PCSK9 Research Articles

Roles of PCSK9 in the Pathogenesis of Periodontal Disease.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors are FDA-approved drugs recommended for high-risk patients with LDL-cholesterol (LDL-c) levels ≥ 70 mg/dl. Several studies have also investigated the relationship between PCSK9 and periodontitis. Specifically, studies have investigated the association between periodontitis and periodontal PCSK9 levels in humans, and periodontium status in PCSK9-knockout versus wild-type mice. While a positive association between periodontitis and periodontal PCSK9 levels has been noted, the findings on the comparison of periodontium status between PCSK9-knockout and wild-type mice have been inconsistent. Different methodologies among these studies may explain this discrepancy. Future experimental studies on the impact of pharmacological PCSK9 inhibition on periodontal status as well as observational studies comparing periodontium status between patients receiving PCSK9 inhibitors and those receiving other lipid-lowering drugs will shed light on the role of PCSK9 in periodontal health and disease.

The Link between miRNAs and PCKS9 in Atherosclerosis.

Cardiovascular disease (CDV) represents the major cause of death globally. Atherosclerosis, as the primary cause of CVD, is a chronic immune-inflammatory disorder with complex multifactorial pathophysiology encompassing oxidative stress, enhanced immune-inflammatory cascade, endothelial dysfunction, and thrombosis. An initiating event in atherosclerosis is the subendothelial accumulation of low-density lipoprotein (LDL), followed by the localization of macrophages to fatty deposits on blood vessel walls, forming lipid-laden macrophages (foam cells) that secrete compounds involved in plaque formation. Given the fact that foam cells are one of the key culprits that underlie the pathophysiology of atherosclerosis, special attention has been paid to the investigation of the efficient therapeutic approach to overcome the dysregulation of metabolism of cholesterol in macrophages, decrease the foam cell formation and/or to force its degradation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine proteinase that has emerged as a significant regulator of the lipid metabolism pathway. PCSK9 activation leads to the degradation of LDL receptors (LDLRs), increasing LDL cholesterol (LDL-C) levels in the circulation. PCSK9 pathway dysregulation has been identified as one of the mechanisms involved in atherosclerosis. In addition, microRNAs (miRNAs) are investigated as important epigenetic factors in the pathophysiology of atherosclerosis and dysregulation of lipid metabolism. This review article summarizes the recent findings connecting the role of PCSK9 in atherosclerosis and the involvement of various miRNAs in regulating the expression of PCSK9-related genes. We also discuss PCSK9 pathway-targeting therapeutic interventions based on PCSK9 inhibition, and miRNA levels manipulation by therapeutic agents.

PCSK9 and its relationship with HMGB1, TLR4, and TNFα in non-statin and statin-treated coronary artery disease patients.

Despite statin use in coronary artery disease (CAD), significant risk remains, potentially due to increased proprotein convertase subtilisin/kexin-type 9 (PCSK9) production, which raises LDL-C levels and induces inflammation. The exact relationship between PCSK9, inflammatory markers like TNFα, TLR4, CRP, and HMGB1, and monocyte subsets is poorly understood. This study aimed to explore these relationships in non-statin and statin-taking CAD patients. This case-control study included 91 controls and 91 stable CAD patients, divided into no-statin (NS, n = 25), low-dose statin (LDS, n = 25), and high-dose statin (HDS, n = 41) groups. Serum levels of LDL-C, CRP, PCSK9, TLR4, HMGB1, and TNFα were measured. Monocyte subsets were classified using flow cytometry into classical monocytes (CM), intermediate monocytes (IM), and non-classical monocytes (NCM). CAD patients showed elevated PCSK9, LDL-C, and inflammatory markers compared to controls. Statin groups (LDS, HDS) had lower LDL-C and inflammatory markers but higher PCSK9 than the NS group, with the HDS group showing the lowest LDL-C and inflammatory markers but the highest PCSK9. In the NS group, PCSK9 positively correlated with inflammatory markers (HMGB1, TNFα, TLR4, CRP) and monocyte subsets (IM%, NCM%). In the total statin group (LDS + HDS), PCSK9 negatively correlated with HMGB1, TLR4, and NCM%, for each, respectively, and positively with CM%. Multivariable linear regression showed significant associations between PCSK9 and HMGB1, NCM%, and IM% in the NS group, and HMGB1, NCM%, and TLR4 in the total statin group. In conclusion, we recommend combining PCSK9 inhibitors with statins in high-risk CAD patients. This may enhance statin efficacy, reduce LDL-C, and inhibit the TLR4/NF-кB inflammatory pathway, decreasing atherosclerotic inflammation.

