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Objective: Hyperlipidemia plays a crucial role in increasing the risk of cardiovascular diseases such as atherosclerosis. Recent studies have established that inclisiran positively influences lipid regulation. Nevertheless, its effectiveness in comparison to conventional treatments is still questionable. Hence, a methodical assessment of its effectiveness and safety is required. This research evaluates the efficacy and safety of inclisiran, PCSK9 inhibitors, and the combination of statins with ezetimibe in the treatment of hyperlipidemia via a network meta-analysis of randomized controlled trials (RCTs). Methods: We performed an extensive search of English-language publications in the PubMed, Medline, Embase, and Cochrane Library databases until April 2024. We conducted a web-based meta-analysis and reported in accordance with the guidelines. We selected the percentage change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) as efficacy evaluation metrics and the incidence of adverse events as safety evaluation metrics for analysis and comparison. Result: We incorporated 33 studies involving 23,375 patients, evaluating three interventions regarding their effects on LDL-C, TC, TG, HDL-C, and adverse events. All treatments improved metrics over placebo. Inclisiran significantly reduced LDL-C compared to statins (mean − 15.21, 95% CI [-25.19, -5.23]) but showed no significant difference from statin + ezetimibe. Surface under the cumulative ranking curve (SUCRA) rankings placed inclisiran highest for LDL-C reduction (26.2%). The combination of statin and ezetimibe was the most efficacious for triglyceride reduction (mean 17.2, 95% CI [10.22, 24.19]; mean 15.61, 95% CI [16.87, 24.35]). The safety profiles were comparable across treatments. Conclusion: Inclisiran with its superior LDL-C reduction and low frequency of administration, appears promising for hyperlipidemia treatment, particularly for patients with adherence issues or side effects from other medications. Systematic review registration: CRD42024550852 [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion injury is accompanied by ferroptosis mediated by reactive oxygen species and iron ions, which aggravates myocardial tissue damage. The present study aims to explore the molecular mechanism underlying the mitigating effects f PCSK9 on myocardial ischemia-reperfusion injury. MI/R rat model and OGD/R induced H9c2 model were established. The interaction between PCSK9 inhibitor and LRP8 was predicted by STRING database and verified by Immunoprecipitation assay experiment. CCK-8 kit results confirmed that PCSK9 inhibitor effectively protected against cardiomyocyte damage induced by OGD/R. TTC and histological examination via H&E staining revealed a significant alleviation of myocardial infarction and pathological alterations upon treatment with the PCSK9 inhibitor. Besides, DCFH-DA staining and biochemical kit results showed that PCSK9 inhibitor could regulate the changes of ferroptosis related indicators [ROS, iron level, MDA, SOD] and inhibit ferroptosis. Rescue experiments showed that PCSK9 inhibitors targeted LRP8 expression and inhibited GPX4/ROS-mediated ferroptosis in I/R-induced rats. Our study suggested that PCSK9 inhibitors could attenuate myocardial I/R injury, with the underlying mechanism intimately tied to the targeted modulation of LRP8/GPX4-mediated ferroptosis. [ABSTRACT FROM AUTHOR]

Objective Hyperlipidemia plays a crucial role in increasing the risk of cardiovascular diseases such as atherosclerosis. Recent studies have established that inclisiran positively influences lipid regulation. Nevertheless, its effectiveness in comparison to conventional treatments is still questionable. Hence, a methodical assessment of its effectiveness and safety is required. This research evaluates the efficacy and safety of inclisiran, PCSK9 inhibitors, and the combination of statins with ezetimibe in the treatment of hyperlipidemia via a network meta-analysis of randomized controlled trials (RCTs). Methods We performed an extensive search of English-language publications in the PubMed, Medline, Embase, and Cochrane Library databases until April 2024. We conducted a web-based meta-analysis and reported in accordance with the guidelines. We selected the percentage change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) as efficacy evaluation metrics and the incidence of adverse events as safety evaluation metrics for analysis and comparison. Result We incorporated 33 studies involving 23,375 patients, evaluating three interventions regarding their effects on LDL-C, TC, TG, HDL-C, and adverse events. All treatments improved metrics over placebo. Inclisiran significantly reduced LDL-C compared to statins (mean − 15.21, 95% CI [-25.19, -5.23]) but showed no significant difference from statin + ezetimibe. Surface under the cumulative ranking curve (SUCRA) rankings placed inclisiran highest for LDL-C reduction (26.2%). The combination of statin and ezetimibe was the most efficacious for triglyceride reduction (mean 17.2, 95% CI [10.22, 24.19]; mean 15.61, 95% CI [16.87, 24.35]). The safety profiles were comparable across treatments. Conclusion Inclisiran with its superior LDL-C reduction and low frequency of administration, appears promising for hyperlipidemia treatment, particularly for patients with adherence issues or side effects from other medications. Systematic review registration CRD42024550852

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Aims Proprotein convertase anti-subtilisin–kexin type 9 inhibitors (PCSK9Is) improve plaque volume and composition and reduce major adverse coronary events in chronic coronary artery disease. We evaluated the effects of the short-term use of PCSK9Is on coronary plaque stability in patients with acute coronary syndrome (ACS) using optical coherence tomography (OCT). Methods and results This is a multicentre, open-label randomized controlled trial. The enrolled 80 subjects met the inclusion criteria. Of these, 52 patients (age 60 ± 11 years, 38 men, 14 women) with ST-elevated ACS had undergone successful primary percutaneous coronary intervention with LDL-cholesterol (LDL-C) levels > 70 mg/dL while receiving high-intensity statins. Participants were randomly assigned to the PCSK9I group (evolocumab 420 mg for 3 months, n = 29) or the standard of care (SoC) group (n = 23). Optical coherence tomography was performed at baseline (BL) and 3 and 9 months after randomization to assess lipid-rich plaques in non-culprit lesions. The change in the minimum fibrous cap thickness (MFCT) from BL to 9 months was the primary endpoint. The percentage change in LDL-C levels from BL to 3 months was significantly greater in the PCSK9I group (−67.8 ± 21.5% in the PCSK9I group vs. −16.3 ± 21.8% in the SoC group; P < 0.0001), and the difference between the two groups disappeared from BL to 9 months (−20.0 ± 37.8% in the PCSK9I group vs. −6.7 ± 34.2% in the SoC group; P = 0.20). The changes in MFCT from BL to 9 months were significantly greater in the PCSK9I group, even after PCSK9I discontinuation {100 μm [interquartile range (IQR): 45–180 μm] vs. 50 μm [IQR: 0–110 μm]; P = 0.032}. Conclusion Combination treatment with PCSK9Is and statins resulted in more marked plaque stabilization after ACS than SoC alone, and this effect persisted for 6 months after PCSK9I discontinuation. Registration Adage-Joto study, UMIN ID No. 26516. [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

