the baseline levels(P＜0.05,P＜0.01),and the LDL-C level at the week was notably lower in the very elderly group than the convention-al treatment group(1.36±0.44 mmol/L vs 1.87±0.56 mmol/L,P＜0.01).But no difference was seen in the incidence of MACE between the 2 groups(12.2％vs 16.0％,P＞0.05),either in sur-vival rate between them(P=0.576).Conclusion For patients of all ages,evolocumab has good short-term efficacy in lipid control,and for those over 75 years old,the drug also shows good effi-cacy and sound safety.

Systematic review of pharmacoeconomic evaluation on PCSK9 inhibitors for the prevention of cardiovascular disease in patients with hypercholesterolemia / 中国药房

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.

Prevention and safety of evolocumab and alirocumab in ischemic stroke: a Meta analysis / 中华神经医学杂志

Objective:To evaluate the preventive role and safety of evolocumab and alirocumab in ischemic stroke in hyperlipidemia and atherosclerotic high-risk cardiovascular patients.Methods:PubMed, Embase, Web of Science, Cochrane Library, Wanfang, and CNKI databases were searched for randomized controlled trials (RCTs) comparing evolocumab or alirocumab (experimental group) with placebo or usual care (control group) in hyperlipidemia and atherosclerotic high-risk cardiovascular patients from database inception to March 2023. References were screened and data were extracted according to the preset inclusion and exclusion criteria; incidence of ischemic stroke was as the efficacy index, and incidences of cardiovascular death, cognitive impairment, aminotransferase increased for more than 3 times and creatine kinase increased for more than 3 times were as the safety index. Cochrane Reviewer Handbook 2.0 was used to evaluate the RCTs literature quality. Meta analysis was performed using Stata software.Results:A total of 11 articles were included, including 12 studies with a total of 53 666 patients. Compared with the control group, the incidence of ischemic stroke in the experimental group was significantly decreased (risk difference [ RD]=-0.004, 95% CI: -0.005--0.002, P<0.001); there were no significant differences in the incidence of cardiovascular death, cognitive impairment, aminotransferase increased for more than 3 times and creatine kinase increased for more than 3 times between the 2 groups ( RD=-0.001, 95% CI: -0.004-0.001, P=0.401; RD=0.000, 95% CI: -0.003-0.002, P=0.638; RD=-0.001, 95% CI: -0.004-0.002, P=0.443; RD=-0.001, 95% CI: -0.003-0.000, P=0.137). Subgroup analysis was performed according to drugs: compared with the control group, the incidence of ischemic stroke was significantly reduced in the evolocumab group and alirocumab group ( RD=-0.004, 95% CI: -0.007--0.001, P=0.006; RD= -0.003, 95% CI: -0.006-0.000, P=0.024); there were no significant differences in incidences of cardiovascular death ( RD=0.001, 95% CI: -0.002-0.004, P=0.619; RD=-0.003, 95% CI: -0.007-0.001, P=0.100), cognitive impairment ( RD=0.001, 95% CI:-0.002-0.004, P=0.463; RD=-0.002, 95% CI: -0.005-0.001, P=0.145), aminotransferase increased for more than 3 times ( RD=0.000, 95% CI: -0.003-0.003, P=0.888; RD=-0.002, 95% CI: -0.007-0.003, P=0.392) or creatine kinase increased for more than 3 times ( RD=0.000, 95% CI: -0.002-0.002, P=0.668; RD=-0.002, 95% CI: -0.005-0.000, P=0.106) between the evolocumab group and alirocumab group. Subgroup analysis was performed according to the medication duration: compared with the control group, no significant differences in incidences of cardiovascular death ( RD=0.000, 95% CI:-0.022-0.022, P=1.000; RD=-0.003, 95% CI: -0.009-0.002, P=0.193; RD=-0.001, 95% CI:-0.004-0.002, P=0.521), cognitive impairment ( RD=-0.003, 95% CI: -0.014-0.008, P=0.569; RD=-0.001, 95% CI: -0.006-0.004, P=0.696; RD=0.000, 95% CI: -0.003-0.002, P=0.735), aminotransferase increased for more than 3 times ( RD=-0.002, 95% CI: -0.016-0.012, P=0.749; RD=-0.002, 95% CI: -0.013-0.010, P=0.773; RD=-0.001, 95% CI: -0.004-0.002, P=0.489) or creatine kinase increased for more than three times ( RD=-0.015, 95% CI: -0.032-0.003, P=0.099; RD= -0.011, 95% CI: -0.025-0.002, P=0.104; RD=0.000, 95% CI: -0.002-0.001, P=0.722) were noted among medication duration<1 year group, medication duration of 1-2 years group and medication duration>2 years group. Conclusion:Both evolocumab and alirocumab can reduce the incidence of ischemic stroke in hyperlipidemia and atherosclerotic high-risk cardiovascular patients, with good safety.