Abstract 4136741: Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Lipid Reduction: A Network Meta-Analysis

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors offer additional lipid reduction beyond that achieved with statins. However, the optimal PCSK9 therapy for lowering lipid levels in patients with hypercholesterolemia and/or hyperlipidemia on background statin therapy remains unclear. Methods: PubMed and EMBASE databases were searched for RCTs assessing tafolecimab, evolocumab or alirocumab vs. placebo (administrated Q2W or Q4W, 12-week treatment) in patients with hypercholesterolemia and/or hyperlipidemia on medium-intensity statin up to March 28, 2024. The outcomes of interest were the percentage change in low-density lipoprotein cholesterol (LDL-C) or lipoprotein(a) from baseline to the 12th week. A frequentist random-effect network meta-analysis was applied to calculate MD and 95% CI using Stata 16.0 software. Results: A total of 4960 patients [PCSK9 inhibitors (n=3230), placebo (n=1730)] across 13 RCTs were included. At week 12, tafolecimab, evolocumab and alirocumab (either Q2W or Q4W) all induced significant reductions in LDL-C levels compared to placebo ( Figure ). The efficacy of evolocumab Q2W was significantly higher compared with alirocumab Q2W (MD=-18.67%, 95% Cl [-29.59%, -7.74%]), while similar LDL-C reduction was observed in tafolecimab Q2W vs. alirocumab Q2W and evolocumab Q2W vs. tafolecimab Q2W. Furthermore, tafolecimab Q4W and evolocumab Q4W were more effective in lowering LDL-C levels compared to alirocumab Q4W (tafolecimab vs. alirocumab: MD=-23.66%, 95% Cl [-32.58%, -14.74%]; evolocumab vs. alirocumab: MD=-25.84%, 95% Cl [-34.21%, -17.46%]), while there was no difference between evolocumab Q4W and tafolecimab Q4W. Lastly, the ranking of the effects for reducing lipoprotein(a) levels was as follows: tafolecimab > evolocumab> alirocumab (either Q2W or Q4W). Conclusions: In patients with hypercholesterolemia and/or hyperlipidemia treated with medium-intensity statins, tafolecimab and evolocumab (either Q2W or Q4W) might be preferred choices for lowering LDL-C. Additionally, tafolecimab (either Q2W or Q4W) appears to be the most effective agent for reducing lipoprotein(a) levels.

Abstract 4138035: Inclisiran in Routine Clinical Practice: Results from a Nationwide Study of >5,000 Patients

Introduction: Inclisiran is a small interfering RNA drug which inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Inclisiran was recently approved for the treatment of hypercholesterolemia and durably lowers LDL levels by around 50% with injections once every six months based on the results of large, randomized controlled trials. However, no nationwide studies have evaluated the use or effectiveness of Inclisiran in routine clinical practice. Goals/Aims: To characterize the use and effectiveness of Inclisiran in routine clinical practice in a large nationwide cohort. Methods/Approach: We used the Truveta healthcare database, a large nationwide database of electronic health records, to study patients who were administered Inclisiran up to September 2023. Patient demographic characteristics and lipid levels before and after treatment were summarized. Means and 95% confidence intervals were estimated using t-tests. Results/Data: A total of 5,256 patients (median age 71, first quartile 65, third quartile 76) were prescribed Inclisiran, of whom 2,919 (55.5%) were Female. In terms of race, most of the patients identified as White (81.0%), and a smaller proportion as African American (7.3%), Asian (2.1%), or American Indian/Alaska Native (0.5%); 7.3% of patients identified as more than one race or did not provide race data. Mean LDL and HDL levels (mg/dL) before Inclisiran were 125 (95% CI 123-127) and 51 (95% CI 51-52) respectively and after Inclisiran were 88 (95% CI 85-90) and 50 (95% CI 49-51) respectively. The mean difference in LDL after treatment was -39 (95% CI -42 to -37) mg/Dl for a mean percent change of -22% (95% CI -25% to -19%). Effects of Inclisiran on LDL levels are shown in Figure 1. At the conference, we will compare effects of Inclisiran to those of Alirocumab and Evolocumab (two older monoclonal antibodies against PCSK9) using a propensity score overlap weighting design. Conclusions: In a large cohort of patients administered Inclisiran in routine clinical practice, Inclisiran use was associated with substantial decreases in LDL levels, but those decreases were nonetheless smaller than the effects seen in randomized controlled trials of the drug.

