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Background: VERVE-101 is an investigational in vivo CRISPR base editing medicine designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower LDL-cholesterol (LDL-C). We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of non-human primates and a murine F1 progeny study.Methods: Cynomolgus monkeys were dosed with a single intravenous infusion of a vehicle control (N=10) or VERVE-101 at a dose of 0.75 mg/kg (N=4) or 1.5 mg/kg (N=22) with subsequent follow-up out to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male non-human primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu).Results: Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 of 67% and 83% and reductions of LDL-C of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days following dosing. Liver safety monitoring noted a transient rise in ALT and AST concentrations following infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male non-human primates, sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals.Conclusions: VERVE-101 was well-tolerated in in non-human primates and led to 83% lower blood PCSK9 protein and 69% lower LDL-C with durable effects up to 476 days following dosing. These results have supported initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

• Ancillary analysis of French patients enrolled in ODYSSEY APPRISE. • Trial conducted to determine lipid-lowering efficacy and safety of alirocumab. • Real-life setting: patients at high cardiovascular risk with hypercholesterolaemia. • Statins and ezetimibe are the first and second-line therapies. • These therapies are used even less in France than in other countries. • Alirocumab was well tolerated, safe and highly effective at reducing LDL-C. • This supports PCSK9 use to manage hypercholesterolaemia in high-risk CV patients. Recently, a multicentre, prospective, single-arm, phase 3b, open-label trial was conducted to determine the safety and efficacy of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in a real-life setting. This study enrolled patients at high cardiovascular risk, with heterozygous familial hypercholesterolaemia (HeFH) or non-familial hypercholesterolaemia (non-FH). Results showed that alirocumab was well tolerated and resulted in a clinically significant reduction in low-density lipoprotein cholesterol (LDL-C). This ancillary analysis aimed to describe the characteristics of the French patients enrolled in the study, the main results observed in this population according to their familial hypercholesterolaemia status, and adherence to treatment. French data were analysed separately from the original dataset of the study. Among 215 French patients in the ODYSSEY APPRISE trial, 63.7% had non-FH, with a mean LDL-C concentration of 5.0 ± 1.8 mmol/L at baseline. The mean duration of alirocumab exposure was 72.4 ± 42.5 weeks, with only 48.4% of patients receiving statins concomitantly. At week 12, a mean reduction in LDL-C of 56.5 ± 17.8% was observed: 51.2 ± 22.8% in HeFH; 59.5 ± 13.2% in non-FH. This improvement in LDL-C started from week 4 and remained stable and sustained until week 120 in both populations. The overall incidence of severe treatment-emergent adverse events (TEAEs) was 33.5%. The most frequent TEAEs were myalgia (15.8%) and asthenia (15.3%). No tolerance or efficacy differences were observed between patients with or without established coronary artery disease or other cardiovascular disease, whatever the age of these events or considering the concomitant use of other lipid-lowering therapies. In the French setting, alirocumab was well tolerated, safe and highly effective at reducing LDL-C. These findings support the use of alirocumab to manage hypercholesterolaemia in patients at high cardiovascular risk. [ABSTRACT FROM AUTHOR]

Abstract Background Despite advances in surgical and postoperative care, myocardial injury or infarction (MI) is still a common complication in patients undergoing coronary artery bypass surgery (CABG). Several studies that aimed to reduce postoperative myocardial injury, including those investigating statin loading, have been conducted but did not indicate any clear benefits. Evolocumab, a PCSK9 inhibitor, has been reported to lower lipids and prevent ischemic events in various medical conditions. However, the effect of evolocumab in cardiovascular surgery has not been evaluated. The objective of this trial is to evaluate the cardioprotective effects of evolocumab in elective CABG patients with multivessel coronary artery disease. Methods EVOCABG is a prospective, randomized, open, controlled, multicenter, superiority, phase III clinical trial. Patients with multivessel coronary artery disease without initial cardiac enzyme elevation will be recruited (n=100). Participants will be randomly allocated into two groups: a test group (evolocumab (140mg) administration once within 72 h before CABG) and a control group (no administration). The primary outcome is the change in peak levels of serum cardiac marker (troponin-I) within 3 days of CABG surgery compared to the baseline. Secondary outcomes include post-operative clinical events including death, myocardial infarction, heart failure, stroke, and atrial fibrillation. Discussion This trial is the first prospective randomized controlled trial to demonstrate the efficacy of evolocumab in reducing ischemic-reperfusion injury in patients undergoing CABG. This trial will provide the first high-quality evidence for preoperative use of evolocumab in mitigating or preventing ischemic-reperfusion-related myocardial injury during the surgery. Trial registration Clinical Research Information Service (CRIS) of the Republic of Korea KCT0005577 . Registered on 4 November 2020.

The aim of this study was to evaluate whether there were significant sex x time interactions in lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) response to treatment with the Proprotein Convertase Subtilisin/Kexin type 9 inhibitor (PCSK9i) Evolocumab, in a real-life clinical setting. For this purpose, we pooled data from 176 outpatients (Men: 93; Women: 83) clinically evaluated at baseline and every six months after starting Evolocumab. Individuals who had been on PCSK9i for less than 30 months and nonadherent patients were excluded from the analysis. Over time, absolute values of Lp(a) plasma concentrations significantly decreased in the entire cohort (p-value < 0.001) and by sex (p-value < 0.001 in men and p-value = 0.002 in and women). However, there were no sex-related significant differences. Absolute plasma concentrations of LDL-C significantly decreased over time in the entire cohort and by sex (p-value < 0.001 always), with greater improvements in men compared to women. The sex x time interaction was statistically significant in LDL-C (all p-values < 0.05), while absolute changes in Lp(a) were not influenced by either sex or time (all p-value > 0.05). Our data partially reinforce the presence of differences in response to treatment to PCSK9i between men and women and are essential to gain a better understanding of the relationship between LDL-C and Lp(a) lowering in response to PCSK9i. Further research will clarify whether these sex-related significant differences translate into a meaningful difference in the long-term risk of ASCVD.

Lipoprotein(a) (Lp(a)) molecule includes two protein components: apolipoprotein(a) and apoB100. The molecule is the main transporter of oxidized phospholipids (OxPL) in plasma. The concentration of this strongly atherogenic lipoprotein is predominantly regulated by the LPA gene expression. Lp(a) is regarded as a risk factor for several cardiovascular diseases. Numerous epidemiological, clinical and in vitro studies showed a strong association between increased Lp(a) and atherosclerotic cardiovascular disease (ASCVD), calcific aortic valve disease/aortic stenosis (CAVD/AS), stroke, heart failure or peripheral arterial disease (PAD). Although there are acknowledged contributions of Lp(a) to the mentioned diseases, clinicians struggle with many inconveniences such as a lack of well-established treatment lowering Lp(a), and common guidelines for diagnosing or assessing cardiovascular risk among both adult and pediatric patients. Lp(a) levels are different with regard to a particular race or ethnicity and might fluctuate during childhood. Furthermore, the lack of standardization of assays is an additional impediment. The review presents the recent knowledge on Lp(a) based on clinical and scientific research, but also highlights relevant aspects of future study directions that would approach more suitable and effective managing risk associated with increased Lp(a), as well as control the Lp(a) levels.

