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Background Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have been demonstrated to produce significantly greater reduction in LDL cholesterol levels and cardiovascular events than standard statin therapy. However, evidence on the impact of PCSK9 inhibitors on coronary plaque composition and morphology is limited. Methods In this open-label randomized study, eligible patients with intermediate coronary lesions and elevated LDL cholesterol values were randomized to either alirocumab 75 mg Q2W plus statin (atorvastatin 20 mg/day or rosuvastatin 10 mg/day) therapy or standard care. Optical coherence tomography (OCT) assessments for target lesions were obtained at baseline and at 36 weeks of follow-up. Results LDL cholesterol levels were significantly decreased in both the alirocumab and standard care arms, whereas the absolute reduction in LDL cholesterol was significantly greater in patients treated with alirocumab (1.72 ± 0.51 vs. 0.96 ± 0.59, P  < 0.0001). Compared with standard care, the addition of alirocumab to statins was associated with significantly greater increases in minimum fibrous cap thickness (18.0 [10.8–29.2] μm vs 13.2 [7.4–18.6] μm; P  = 0.029), greater increases in minimum lumen area (0.20[0.10–0.33] mm 2 vs 0.13 [0.12–0.24] mm 2 ; P  = 0.006) and a greater diminution in maximum lipid arc (15.1̊ [7.8–24.5] vs. 8.4̊ [2.0–10.5]; P  = 0.008). Conclusions The addition of alirocumab to statins can not only provide additional LDL cholesterol lowering effects but also have a potential role in promoting a more stable plaque phenotype. Trial registration ClinicalTrials.gov Identifier: NCT04851769. Registered 2 Mar 2019.

Background MicroRNAs (miRNAs) are involved in the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), one of the regulators of low-density lipoprotein cholesterol (LDL-C) metabolism, and are directly involved in the atherosclerotic process. The aim of this study was to verify whether treatment with PCSK9 inhibitors (PCSK9i) and changes in the expression of miRNAs involved in PCSK9 metabolism are associated with arterial wall properties in stable post-myocardial infarction (MI) patients with insufficiently regulated LDL-C levels and significantly increased Lp(a) levels. Methods Ninety-five patients after MI were enrolled and randomized to a placebo ( N  = 31) or PCSK9i group ( N  = 64). The treatment group received subcutaneous alirocumab 150 mg or evolocumab 140 mg, every 2 weeks. Blood for biochemical and epigenetic analysis was taken and ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima–media thickness (c-IMT) and pulse wave velocity (PWV) were performed initially and after 6 months of treatment. The expression of the selected 5 miRNAs (miR-191-5p, miR-224-5p, miR-337-3p, miR-483-5p, and miR-552-3p) was quantified using quantitative polymerase chain reaction. Results A decrease in c-IMT was associated with a decrease in the expression of miR-337-3p ( ρ  = 0.329; p  = 0.010) and miR-483-5p ( ρ  = 0.324; p  = 0.012). We did not detect any associations between miRNA changes and FMD or PWV. Conclusions Our results suggest that changes in the selected miRNAs are associated with changes in the morphological properties of the arterial wall. We have shown that the decrease in miR-483-5p expression present a good indicator of the regression of morphological atherosclerotic change. The trial registration : The study is registered with CinicalTrials under the number NCT04613167, date of registration November 2nd, 2020. Approval for this study was obtained from the National Medical Ethics Committee of the Republic of Slovenia (reference number: KME 0120-357/2018/8).