Abstract 4131951: The Safety Profile Of Inclisiran In Patients With Dyslipidemia And Intermediate To High Atherosclerotic Cardiovascular Disease Risk: A Systematic Review And Meta-Analysis

Introduction: Inclisiran is a novel drug that employs ribonucleic acid (RNA) interference to lower levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, thereby improving the clearance of low-density lipoprotein (LDL) cholesterol from the bloodstream. It is given through subcutaneous injections at specified intervals and significantly reduces LDL cholesterol levels in patients with dyslipidemia and with intermediate to high risk of atherosclerotic cardiovascular disease (ASCVD). Goal: We aim to evaluate the safety of the use of inclisiran in patients with dyslipidemia and intermediate to high ASCVD risk. Methods: Three electronic databases of MEDLINE, Web of Science, and Embase were searched from inception to May 5th 2024 to identify relevant randomized controlled trials (RCTs) comparing safety profiles of inclisiran versus the control group . The primary outcome was all-cause mortality. Secondary outcomes were major adverse cardiovascular events (MACE), injection-site reaction and all treatment-emergent adverse events (TEAE). The effect estimates of outcomes were assessed using risk ratio (RR) with a 95% confidence interval (CI). Random-effects meta-analysis was conducted using the restricted maximum likelihood method given the inter-study variance was inevitable. The subgroup analysis was performed based on different dosing regimens. Results: We included 7 RCTs enrolling 4790 patients (63.8 ± 9.7 years, 66.8 % males) who received inclisiran. Compared to the control group, the use of inclisiran did not yield a significant effect on all-cause mortality (RR, 0.92; 95% CI, 0.54 to 1.54; I 2 = 0%), MACE (RR, 0.98; 95% CI, 0.82 to 1.17; I 2 = 0%), and TEAE (RR, 1.76; 95% CI, 0.74 to 4.15; I 2 = 74%). However, inclisiran use significantly increased injection-site reaction (RR, 7.08; 95% CI, 3.42 to 14.64; I 2 = 27%). Results are illustrated in the accompanying figure. Conclusions: Inclisiran use significantly increased injection-site reaction, with no increase in mortality and TEAE. Further trials are required to comprehensively assess the safety of inclisiran in the management of dyslipidemia in patients with ASCVD risk.

Variants in LPA are associated with Familial Hypercholesterolaemia: whole genome sequencing analysis in the 100,000 Genomes Project.

Familial Hypercholesterolaemia (FH) is an inherited disease of high LDL-cholesterol (LDL-C) caused by defects in LDLR, APOB, APOE and PCSK9 genes. A pathogenic variant cannot be found in ∼60% of clinical FH patients. Using whole genome sequencing (WGS) we examined genetic determinants of FH. WGS data generated by the 100,000 Genomes Project (100KGP) included 536 FH patients diagnosed using the FH Simon Broome criteria. Rare variants in known FH genes were analysed. Genome-wide association study (GWAS) between 443 FH variant-negative unrelated FH cases and 77,275 control participants of the 100KGP was run using high coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (Lp(a) PRS) were computed. An FH-causing variant was found in 17.4% of FH cases. GWAS identified the LPA gene locus being significantly associated (p<1x10-8). FH variant-negative participants had higher LDL and Lp(a) PRSs in comparison to the controls (p<1.0×10-16 and p<4.09×10-6, respectively). Similar associations were found in the monogenic FH with both LDL and Lp(a) PRSs being higher than in controls (p<4.03×10-4 and p<3.01x10-3, respectively). High LDL PRS was observed in 36.4% of FH variant-negative cases, whereas high Lp(a) PRS in 18.5%, with 7.0% having both high LDL and Lp(a) PRSs. This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogenous architecture of hypercholesterolaemia, with the LPA gene playing a significant role. Both Lp(a) and LDL-C should be measured for precision FH diagnosis. Specific therapies to lower Lp(a) should be targeted to those who will benefit most.

Histone demethylase JMJD1C advances macrophage foam cell formation and atherosclerosis progression by promoting the transcription of PCSK9.

Macrophage is considered as a critical driving factor in the progression of atherosclerosis (AS), and epigenetic heterogeneity contributes important mechanisms in this process. Here, we identified that a histone demethylase jumonji domain-containing protein 1C (JMJD1C) is a promising biomarker for atherosclerotic cerebral infarction through clinical analysis. Then, AOPE-/- mice fed with a high fat diet and RAW264.7 cells induced by oxidized low-density lipoprotein (ox-LDL) were used as AS models to verify the function of JMJD1C in AS development in vivo and in vitro. JMJD1C knockdown significantly reduced plaque area, inflammation and endothelial damage in AS model mice, and also alleviated foam cell formation, inflammatory cytokines production and cell apoptosis in ox-LDL-treated RAW264.7 cells. Mechanistically, JMJD1C promoted the transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9) through mediating H3 Lysine 9 demethylation. The effects of JMJD1C knockdown on ox-LDL-induced macrophages were blocked by PCSK9 overexpression. Altogether, our study proves that JMJD1C advances macrophage foam cell formation, inflammation and apoptosis to accelerate AS progression through H3 demethylation of PCSK9. The findings underscore the important role of JMJD1C-mediated histone modification in macrophage regulation and AS progression, which brings a new insight into the pathobiology of AS.