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Objective: This study was aimed at investigating the effects of preoperative treatment with a loading dose of statins combined with a PCSK9 inhibitor on coronary blood perfusion and short-term cardiovascular adverse events in patients with ST-segment elevation myocardial infarction (STEMI). Method: Sixty-five patients with STEMI who had visited the Shanxi Cardiovascular Disease Hospital between May 2018 and May 2021 were enrolled in the study. The enrolled patients had no history of oral statins or antiplatelet therapy. The patients were divided into a combined treatment group (loading dose of statins combined with PCSK9 inhibitors, 35 patients) and a routine treatment group (loading dose of statins only, 30 patients). The primary endpoints were thrombolysis in myocardial infarction (TIMI) blood flow grading, corrected TIMI frame count (CTFC), and TIMI myocardial perfusion grading (TMPG), immediately after and 30 days after the operation. The secondary endpoint was a composite endpoint of cardiovascular death, nonfatal myocardial infarction, and target vessel revascularization 30 days after the operation. Results: The combined treatment group had significantly lower CTFC (14.09 ± 8.42 vs 26 ± 12.42, P = 0.04) and better TMPG (2.74 ± 0.61 vs 2.5 ± 0.73, P = 0.04) than the routine treatment group immediately after the operation. Similarly, the combined treatment group had a significantly lower CTFC (16.29 ± 7.39 vs 26.23 ± 11.53, P = 0.04) and significantly better TMPG (2.94 ± 0.24 vs 2.76 ± 0.43, P = 0.01) than the routine treatment group 1 month after the operation. Conclusion: Preoperative treatment with a loading dose of high-intensity statins combined with PCSK9 inhibitors increased coronary blood flow and myocardial perfusion after emergency thrombus aspiration in patients with STEMI. However, the treatment did not significantly decrease the incidence of cardiovascular death, nonfatal myocardial infarction, or target vessel revascularization. [ABSTRACT FROM AUTHOR]

Background: Previous meta-analyses have investigated the efficacy of lipid-lowering therapies for atherosclerotic cardiovascular disease; however, few have focused on patients with acute coronary syndrome (ACS). This meta-analysis aimed to compare the benefits of intensive lipid-lowering therapy with those of background statin therapy in patients with ACS., Methods: Searches were performed on PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases for articles published until April 13, 2023. Randomized controlled trials that compared intensive lipid-lowering therapies and background statin therapies in patients with prior ACS and recorded the outcome of three-point major cardiovascular events (MACE) were included. The risk ratio (RR) with 95% confidence interval (CI) was used as a measure of primary and secondary outcomes., Results: Nine trials involving 38,640 patients with ACS were identified. Pooled results suggested that intensive lipid-lowering therapies are associated with a reduction in the risk of three-point MACE (RR, 0.88; 95% CI, 0.83-0.94; p  < 0.001), recurrent ACS (RR, 0.82; 95% CI, 0.71-0.96; p  = 0.013), nonfatal myocardial infarction (MI) (RR, 0.87; 95% CI, 0.81-0.93; p  < 0.001), stroke (RR, 0.83; 95% CI, 0.73-0.94; p  = 0.003), and unstable angina-related hospitalization (RR, 0.57; 95% CI, 0.33-0.99; p  = 0.046), but not all-cause mortality (RR, 0.94; 95% CI, 0.82-1.07; p  = 0.329), cardiovascular disease-related mortality (RR, 0.96; 95% CI, 0.88-1.06; p  = 0.457) or coronary revascularization (RR, 0.89; 95% CI, 0.79-1.00; p  = 0.057)., Conclusions: Intensive lipid-lowering therapies may reduce the risk of three-point MACE, recurrent ACS, nonfatal MI, stroke, and hospitalization for unstable angina in patients with ACS undergoing background statin therapy. These results may assist in clinical decision-making for the secondary prevention of cardiovascular events to initiate intensive lipid-lowering therapies immediately after ACS.

Aim: Children with heterozygous familial hypercholesterolaemia (HeFH) show greater carotid intima-media thickness (cIMT). Evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody, substantially reduced low-density lipoprotein cholesterol (LDL-C) and modestly reduced lipoprotein(a) in children with HeFH. We investigated evolocumab's effect on cIMT progression., Methods: HAUSER-RCT was a randomised, placebo-controlled trial. 157 paediatric patients with FH (age: 10-17 years) and LDL-C >130mg/dL despite statin therapy received monthly evolocumab 420mg or placebo for 24 weeks. Patients who continued into an open-label extension (HAUSER-OLE; n=150) received 80 weeks of monthly evolocumab plus statins. cIMT was measured by B-mode ultrasound scanning of right and left common carotid artery at baseline; week 24 of RCT [day 1 OLE]; and weeks 24, 48, and 80 of OLE. Descriptive analysis of cIMT was a prespecified HAUSER secondary endpoint, and inferential tests reported here were post-hoc., Results: 151 patients had evaluable cIMT summary scores at ≥1 visit. From RCT baseline to week 24, mean cIMT increased by 0.006mm (SD=0.05) with placebo (n=37) and decreased by 0.003mm (SD=0.05) with evolocumab (n=76). From RCT baseline to OLE week 80, mean cIMT summary score decreased by 0.019mm (SD=0.04) and 0.012mm (SD=0.05), respectively, in patients who initially received placebo (n=34, P=0.007) versus receiving evolocumab throughout (n=59, P=0.067). Across patients who received evolocumab in OLE, mean cIMT significantly decreased by 0.011mm (SD=0.05) from OLE day 1 to week 80 (n=94, P=0.034)., Conclusions: In children with HeFH, evolocumab plus statin treatment up to 104 weeks led to regression in carotid arterial wall thickening., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection that has a high mortality rate. Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease secreted by the liver. Its binding to the low-density lipoprotein (LDL) receptor enhances its degradation, causing an increase in LDL levels in the blood. Objectives : Administering a PCSK9 inhibitor leading to an increase in lipid uptake by the liver may positively affect septic patients due to the increased removal of endotoxins. Methods : This preliminary study aimed to examine the safety of PCSK9 inhibitor use in septic and septic shock patients. We treated five septic patients in the intensive care unit with 300 mg of alirocumab following serious adverse events for 28 days. Results : Four of our patients did not experience any adverse events, and all of them survived. One patient died after discharge from the intensive care unit, and this death was presumably not related to the study drug. The patients rapidly recovered from the inflammatory stage of sepsis. Conclusions : Alirocumab appears safe in severe sepsis and septic shock patients. The outcome data are promising. Only a basic safety profile can be assessed based on this pilot study. Further study with a PCSK-9 inhibitor in septic or septic shock patients is required to further determine its benefit in ICU patients.