Effectiveness，Safety and Economy of Evolocumab in the Treatment of Hypercholesterolemia ：A Rapid Health Technology Assessment / 中国药房

OBJECTIVE：To rapidly evaluate the effectiveness ，safety and economy of evolocumab in the treatment of hypercholesterolemia so as to provide evidence-based reference for clinical drug selection and decision. METHODS ：Retrieved from PubMed，Cochrane Library ，CNKI，Wanfang database and HTA relative official website ，HTA reports ，systematic evaluation/ Meta-analysis and pharmacoeconomic studies about evolocumab alone or combined with standard plan versus standard plan or placebo or ezetimibe in the treatment of hypercholesterolemia were collected during the inception to Jan. 2020. Based on literature screening and data extraction ，HTA checklist ，system evaluation measurement tool AMSTAR- 2 scale，comprehensive healthy economic evaluation report standard scale were used to evaluate the quality of included HTA reports ，systematic evaluation/ Meta-analysis and pharmacoeconomic literatures. Quantitative description was performed for effectiveness and safety results ，and qualitative description was performed for economic evaluation results. RESULTS ：A total of 13 literatures were included ，involving 6 Meta-analysis and 7 economic studies. The quality of Meta-analysis literatures was low ，and the quality of economic research was good. In terms of effectiveness ，compared with placebo or ezetimibe ，evolocumab significantly reduced the levels of LDL-C ，TC， TG and VLDL-C ，the incidence of cardiovascular events ，myocardial infarction ，coronary ischemia and stroke ，while increased the level of HDL-C （P＜0.05）. There was no statisti cal significance in the risk of hospitalizatio n，cardiac mortality or cardiovascular disease mortality in patients with unstable angina pectoris between placebo and evolocumab （P＞0.05）. In terms ofsafety，there was no significant difference in the incidence of 6237545。E-mail：zhangxu1130@163.com any adverse events ，any treatment emergency adverse events and back pain ，musculoskeletal and connective tissue diseases between evolocumab and placebo （P＞0.05）. In terms of economy，additional use of evolocumab ，based on standard plan ，had a cost-effectiveness advantage for patients with high-risk atherosclerotic cardiovascular disease （ASCVD）whose blood lipids were still not up to standard. CONCLUSIONS ：Evolocumab has good effectiveness and safety in the treatment of hypercholesterolemia. For high-risk patients with ASCVD whose blood lipids are still not up to standard after standard plan ，evolocumab has certain economy and can be used as an alternative.