Correlation of Eight (8) Polymorphisms and Their Genotypes with the Risk Factors of Cardiovascular Disease in a Black Elderly Population

Single nucleotide polymorphisms (SNPs) have been associated with the development of cardiovascular diseases (CVDs). This study correlated eight SNPs with the risk factors of CVD in a black elderly population. Genotyping was used to detect eight polymorphisms; rs675 (ApoA-IV), rs699 (Angiotensinogen (AGT)), rs247616 and rs1968905 (Cholesteryl ester transfer protein (CETP)), rs1801278 (Insulin receptor substrate 1 (IRS-1)), rs1805087 (Methylenetetrahydrofolate reductase (MTHFR)) and rs28362286 and rs67608943 (Proprotein convertase subtilisin/kexin type 9 (PCSK9)), as well as their genotypes in deoxyribonucleic acid (DNA) extracted from peripheral blood. The cardiovascular risk (CVR) measurements were conducted on a Konelab 20i Thermo Scientific autoanalyzer and an enzyme-linked immunoassay (ELISA) assay. International Business Machines Corporation (IBM)® Statistical Package for the Social Sciences ® (SPSS) version 28 was used for statistical analysis. The heterozygous and homozygous genotypes of the eight polymorphisms were detected with the corresponding CVD risk factors. Subgroup analysis indicated that certain genotype carriers exhibited variations in their concentrations of CVR factors compared to others; however, these differences did not reach statistical significance. For example, carriers of the G genotype of the rs699 polymorphism showed marginally different blood pressure readings compared to the AG genotype carriers. The multiple linear regression analysis indicated that the only significant association was between PCSK9 and the rs28362286 (p = 0.029) polymorphism. The findings of our study show that single nucleotide polymorphisms are disseminated across the human genome. The heterozygous and homozygous genotypes of the SNPs require further investigation as they may have independent and possible collective roles in increasing the risk of CVDs.

Engineered PsCas9 enables therapeutic genome editing in mouse liver with lipid nanoparticles

Clinical implementation of therapeutic genome editing relies on efficient in vivo delivery and the safety of CRISPR-Cas tools. Previously, we identified PsCas9 as a Type II-B family enzyme capable of editing mouse liver genome upon adenoviral delivery without detectable off-targets and reduced chromosomal translocations. Yet, its efficacy remains insufficient with non-viral delivery, a common challenge for many Cas9 orthologues. Here, we sought to redesign PsCas9 for in vivo editing using lipid nanoparticles. We solve the PsCas9 ribonucleoprotein structure with cryo-EM and characterize it biochemically, providing a basis for its rational engineering. Screening over numerous guide RNA and protein variants lead us to develop engineered PsCas9 (ePsCas9) with up to 20-fold increased activity across various targets and preserved safety advantages. We apply the same design principles to boost the activity of FnCas9, an enzyme phylogenetically relevant to PsCas9. Remarkably, a single administration of mRNA encoding ePsCas9 and its guide formulated with lipid nanoparticles results in high levels of editing in the Pcsk9 gene in mouse liver, a clinically relevant target for hypercholesterolemia treatment. Collectively, our findings introduce ePsCas9 as a highly efficient, and precise tool for therapeutic genome editing, in addition to the engineering strategy applicable to other Cas9 orthologues.

Influence of APOE4 genotype on PCSK9-lipids association in cerebrospinal fluid and serum of patients in the Alzheimer's disease continuum.

Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified. We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype. We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients. CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p = 0.027 and +32.7%, p = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = -0.444, p = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = -0.786, p = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p = 0.004), driven by APOE4 carriers (r = 0.544, p = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p = 0.039) in AD. None of these results were found in MCI-AD patients. PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum.

Aerobic exercise alleviates statin-induced PCSK9 upregulation by increasing epoxyeicosatrienoic acid levels through the FoxO3a-Sirt6 axis