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a proprotein convertase that increases plasma low-density lipoprotein cholesterol (LDL-C) levels by triggering the degradation of LDL receptors (LDLRs). Beyond the regulation of circulating LDL-C, PCSK9 also has direct atherosclerotic effects on the vascular wall and is associated with coronary plaque inflammation. Interestingly, emerging data show that women have higher circulating PCSK9 concentrations than men, suggesting that the potential roles of PCSK9 may have different impacts according to sex. In this review, we summarize the studies concerning sex difference in circulating levels of PCSK9. In addition, we report on the sex differences in the relations of elevated circulating PCSK9 levels to the severity and prognosis of coronary artery disease, the incidence of type 2 diabetes mellitus, and neurological damage after cardiac arrest and liver injury, as well as inflammatory biomarkers and high-density lipoprotein cholesterol (HDL-C). Moreover, sex difference in the clinical efficacy of PCSK9 inhibitors application are reviewed. Finally, the underlying mechanisms of sex difference in circulating PCSK9 concentrations and the clinical implications are also discussed. [ABSTRACT FROM AUTHOR]

Familial heterozygous hypercholesterolemia is a genetic disease that is most often due to mutations in LDL receptor genes. Early diagnosis and appropriate treatment can reduce the risk of early cardiovascular disease or death. Pharmacological control of dyslipidemia plays a key role in achieving targeted plasma lipid levels, especially in the control of LDL-C levels. The drugs used for this purpose range from well-known statins to new drug molecules such as Lomitapide, siRNA and PCSK9 inhibitors. The group of PCSK9 inhibitors is reimbursed by the National Health Insurance Fund in Bulgaria. A combination of medications is often required to achieve targeted lipid levels and prevent complications. [ABSTRACT FROM AUTHOR]

Among the diseases causing human death, cardiovascular disease (CVD) remains number one according to the World Health Organization report in 2021. It is known that atherosclerosis is the pathological basis of CVD. Lowdensity lipoprotein (LDL) plays a pivotal role in the initiation and progression of atherosclerotic CVD (ASCVD). LDL cholesterol (LDL-C) is the traditional biological marker of LDL. However, large numbers of patients who have achieved the recommended LDL-C goals still have ASCVD risk. In multiple prospective studies, LDL particle (LDL-P) is reported to be more accurate in predicting CVD risk than LDL-C. LDL-Ps differ in size, density and chemical composition. Numerous clinical studies have proved that the atherogenic mechanisms of LDL-Ps are determined not only by LDL number and size but also by LDL modifications. Of note, small dense LDL (sdLDL) particles possess stronger atherogenic ability compared with large and intermediate LDL subfractions. Besides, oxidized LDL (ox-LDL) is another risk factor in atherosclerosis. Among the traditional lipid-lowering drugs, statins induce dramatic reductions in LDL-C and LDL-P to a lesser extend. Recently, proprotein convertase subtilsin/kexin type 9 inhibitors (PCSK9i) have been demonstrated to be effective in lowering the levels of LDL-C, LDL-P, as well as CVD events. In this article, we will make a short review of LDL metabolism, discuss the discordance between LDL-C and LDL-P, outline the atherogenic mechanisms of action of LDL by focusing on sdLDL and ox-LDL, summarize the methods used for measurement of LDL subclasses, and conclude the advances in LDL-lowering therapies using statins and PCSK9i. [ABSTRACT FROM AUTHOR]

Hyperlipidemia and oxidative stress with elevated oxidized low-density lipoprotein (ox-LDL) exacerbate hepatic inflammation and fibrosis. The plasma level of low-density lipoprotein (LDL) is controlled by proprotein convertase subtilisin/kexin 9 (PCSK9). Alirocumab is a monoclonal antibody that decreases LDL via inhibiting PCSK9 function. Apart from lipid-lowering effects, alirocumab exerts anti-inflammation, anti-angiogenesis and anti-oxidant effects. This study aims to investigate the impact of alirocumab treatment on common bile duct ligation (BDL)-induced biliary cirrhotic rats. After a 4-week treatment of alirocumab, the hemodynamic data, blood biochemistry, ox-LDL level, oxidative stress markers, severity of hepatic encephalopathy and abnormal angiogenesis of BDL rats were measured and compared to the control group. BDL rats presented cirrhotic pictures and elevated ammonia, total cholesterol, LDL and ox-LDL levels compared to the control group. Alirocumab decreased plasma levels of total cholesterol, LDL, and oxidative stress markers; however, it did not affect the hemodynamics, liver and renal biochemistry, and the plasma levels of ammonia and ox-LDL. The motor activities, portal-systemic collaterals and mesenteric vascular density were not significantly different between alirocumab-treated and control groups. In addition, it did not affect hepatic inflammation, intrahepatic angiogenesis, liver fibrosis and free cholesterol accumulation in the liver of BDL rats. In conclusion, PCSK9 inhibition by alirocumab treatment ameliorates hyperlipidemia and systemic oxidative stress in biliary cirrhotic rats. However, it does not affect the plasma level of ox-LDL, intrahepatic inflammation and fibrosis. In addition, PCSK9 inhibition has a neutral effect on abnormal angiogenesis and hepatic encephalopathy in biliary cirrhotic rats. [ABSTRACT FROM AUTHOR]

Aims Injectable medicines are increasingly used to manage risk factors for cardiovascular (CV) events, such as dyslipidaemia and diabetes. These include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Little is known about perceptions of injectable therapies among CV healthcare professionals (HCPs). This study explores their views to identify relevant facilitators and barriers to the use of injectables with CV benefit. Methods and results A 22-question survey was distributed internationally via online channels. In total, 192 anonymous responses were received (43.7% physicians, 32.6% nurses, 16.8% pharmacists, 6.8% others). Among respondents with experience of these medicines, 69.1% had used an injectable PCSK9 inhibitor and 67.0% had used an injectable GLP-1 receptor agonist. Commonly raised issues were resource problems (36.5%), lack of knowledge among colleagues (32.3%), paperwork (32.3%), and lack of patient knowledge (28.1%). Key barriers respondents felt made patients decline these treatments were fear of injection (56.6%), lack of awareness or education (26.4%), and administration issues (15.1%); potential reasons for discontinuation included side effects (46.4%), perceived lack of benefit (28.6%), and local reactions (21.4%). The main topics around injectables requiring further support included managing non-adherent patients (16.2%), troubleshooting with patients (16.2%), and educating colleagues about injectables (12.2%). Preferred educational methods to support HCPs were face-to-face training (43.5%) and online learning (26.1%); favoured formats were based on role playing and case studies. Conclusion Healthcare professionals highlighted various potential barriers to initiation, continuation, and adherence with injectable therapies in CV medicine. Although some require healthcare system changes, many could be addressed through simple measures based primarily on enhanced training and support for patients and HCPs. [ABSTRACT FROM AUTHOR]

