Effects of PCSK9 inhibitors on blood lipids and inflammatory factors in patients with coronary heart disease / 中国临床药理学与治疗学

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.

Efficacy and safety of alirocumab versus ezetimibe in high cardiovascular risk Chinese patients with hyperlipidemia: ODYSSEY EAST Study-Chinese sub-population analysis / 中华心血管病杂志

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.

The triglyceride-lowering effects of PCSK9 inhibitor differ in patients with different baseline triglyceride levels / 南方医科大学学报

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.

Advances in natural products with function of PCSK9 regulation and their action mechanism / 中草药

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the highligh of lipid-lowering therapy due to its effect on LDL-C in the cardiovascular field. PCSK9 inhibitor has become the hot spot in biological preparations in these years, but the properties of adverse reaction, high price and injection-methods of biologicals limit its development. Currently, it was reported that many traditional Chinese medicine and natural products had the functions of regulating PCSK9. This paper summarized the regulation and mechanisms of traditional Chinese medicine monomers, active ingredients, compounds and natural products on PCSK9 so as to provide references for the development of small-molecule inhibitors of PCSK9.

Lipid-lowering therapy in the post-statin era / 中华全科医师杂志

Atherosclerotic cardiovascular disease is one of the leading causes of death and disability worldwide.Dyslipidemia mainly with elevated LDL-C is closely related to atherosclerotic cardiovascular disease.Statins are the most effective drugs for lowering LDL-C and play an important role in the prevention and treatment of atherosclerotic cardiovascular disease.However,a considerable number of patients receiving statin therapy can not tolerate its adverse reactions or their low-density lipoprotein can not meet the standard,and the cardiovascular risk remains high.The clinical application of new lipid-lowering drugs such as ezetimibe,PCSK9 inhibitors and cholesterol ester transfer protein(CETP) inhibitors has marked the post-statin era of lipid-lowering therapy.

Clinical research of PCSK9 inhibitors in reducing low density lipoprotein cholesterol / 上海交通大学学报（医学版）

Elevated low density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Studies show that proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulation enzyme and serves a pivotal function in the degradation of low density lipoprotein receptor, which contributes to the decrease in hepatic cholesterol uptake and increase in circulating LDL-C. PCSK9 inhibitor can significantly elevate the surface of low density lipoprotein receptor of liver cells and bond more LDL-C to decrease the level of LDL-C. Thus PCSK9 has emerged as a popular target for the development of new cholesterol lowering drugs and therapeutic intervention of cardiovascular disease. In this article, the history, mechanism of action, metabolic effects of PCSK9 and the clinical outcomes of PCSK9 inhibitors will be briefly reviewed.

Updates in the management of Dyslipidaemia in the high and very high risk individual for CV risk reduction

mortality and an important cause of morbidity in Malaysiafor several years. To reduce global cardiovascular (CV) riskin the population, primary preventive strategies need to beimplemented. Hypercholesterolaemia is one of the majorrisk factors for CVD. This paper is an expert review on themanagement of hypercholesterolemia focusing on high andvery high risk individuals. In low and Intermediate riskindividuals, therapeutic lifestyle changes (TLC) and ahealthy lifestyle alone may suffice. In high and very high riskindividuals, drug therapy in conjunction with TLC arenecessary to achieve the target LDL-C levels which havebeen shown to slow down progression and sometimes evenresult in regression of atherosclerotic plaques. Statins arefirst-line drugs because they have been shown in numerousrandomized controlled trials to be effective in reducing CVevents and to be safe. In some high risk individuals, despitemaximally tolerated statin therapy, target Low DensityLipoprotein Cholesterol (LDL-C) levels are not achieved.These include those with familial hypercholesterolaemia andstatin intolerance. This paper discusses non-statintherapies, such as ezetimibe and the newer Proproteinconvertase subtilisin/kexin type 9 Inhibitors (PCSK9-i).