BackgroundStatins are the cornerstone of low-density lipoprotein cholesterol (LDL-C)-lowering therapy; however, the therapeutic efficacy of statins in countering atherosclerotic cardiovascular disease (ASCVD) is compromised by the concurrent elevation of proprotein convertase subtilisin/kexin type 9 (PCSK9), a pivotal molecule that increases LDL-C levels. Aerobic exercise lowers PCSK9 levels, but the underlying mechanism remains unclear. Therefore, we investigated how aerobic exercise can ameliorate statin-induced increases in PCSK9 levels. MethodsThree-week-old male American Institute of Cancer Research (ICR) mice were fed a high-fat-cholesterol diet (HFD) for 12 weeks and then administered atorvastatin alone or atorvastatin combined with aerobic exercise (Statin+Ex). Moreover, a total of 165 participants with stable coronary heart disease (CHD) enrolled at the inpatient and outpatient departments of the Second Xiangya Hospital of Central South University from January 2018 to July 2020 were randomized into the Statin group (male/female = 51/33) and Statin+Ex group (male/female = 52/29). Patients in the Statin+Ex group underwent treadmill exercise of 45–60 min/day for 7 days. ResultsAerobic exercise effectively alleviated statin-induced PCSK9 upregulation in human patients with CHD and hypercholesterolemic ICR mice (all p< 0.05). Mechanistically, our findings revealed that aerobic exercise induced elevated epoxyeicosatrienoic acids (EETs) plasma levels while concurrently reducing the activity of soluble epoxide hydrolase (sEH) (all p < 0.05), an enzyme responsible for EETs degradation. Further, EETs significantly suppressed PCSK9 expression, subsequently reducing the LDL-C levels (all p < 0.05); this effect was mediated via the activation of the Forkhead box O3a-Silent mating type information regulation 2 homolog 6 (FoxO3a-Sirt6) axis, with no impact on the Sterol Regulatory Element Binding Protein 2 and 3-hydroxy-3-methylglutaryl-CoA reductase(SREBP2-HMGCR) pathway. ConclusionOur study sheds light on the paradigm of "Exercise is Medicine", providing evidence to support the use of statins combined with exercise in reducing LDL-C levels, and unveils potential avenues for clinical applications of sEH inhibitors, presenting novel prospects for therapeutic interventions in ASCVD.

Clinical pharmacokinetics and pharmacodynamics of ongericimab: A potential long-acting PCSK9 monoclonal antibody in healthy subjects and patients with hypercholesterolemia: Randomized, double-blind, placebo-controlled phase Ia and Ib/II studies.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein-cholesterol (LDL-C) by decreasing the expression of the LDL-receptor on hepatic cells. Ongericimab (JS002) is a novel PCSK9 monoclonal antibody that exhibits a long-acting LDL-C lowering effect by exclusively inhibiting PCSK9 in pre-clinical studies. Two randomized, double-blind, placebo-controlled trials were conducted to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacokinetic, and pharmacodynamic profiles of ongericimab in healthy subjects and patients with hypercholesterolemia. Eighty-four healthy subjects in the phase Ia study received a single dose of placebo or ongericimab (15-450 mg). Ninety patients with hypercholesterolemia in the phase Ib/II study received placebo or ongericimab 150 mg Q2W, 300 mg Q4W, or 450 mg Q4W for 12 weeks. Ongericimab exhibited non-linear kinetics. The apparent clearance decreased as the dosage increased, with terminal elimination half-life (t1/2) values of 4.5-6.5 days. Overall, ongericimab was well tolerated in both studies. A single dose of ongericimab reduced LDL-C levels by 30%-73% in healthy subjects, and repeated doses of ongericimab reduced LDL-C levels by 67%-80% in patients with hypercholesterolemia. At the end of the dosing interval in the phase Ib/II study, over 70% of patients' LDL-C levels decreased by more than 50% from baseline. The results showed that ongericimab had a significant long-acting LDL-C lowering effect with good safety and potential for clinical application.

Beyond LDL-cholesterol: effects of alirocumab on the human apolipoproteome

Abstract Introduction The PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) trial enrolled 300 participants with longitudinal plasma samples available at four time points (enrollment, 24 hours, 4 weeks, 52 weeks), of which 266 completed the 52-week follow-up. Purpose Expanding on a previous investigation employing apolipoprotein proteomics in patients with coronary heart disease, the current study aimed to evaluate the impact of the monoclonal antibody alirocumab on apolipoprotein and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. Methods A mass spectrometry assay was employed to quantify 15 apolipoproteins. Linear mixed-effects models assessed the impact of timepoints and treatments (alirocumab: n = 131, placebo: n = 135, in addition to statins) on apolipoprotein levels. Results Alirocumab led to a fast rise in PCSK9 levels, with a marked increase [inter-quartile range] of 262% [207%] as early as 24 hours after treatment initiation, followed by more pronounced elevations at 4 weeks and 52 weeks, reaching 1575% [813%] and 1480% [747%], respectively (P &amp;lt; 0.001 for all comparisons). At 52 weeks, the ApoB reduction compared with enrollment was -75% [10%] with alirocumab vs. -43% [19%] with placebo (P &amp;lt; 0.001, between groups), while the change in LDL-C was -88% [9%] with alirocumab vs. -54% [19%] with placebo (P &amp;lt; 0.001). Alongside significantly greater reductions in ApoC2 (P = 0.0041) and ApoC3 (P &amp;lt; 0.001) with alirocumab, ApoE changed by -41.6% [21.1%] with alirocumab compared to -15.4% [24.5%] with placebo (P &amp;lt; 0.001). Overall, there was no impact on Apo(a) levels compared to baseline. Conclusion The rapid increase in PCSK9 levels after 24 hours suggests immediate immunocomplex formation. A compensatory rise in PCSK9 production may contribute to later elevations. Alirocumab not only lowered LDL-C but also achieved a sustained reduction in very low-density lipoprotein-associated apolipoproteins (ApoC2, ApoC3, and ApoE), indicating additional benefits of PCSK9 inhibitors.