Copyright of Zeitschrift für Herz-, Thorax- und Gefaesschirurgie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BackgroundAtherosclerotic 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.MethodsThe 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.ResultsThis 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.ConclusionsBased 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 RegistrationPROSPERO [CRD42023459558].

Abstract Familial hypercholesterolemia (FH) is a genetic disease characterized by elevated LDL-C levels. In this study, two FH probands and 9 family members from two families from northeastern Thailand were tested for LDLR, APOB, and PCSK9 variants by whole-exome sequencing, PCR-HRM, and Sanger sequencing. In silico analysis of LDLR was performed to analyse its structure‒function relationship. A novel variant of LDLR (c.535_536delinsAT, p.Glu179Met) was detected in proband 1 and proband 2 in homozygous and heterozygous forms, respectively. A total of 6 of 9 family members were heterozygous for LDLR p.Glu179Met variant. Compared with proband 2, proband 1 had higher baseline TC and LDL-C levels and a poorer response to lipid-lowering therapy combined with a PCSK9 inhibitor. Multiple sequence alignment showed that LDLR p.Glu179Met was located in a fully conserved region. Homology modelling demonstrated that LDLR p.Glu179Met variant lost one H-bond and a negative charge. In conclusion, a novel LDLR p.Glu179Met variant was identified for the first time in Thai FH patients. This was also the first report of homozygous FH patient in Thailand. Our findings may expand the knowledge of FH-causing variants in Thai population, which is beneficial for cascade screening, genetic counselling, and FH management to prevent coronary artery disease.

Atherosclerotic cardiovascular disease (ASCVD) remains the main cause of death worldwide, and thus its prevention, early diagnosis and treatment is of paramount importance. Dyslipidemia represents a major ASCVD risk factor that should be adequately managed at different clinical settings. 2023 guidelines of the Hellenic Atherosclerosis Society focus on the assessment of ASCVD risk, laboratory evaluation of dyslipidemias, new and emerging lipid-lowering drugs, as well as diagnosis and treatment of lipid disorders in women, the elderly and in patients with familial hypercholesterolemia, acute coronary syndromes, heart failure, stroke, chronic kidney disease, diabetes, autoimmune diseases, and non-alcoholic fatty liver disease. Statin intolerance is also discussed.

The article discusses the use of gene editing as a potential therapy for reducing cholesterol levels in individuals with atherosclerotic cardiovascular disease (ASCVD). The current standard treatment for ASCVD involves the use of statins, but low adherence to these medications has led to the need for alternative therapies. The article explores different approaches to targeting PCSK9, a protein that plays a role in cholesterol regulation, including monoclonal antibodies, RNA interference, and gene editing using CRISPR/Cas9. The authors present the results of a phase 1b clinical trial evaluating the safety and tolerability of a gene editing therapy called VERVE-101 in patients with hypercholesterolemia. While the therapy showed promising results in reducing PCSK9 protein levels and LDL cholesterol, there were also some serious adverse events reported. The authors emphasize the need for further research to determine the long-term safety and efficacy of gene editing therapies for lipid-lowering. [Extracted from the article]

Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have been shown to regulate lipid metabolism and reduce the risk of cardiovascular events. This study explores the effect and potential mechanism of PCSK9 inhibitors on lipid metabolism and coronary atherosclerosis. HepG2 cells were incubated with PCSK9 inhibitor. ApoE-/- mice were fed with a high fat to construct an atherosclerosis model, and then treated with PCSK9 inhibitor (8 mg/kg for 8 w). PCSK9 inhibitor downregulated microRNA (miRNA)-130a-3p expression in a dose-dependent manner. And, miR-130a-3p could bind directly to the 3' untranslated region (3'-UTR) region of LDLR to down-regulate LDLR expression in HepG2 cells, as confirmed by the luciferase reporter gene assay. In addition, miR-130a-3p overexpression significantly attenuated the promoting effect of PCSK9 inhibitor on LDLR and DiI-LDL uptake in HepG2 cells. More importantly, in vivo experiments confirmed that PCSK9 inhibitor could significantly inhibit miR-130a-3p levels and promote LDLR expression in liver tissues, thus regulating serum lipid profile and alleviating the progression of coronary atherosclerosis. PCSK9 inhibitor could moderately improve coronary atherosclerosis by regulating miR-130a-3p/LDLR axis, providing an exploitable strategy for the treatment of coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

Ischemic stroke, the most prevalent and serious manifestation of cerebrovascular disease, is the main cause of neurological problems that require hospitalization, resulting in disability and death worldwide. Currently, clinical practice focuses on the effective management of blood lipids as a crucial approach to preventing and treating ischemic stroke. In recent years, a great breakthrough in ischemic stroke treatment has been witnessed with the emergence and use of a novel lipidlowering medication, Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. And its remarkable potential for reducing the occurrence of ischemic stroke is being acknowledged. This article aims to provide a comprehensive review, encompassing the association between PCSK9 and the heightened risk of ischemic stroke, the mechanisms, and the extensive evidence supporting the proven efficacy of PCSK9 inhibitors in clinical practice. Through this present study, we can gain deeper insights into the utilization and impact of PCSK9 inhibitors in treating ischemic stroke. [ABSTRACT FROM AUTHOR]