• The cardiovascular benefit from LDL-C lowering is proportional to the magnitude of reduction. • Evolocumab reduces LDL-C levels by approximately 60% when measured at drug trough. • Time-averaged estimates include both peaks and troughs of drug effect. • Time-averaged LDL-C reduction with evolocumab vs placebo was 65–68%. • Time-averaged measures may better estimate long-term cardiovascular benefit. LDL-C is the pivotal risk factor for atherosclerotic cardiovascular disease, and the benefit from LDL-C lowering is proportional to the magnitude of reduction. Clinical trials demonstrate that evolocumab reduces LDL-C levels by approximately 60% when measured at the trough of drug effect, which may underestimate cumulative LDL-C reduction. We obtained a time-averaged estimate of LDL-C lowering that included both peaks and troughs. Pooled analysis of 5 phase 2 trials included patients with hypercholesterolemia who received placebo or evolocumab (140 mg every 2 weeks [Q2W] or 420 mg monthly [QM]). Percent changes from baseline LDL-C and free serum PCSK9 were averaged across weeks 9–12. In 372 patients, time-averaged percent reduction from baseline in LDL-C with evolocumab vs placebo was 67.6% (95% CI: 63.9–71.3) with Q2W dosing and 65.0% (95% CI: 60.7–69.3) with QM dosing. The time-averaged measure yielded LDL-C reductions for evolocumab that exceeded measurements at the end of dosing intervals and may provide a better estimate of cardiovascular benefit during long-term therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. The aim of this study was to explore the molecular mechanism of LDLR c.501C>A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients. Methods The whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of LDLR variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months. Results All members of the two families with the LDLR c.501C>A variant showed high levels of LDLC. The relationship between the clinical phenotype and LDLR variants was confirmed in the current study. Both in silico and in vitro analyses showed that LDLR c.501C>A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients. Conclusions LDLR c.501C>A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with LDLR c.501C>A variant.

SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pace of vaccination COVID-19 will probably remain a global burden to health systems for a long time. Unfortunately, the necessary prevention and treatment strategies of COVID-19 have led to restriction measures that are hampering the routine care of common chronic metabolic conditions like hypercholesterolemia. It is of particular concern that during the acute phase of COVID-19, the control of pre-existing metabolic diseases tends to get worse which again increases the risk for complications and a poor outcome in these patients. A significant contributor to these complications is endothelial dysfunction which is associated with COVID-19. This Commentary will discuss the impact of COVID-19 on endothelial function particularly in patients with familial hypercholesterolemia (FH), a metabolic inherited disease known to in itself adversely affect endothelial function. There should be no hesitation to continue with statin therapy in severe hypercholesterolemic patients with COVID-19. We argue that in FH patients with COVID-19 the clinicians need even consider intensifying statin therapy as well as the addition of other lipid-lowering agents, such as proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors. In contrast to statins, the PCSK9 inhibitors lower lipoprotein(a) [Lp(a)] level, and, accordingly, these latter drugs need to be considered particularly in FH patients with an elevated level of Lp(a). This call applies to the in-hospital stay and also beyond. When considering that the vasculopathic effects of COVID-19 may persist, a long-term follow-up of individualized therapies in FH patients is warranted.

Background The emergence of PCSK9i (proprotein convertase subtilisin kexin type 9 inhibitor) and icosapent ethyl (IPE) has expanded the role of lipid‐lowering therapies beyond statins. Despite recommendations by clinical practice guidelines, their national eligibility and use rates remain unclear. Methods and Results In the National Health and Nutrition Examination Survey data from 2017 to 2020, we assessed eligibility and the use of statins, PCSK9i, and IPE among US adults according to American College of Cardiology/American Heart Association guideline recommendations. Eligibility for PCSK9i and IPE were determined in the following 2 scenarios: (1) assuming existing lipid‐lowering therapy as the maximum tolerated before assessing eligibility for novel therapies and (2) assessing eligibility after assuming initiation and maximal escalation of preexisting lipid‐lowering therapies and accounting for expected lipid improvements. Of 2729 sampled individuals, representing 149.3 million adults, 1376 had indications for statins, representing 65.8 million or 44.0% (95% CI, 40.9%–47.2%) of adults. Current statin use was 45% of those eligible and was low across demographic groups. A total of 9.7 and 11.6 million adults would benefit from PCSK9i and IPE, respectively, based on lipid profiles and existing therapies. Assuming maximal escalation of statins and addition of ezetimibe, 4.1% (95% CI, 2.8%–5.4%) of adults or 6.1 million would benefit from PCSK9i and 6.8% (95% CI, 5.4%–8.3%) or 10.2 million from IPE. Conclusions Six and 10 million individuals have clinical profiles whereby PCSK9i and IPE, respectively, would be expected to improve cardiovascular outcomes even after maximum escalation of statins and ezetimibe use, but remain undertreated with lipid‐lowering therapies. Optimal use of lipid‐targeted agents that include these novel agents is needed to improve population health outcomes.

Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of coronary artery disease and peripheral vascular disease, including stroke. Recent guidelines recommend considering low-density lipoprotein cholesterol (LDL-C)-lowering therapies, such as statins (preferably), ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to prevent the occurrence or recurrence of stroke, adhering to the “lower is better” approach. In this review, we examined the evidence supporting lipid-lowering medications like statins, ezetimibe, and PCSK9 inhibitors for secondary stroke prevention and dyslipidemia management in different stroke subtypes. Stroke guidelines advocate for administering the maximum tolerable dose of statins as the primary treatment and as soon as possible despite the potential for new-onset diabetes mellitus and possible muscle and liver toxicity due to their demonstrated benefits in secondary prevention of cardiovascular diseases and mortality reduction. When statin use is insufficient for LDL lowering, ezetimibe and PCSK9 inhibitors are recommended as complementary therapies. It is essential to establish lipid-lowering therapy goals based on the stroke subtype and the presence of comorbidities.

Background Individuals with chronic kidney disease (CKD) are at a very high risk for atherosclerotic cardiovascular disease (ASCVD). New lipid-lowering agents offer hope of improved outcomes where traditional agents have been less efficacious, yet the cost of these agents needs consideration in this population before their widespread application. Objective We sought to evaluate the cost-effectiveness of novel lipid-lowering therapies for a CKD population. Methods We searched four electronic databases, one government registry and the reference lists of included literature to identify cost-effectiveness analyses of novel lipid-lowering agents in CKD. Costs were converted to a single currency to allow cross-country comparisons. Completeness of reporting was analysed using the Consolidated Health Economic Evaluation Reporting Standards checklist. Results were synthesized in narrative form with graphical representation of cost-effectiveness ratios. Results Of the 1041 identified studies, 4 met the inclusion criteria. None were specific to a CKD-only population. All examined the impact of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) in the secondary prevention of ASCVD. Incremental cost-effectiveness ratios of new agents compared with standard care were between €7288 and €112 530 per quality-adjusted life year gained. Cost-effectiveness was sensitive to the degree of cardiovascular risk of the underlying populations. Conclusion This review found PCSK9is were moderately cost-effective in populations with high cardiovascular risk. People with CKD were included as an undifferentiated subpopulation in the primary studies, but application of these findings to CKD-specific populations should be interpreted with caution. There is insufficient evidence for a health economic case to support novel lipid-lowering therapies for advanced CKD. [ABSTRACT FROM AUTHOR]