Proprotein convertase subtilisin/kexin type 9 levels and the risk of cardiovascular events in statin-treated patients with cardiovascular disease

Abstract Background Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the risk of cardiovascular events. Although PCSK9 is cleaved by furin and becomes biologically inactive, previous studies have employed measurement methods which cannot distinguish furin-cleaved and uncleaved form of PCSK9. Methods This study is a prespecified sub-study of the REAL-CAD study which is a prospective, multicenter, randomized trial to compare high- versus low-dose statin in patients with stable coronary artery disease (CAD). The substudy primary endpoint was a composite of major adverse cerebrovascular and cardiovascular events (MACCE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. In a case-cohort study, sub-cohort was randomly selected samples from the total cohort as tripling the number of cases with MACCE. Serum mature (uncleaved) and furin-cleaved PCSK9 levels obtained at 6 months after randomization were measured among participants who subsequently developed MACCE and among randomly selected participants. Their relationships with cardiovascular events were assessed according to the quartiles. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). Results From 1,478 patients in the sub-cohort, the Cox proportional hazards models with a pseudolikelihood method for case-cohort design revealed that the risk of primary endpoint in patients in the highest quartile of mature PCSK9 concentrations was similar to the lowest quartile (HR 0.809; 95%CI, 0.541-1.209). Similarly, HRs for the highest to lowest quartiles of furin-cleaved PCSK9s was 0.948 [95%CI, 0.645-1.392] (P=0.784). As compared to the lowest quartile, both serum mature and furin-cleaved PCSK9 levels did not predict the cardiovascular events. Conclusions Serum mature and furin-cleaved PCSK9 levels did not provide useful information in the assessment of future cardiovascular events in statin-treated patients with stable CAD.Study FlowThe weighted Kaplan-Meier cueves

The impact of discontinuing proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors on clinical outcomes

Abstract Background/Introduction Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have demonstrated efficacy in lowering low-density lipoprotein cholesterol (LDL-C) levels and reducing the risk of cardiovascular events. Despite these advantages, some patients are unable to continue the use of PCSK9 inhibitors due to financial or other reasons. Limited clinical studies have been conducted to investigate the clinical outcomes of patients discontinuing PCSK9 inhibitors for various reasons. Purpose This study aims to specifically investigate patients who were unable to continue PCSK9 inhibitors, with a particular focus on those discontinuing due to financial or other reasons. The primary objective is to assess the impact of discontinuation on major adverse cardiovascular events (MACE). Methods This study focused on 205 Japanese patients who received PCSK9 inhibitors between July 2016 and December 2023. The clinical outcomes of patients who continued or discontinued PCSK9 inhibitors were comprehensively compared. The primary endpoint was major adverse cardiovascular events (MACE), encompassing cardiovascular death, coronary revascularization, target lesion revascularization (TLR), and fatal or non-fatal myocardial infarction (MI). Results Among 205 patients (median age: 69 years; interquartile range [IQR]: 60-76 years 68% male), the median follow-up was 413 days (IQR, 49-1148 days). At one year, the median LDL-C was 43mg/dL, and 158 patients (77%) achieved LDL-C &amp;lt;70 mg/dL. During the follow-up, 64% (131 patients) continued PCSK9 inhibitors, while 36% (74 patients) discontinued. Of the discontinuation group, 30% (22 patients) cited financial problems, 24% (18 patients) clinical stability, and 12% (9 patients) patient preference. Multivariate Cox regression analysis revealed that the group discontinuing PCSK9 inhibitors had a higher incidence of MACE than the group that continued (hazard ratio: 1.84; 95% confidence interval: 1.02 to 3.55; p=0.05). Conclusions This study suggests an increased risk of MACE when PCSK9 inhibitors are discontinued for financial or other reasons. This insight is vital for healthcare management and decision-making among medical practitioners.PCSK9: continuation vs discontinuation

Association between PCSK9 inhibitor with cause-specific morality amongst cancer survivors