Pharmacological Strategies beyond Statins: Ezetimibe and PCSK9 Inhibitors

Dyslipidemia, highly elevated, low-density lipoprotein (LDL) cholesterol, is a major cardiovascular risk factor. Statins have been proven to effectively reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and are recommended as a first-line therapy for the primary and secondary prevention of ASCVD. However, statins may not be sufficient in decreasing LDL cholesterol levels and pose a significant on-treatment residual risk of major cardiovascular events (i.e., residual cholesterol risk) according to meta-analyses of statin trials. Current guidelines for cholesterol management to achieve additional LDL cholesterol reduction and reduce ASCVD risk recommend two hyperlipidemic agents besides statins. Use of ezetimibe, a cholesterol absorption inhibitor, leads to additional LCL cholesterol reduction and decreased ASCVD risk, when added to statin therapy, without raising significant safety concerns. Furthermore, in combination with a mild-to-moderate statin intensity, ezetimibe is used in situations of statin-associated adverse effects such as myalgia and the combination therapy is relatively safer. Monoclonal antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab, and evolocumab, have been approved to lower LDL cholesterol level. While there are drawbacks to the use of PCSK9 inhibitors, including high cost and adverse events such as injection site reaction, they significantly decreased serum LDL cholesterol levels and thereby ASCVD risks when added to maximally tolerated statin therapy.

Inhibición de PCSK9: una nueva alternativa para reducir el colesterol y prevenir la enfermedad cardiovascular aterosclerosa / Inhibition of PCSK9: a new alternative for cholesterol reduction and prevention of atherosclerotic cardiovascular disease

Resumen La enfermedad cardiovascular aterosclerosa ocupa el primer lugar mundial en morbilidad y mortalidad. El principal factor de riesgo de enfermedad es el colesterol unido a lipoproteínas de baja densidad (C-LDL). El tratamiento farmacológico de elección para reducir el C-LDL son las estatinas; sin embargo, han sido insuficientes para eliminar el riesgo cardiovascular, especialmente en pacientes con formas primarias de hipercolesterolemia relacionadas con mutaciones genéticas, o intolerantes a estatinas. Es de gran importancia el desarrollo de nuevos fármacos para abatir el riesgo que persiste a pesar de la administración de estatinas. La proconvertasa subtilisina-kexina 9 (PCSK9) es un regulador primordial de la cantidad de receptores de LDL, ya que su función es dirigir dichos receptores a su destrucción lisosomal. El advenimiento de anticuerpos monoclonales para bloquear la PCSK9 ha permitido mejorar la cantidad y eficiencia de los receptores de LDL, de esto resulta la disminución notable del colesterol circulante. Hasta el momento, la eficacia e inocuidad de estos anticuerpos resultan aceptables, y los datos preliminares en cuanto a su efecto en la reducción de la morbilidad y mortalidad cardiovasculares son alentadores.

Abstract Atherosclerotic cardiovascular disease represents the leading cause of morbidity and mortality in most countries. The main risk factor for developing this disease is low density lipoprotein cholesterol (LDL-C). The pharmacological treatment of choice for reducing LDL-C is statins; however, in spite of the widespread use of statins, these drugs have been insufficient to eliminate cardiovascular risk. This residual risk is most relevant in patients with primary forms of hypercholes-terolemia associated with genetic mutations, or in those who are intolerant to statins. The development of new drugs to reduce residual cardiovascular risk is of vital importance. Proprotein convertase subtilisin-kexin 9 (PCSK9) is an important regulator of the amount of LDL receptors since its function is to direct these receptors to their lysosomal destruction. The development of monoclonal antibodies to block extracellular PCSK9 has allowed us to improve the quantity and efficiency of LDL receptors, resulting in a significant decrease in plasma cholesterol. Efficacy and safety of these antibodies is currently considered acceptable and preliminary data are encouraging but still insufficient to assess the favorable impact of these antibodies in reducing cardiovascular morbidity and mortality.

Research progress in proprotein convertase subtilisin/kexin type 9 monoclonal antibody / 中华临床营养杂志

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in lipid reg-ulation through interaction with low-density lipoprotein cholesterol receptors , and several types of PCSK 9 inhibi-tors are gradually becoming research hotspots due to their lipid lowering effect .Among them PCSK9 monoclonal antibodies are the closest to clinical application , and a number of phase Ⅲclinical trials in PCSK9 monoclonal antibodies have been completed in recent years .We systemically reviewed the current clinical research on PC-SK9 monoclonal antibodies in this paper , in order to understand their efficacy and long-term safety in reducing the risk of cardiovascular diseases .