Limited data have been reported on the use of proprotein convertase subtilisin/kexin type 9 (PCSK 9) inhibitors during pregnancy in women with familial hypercholesterolemia (FH). Here, we present the first case of initiating evolocumab (PCSK9 inhibitor) in a compound heterozygous FH mother. The patient was a 34‐year‐old primipara with severe dyslipidemia and a history of coronary artery bypass surgery. An elevated low‐density lipoprotein cholesterol (LDL‐C) level of 420 mg/dL was detected in the first trimester and persistently increased throughout pregnancy. Evolocumab was administered at 31 and 35 weeks of gestation, showing a positive effect on stabilizing LDL‐C levels. Planned delivery with labor analgesia was performed at 38 + 4 weeks. Both the mother and infant were discharged without any notable complications. Hence, evolocumab, an IgG2 monochromatic antibody with little placental permeability, may be an alternative medication with limited influence on infants. Further studies are needed to assess the safety of evolocumab administration during pregnancy. [ABSTRACT FROM AUTHOR]

Objective: This study explores the potential causal association between proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and tumor development using Mendelian randomization (MR) based on drug targets. Methods: Instrumental variables within ±100 kb of the PCSK9 gene locus, impacting low-density lipoprotein cholesterol (LDL-C), were utilized for MR analysis. Coronary heart disease (CHD) served as a positive control to validate the causal relationship between PCSK9 inhibitors and various cancers. We employed reverse MR to address the reverse causation concerns. Data from positive controls and tumors were sourced from OpenGWAS. Results: MR analysis suggested a negative causal relationship between PCSK9 inhibitors and both breast and lung cancers (95%CIBreast cancer 0.81~0.99, p = 2.25 × 10−2; 95%CILung cancer 0.65~0.94, p = 2.55 × 10−3). In contrast, a positive causal link was observed with gastric, hepatic, and oral pharyngeal cancers and cervical intraepithelial neoplasia (95%CIGastric cancer 1.14~1.75, p = 1.88 × 10−2; 95%CIHepatic cancer 1.46~2.53, p = 1.16 × 10−2; 95%CIOral cavity and pharyngeal cancer 4.49~6.33, p = 3.36 × 10−4; 95%CICarcinoma in situ of cervix uteri 4.56~7.12, p = 6.91 × 10−3), without heterogeneity or pleiotropy (p > 0.05). Sensitivity analyses confirmed these findings. The results of MR of drug targets suggested no causal relationship between PCSK9 inhibitors and bladder cancer, thyroid cancer, pancreatic cancer, colorectal cancer, malignant neoplasms of the kidney (except for renal pelvis tumors), malignant neoplasms of the brain, and malignant neoplasms of the esophagus (p > 0.05). Reverse MR helped mitigate reverse causation effects. Conclusions: The study indicates a divergent causal relationship of PCSK9 inhibitors with certain cancers. While negatively associated with breast and lung cancers, a positive causal association was observed with gastric, hepatic, oral cavity, and pharyngeal cancers and cervical carcinoma in situ. No causal links were found with bladder, thyroid, pancreatic, colorectal, certain kidney, brain, and esophageal cancers. [ABSTRACT FROM AUTHOR]

Scientific relevance. The main cause of cardiovascular pathologies is atherosclerosis, which is secondary to lipid metabolism disorders, in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. Dyslipidaemia treatment with the largest evidence base predominantly includes statins in combination therapy, but their use is limited by into lerance in some patients. Alternatively, the treatment may include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.Aim. The study aimed to analyse the applicability of PCSK9 inhibitors in patients with statin intolerance.Discussion. According to the literature analysis, the most common presentation of statin intolerance is statin-associated muscle symptoms. The pathogenesis of statin-associated adverse events is mainly mediated by HMGCoA reductase inhibition, treatment effects on cellular and subcellular processes and skeletal muscles, and patients’ genetic makeup. The mechanism of action of PCSK9 inhibitors is entirely different and involves binding and inactivation of the PCSK9 protein, which lowers blood LDL cholesterol levels. PCSK9 inhibitors have been associated with some adverse drug reactions, most notably immunogenicity; however, PCSK9 inhibitors effectively reduce LDL levels even if patients develop antibodies.Conclusions. Therefore, PCSK9 inhibitors are a safe, well-tolerated, and effec tive therapeutic strategy for hyperlipidaemia in patients with statin intolerance.

Abstract Background Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. The primary objective of this study was to identify the major pathogenic mutations in a Chinese family with FH. Methods Whole-genome sequencing (WGS) was used to identify variants of FH-related genes, including low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). Bioinformatics software was used to predict signal peptides, transmembrane structures, and spatial construction information of the mutated sequences. Western blotting was performed on the mutant protein to determine the presence of the major structural domains of the LDLR. The PCSK9 and APOB genes were screened and analyzed. Moreover, the proband and his brother were treated with a PCSK9 inhibitor for 1 year, and the effect of the treatment on lipid levels was assessed. Results WGS revealed two potentially pathogenic mutations in the LDLR gene. One was a novel mutation, c.497delinsGGATCCCCCAGCTGCATCCCCCAG (p. Ala166fs), and the other was a known pathogenic mutation, c.2054C>T (p. Pro685Leu). Bioinformatics prediction and in vitro experiments revealed that the novel mutation could not be expressed on the cell membrane. Numerous gene variants were identified in the APOB gene that may have a significant impact on the family members with FH. Thus, it is suggested that the severe manifestation of FH in the proband primarily resulted from the cumulative genetic effects of variants in both LDLR and APOB. However, a subsequent study indicated that treatment with a PCSK9 inhibitor (Evolocumab) did not significantly reduce the blood lipid levels in the proband or his brother. Conclusions The cumulative effect of LDLR and APOB variants was the primary cause of elevated blood lipid levels in this family. However, PCSK9 inhibitor therapy did not appear to be beneficial for the proband. This study emphasizes the importance of genetic testing in determining the most suitable treatment options for patients with FH.