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has emerged as a novel pharmacotherapy for dyslipidemia and been shown to be effective in reducing the risks of atherosclerotic cardiovascular diseases. PCSK9 is aberrantly expressed in a broad spectrum of cancers and has been demonstrated to contribute to cancer prognosis. However, no prior study has investigated the associations between PCSK9 inhibitors (PCSK9i) with cardiovascular and cancer mortality amongst cancer survivors. Purpose This study investigated the effects of PCSK9i on cause-specific mortality amongst cancer survivors. Methods This retrospective study used data from the Tianjin Coronary Artery Disease Cohort, which included medical data from 71 secondary or tertiary hospitals in Tianjin, China. Adult patients with coronary artery disease (CAD) diagnosed with incident cancer between 2017 and 2023 were enrolled in this study. Propensity score matching with a 1:3 ratio for PCSK9i users versus non-users was performed. The primary outcomes included all-cause mortality, cardiovascular mortality, and cancer mortality. Multivariable Cox regression was used to test associations between PCSK9i with outcomes, adjusting for age, gender, cardiovascular and non-cardiovascular comorbidities, lipid-lowing agents and other medication use, lipid level, as well as cancer characteristics. Multivariable competing risk analysis was used as sensitivity analysis. Results A total of 62,341 incident cancer patients were identified. After matching, 424 PCSK9i users and 1,272 non-users were included in this study. During a median follow-up of 1,009 days, 315 patients died, among which 98 died due to cardiovascular cause, 146 died due to cancer cause. Compared to non-users, cancer patients treated with PCSK9i presented with significantly lower risk of all-cause mortality (hazard ratio [HR], 0.33; 95% confidence interval [CI] 0.23-0.47; p &amp;lt;0.001), after adjusting for potential confounders. In addition, PCSK9i therapy was associated with a 63% lower risk of cardiovascular mortality (HR, 0.37; 95%CI 0.20-0.69; p=0.002) and a 75% lower risk of cancer-related mortality (HR, 0.25; 95%CI 0.14-0.45; p&amp;lt;0.001), in relation to non-PCSK9i group. Sensitivity analysis using multivariable competing risk model also suggested a significant association between PCSK9i treatment with reduced risk of cardiovascular mortality (HR, 0.41; 95%CI 0.22-0.76; p=0.005) and cancer mortality (HR, 0.26; 95%CI 0.15-0.48; p&amp;lt;0.001) among cancer survivors. Conclusion The use of PCSK9i was associated lower risks of all-cause, cardiovascular-related, and cancer-related mortality amongst cancer survivors. These findings potentially indicate benefits of PCSK9i beyond adverse cardiovascular events related to atherosclerosis.

Comparing PCSK9 inhibitor prescription rates within high-risk populations: diabetes mellitus, multi-territory vascular disease, multivessel and recurrent coronary artery disease

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are subsidised in Australia for treatment of hypercholesterolemia in particularly high-risk patients with atherosclerotic cardiovascular disease (ASCVD). These high-risk groups are defined as: diabetes mellitus (with age≥60, Aboriginal or Torres Strait Islander origin or microalbuminuria), recurrent ASCVD (≥2 events within 5 years), multivessel coronary disease (≥50% stenosis in ≥2 large vessels) and multi-territory vascular disease (concurrent cerebrovascular or peripheral vascular disease). Methods A retrospective observational analysis was conducted on high-risk patients with LDL&amp;gt;2.6 admitted to a quaternary hospital with ASCVD between 2020-2022. Australian Pharmaceutical Benefits Scheme (PBS) criteria was applied to assess and compare PCSK9 inhibitor eligibility and prescription rates within high-risk populations. Results In total, 477 ASCVD patients with LDL&amp;gt;2.6 were included. This was further categorised into: multivessel coronary disease (n=239, 50.1%), diabetes mellitus (n=60, 12.6%), recurrent ASCVD (n=55, 11.5%) and multi-territory vascular disease (n=32, 6.7%), p&amp;lt;0.001. When 2020 PBS criteria was applied, the number of eligible patients were 16/239 (6.7%), 5/60 (8.3%), 13/55 (23.6%) and 4/32 (12.5%) respectively, p=0.002. Of PBS eligible patients, the number prescribed PCSK9 inhibitors were: 7/16 (43.8%) for multi-vessel coronary disease, 1/5 (20%) for diabetes mellitus, 4/13 (30.8%) for recurrent ASCVD and 1/4 (25%) for multi-territory vascular disease patients (p=0.73). Conclusion Although there was a significantly higher prevalence and proportion of eligible multivessel coronary disease patients, prescribing rates for PCSK9 inhibitor therapy remain low amongst all high-risk eligible groups including diabetes mellitus, multi-territory vascular disease, multivessel and recurrent coronary artery disease.

