Incorporation of PCSK9 inhibitors into prevention of atherosclerotic cardiovascular disease

Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has become recently more complex than ever, leaving the clinicians perplexed with outdated guidelines and emerging evidence about new LDL-C lowering therapies. 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines have focused on high intensity statin therapy for specific groups of patients, while abandoning long established LDL-C goals, a strategy which no longer seems valid. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors have emerged as the add-on therapy on top of statins and/or ezetimibe for the treatment of hypercholesterolemia and ASCVD prevention. In several clinical trials, PCSK9 inhibitors have demonstrated their safety and robust LDL-C-lowering power. One completed cardiovascular (CV) outcomes trial (FOURIER; Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk) has demonstrated that PCSK9 inhibition reduces rates of CV death as well as non-fatal stroke and MI, while another major CV outcome trial is under way (ODYSSEY-OUTCOMES). Several trials studying CV benefits of novel LDL-C-lowering therapies are also being conducted. Prompt revision of ACC/AHA guidelines is necessary. In the meantime, physicians need to use clinical judgment integrating the most recent evidence into their practice.     

PCSK9抑制剂对动脉粥样硬化性心血管疾病有效性及安全性的meta分析

目的 系统评价PCSK9抑制剂对动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease, ASCVD)患者的有效性及安全性。方法 计算机检索PubMed、Embase、Cochrane图书馆和临床试验注册平台Clinical Trails.gov,检索年限从建库至2022年5月。筛选并纳入PCSK9抑制剂治疗ASCVD患者的随机对照试验(randomized controlled trials, RCTs),应用Review Manager 5.4软件对符合标准的RCTs进行meta分析。结果 共纳入10项随机对照试验,共计54 472例患者。有效性分析结果显示：与对照组相比,PCSK9抑制剂可降低ASCVD患者低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)水平49.26%(95%CI:-54.00～-44.52,P<0.01),并显著降低了其他5项血脂水平;PCSK9抑制剂组动脉粥样硬化斑块体积百分比(percent atheroma volume, PAV)降低1.1%...     

PCSK9抑制剂在冠状动脉粥样硬化性心脏病治疗中的研究进展

动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease,ASCVD)是目前临床上较为常见的心血管疾病之一,其发病原因主要与动脉粥样硬化有关,故降低胆固醇、低密度脂蛋白,延缓动脉粥样硬化进展是ASCVD防治的基础,临床首选药物为他汀类药物.但长期临床实践发现,仍有部分ASC...     

Alirocumab in lipoprotein apheresis: A synergy for patients with high-Lp(a)

Until today lipoprotein apheresis (LA) is considered the most effective treatment for patients with high-Lp(a) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are often combined with LA to dampen the rebound in lipoprotein concentrations. The aim of the present work is to evaluate the effect of dose-adjustment strategy for alirocumab in a small cohort of high-Lp(a) subjects with ischemic heart disease and in chronic LA treatment. Chronic LA effect on Lp(a) levels is a significant reduction in pre-LA Lp(a) concentrations compared to native Lp(a) value (118 [116–119] mg/dl vs 150 [137–155] mg/dl; p < 0.001). Furthermore, the administration of Arilocumab 75 mg after 7 days from LA shows a significant pre-LA reduction in the Lp(a) concentrations respect to those obtained with administration immediately after the LA treatment. In high-Lp(a) patients treated with chronic LA the deferred addition of alirocumab, resulted in lower LDL-cholesterol and Lp(a) values.     

PCSK9 inhibitors and LDL reduction: pharmacology,clinical implications,and future perspectives

Introduction: PCSK9 inhibitors are monoclonal antibodies to proprotein convertase-subtilisin/kexin type 9 which significantly reduce LDL cholesterol concentration in vivo by inhibiting degradation of the LDL receptor in hepatocytes. The introduction of PCSK9 inhibitors heralded a new era of intensive LDL-C reduction with LDL-C concentrations lowered below levels ever thought possible with conventional treatments such as statins. With their introduction considerations regarding cost, clinical outcomes and long-term safety are paramount.