Background: Despite advances in surgical and postoperative care, myocardial injury or infarction (MI) is still a common complication in patients undergoing coronary artery bypass surgery (CABG). Several studies that aimed to reduce postoperative myocardial injury, including those investigating statin loading, have been conducted but did not indicate any clear benefits. Evolocumab, a PCSK9 inhibitor, has been reported to lower lipids and prevent ischemic events in various medical conditions. However, the effect of evolocumab in cardiovascular surgery has not been evaluated. The objective of this trial is to evaluate the cardioprotective effects of evolocumab in elective CABG patients with multivessel coronary artery disease.Methods: EVOCABG is a prospective, randomized, open, controlled, multicenter, superiority, phase III clinical trial. Patients with multivessel coronary artery disease without initial cardiac enzyme elevation will be recruited (n=100). Participants will be randomly allocated into two groups: a test group (evolocumab (140mg) administration once within 72 h before CABG) and a control group (no administration). The primary outcome is the change in peak levels of serum cardiac marker (troponin-I) within 3 days of CABG surgery compared to the baseline. Secondary outcomes include post-operative clinical events including death, myocardial infarction, heart failure, stroke, and atrial fibrillation.Discussion: This trial is the first prospective randomized controlled trial to demonstrate the efficacy of evolocumab in reducing ischemic-reperfusion injury in patients undergoing CABG. This trial will provide the first high-quality evidence for preoperative use of evolocumab in mitigating or preventing ischemic-reperfusion-related myocardial injury during the surgery.Trial Registration: Clinical Research Information Service (CRIS) of the Republic of Korea KCT0005577 . Registered on 4 November 2020. [ABSTRACT FROM AUTHOR]

Keywords: long-covid; endothelial dysfunction; familial hypercholesterolemia; PCSK9 inhibitor; statin; stroke; CHD EN long-covid endothelial dysfunction familial hypercholesterolemia PCSK9 inhibitor statin stroke CHD 1 5 5 05/16/22 20220511 NES 220511 Introduction Follow-up studies have revealed that during the severe acute respiratory syndrome (SARS) caused by coronavirus SARS-CoV epidemic between 2002 and 2003, a significant proportion of those infected had a deterioration in the general health and exercise capacity, especially during the 24 months post-infection ([12]; [34]). In fact, because the long COVID symptoms are frequent among COVID-19 patients (about 30% or more) who have been hospitalized, the American Heart Foundation has initiated an extensive program in order to determine if those individuals who have ASCVD or have survived stroke are more prone to develop long COVID (https://newsroom.heart.org/news/10-million-invested-to-study-long-term-impact-of-covid-19-on-heart-and-brain-health). Long COVID or Post-COVID Syndrome Long COVID or the post-COVID-19 syndrome has been defined as a condition characterized by persistent symptoms lasting more than 2 months after the onset of SARS-CoV-2 infection ([20]). [Extracted from the article]

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

• Persistence to PCSK9i increased within an integrated specialty pharmacy care model. • Medication access was not a main contributor to PCSK9 inhibitor non-persistence. • LDL-C values of persistent patients were similar to other real-world studies. • Specialty pharmacists are positioned to help increase persistence to PCSK9i therapy. Nearly 40% of patients do not continue proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapy after 6 months, despite their ability to lower low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events. Limited work has assessed persistence to PCSK9i therapy in an integrated specialty pharmacy model. To assess rates of persistence to PCSK9i therapy and report reasons for non-persistence in patients serviced within an integrated specialty pharmacy. We conducted a single-center, retrospective review of patients prescribed a PCSK9i at an academic health system between September 2015 and August 2018. Persistence was calculated as a binary measure (yes/no) of whether the patient was still receiving PCSK9i therapy at 3-, 12-, and 24-months; frequency distributions described reasons for non-persistence and descriptive statistics described the change in LDL-C from baseline to 24 months. 477 patients met inclusion criteria, 53% were male with median age of 63 years [IQR 56-70]. Median LDL-C at baseline was 157mg/dL and 86% had an atherosclerotic cardiovascular disease indication. Persistence at 3-, 12-, and 24-months was 94%, 80%, and 68%, respectively. Of the 262 patients persistent on PCSK9i therapy at 24 months with LDL-C values available, median LDL-C was 65 mg/dL. The most common reasons for non-persistence at 24 months included medication adverse effects (54%) and loss to follow-up (17%). High rates of persistence to PCSK9i were seen in patients receiving care within an integrated specialty pharmacy model compared with rates in previous studies, suggesting specialty pharmacists may play a role in mitigating many common reasons for PCSK9i non-persistence. [ABSTRACT FROM AUTHOR]

Background Injection site reactions (ISRs) are known side effects of the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor alirocumab. Transient ISR to alirocumab after a long phase of good tolerability have not been reported previously. Case summary A 55-year-old woman (Patient 1) and a 77-year-old man (Patient 2) were treated with alirocumab for the management of dyslipidaemia. Both patients tolerated the treatment without side effects for 7 and 2 months, respectively. After an upper respiratory tract infection in Patient 1 and a first COVID-19 vaccination in Patient 2, both patients suddenly developed ISR with erythema, calor, and itching upon 2 (Patient 1) and 1 (Patient 2) subsequent injection(s), respectively. Symptoms resolved with local steroids, oral antihistamines, and cooling. After termination of the presumed immune system activated state, alirocumab was well tolerated again in both patients without recurrence of any ISR upon repeated applications. Discussion These are the first cases to report transient ISR to a PCSK9 inhibitor, possibly triggered by activation of the immune system, after prolonged good tolerability. Based on the transient and benign nature of the reaction, such patients should be encouraged to continue supervised treatment, as tolerability may return after resolution of the pro-inflammatory state. [ABSTRACT FROM AUTHOR]

Summary: Background: Cardiovascular disease (CVD) is the most frequent cause of death in Austria. The European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommend intensive lipid lowering therapy (LLT) in patients at high or very high CV risk. Lipid management and achievement of low-density lipoprotein cholesterol (LDL-C) goals in Austria have not recently been assessed. Methods: Subgroup analysis for Austria of a European 18 country, cross-sectional, observational study. Patients received LLT for primary (PP) or secondary prevention (SP). Data including LLT in the preceding 12 months and most recent LDL‑C were collected during a single visit between June 2017 and November 2018. Achievement of the risk-based 2016 and 2019 ESC/EAS LDL‑C goal while receiving stabilized LLT was assessed. Results: A total of 293 patients were enrolled from 8 Austrian sites, of which 200 (PP = 104, SP = 96) received stabilized LLT at the LDL‑C measurement date. Overall, 58% (71% PP, 43% SP) and 38% (52% PP, 23% SP) achieved the risk-based 2016 and 2019 goals, respectively. Most patients received moderate-intensity statin monotherapy (46%), while 34% used high-intensity statin monotherapy. Combination therapy of moderate/high-intensity statin with ezetimibe (12%), or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors with statin ± ezetimibe (1%), was used infrequently. Conclusion: The current Austrian routine lipid management using mainly moderate-intensity or high-intensity statin monotherapy is insufficient to attain ESC/EAS guideline goals, in particular the more stringent 2019 recommendations, a situation comparable to other participating European countries. In addition to switching to and optimizing doses of high-intensity statins, a combination with ezetimibe or PCSK9 inhibitors will be needed in many cases. [ABSTRACT FROM AUTHOR]