Abstract Objective Assess the risk of new and worsening cancer events among participants who received the lipid‐lowering therapy alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. Design Pooled post hoc analysis. Setting Six phase 3 or phase 4 placebo‐controlled randomised trials with alirocumab. Participants A total of 24,070 patients from the safety population with complete dosing data (alirocumab, n = 12,533; placebo, n = 11,537). Intervention Alirocumab 75 mg, alirocumab 150 mg, alirocumab 75 mg increasing to 150 mg if low‐density lipoprotein cholesterol

BackgroundMyasthenia gravis is a rare chronic autoimmune neuromuscular disorder mainly caused by autoantibodies to the nicotinic acetylcholine receptor. Cholesterol is an essential molecule that affects the distribution and proper functioning of this receptor. Several reports have described the potential worsening of myasthenia gravis in patients treated with statins.Case presentationThe patient was an obese 72 years old man, past smoker, diagnosed with ischaemic heart disease, type 2 diabetes mellitus and lipid metabolism disorder. Statin treatment was not implemented because of chronic myasthenia gravis and PCSK9i monotherapy [Repatha (evolucamab), 140 mg] was implemented to treat dyslipidaemia. Within 24 h after the first dose of PCSK9i the patient developed severe muscle weakness, joint pain, fever, and general discomfort, lasting for several days. Despite strong advice against the second dose administration, this was self-administered approximately 2 weeks later, leading to report significant worsening of the muscle problems, leading to the patient admittion to the neurology department where he was being treated for myasthenia gravis attack.ConclusionBased on the neurologist's conclusion, it can be assumed that in this case, treatment with PCSK9i resulted in significant worsening of the patient's chronic disease.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a “high-risk” patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30–40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in nonhuman primates under good laboratory practices toxicity indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C-lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD.

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. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. The primary objective of this study was to identify the major pathogenic mutations in a Chinese family with FH. Methods: Whole-genome sequencing (WGS) was used to identify variants of FH-related genes, including low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). Bioinformatics software was used to predict signal peptides, transmembrane structures, and spatial construction information of the mutated sequences. Western blotting was performed on the mutant protein to determine the presence of the major structural domains of the LDLR. The PCSK9 and APOB genes were screened and analyzed. Moreover, the proband and his brother were treated with a PCSK9 inhibitor for 1 year, and the effect of the treatment on lipid levels was assessed. Results: WGS revealed two potentially pathogenic mutations in the LDLR gene. One was a novel mutation, c.497delinsGGATCCCCCAGCTGCATCCCCCAG (p. Ala166fs), and the other was a known pathogenic mutation, c.2054C>T (p. Pro685Leu). Bioinformatics prediction and in vitro experiments revealed that the novel mutation could not be expressed on the cell membrane. Numerous gene variants were identified in the APOB gene that may have a significant impact on the family members with FH. Thus, it is suggested that the severe manifestation of FH in the proband primarily resulted from the cumulative genetic effects of variants in both LDLR and APOB. However, a subsequent study indicated that treatment with a PCSK9 inhibitor (Evolocumab) did not significantly reduce the blood lipid levels in the proband or his brother. Conclusions: The cumulative effect of LDLR and APOB variants was the primary cause of elevated blood lipid levels in this family. However, PCSK9 inhibitor therapy did not appear to be beneficial for the proband. This study emphasizes the importance of genetic testing in determining the most suitable treatment options for patients with FH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Some data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels. Methods The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab. Results Over median follow-up of 2.8 years (interquartile range 2.3 − 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 − 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide and the risk of a major cardiovascular event is highest among those with established disease. Ongoing management of these patients relies on the accurate assessment of their response to any prescribed therapy, and their residual risk, in order to optimize treatment. Recent international guidelines and position statements concur that the plasma concentration of apolipoprotein B (apoB) is the most accurate measure of lipoprotein associated ASCVD risk. This is especially true for the growing number of individuals with diabetes, obesity, or the metabolic syndrome, and those on statin therapy. Most guidelines, however, continue to promote LDL-C as the primary risk marker due to uncertainty as to whether the greater accuracy of apoB is sufficient to warrant a paradigm shift. Recommendations regarding apoB measurement vary, and the information provided on how to interpret apoB results is sometimes insufficient, particularly for non-lipid specialists. Misinformation regarding the reliability of the assays is also frequently repeated despite its equivalent or better standardization than many other diagnostic assays. Thus, demand for apoB testing is relatively low, which means there is little incentive to increase its availability or reduce its cost. In this review, we examine the results of recent clinical outcomes studies and meta-analyses on the relative values of apoB, LDL-C, and non-HDL-C as markers of ASCVD risk. Although there is seemingly minimal difference among these markers when only population-based metrics are considered, it is evident from our analysis that, from a personalized or precision medicine standpoint, many individuals would benefit, at a negligible total cost, if apoB measurement were better integrated into the diagnosis and treatment of ASCVD. [ABSTRACT FROM AUTHOR]