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C), and premature atherosclerotic cardiovascular disease. Depending on residual LDL receptor (LDLR) function, most HoFH patients respond modestly to statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, LDL-C typically remains markedly elevated necessitating additional therapies, including apheresis. Gemcabene is a novel lipid-lowering agent with a mechanism of action independent of the LDLR, which has previously demonstrated the ability to reduce levels of LDL-C on top of maximally tolerated statins. The present study (COBALT-1) assessed efficacy, tolerability, and safety of gemcabene as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients. Eight patients with either a clinical or genetic diagnosis of HoFH on stable standard of care, including statins, ezetimibe, and PCSK9 inhibitors, were treated with gemcabene in an open-label study for 12 weeks. DNA analysis for mutations in the LDLR, apolipoprotein B, and PCSK9 genes was performed. Patients received 300 mg gemcabene for the first 4 weeks, 600 mg for the next 4 weeks, and 900 mg for the final 4 weeks. All patients completed the 12-week study. Mean change from baseline in LDL-C was −26% (p = 0.004) at Week 4 (300 mg), −30% (p = 0.001) at Week 8 (600 mg), and −29% (p = 0.001) at Week 12 (900 mg). In conclusion, the COBALT-1 study demonstrates gemcabene has potential to significantly reduce LDL-C levels when used as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients.

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer’s disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE -genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm ( p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm ( p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant ( p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, ( p ’s>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer’s disease.

Purpose of Review To summarize selected late-breaking science on cardiovascular (CV) disease prevention presented at the 2023 European Society of Cardiology (ESC) congress. Recent Findings The NATURE-PARADOX was a naturally randomized trial that used genetic data from the UK Biobank registry to create “cumulative exposure to low-density lipoprotein-cholesterol (LDL-C)” biomarker and evaluate its association with major CV events regardless of plasma LDL-C levels or age. Safety and efficacy data of inclisiran, a PCSK9-interfering mRNA (PCSK9i) administered subcutaneously twice annually, were presented. Data on two new PCSK9is were presented, recaticimab, an oral drug, and lerodalcibep, a subcutaneous drug with a slightly different architecture than currently available PSCK9is. A phase 1 trial on muvalaplin, an oral lipoprotein (a) inhibitor, was presented. An atherosclerotic CV disease (ASCVD) risk prediction algorithm for the Asian population using SCORE2 data was presented. Long-term follow-up of patients enrolled in the CLEAR outcomes trial showed sustained and more significant ASCVD risk reduction with bempedoic acid in high-risk patients. Summary The late-breaking clinical science at the 2023 congress of the ESC extends the known safety and efficacy data of a PCSK9i with the introduction of new drugs in this class. Using cumulative exposure to LDL-C rather than a single value will help clinicians tailor the LDL-C reduction strategy to individual risk and is an important step towards personalized medicine.

Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo. The development programme for a third humanised monoclonal antibody, bococizumab, was terminated early due to the presence of neutralising antibodies reducing its efficacy over time. Results from the first cardiovascular outcomes trial, FOURIER, have demonstrated significant reductions in cardiovascular events in a population with stable cardiovascular disease over a 2-year period. The ODYSSEY OUTCOMES trial comparing alirocumab to placebo is expected to report in 2018 and provide cardiovascular outcome data in a post acute coronary syndrome population. Monoclonal antibodies have an injection burden of 12–26 injections per year. An alternative approach to reducing PCSK9 is to inhibit translation of the messenger RNA for PCSK9. The phase II ORION-1 study using inclisiran, a small interference RNA to PCSK9, suggested that two doses of inclisiran produced time averaged reductions in LDL cholesterol of 50% over 9 months. The ORION-4 cardiovascular outcome trial will assess the cardiovascular benefits of two injections per year using inclisiran. With further outcome trials expected, appropriate patient selection will be key considering the higher drug costs of these therapies.