Abstract Background To assess the effects of proprotein convertase subtilisin/kexin type 9 inhibitor (evolocumab) on lipoprotein particles subfractions with Nuclear Magnetic Resonance spectroscopy in patients with acute coronary syndromes. Methods A total of 99 consecutive patients with ACS were enrolled and assigned to either the experimental group (n = 54) or the control group (n = 45). The combination therapy of PCSK9 inhibitor (Repatha®, 140 mg, q2w) and moderate statin (Rosuvastatin, 10 mg, qn) was administered in the experimental group, with statin monotherapy (Rosuvastatin, 10 mg, qn) in the control group. The therapeutic effects on lipoprotein particle subfractions were assessed with NMR spectroscopy after 8 weeks treatment, and the achievement of LDL-C therapeutic target in both groups were analyzed. Results In the experimental group, after 8 weeks of evolocumab combination treatment, the concentrations of blood lipids (TC, LDL-C and its subfractions [LDL-1 to 6], VLDL-C and its subfractions [VLDL-1 to 5], IDL-C, and HDL-C), lipoprotein particles, and their subfractions [VLDL-P, IDL-P, LDL-P, and its subfractions [LDL-P1 to 6], apoB, and LP(a)] demonstrated therapeutic benefits with statistical significance (P

Statins, in addition to healthy lifestyle interventions, are the cornerstone of lipid-lowering therapy. Other low-density lipoprotein (LDL)-lowering drugs include ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. As new evidence emerges from new clinical trials, therapeutic goals change, leading to renewed clinical guidelines. Nowadays, LDL goals are getting lower, leading to the “lower is better” paradigm in LDL-cholesterol (LDL-C) management. Several observational studies have shown that LDL-C control in real life is suboptimal in both primary and secondary preventions. It is critical to enhance the adherence to guideline recommendations through shared decision-making between clinicians and patients, with patient engagement in selecting interventions based on individual values, preferences, and associated conditions and comorbidities. This narrative review summarizes the evidence regarding the benefits of lipid-lowering drugs in reducing cardiovascular events, the pleiotropic effect of statins, real-world data on overtreatment and undertreatment of lipid-lowering therapies, and the changing LDL-C in targets in the clinical guidelines of dyslipidemias over the years.

A recent meta-analysis of over 20,000 individuals showed that hospitalized COVID-19 patients with acute myocardial injury had more than fourfold higher mortality than those without such injury. Since the COVID-19 pandemic exacerbates already existing health inequalities, there is an urgent need to create measures to protect the most vulnerable patient groups, including those with a pre-existing increased risk of atherosclerotic cardiovascular disease (ASCVD). A typical example is familial hypercholesterolemia (FH), a common genetic disease affecting over 30 million individuals worldwide. If left untreated or undertreated, FH patients suffer from complications of premature ASCVD, such as acute coronary syndromes, resulting in acute myocardial injury/infarction. A recent population-based analysis provided strong evidence suggesting that COVID-19 poses an even higher risk for myocardial injury in FH patients. From the long-term preventive point of view, it is important to note that, in addition to the acutely elevated risk of myocardial injury, an elevated risk of ASCVD and its complications will persist after COVID-19. The decline in outpatient preventive care during the pandemic is likely to influence ASCVD risk and outcomes, particularly in high-risk patients, such as those with FH. This commentary aims to raise global awareness of the challenges that clinicians treating FH patients continue to face during the COVID-19 pandemic, with two low- to middle-income countries, South Africa and Brazil, serving as examples. [ABSTRACT FROM AUTHOR]

Aims This study aimed to determine the effects of a proprotein convertase subtilisin-kexin type 9 inhibitor (PCSK9i) on coronary plaque volume and lipid components in patients with a history of coronary artery disease (CAD). Methods and results This prospective, open-label, single-centre study analysed non-culprit coronary segments using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) at baseline and follow-up angiography. Following changes in the lipid-lowering treatment based on the most recent guideline, the enrolled subjects were divided into two groups: treatment with PCSK9i and statins (PCSK9i: 21 patients and 40 segments) and statins only (control: 32 patients and 50 segments). The absolute and percent LDL-C reductions were significantly greater in the PCSK9i group than in the control group (between group difference: 59.3 mg/dL and 46.4%; P  <   0.001 for both). The percent reduction in normalized atheroma volume and absolute reduction in percent atheroma volume (PAV) were also significantly greater in the PCSK9i group (P  <   0.001 for both). Furthermore, the PCSK9i group showed greater regression of maximal lipid core burden index for each of the 4-mm segments (maxLCBI4mm) than the control group (57.0 vs. 25.5; P  =   0.010). A significant linear correlation was found between the percent changes in LDL-C and maxLCBI4mm (r  = 0.318; P  =   0.002), alongside the reduction in PAV (r  = 0.386; P  <   0.001). Conclusion The lipid component of non-culprit coronary plaques was significantly decreased by PCSK9i. The effects of statin combined with PCSK9i might be attributed to the stabilization and regression of residual vulnerable coronary plaques in patients with CAD. [ABSTRACT FROM AUTHOR]