Background: Evolocumab has been demonstrated to significantly reduce ischemic cardiovascular events in patients with stable coronary heart disease. However, it is currently unclear whether this benefit extends to patients with acute coronary syndrome (ACS) and multivessel disease (MVD) undergoing percutaneous coronary intervention (PCI). The objective of this study was to assess the safety, efficacy and feasibility of the early addition of evolocumab to statin treatment for ACS patients with MVD undergoing PCI. Methods: The authors conducted a multicenter, retrospective cohort study involving 1199 ACS patients with MVD undergoing PCI and with elevated low-density lipoprotein cholesterol (LDL-C) levels. Patients were divided into an evolocumab group or a standard-of-care group based on evolocumab use or not. The 18-month primary efficacy endpoint was a composite of ischemic stroke, death from cardiac causes, recurrent myocardial infarction (MI), unplanned coronary revascularization or unstable angina requiring hospitalization. The principal secondary efficacy endpoint was a composite of ischemic stroke, death from cardiac causes or recurrent MI. Results: After propensity score matching, the addition of evolocumab to statin treatment lowered LDL-C levels by 42.62% compared with statin therapy alone at 18 months, from a mean baseline level of 3.37-0.75 mmol/L (p < 0.001). Relative to standard therapy, evolocumab added to statins was associated with significant reductions in the primary efficacy endpoint (8.3% vs. 13.3%; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.39 to 0.91; p = 0.017) and the principal secondary efficacy endpoint (6.1% vs. 10.2%; adjusted HR, 0.61; 95% CI, 0.37 to 0.99; p = 0.048) after multivariable Cox regression adjustment. The treatment effect of evolocumab was consistent across all prespecified subgroups. There were no significant between-group differences in terms of adverse events. Conclusions: In ACS patients with MVD taken for PCI, early initiation of evolocumab along with statin treatment was associated with a significant reduction in LDL-C levels and a reduced risk of recurrent cardiovascular events. Clinical Trial Registration: Chinese Clinical Trials Registry, identifier ChiCTR2000035165. Date: 2 August 2020. URL: https://www.chictr.org.cn/. [ABSTRACT FROM AUTHOR]

Objective: Assess the risk of new and worsening cancer events among participants who received the lipid‐lowering therapy alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. Design: Pooled post hoc analysis. Setting: Six phase 3 or phase 4 placebo‐controlled randomised trials with alirocumab. Participants: A total of 24,070 patients from the safety population with complete dosing data (alirocumab, n = 12,533; placebo, n = 11,537). Intervention: Alirocumab 75 mg, alirocumab 150 mg, alirocumab 75 mg increasing to 150 mg if low‐density lipoprotein cholesterol <50 mg/dL not achieved, or placebo, all every 2 weeks. All participants received background high‐intensity or maximum‐tolerated statin therapy. Outcomes and Measures: The first new or worsening incident cancer events were assessed during the treatment‐emergent adverse event period. Four outcomes were evaluated: any‐neoplasm, malignant neoplasms, broad definition of hormone‐sensitive cancers, and stricter definition of hormone‐sensitive cancers. Sub‐distribution hazard ratios and 95% confidence intervals (CIs) were estimated using a competing risk framework, with death as a competing risk. Results: Considering both treatment arms in aggregate, 969 (4.03%), 779 (3.24%), 178 (0.74%) and 167 (0.69%) patients developed any neoplasm, malignant neoplasms, broad definition of hormone‐sensitive cancer and strict definition of hormone‐sensitive cancer events, respectively. There was no significant difference in the risk of having any neoplasm in the alirocumab versus the placebo group (sub‐distribution hazards ratio [95% CI], 0.93 [0.82–1.1]; p = 0.28). A nominally lower risk of having any neoplasms with alirocumab was observed among subjects aged ≥64 years (sub‐distribution hazards ratio 0.83; 95% CI, 0.70–0.99). Conclusions: Intensive low‐density lipoprotein cholesterol lowering with a proprotein convertase subtilisin/kexin type 9 inhibitor combined with statin does not appear to increase the risk of new or worsening cancer events. [ABSTRACT FROM AUTHOR]

Lipoprotein apheresis (LA) is a therapeutic option for patients with severe hypercholesterolemia who have persistently elevated LDL-C levels despite attempts at drug therapy. MicroRNAs (miRNAs), important posttranscriptional gene regulators, are involved in the pathogenesis of atherosclerosis. Our study aimed to monitor the dynamics of twenty preselected circulating miRNAs in patients under long-term apheresis treatment. Plasma samples from 12 FH patients (men = 50%, age = 55.3 ± 12.2 years; mean LA overall treatment time = 13.1 ± 7.8 years) were collected before each apheresis therapy every sixth month over the course of four years of treatment. Eight complete follow-up (FU) samples were measured in each patient. Dynamic changes in the relative quantity of 6 miRNAs (miR-92a, miR-21, miR-126, miR-122, miR-26a, and miR-185; all p < 0.04) during FU were identified. Overall apheresis treatment time influenced circulating miR-146a levels (p < 0.04). In LDLR mutation homozygotes (N = 5), compared to heterozygotes (N = 7), we found higher plasma levels of miR-181, miR-126, miR-155, and miR-92a (all p < 0.03). Treatment with PCSK9 inhibitors (N = 6) affected the plasma levels of 7 miRNAs (miR-126, miR-122, miR-26a, miR-155, miR-125a, miR-92a, and miR-27a; all p < 0.04). Long-term monitoring has shown that LA in patients with severe familial hypercholesterolemia influences plasma circulating miRNAs involved in endothelial dysfunction, cholesterol homeostasis, inflammation, and plaque development. The longer the treatment using LA, the better the miRNA milieu depicting the potential cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background: A statin alone or non-statins as add-ons have been introduced to intensive low-density lipoprotein cholesterol (LDL-C) -lowering therapy in patients at risk for high cardiovascular disease (CVD). The purpose of this study was to evaluate the effectiveness and safety of different rosuvastatin-based regimens for patients at high risk. Methods: Three hundred patients at high CVD risk were randomly assigned to the statin group (rosuvastatin, 20 mg/d), statin_EZ group (statin 10 mg/d + ezetimibe 10 mg/d), statin_pcsk group (statin 10 mg/d + alirocumab 75 mg/2 weeks) or combine3 group (statin 10 mg/d + ezetimibe 10 mg/d + alirocumab 75 mg/2 weeks). The primary outcome measure was cholesterol levels after 24 weeks of follow-up. Secondary outcomes included safety markers and the proportion of patients achieving the 70 mg/dL (1.8 mmol/L) target for LDL-C. A logistic regression model was performed to explore the factors affecting lipid target achievement. Results: The total cholesterol (TC) and LDL-C levels in the four groups after treatment were significantly lower than those before treatment. TC and LDL-C levels after treatment were significantly different among the four groups (p < 0.05). The levels in both the combine3 and statin_pcsk9 groups were significantly lower than those in the statin and statin_EZ groups (p < 0.05), but there was no significant difference between the combine3 and statin_pcsk9 groups. Fifty-one participants (69%) in the statin_pcsk9 group and 56 participants (78%) in the combine3 group achieved the target. Body mass index (BMI) and hypertensive status were related to LDL-C target achievement. The incidence of adverse events in the four groups was low. Conclusions: The combination of a statin and a PCSK9 inhibitor was safe and more effective for the treatment of high-risk CVD patients, while the addition of ezetimibe was unable to significantly lower lipid levels any further. The rate of achieving the target was higher in patients with hypertension and a low BMI. [ABSTRACT FROM AUTHOR]