Background Epidemiological studies substantiated that subjects with elevated lipoprotein(a) [Lp(a)] have a markedly increased cardiovascular risk. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers both LDL cholesterol (LDL-C) as well as Lp(a), albeit modestly. Effects of PCSK9 inhibition on circulating metabolites such as lipoprotein subclasses, amino acids and fatty acids remain to be characterized. Methods We performed nuclear magnetic resonance (NMR) metabolomics on plasma samples derived from 30 individuals with elevated Lp(a) (> 150 mg/dL). The 30 participants were randomly assigned into two groups, placebo ( N  = 14) and evolocumab ( N  = 16). We assessed the effect of 16 weeks of evolocumab 420 mg Q4W treatment on circulating metabolites by running lognormal regression analyses, and compared this to placebo. Subsequently, we assessed the interrelationship between Lp(a) and 14 lipoprotein subclasses in response to treatment with evolocumab, by running multilevel multivariate regression analyses. Results On average, evolocumab treatment for 16 weeks resulted in a 17% (95% credible interval: 8 to 26%, P  < 0.001) reduction of circulating Lp(a), coupled with substantial reduction of VLDL, IDL and LDL particles as well as their lipid contents. Interestingly, increasing concentrations of baseline Lp(a) were associated with larger reduction in triglyceride-rich VLDL particles after evolocumab treatment. Conclusions Inhibition of PCSK9 with evolocumab markedly reduced VLDL particle concentrations in addition to lowering LDL-C. The extent of reduction in VLDL particles depended on the baseline level of Lp(a). Our findings suggest a marked effect of evolocumab on VLDL metabolism in subjects with elevated Lp(a). Trial registration Clinical trial registration information is registered at ClinicalTrials.gov on April 14, 2016 with the registration number NCT02729025 .

Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Background Maternal and fetal Low Density Lipoprotein-Cholesterol (LDL-C) concentrations are compromised in intrauterine growth restriction (IUGR). Generally, LDL-C catabolism is under control of PCSK9 by binding to the LDL-receptor leading to its degradation. Hence, we hypothesized a role for PCSK9 in the modulation of lipid metabolism and placental transport in IUGR. Methods 172 women, 70 IUGR and 102 controls were included in the study. Maternal and fetal serum PCSK9 levels and lipid profiles including LDL-C were measured. Placental LDL-receptor and PCSK9 expressions were estimated by tissue microarray immunohistochemistry, and analyzed by two blinded observers using an immunoreactivity score. Non-parametric tests and multivariate regression analyses were used for statistical estimations. Results PCSK9 levels in the maternal and fetal compartment independently predicted LDL-C levels (maternal compartment: adjusted R 2  = 0.2526; coefficient b i  = 0.0938, standard error s bi =0.0217, r partial  = 0.4420, t -value = 4.323, p  < 0.0001; fetal compartment: adjusted R 2  = 0.2929; b i  = 0.1156, s bi =0.020, r partial  = 0.5494, t-value = 5.81, p  < 0.0001). We did not find significant differences in maternal PCSK9 concentrations between IUGR and controls. However, we found lower fetal serum PCSK9 concentrations in IUGR than in controls (IUGR median 137.1 ng/mL (95% CI 94.8-160.0) vs. controls 176.8 (154.6-202.5), p  = 0.0005). When subgrouping according to early onset, late onset IUGR, and fetal gender differences remained consistent only for male neonates born before 34 weeks of gestation. In the placenta we found no correlation between PCSK9 and LDL-receptor expression patterns. However, the LDL-receptor was significantly upregulated in IUGR when compared to controls ( p  = 0.0063). Conclusions Our results suggest that PCSK9 play a role in impaired fetal growth by controlling fetal LDL-C metabolism, which seems to be dependent on gestational age and fetal gender. This underlines the need to identify subgroups of IUGR that may benefit from individualized and gender-specific pharmacotherapy in future studies.

Despite its success in achieving the long-term survival of 10–30% of treated individuals, immune therapy is still ineffective for most patients with cancer 1 , 2 . Many efforts are therefore underway to identify new approaches that enhance such immune ‘checkpoint’ therapy 3 – 5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9—a key protein in the regulation of cholesterol metabolism 6 – 8 —can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9’s cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9—either through genetic deletion or using PCSK9 antibodies—increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer. Inhibiting the PCSK9 protein, a regulator of cholesterol metabolism, enhances immune checkpoint therapy in mouse models of cancer, in a manner that depends on the regulation of antigen-presenting MHC I molecules.