• A low percent initiate a PCSK9 inhibitor within 89 days of a myocardial infarction • Other lipid-lowering medications predicted early initiation of a PCSK9 inhibitor • Many patients had a recurrent ASCVD event before initiating a PCSK9 inhibitor Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower atherosclerotic cardiovascular disease (ASCVD) event risk. Analyze patient characteristics associated with time to PCSK9i initiation following an acute myocardial infarction (AMI). We analyzed characteristics of patients ≥21 years of age in the Marketscan or Medicare databases who initiated a PCSK9i 0-89 days, 90-179 days, or 180-365 days after an AMI between July 2015 and December 2018 (n=1,705). We estimated the cumulative incidence of recurrent ASCVD events before PCSK9i initiation. Overall, 42%, 25%, and 33% of patients who initiated a PCSK9i did so 0-89 days, 90-179 days, and 180-365 days following AMI hospital discharge, respectively. Taking ezetimibe prior to AMI hospitalization and initiating ezetimibe within 30 days after AMI hospital discharge were each associated with a higher likelihood of PCSK9i initiation in the 0-89 days versus 180-365 days post-discharge (adjusted odds ratio [OR] 1.83, 95% confidence interval [95%CI] 1.35-2.49 and 1.76, 95%CI 1.11-2.80, respectively). Statin use before and statin initiation within 30 days after AMI hospitalization were associated with a lower likelihood of PCSK9i initiation 0-89 days versus 180-365 days post-discharge (adjusted OR 0.64, 95%CI 0.49-0.84 and 0.39, 95%CI 0.28-0.54, respectively). Overall, 8.0%, 10.5%, and 12.5% of patients had an ASCVD event at 90, 180, and 365 days following AMI hospital discharge and before initiating a PCSK9i, respectively. Among patients initiating a PCSK9i after AMI, a low proportion did so within 89 days of hospital discharge. Many patients had a recurrent ASCVD event before treatment initiation. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. A major risk factor for this condition is increased serum low-density lipoprotein cholesterol (LDL-C) levels for which statins have been successful in reducing serum LDL-C to healthy concentrations. However, patients who are statin intolerant or those who do not achieve their treatment goals while on high-intensity statin therapy, such as those with familial hypercholesterolemia, remain at risk. With the discovery of PCSK9 inhibitors, the ability to provide more aggressive treatment for patients with homozygous and heterozygous familial hypercholesterolemia has increased. Ezetimibe reduces LDL-C by 15%-20% when combined with statin. 2 , 3 Protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been found to achieve profound reductions in LDL-C (54%-74%) when added to statins. They have shown dramatic effects at lowering major adverse cardiovascular events (MACE) in high-risk patients 4 with LDL-C levels ≥70 mg/dL and can be used in populations that are statin intolerant or not at goal levels with maximally tolerated statin therapy. PCSK9 inhibitors also produce minimal side effects. Myopathy, a common side effect for patients on statins, has been rare in patients on PCSK9 inhibitors. Randomized trials have shown that reduction in LDL-C has translated to clinical benefits even in patients who have not achieved their LDL-C target. [ABSTRACT FROM AUTHOR]

Abstract Lipoprotein(a) (Lp(a)) is a highly proatherogenic lipid fraction that is genetically determined and minimally responsive to lifestyle or behavior changes. Mendelian randomization studies have suggested a causal link between elevated Lp(a) and heart disease, stroke, and aortic stenosis. There is substantial inter-ethnic variation in Lp(a) levels, with persons of African descent having the highest median values. Monitoring of Lp(a) has historically been limited by lack of standardization of assays. With the advent of novel therapeutic modalities to lower Lp(a) levels including proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and targeted antisense oligonucleotides, it is increasingly important to screen patients who have family or personal history of atherosclerotic cardiovascular disease for elevations in Lp(a). Further study is needed to establish a causal relationship between elevated Lp(a) and cardiovascular disease across diverse ethnic populations.

Abstract For more than half a century, low-density lipoprotein cholesterol (LDL-C) has been recognized as a major risk factor for incident atherosclerotic cardiovascular disease. The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9) in 2003, which prevents LDL-C receptor recycling, identified a new target for drug intervention. Recently, two large-scale randomized clinical outcomes trials involving fully human anti-PCSK9 monoclonal antibodies tested the hypothesis that targeting this pathway would reduce cardiovascular events. Both the FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) and ODYSSEY OUTCOMES trials met their primary efficacy endpoints, confirming findings reported earlier that major adverse cardiovascular events can be reduced by a further lowering of LDL-C beyond that achieved with statin therapy. In both trials, there were incremental reductions in LDL-C of > 50% from baseline, with no major safety concerns, over the trials’ median follow-up time (2.2 and 2.8 years, respectively). While there were differences in design, lipid management and overall results, key messages from both studies were similar. However, post-publication, additional questions have arisen, especially regarding drug effects over the long-term, including a potential mortality benefit.

Atherosclerosis and atherosclerotic-related cardiovascular diseases (ASCVD) are characterized by high serum levels of low-density lipoprotein cholesterol (LDL-C) that can promote the generation of reactive oxygen species (ROS). To answer the need for better LDL-C control in individuals at high and very high risk for CVD, a new injectable innovative family of lipid-lowering (LL) monoclonal antibodies against the protein convertase subtilisin/kexin type 9 (PCSK9) has been approved. However, the effect of these drugs on vascular function, such as ROS generation and arterial stiffness, has not already been extensively described. In this report, we present data from 18 males with high to very high CV risk undergoing LL treatment (LLT) with either statin and ezetimibe or ezetimibe monotherapy, who experienced, after a 2-month treatment with Evolocumab, a significant improvement in blood pressure (BP)-adjusted carotid–femoral pulse wave velocity (cfPWV) (p-value = 0.0005 in the whole cohort, p-value = 0.0046 in the sub-cohort undergoing background LLT with statin and ezetimibe, p-value = 0.015 in the sub-cohort undergoing background LLT with ezetimibe monotherapy), which was significantly associated with a decrease in freshly isolated leukocytes (PBMCS)-derived H2O2 production (p-value = 0.004, p-value = 0.02 and p-value = 0.05, respectively, in the whole cohort, in the statin + ezetimibe sub-cohort, and the ezetimibe sub-cohort). Our observations support the role of systemic oxidative stress in atherosclerosis and give a further rationale for using Evolocumab also for its effect in vascular disorders linked to oxidative processes.

Background: Atherosclerotic cardiovascular disease (ASCVD), a leading cause of global fatalities, has inconsistent findings regarding the impact of muscle symptoms despite promising clinical trials involving PCSK9 inhibitors (PCSK9i) and siRNA as potential therapeutic options., Methods: The databases EMBASE, PubMed, Web of Science, Cochrane, and ClinicalTrials.gov were thoroughly searched without any restrictions on language. Review Manager 5.3 software was utilized to calculate relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences or standardized mean differences with 95%CIs for continuous data. To evaluate publication bias, Egger's test was employed using Stata/SE software., Results: This analysis included 26 studies comprising 28 randomized controlled trials (RCTs) involving a total of 100,193 patients, and 4 different lipid-lowering therapy combinations. For events with creatine kinase >3ULN, evolocumab and alirocumab demonstrated significant advantages compared to inclisiran. Evolocumab showed the best results in terms of both new muscle symptom events and creatine kinase >3ULN., Conclusions: Based on this network meta-analysis (NMA) results, evolocumab has emerged as a promising treatment option for patients with hyperlipidemia and muscle disorders compared to other PCSK9 inhibitors and inclisiran., Systematic Review Registration: PROSPERO [CRD42023459558]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Li, Sun and Yan.)