Background: Some data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels. Methods: The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab. Results: Over median follow-up of 2.8 years (interquartile range 2.3 − 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 − 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 − 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 − 1.94). Conclusion: Treatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts. Trial registration: ClinicalTrials.gov Identifier: NCT01663402. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has been demonstrated to exert a great cardioprotection in cardiometabolic impairments, including atherosclerosis. However, its underlying mechanism remains not fully understood. This study focuses on uncovering the actions of PCSK9 inhibitor on the connection between atherosclerosis and vascular smooth muscle cell (VSMC) behaviors. qRT‐PCR was utilized to detect the expression of SNHG16. Proliferation and migration of VSMC were characterized by Cell Counting Kit‐8 and wound healing assays. The intracellular lipids and foam cell formation were assessed by Oil Red O staining, fluorescence image, and cholesterol quantification kit. Atherosclerosis in vivo was evaluated by imaging the atherosclerotic lesions, hematoxylin‐eosin staining, Oil Red O staining and Masson staining. The interaction between SNHG16 with EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) were investigated by fluorescence in situ hybridization, RNA immunoprecipitation, and chromatin immunoprecipitation assays. A ApoE−/− mice model was used to validate the role of PCSK9 inhibitor and SNHG16 for atherosclerosis. The protective regulation of PCSK9 inhibitor was observed both in high‐fat diet (HFD)‐fed mice and oxidized low‐density lipoprotein (ox‐LDL)‐treated VSMC, as manifested in the decreased the atherosclerotic lesions in vivo, as well as the weakened cell proliferation, migration, and formation of foam cells in vitro. SNHG16 was identified to be a downstream effector of PCSK9 inhibitor‐mediated biological functions, of which knockdown also significantly ox‐LDL‐treated VSMC proliferation, migration, and foam cell formation abilities. SNHG16 epigenetically suppressed TRAF5 via recruiting EZH2. Silencing of TRAF5 abolished the protective effects of SNHG16 knockdown on the pathogenesis of atherosclerosis. Collectively, PCSK9 inhibitor attenuated atherosclerosis by regulating SNHG16/EZH2/TRAF5 axis to impair the proliferation, migration, and foam cell formation of VSMC. [ABSTRACT FROM AUTHOR]

Aim. The analysis of the experience of using PCSK9 inhibitors (alirocumab) in patients with very high cardiovascular risk, аccording to long observations in real clinical practice.Material and methods. In study evaluated the data for 31 people (23 men and 8 women, the average age of those surveyed was 59.4±5.8 years) of very high cardiovascular risk with atherogenic dyslipidemia and no achievement of the target lipid levels. Alirokumab was administered in a dose of 150 mg subcutaneously once every 2 weeks in the day hospital of a multidisciplinary clinic. The primary endpoint was reached the target level of low density lipoprotein cholesterol (HS-LDL) level and/or reduce HS-LDL levels by 50% or more. Liver tests, level of creatinine and glycemia were studied to assess safety; side effects studied/Results. The long-term use of alirocumab (on average 7,5±2,3 months) is well tolerated without adverse reactions and withdrawal syndrome, in the day hospital of a multidisciplinary clinic. 90% of patient have achieved either a target level of HS-LDL less than 1.4 mmol/l or a reduction in HS-LDL by 50% or more. The remaining third of patients achieved both target levels. It can be distinguished a group of patients with a good response to the medication, in the first months of administration of alirokumab.Conclusion. The results of conducting an efficiency assessment for use of the alirocumab in a dose of 150 mg subcutaneously within two weeks showed that this therapy has the high efficacy and good tolerability without any adverse reactions, in the day hospital of a multidisciplinary clinic.

Background: Guidelines advocate for intensive lipid‐lowering in patients with atherosclerotic cardiovascular disease (ASCVD). In May 2020, evolocumab, a proprotein convertase subtilisin‐kexin type 9 (PCSK9) inhibitor, became government subsidised in Australia for patients with ASCVD requiring further low‐density lipoprotein cholesterol (LDL‐C) lowering. Aim: To identify barriers to prescribing PCSK9 inhibitors in hospitalised patients with ASCVD. Methods: A retrospective 3‐month, single‐site, observational analysis was conducted in consecutive patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery. Lipid‐lowering therapy prescriptions, including PSCK9 inhibitors, were assessed using electronic medical records, compared against the Australian Pharmaceutical Benefits eligibility criteria, and barriers to PCSK9 inhibitor use identified. Results: Of 331 patients, 244 (73.7%) underwent PCI and 87 (26.3%) underwent CABG surgery. A lipid profile during or within 8 weeks of admission was measured for 202 (82.8%) patients undergoing PCI and 59 (67.8%) undergoing CABG surgery. In patients taking high‐intensity statins on admission (n = 109), LDL‐C ≥1.4, ≥1.8 and >2.6mmol/L was seen in 64 (58.7%), 44 (40.4%) and 19 (17.4%) patients respectively. High‐intensity statin prescribing at discharge was high (>80%); however, ezetimibe was initiated in zero patients with LDL‐C ≥1.4 mmol/L. There was variable advice given by clinicians for LDL‐C targets. No patients met the criteria for subsidised PSCK9 inhibitor therapy, largely due to lack of qualifying lipid levels following combined statin and ezetimibe therapy. Conclusion: Prescribing of non‐statin LDL‐C‐lowering therapies remains low in patients with ASCVD. Underprescribing of ezetimibe and suboptimal lipid testing rates are barriers to accessing subsidised PCSK9i therapy using current Australian eligibility criteria. [ABSTRACT FROM AUTHOR]