How to Interpret Recent CV Outcome Trials and Future: PCSK9 Inhibitors

Based on evidence from numerous research studies, increased low-density lipoprotein cholesterol (LDL-C) is a clinically important factor for accelerated atherosclerosis and increased cardiovascular risk. The introduction of statin therapy has resulted in marked reductions in LDL-C and has proven to be clinically beneficial in cardiovascular events in patients with high cardiovascular risk. Nonetheless, many patients with elevated LDL-C do not achieve their LDL-C goals with current treatments. In addition, cardiovascular disease remains an important cause of mortality and morbidity worldwide. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors further reduce LDL-C, and potentially reducing cardiovascular events. Several PCSK9 inhibitors are currently under clinical development and some of them have been studied in completed cardiovascular outcome trials, including evolocumab, alirocumab, and bococizumab. The results of the FOURIER trial, which was the first cardiovascular outcome trial to examine the impact of PCSK9 inhibition with evolocumab therapy on cardiovascular events, were reported in March of 2017. The results of the ODYSSEY Outcomes trial with alirocumab therapy were released in March of 2018 at the American College of Cardiology Annual Scientific Session. The SPIRE-1 and -2 trials which examined a PCSK9 inhibitor, bococizumab, were prematurely terminated because of discontinued development of bococizumab in November 2016. This review will discuss 3 recent cardiovascular outcome trials with PCSK9 inhibitors, with an emphasis on clinical implications and future therapeutic perspectives.

Clinical research of PCSK9 inhibitors in reducing low density lipoprotein cholesterol / 上海交通大学学报（医学版）

Elevated low density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease.Studies show that proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulation enzyme and serves a pivotal function in the degradation of low density lipoprotein receptor,which contributes to the decrease in hepatic cholesterol uptake and increase in circulating LDL-C.PCSK9 inhibitor can significantly elevate the surface of low density lipoprotein receptor of liver cells and bond more LDL-C to decrease the level of LDL-C.Thus PCSK9 has emerged as a popular target for the development of new cholesterol lowering drugs and therapeutic intervention of cardiovascular disease.In this article,the history,mechanism of action,metabolic effects of PCSK9 and the clinical outcomes of PCSK9 inhibitors will be briefly reviewed.

New Drugs for Treating Dyslipidemia: Beyond Statins

Statins have been shown to be very effective and safe in numerous randomized clinical trials, and became the implacable first-line treatment against atherogenic dyslipidemia. However, even with optimal statin treatment, 60% to 80% of residual cardiovascular risk still exists. The patients with familial hypercholesterolemia which results in extremely high level of low density lipoprotein cholesterol (LDL-C) level and the patients who are intolerant or unresponsive to statins are the other hurdles of statin treatment. Recently, new classes of lipid-lowering drugs have been developed and some of them are available for the clinical practice. The pro-protein convertase subtilisin/kexintype 9 (PCSK9) inhibitor increases the expression of low density lipoprotein (LDL) receptor in hepatocytes by enhancing LDL receptor recycling. The microsomal triglyceride transport protein (MTP) inhibitor and antisense oligonucleotide against apolipoprotein B (ApoB) reduce the ApoB containing lipoprotein by blocking the hepatic very low density lipoprotein synthesis pathway. The apolipoprotein A1 (ApoA1) mimetics pursuing the beneficial effect of high density lipoprotein cholesterol and can reverse the course of atherosclerosis. ApoA1 mimetics had many controversial clinical data and need more validation in humans. The PCSK9 inhibitor recently showed promising results of significant LDL-C lowering in familial hypercholesterolemia (FH) patients from the long-term phase III trials. The MTP inhibitor and antisesnse oligonucleotide against ApoB were approved for the treatment of homozygous FH but still needs more consolidated evidences about hepatic safety such as hepatosteatosis. We would discuss the benefits and concerns of these new lipid-lowering drugs anticipating additional benefits beyond statin treatment.