Background: Lipid-related risk and residual cardiovascular risk remain high in patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). Significant treatment gaps exist in implementation of pluripotent and effective therapies that reduce these risks., Objective: This study evaluates the efficacy and impact of a dedicated, standalone cardiometabolic clinic designed to address treatment gaps through streamlined management and optimization of treatment strategies., Methods: We retrospectively collected data from the first 400 patients with T2D and ASCVD who underwent treatment at the clinic and presented for at least one follow-up visit. These patients were primarily managed for their cardiometabolic risks and received intensified lipid-lowering therapies, including adjunct non-statin therapies., Results: Significant findings included increased use of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) to 84 % and 65 %, respectively, with 94 % of patients eventually on one therapy and 55 % on dual therapy. Increases in lipid-lowering therapies led to 89 % of patients achieving low-density lipoprotein cholesterol levels below patient-specific thresholds for intensification., Conclusion: This care model effectively manages high-risk patient needs, achieving significant intensification of lipid-lowering therapies and broad use of cardiometabolic drugs, and highlights the clinic's potential to serve as a model for similar high-risk populations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Taher Modarressi reports a relationship with Novo Nordisk Inc that includes: board membership and consulting or advisory. Taher Modarressi reports a relationship with Eli Lilly and Company that includes: speaking and lecture fees. Taher Modarressi reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees. Taher Modarressi reports a relationship with Novartis Pharmaceuticals Corporation that includes: board membership. Taher Modarressi reports a relationship with Abbott Laboratories that includes: speaking and lecture fees. Taher Modarressi reports a relationship with CRISPR Therapeutics that includes: consulting or advisory. Taher Modarressi reports a relationship with Amgen Inc that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Aims We assessed the impact of the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD). Methods and results In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio [HR] 0.81 [95% confidence interval 0.74–0.88]; P < 0.001), with significant individual reductions in acute coronary (HR 0.83 [0.75–0.91]), cerebrovascular (HR 0.77 [0.65–0.92]), and peripheral vascular (HR 0.58 [0.38–0.88]) events. There were 3437 total events (first plus recurrent), with evolocumab reducing total events by 24% (incidence rate ratio 0.76 [0.69–0.85]). The magnitude of reduction in acute arterial events with evolocumab numerically increased over time, with a 16% reduction (HR 0.84 [0.75–0.95]) in the first year followed by a 24% reduction (HR 0.76 [0.67–0.85]) thereafter. Conclusion The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633. [ABSTRACT FROM AUTHOR]

Aims: The serum ratios of the brain‐specific oxysterol 24S‐hydroxycholesterol (24S‐OHC) to cholesterol and to 27‐OHC reflect brain cholesterol turnover. We studied the effect of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) that enhance low‐density lipoprotein receptor activity on serum cholesterol and oxysterol concentrations. Methods: Twenty‐eight hypercholesterolaemic patients (15 males and 13 females) responding insufficiently to maximally tolerated statin and/or ezetimibe therapy were additionally subcutanously treated biweekly with either the PCSK9ab alirocumab (150 mg, n = 13) or evolocumab (140 mg, n = 15). Fasting serum cholesterol was measured by gas chromatography and the oxysterols 24S‐OHC and 27‐OHC using gas chromatography–mass spectrometry before, after 1‐month (n = 28) and after 3‐month (n = 13) treatment. Results: As expected, PCSK9ab treatment lowered serum cholesterol and oxysterol levels after 1 month. The serum ratio of 24S‐OHC to cholesterol increased after 1 month by 17 ± 28% (mean ± standard deviation; 95% confidence interval [CI]: 5.8 to 28%; P <.01) and 24S‐OHC to 27‐OHC by 15 ± 39% (95% CI: 0.2 to 30%; P <.01). Within 3 months, 24S‐OHC to cholesterol increased by 2.8 μg g−1 mo−1 (95% CI: 2.1 to 3.6; P <.01) and 24S‐OHC to 27‐OHC by 0.019 mo−1 (95% CI: 0.007 to 0.032; P <.01). Conclusion: The serum ratios of 24S‐OHC to cholesterol and to 27‐OHC increased after treatment with PCSK9ab. We hypothesize that this is caused by a reduced entrance of 27‐OHC into the brain, increased synthesis of brain cholesterol, increased production of 24S‐OHC and its secretion across the blood–brain barrier. [ABSTRACT FROM AUTHOR]

Background: As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. The aim of this study was to explore the molecular mechanism of LDLR c.501C>A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients. Methods: The whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of LDLR variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months. Results: All members of the two families with the LDLR c.501C>A variant showed high levels of LDLC. The relationship between the clinical phenotype and LDLR variants was confirmed in the current study. Both in silico and in vitro analyses showed that LDLR c.501C>A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients. Conclusions: LDLR c.501C>A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with LDLR c.501C>A variant. [ABSTRACT FROM AUTHOR]

: A 78-year-old man came to our attention after undergoing coronary computed tomography angiography documenting multivessel coronary artery disease. He was started on treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab 140 mg subcutaneously every 2 weeks. Treatment-emergent changes in lipids and lipoproteins were long-lasting, and the medication was well tolerated by the patient in the long-term. Unexpectedly, after 2 years of continuous treatment with evolocumab, serum lipids increased, apparently without any reasonable explanation. During the follow-up visit, the patient was found to have habitually injected evolocumab into his right thumb instead of into the appropriate injection sites (i.e., abdomen, thighs or upper arms) after turning the injector upside down. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of this article is to review current evidence for lipoprotein (a) (Lp(a)) as a risk factor for multiple cardiovascular (CV) disease phenotypes, provide a rationale for Lp(a) lowering to reduce CV risk, identify therapies that lower Lp(a) levels that are available clinically and under investigation, and discuss future directions. Recent Findings: Mendelian randomization and epidemiological studies have shown that elevated Lp(a) is an independent and causal risk factor for atherosclerosis and major CV events. Lp(a) is also associated with non-atherosclerotic endpoints such as venous thromboembolism and calcific aortic valve disease. It contributes to residual CV risk in patients receiving standard-of-care LDL-lowering therapy. Plasma Lp(a) levels present a skewed distribution towards higher values and vary widely between individuals and according to ethnic background due to genetic variants in the LPA gene, but remain relatively constant throughout a person’s life. Thus, elevated Lp(a) (≥50 mg/dL) is a prevalent condition affecting >20% of the population but is still underdiagnosed. Treatment guidelines have begun to advocate measurement of Lp(a) to identify patients with very high levels that have a family history of premature CVD or elevated Lp(a). Lipoprotein apheresis (LA) efficiently lowers Lp(a) and was recently associated with a reduction of incident CV events. Statins have neutral or detrimental effects on Lp(a), while PCSK9 inhibitors significantly reduce its level by up to 30%. Specific lowering of Lp(a) with antisense oligonucleotides (ASO) shows good safety and strong efficacy with up to 90% reductions. The ongoing CV outcomes study Lp(a)HORIZON will provide a first answer as to whether selective Lp(a) lowering with ASO reduces the risk of major CV events. Summary: Given the recently established association between Lp(a) level and CV risk, guidelines now recommend Lp(a) measurement in specific clinical conditions. Accordingly, Lp(a) is a current target for drug development to reduce CV risk in patients with elevated levels, and lowering Lp(a) with ASO represents a promising avenue. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.Objectives: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.Methods: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL).Results: In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (Pinteraction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43.Conclusions: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402). [ABSTRACT FROM AUTHOR]