Primarily a consequence of sedentary lifestyle, atherosclerosis has already reached pandemic proportions, and with every year the burden of it is only increasing. As low-density lipoprotein cholesterol (LDL-C) represents a crucial factor in atherosclerosis formation and progression, stringent lipid-lowering therapy could conceivably be the key to preventing the unfavorable outcomes that arise as a consequence of atherosclerosis. The use of statins in lipid-lowering is often burdened by adverse events or is insufficient to prevent cardiovascular events as a monotherapy. Therefore, in the present review, the authors aimed to discuss the underlying mechanisms of dyslipidemia and associated atherosclerotic cardiovascular disease (ASCVD) and preclinical and clinical trials of novel therapeutic approaches to its treatment, some of which are still in the early stages of development. Apart from novel therapies, a novel change in perspective is needed. Specifically, the critical objective in the future management of ASCVD is to embrace emerging evidence in the field of atherosclerosis, because clinicians are often burden by common practice and personal experience, both of which have so far been shown to be futile in the setting of atherosclerosis. [ABSTRACT FROM AUTHOR]

• Lipid-lowering therapy with statins or PCSK9i is associated with IPN regression. • Longer duration of statin therapy is associated with reduced carotid IPN. • No association between change in IPN and change in serum lipids/inflammatory markers. • Therapeutic IPN effects may represent a pathway distinct from serum lipid depletion. Intraplaque neovascularization (IPN), a key feature of vulnerable carotid plaque, is associated with adverse cardiovascular (CV) events. Statin therapy has been shown to diminish and stabilize atherosclerotic plaque, but its effect on IPN is uncertain. This review investigated the effects of common pharmacologic anti-atherosclerotic therapies on carotid IPN. Electronic databases (MEDLINE, EMBASE and Cochrane Library) were searched from inception until July 13, 2022. Studies evaluating the effect of anti-atherosclerotic therapy on carotid IPN among adults with carotid atherosclerosis were included. Sixteen studies were eligible for inclusion. Contrast-enhanced ultrasound (CEUS) was the most common IPN assessment modality (n=8), followed by dynamic contrast-enhanced MRI (DCE-MRI) (n=4), excised plaque histology (n=3) and superb microvascular imaging (n=2). In fifteen studies, statins were the therapy of interest and one study assessed PCSK9 inhibitors. Among CEUS studies, baseline statin use was associated with a lower frequency of carotid IPN (median OR = 0.45). Prospective studies showed regression of IPN after 6-12 months of lipid-lowering therapy, with more regression observed in treated participants compared to untreated controls. Our findings suggest that lipid-lowering therapy with statins or PCSK9 inhibitors is associated with IPN regression. However, there was no correlation between change in IPN parameters and change in serum lipids and inflammatory markers in statin-treated participants, so it is unclear whether these factors are mediators in the observed IPN changes. Lastly, this review was limited by study heterogeneity and small sample sizes, so larger trials are needed to validate findings. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Methods and results In 18 924 patients with recent acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score–matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median of 8.3 months from randomization, after a median of 6.0 months with LDL-C <0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than those of the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C vs. 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047). Conclusion A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with a lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years. Trial registration ClinicalTrials.gov NCT01663402 [ABSTRACT FROM AUTHOR]

Aim: To present a patient with FH (familial hypercholesterolemia) and panhypopituitarism in whom, despite triple hypolipidemic therapy, the target LDL cholesterol was approximately reached only after the introduction of somatotropin replacement therapy, which is not otherwise necessary for adults with panhypopituitarism.Case report: A 54-year-old patient was referred for endocrinological evaluation at the Rijeka Clinical Hospital. In 2005, the patient underwent percutaneous coronary intervention with stent placement in the right coronary artery, endovascular treatment of femoral artery stenosis, he also suffers from arterial hypertension, dyslipidemia, type 2 diabetes and grade 3 obesity (BMI 43.5 kg/m²). In the treatment of erectile dysfunction and polyuria in 2018, panhypopituitarism was established. The patient regularly took the recommended hormone replacement therapy (hydrocortisone, levothyroxine, desmopressin, testosterone undecanoate) in addition to chronic therapy (metformin, fenofibrate, atorvastatin, ezetimibe, clopidogrel, nebivolol, lercanidipine). Despite the maximum dose of high-potency statin and ezetimibe, markedly elevated levels of LDL cholesterol (8.0 mmol/L), total cholesterol (10.5 mmol/L), triglycerides (3.8 mmol/L) and decreased HDL cholesterol (0.6 mmol/L) were found. Given the anamnestic data, laboratory findings and the Duch Lipid Clinical Network scoring system, which was 12, the diagnosis of familial hypercholesterolemia was very likely and, in addition to current hypolipemia therapy, the treatment with PCSK-9 inhibitor was recommended. Three months after the introduction of PCSK9i into therapy, LDL cholesterol (2.3), total cholesterol (4.0) and triglycerides (1.8) were significantly reduced, and HDL values (0.9) increased. Given the presumed beneficial effect of growth hormone replacement therapy, somatotropin was recommended, which the patient took in the course of further treatment, and the LDL value was further reduced at the next follow-up examination (1.6), with a beneficial effect on other lipid parameters. (total cholesterol 3.5, triglycerides 2.5, HDL 0.8, non-HDL 2.7). Conclusion: There are few studies that deal with the relationship between growth hormone replacement therapy and dyslipidemia, and triple hypolipidemic therapy is recommended in the treatment of dyslipidemia. In our patient, who has FH and panhypopituitarism, the use of a combination of statins, ezetimibe, PCSK9i and somatotropin has almost reached the target values of LDL, which may suggest that further research is needed in this area to define therapeutic guidelines. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a genetic disorder that affects about 1 in 250 people and increases the likelihood of having coronary heart disease at a younger age. We present the case of a 55-year-old patient, known with inferior and anterior myocardial infarction treated by percutaneous coronary intervention and coronary artery bypass grafts, Leriche syndrome, aortic abdominal aneurysm, and bilateral renal stents—pathologies with onset at a young age—who was admitted for fast-paced palpitations, accompanied by increased fatigue. The coronarography did not reveal any acute lesions, but the presence of ventricular tachycardia at admission required the implantation of a cardiac defibrillator. Since the patient presented with early onset severe systemic atherosclerosis, with a lipid profile dominated by hypo-HDL, doubled by an apolipoprotein A1 deficiency, we considered the diagnosis of familial hypercholesterolemia. Due to the high-risk profile, the association between a statin and a PCSK9 inhibitor was initiated at discharge. At the 1-month follow-up control, a significant reduction of LDL-C has been achieved, with a simultaneous increase of HDL-C serum levels.