Areas covered: This review examines the pharmacology of PCSK9 inhibitors and summarizes the current evidence base for use in clinical practice from an efficacy, safety, and cardiovascular outcome perspective including recently presented data on alirocumab. It also examines the potential role of these agents into the future. Potential issues with PCSK9 inhibitors are examined and future pharmacologic targets are examined including siRNA and PCSK9 vaccination.

Expert commentary: It is clear that the PCSK9 inhibitors are highly effective in the lowering of LDL cholesterol. However, this reduction comes at a large financial cost, and although early outcome data has been positive, the role of PCSK9 inhibition remains confined to limited patient groups at present. As more long-term data is gathered on clinical outcomes and safety, the role for these agents may expand.     

Circulating PCSK9 is lowered acutely following surgery

Background

A decrease in serum low‐density lipoprotein cholesterol (LDL‐C) is well documented after acute stress. Plasma proprotein convertase subtilisin kexin 9 (PCSK9), which promotes degradation of low‐density lipoprotein receptor (LDL‐R) resulting in reduced plasma clearance of low‐density lipoproteins (LDL) and an increase in serum LDL‐C, would be predicted to decrease. Yet, a few studies have demonstrated an increase 1‐8 days after acute stress. Our objective was to assess the earlier status of plasma PCSK9, within the first 24 hours of onset of stress.

Methods

We measured serum lipids and plasma PCSK9 in 39 patients before and soon after an elective surgical procedure (abdominal aortic aneurysm (AAA) repair).

Results

We observed an early decrease in PCSK9 following surgery, as well as a decrease in total cholesterol (TC), LDL‐C, high‐density lipoprotein cholesterol (HDL‐C), non–high‐density lipoprotein cholesterol (non‐HDL‐C) and triglycerides (TG).

Conclusion

Unlike other studies which showed an increase in PCSK9 after the onset of stress, our study detected a fall in PCSK9 following acute surgical stress. The observed difference is likely due to the earlier timing of PCSK9 measurement in our study. Further studies involving serial poststress measurements for several days are needed to determine whether PCSK9 behaves as an acute‐phase reactant, whether it displays a biphasic response to acute stress, and whether changes in circulating PCSK9 are responsible for lipoprotein changes observed after surgical stress. (Clinical Trial Registration: ClinicalTrials.gov study ID NCT00493389)

     

Proprotein convertase subtilisin kexin 9 inhibitors: next generation in lipid-lowering therapy

Introduction: Statins reduce low-density lipoprotein cholesterol (LDL-C) and are currently the mainstay in the treatment of hyperlipidaemia and subsequently the prevention of atherosclerotic cardiovascular disease (CVD). Nevertheless, there is a need to further lower LDL-C, especially in subjects with severe forms of hypercholesterolaemia despite maximum doses of conventional drugs and/or in those intolerant to existing therapies.

Areas covered: Emerging therapeutic approaches to lowering LDL-C involve blocking LDL-receptor degradation by serum proprotein convertase subtilisin kexin 9 (PCSK9). Human monoclonal antibodies that target PCSK9 and its interaction with the LDL-receptor (AMG145, REGN727 and RN316) have been tested in Phase I – III clinical trials for the treatment of hyperlipidaemia in patients at high CVD risk.

Expert opinion: These new agents are administered subcutaneously and have been shown to have major LDL-C and apoB lowering effects either alone or in combination with statins. These novel agents are generally well tolerated and once long-term safety data are available they appear promising therapeutic platforms for the treatment of patients with hypercholesterolaemia at risk for or with CVD not controlled by conventional therapies.     

Urinary incontinence—pharmacotherapy options

Abstract

Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach.

• Key messages

• Lipid lowering agents with “pleiotropic” effects provide a more effective approach to CV prevention

• In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2?mg/L had a higher benefit in terms of reduction in major CV events

• The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent

     

Alirocumab for the treatment of hyperlipidemia in high-risk patients: an updated review

Introduction: Alirocumab is a fully human immunoglobulin G1 monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) approved for the treatment of hypercholesterolemia in high-risk patients. The objective is to provide an updated review of the recent data published for alirocumab.