Unraveling immune checkpoint inhibitors effects on atherosclerosis: mechanisms and preventive approaches

Abstract Background Immune checkpoint inhibitors (ICIs) represent a novel and rapidly evolving field in cancer treatment. Despite increasing reports of accelerated atherosclerosis and ICI-related atherosclerotic cardiovascular (CV) events in clinical studies and case reports, there is a notable lack of data concerning the underlying mechanisms, appropriate monitoring, and potential interventions. Objectives To explore the role of ICIs in triggering and/or accelerating the atherosclerotic process, with a specific focus on the involvement of CD8+ T-cells. Additionally, we aimed to evaluate and compare the potential beneficial effects of statins and Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors on atherosclerosis under ICIs treatment. Methods Thirty 8-week-old C57BL mice were divided into six groups as follows: (1) Control, normal diet; (2) Control, atherogenic diet; (3) Atherogenic diet + anti PD-1; (4) Atherogenic diet + statins + anti-PD1; (5) Atherogenic diet + PCSK9-i + anti PD-1; (6) Atherogenic diet + PCSK9 inhibitors. At 16 weeks, the carotid arteries and heart were removed for histological examination, and serum was withdrawn for blood work and further analysis. Results Anti-PD1 treatment resulted in extensive lymphocytic infiltration of the carotid intima, primarily constituted of CD8+ T cells. This infiltration was significantly attenuated when statins or PCSK-9 inhibitors were used in conjunction with anti-PD1 treatment. Serum analysis for CD4+ and CD8+ T cells by ELISA revealed no difference in CD4+ abundance between the groups. However, plasma CD8+ T cells were significantly increased with anti-PD1 treatment, and furthermore, when PCSK9 inhibitors were used in combination; but not when statins were used. Conclusion The induction of CD8+ T cell infiltration in the arterial carotid walls by anti-PD-1 was prevented with the use of either statins or PCSK9 inhibitors. In the plasma, while statins reduced the hyper-expression of CD8+ T cells observed under PD-1 treatment, PCSK9 inhibitors enhanced this expression. This may provide a first indication of the potential benefit of PCSK9 inhibitor treatment for both preventing arterial inflammation and enhancing the desired anti-tumor immune response under ICIs treatment. Figure legend: 1A. A cross-section of the carotid artery after 16 weeks of treatment, stained with H&amp;E. Magnification is X100. 1B. A cross-section of the carotid artery after 16 weeks of treatment, stained with anti-CD8 Ab. Magnification is X100. 1C. quantitative CD8+ T cells staining in the carotid arteries. 1D. quantitative results of ELISA for plasma CD8+ T cells.

PCSK9 inhibitors and coronary atherosclerotic plaque modification: a meta-analysis

Abstract Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a promising class of medications, primarily recognized for their potent cholesterol-lowering effects. Beyond their established role in reducing low-density lipoprotein cholesterol levels, recent studies suggest a potential impact of PCSK9 inhibitors on the modification of coronary atherosclerotic plaques. Purpose The purpose of this meta-analysis is to comprehensively synthesize data from relevant clinical studies and trials that have investigated the effects of PCSK9 inhibitors on coronary atherosclerotic plaque characteristics. Methods We performed a literature search for studies assessing the evolution of coronary atherosclerotic plaques after treatment with a PCSK9 inhibitor compared to a control group. We excluded reviews, editorials, case reports/case series, and studies that did not use PCSK9 inhibitors or did not have a control group for comparison. The main outcomes of interest were the changes in percent atheroma volume (PAV), total atheroma volume (TAV), minimal fibrous cap thickness (FCT), lipid arch, as well as the number of patients with improved PAV at follow-up. Effect sizes are presented as standardized mean difference (SMD) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) and were pooled based on a random-effects model. Publication bias was assessed by funnel plot inspection and egger’s regression test. Results The literature search yielded 189 results. After application of the exclusion criteria, a total of 8 studies were selected for data extraction and inclusion in the meta-analysis. Concerning the intravascular ultrasound findings PCSK9 inhibitors induced greater reductions in PAV (SMD -2.70, 95% CI -5.24 to -0.15, p=0.04) (Figure 1) and TAV (SMD -2.46, 95% CI -4.68 to -0.23, p=0.03) (Figure 2), with a greater proportion of patients exhibiting an improvement in PAV (RR 1.30, 95% CI 1.20 to 1.41, p&amp;lt;0.01). Moving to optical coherence tomography parameters, patients treated with PCSK9 inhibitors had an increase in minimal FCT (SMD 2.09, 95% CI 0.12 to 4.07, p=0.04) and a lower lipid arch (SMD -0.64, 95% CI -0.97 to -0.32, p&amp;lt;0.01). Funnel plot inspection and egger’s regression test did not indicate the presence of publication bias. Conclusion This meta-analysis suggests that PCSK9 inhibitors use is associated with a favorable coronary atherosclerotic plaque remodeling.Figure 1Figure 2