Areas covered: The efficacy and safety of alirocumab has been initially evaluated in a comprehensive phase 3 program conducted in more than 6 000 patients with primary non-familial and heterozygous familial hypercholesterolemia: alirocumab reduced LDL-cholesterol up to 62% in phase 3 with every 2-week dosing compared with placebo, and up to 36% compared with ezetimibe, with an excellent safety and tolerability profile. Herein, the author describes new efficacy and safety data obtained from complementary analyses of the phase 3 program submitted for approval and reports data from new specific trials.

Expert commentary: Based on current high pricing, the patient groups prioritized for alirocumab treatment are patients with heterozygous familial hypercholesterolemia and patients with atherosclerotic cardiovascular disease who have substantially elevated LDL cholesterol on maximally tolerated statin plus ezetimibe therapy. The ongoing ODYSSEY OUTCOMES trial will provide important information on the cost-effectiveness of alirocumab treatment.     

Evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low‐density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia: A case report

A 49 years old woman (weight 68 kg, BMI 27.3 kg/m²) with heterozygous familial hypercholesterolemia (HeFH) and multiple statin intolerance with muscle aches and creatine kinase elevation, presented at the Outpatient Lipid Clinic of Verona University Hospital in May 2015. Hypercholesterolemia was firstly diagnosed during adolescence, followed in adulthood by a diagnosis of Cogan's syndrome, a rheumatologic disorder characterized by corneal and inner ear inflammation. No xanthomas, corneal arcus, or vascular bruits were detectable at physical examination. Screening for macrovascular complications did not reveal relevant damages. Ongoing medical therapy included salicylic acid, methylprednisolone, methotrexate, and protonic‐pump inhibitor. In the absence of specific lipid‐lowering therapy, plasma lipid levels at first visit were: total‐cholesterol = 522 mg/dL, LDL‐cholesterol = 434 mg/dL, HDL‐cholesterol = 84 mg/dL, triglycerides = 120 mg/dL, Lp(a) = 13 mg/dL. On December 2015, evolocumab 140 mg sc every 2 weeks was initiated. After a 24‐week treatment, the LDL‐cholesterol levels decreased by an average of 21.2% to 342 ± 22 mg/dL (mean ± SD). On May 2016, LDL‐apheresis (H.E.L.P.system) was started as add‐on therapy. Compared to the average levels obtained during the evolocumab monotherapy period, the LDL‐cholesterol was reduced by 49.4%, thus reaching an inter‐apheresis level (mean ± SD) of 173 ± 37 mg/dL. This report suggests that a combination therapy with evolocumab and lipoprotein‐apheresis may have synergic effects on circulating lipid levels. Its relevance as a highly effective treatment option for hyperlipidemia in HeFH patients warrants further investigation in larger datasets.     

Alirocumab: PCSK9 inhibitor for LDL cholesterol reduction

The proof of concept that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition affects cholesterol levels was first established after the demonstration that PCSK9 loss-of-function mutations result in a significant drop in circulating LDL cholesterol levels. Subsequent studies revealed that PCSK9 binds the epidermal growth factor precursor homology domain-A on the surface LDL Receptor (LDLR) and directs LDLR and PCSK9 for lysosomal degradation. Alirocumab (also known as SAR236553/REGN727) is a monoclonal antibody that binds circulating PCSK9 and blocks its interactions with surface LDLR. Alirocumab clinical trials with different doses on different administration schedules were shown to significantly reduce LDL cholesterol both as a mono-therapy and in combination with statins or ezetimibe. Although there is great potential for anti-PCSK9 therapies in the management of cholesterol metabolism, there is no clear evidence yet that blocking PCSK9 reduces cardiovascular disease outcome. This is being investigated in ongoing Phase III clinical trials with alirocumab.     

Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics

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Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis

BackgroundIn parallel to the increasing prevalence of metabolic syndrome, the prevalence of hepatic steatosis has also increased dramatically worldwide. Hepatic steatosis is a major risk factor of hepatic cirrhosis, cardiovascular disease and type 2 diabetes. Circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been positively associated with the metabolic syndrome. However, the association between PCSK9 and the liver function is still controversial.ObjectiveThe objective of this study is to investigate the association between circulating PCSK9 levels and the presence of hepatic steatosis, as well as with liver biomarkers in a cohort of healthy individuals.MethodsTotal PCSK9 levels were measured by an in-house ELISA using a polyclonal antibody. Plasma albumin, alkaline phosphatase, ALT, AST, total bilirubin and GGT were measured in 698 individuals using the COBAS system. The presence of hepatic steatosis was assessed using ultrasound liver scans.ResultsIn a multiple regression model adjusted for age, sex, insulin resistance, body mass index and alcohol use, circulating PCSK9 level was positively associated with albumin (β = 0.102, P = 0.008), alkaline phosphatase (β = 0.201, P < 0.0001), ALT (β = 0.238, P < 0.0001), AST (β = 0.120, P = 0.003) and GGT (β = 0.103, P = 0.007) and negatively associated with total bilirubin (β = -0.150, P < 0.0001). Tertile of circulating PCSK9 was also associated with hepatic steatosis (OR 1.48, 95% CI 1.05–2.08, P = 0.02).ConclusionOur data suggest a strong association between PCSK9 and liver biomarkers as well as hepatic steatosis. Further studies are needed to explore the role of PCSK9 on hepatic function.     

PCSK9 and resistin at the crossroads of the atherogenic dyslipidemia

The atherogenic dyslipidemia is a pathophysiological lipid triad, composed of high triglycerides and low-density lipoprotein and low high-density lipoprotein. The dyslipidemia is highly prevalent in individuals who are obese, insulin resistant and those with Type 2 diabetes and is the major contributing factor to the high atherosclerotic cardiovascular disease risk in these subjects. The primary initiating event in atherogenic dyslipidemia development is the hepatic overproduction of very-low-density lipoprotein (VLDL). The intracellular and extracellular protein triggers of hepatic VLDL production were not known until the recent identification of the causal roles of PCSK9 and resistin. Both PCSK9 and resistin act in large part by targeting and reducing the hepatic degradation of VLDL apoB through distinctly different mechanisms. In the current review, we discuss both the individual roles and the interaction of these proteins in driving atherogenic dyslipidemia, and thus, atherosclerotic cardiovascular disease progression in humans. We further explore the important therapeutic implications of these findings.     

东莞汉族人PCSK9基因SNP与冠心病及其预后关系探讨

目的探讨东莞汉族人PCSK9基因E670G位点SNP与冠心病(CAD)及其预后的关系。方法选择在该院CAD患者100例及非CAD患者100例为研究对象,取患者血液,提取DNA并采用PCR法分析PCSK9基因E670G位点SNP,并采用基因测序法验证。采用酶法检测患者血脂水平,并随访CAD患者采用他汀类治疗后血清脂质水平的变化、心血管事件发生率。结果冠心病(CAD)组血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)水平显著高于健康对照组,HDL-C显著低于健康对照组,差异具有统计学意义(P0.05)。基因型主要为AA即298bp和152bp的纯合子,其次为AG即450bp和298bp、152bp的杂合子,尚未检测到450bp GG纯合子基因型,等位基因频率分布符合Hardy-Weinberg平衡。CAD组患者AA基因型的患者LDL-C水平显著低于AG基因型,HDL-C水平显著高于AG基因型的患者(P0.05)。随访半年发生心血管的例数总共为27例,AA基因型占66.7%,AG基因型占33.3%,G等位基因携带者心血管事件例数和平均病变支数差异具有统计学意义(P0.05)。结论 PCSK9基因E670G多态性与LDL-C、HDL-C水平及CAD病变程度相关,CAD患者中G等位基因的携带可能增加发病概率和再发病风险。