Background and aims: Extremely elevated levels of low-density lipoprotein-cholesterol (LDL-C) contribute to long-term chronic systemic inflammation in homozygous familial hypercholesterolemia (HoFH) patients. The aims of this study is to describe the inflammatory profile of HoFH patients and explore the effect of a PCSK9 inhibitor (PCSK9i) on a series of inflammatory biomarkers, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-HDL ratio (MHR), monocyte-lymphocyte ratio (MLR) and mean platelet volume-lymphocyte ratio (MPVLR). Methods: In this prospective cohort study, 25 definitive HoFH patients on high-intensity statins plus ezetimibe were administered subcutaneous injections of 420 mg PCSK9i every 4 weeks (Q4W). The biochemical parameters and inflammatory profile were analyzed on the day before PCSK9i therapy and 3 months and 6 months after PCSK9i therapy. Results: HoFH on the maximum tolerated statin dose plus ezetimibe displayed elevated lipid and disturbed blood biomarker profiles. After 3 months of add-on PCSK9i therapy, a significant reduction in LDL-C was observed. Moreover, the percentage and count of neutrophils, monocyte counts, MPV, and two inflammatory biomarkers, the NLR and MLR, were reduced. However, at 6 months of PCSK9i treatment, the NLR and MLR returned to pre-PCSK9i treatment levels. Conclusions: PCSK9i induces a transient decrease in the NLR and MLR in HoFH patients in a lipid-lowering independent manner.

Xiaoming Jia,1 Mahmoud Al Rifai,1 Anum Saeed,2 Christie M Ballantyne,1 Salim S Virani1,3 1Department of Medicine, Baylor College of Medicine, Houston, TX, USA; 2Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 3Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USACorrespondence: Salim S Virani, Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX, 77030, USA, Tel +1 713-440-4410, Email virani@bcm.eduAbstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are potent medications in the toolkit for treatment of atherosclerotic cardiovascular disease. These agents have been well studied in clinical trials supporting their efficacy in dramatically reducing low-density lipoprotein cholesterol (LDL-C) and impact on cardiovascular outcomes. Since the approval of commercial use for PCSK9 inhibitors in 2015, we have also gained significant experience in the use of these therapeutics in the real-world setting. In this article, we review current guideline recommendations, clinical trial evidence on efficacy and safety as well as data on cost-effectiveness, prescription and adherence. We focus primarily on the monoclonal antibody class of PCSK9 inhibitors in this review while also touching on other types of therapeutics that are under development.Keywords: PCSK9 inhibitor, CVD prevention, lipids

Introduction:Lipid disorders are one of the most common modifiable risk factors for cardiovascular disease. Until now, the mainstay of dyslipidemia treatment was the use of widely available statins. These drugs, despite significantly lowering cholesterol and bringing its concentration to desired values were associated with a number of side effects. In addition, the need for daily use of statins is inconvenient for patients and leads to their irregular use and, consequently, failure to achieve the desired effect. The new drug, inclisiran, which is a PCSK9 inhibitor, represents the future in the treatment of lipid disorders. Studies conducted to date have explored the drug's mechanism of action, frequency of administration to achieve the desired effect, and side effects. The results of these studies have confirmed the significant efficacy of inclisiran,which may become a major form of treatment for dyslipidemia in the future. Purpose of the work: This article reviews the state of knowledge based on available studies on inclisiran. The aim of the review is to present the most important information about this drug related to the mechanism of action, effects on the body or assessment of efficacy. Materials and methods: The authors, based on databases such as PubMed, Scopus and Google Scholar, created a paper summarizing a review of currently available publications, concerning a new drug in the treatment of dyslipidemia- inclisiran. The authors searched for available information , using terms under the heading "key words" contained in other scientific papers. Summary Inclisiran is a novel drug that represents the future in the treatment of dyslipidemia. Due to the lack of systemic effect, it has insignificant side effects, and the need for such rare administration will allow to obtain the desired lipid concentrations even in patients who do not cooperate.

Introduction: Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke worldwide. Evolocumab, a proprotein convertase subtilisin/kexin type-9 inhibitor (PCSK9i), effectively lowers low-density lipoprotein (LDL) and produces favorable changes in coronary atherosclerosis. This study aimed to determine the effects of PCSK9i on intracranial plaques in moderate-intensity statin-treated individuals with ICAS. Methods: This prospective, observational study monitored the imaging and clinical outcomes of individuals with ICAS who were consecutively treated with moderate-intensity statins with or without PCSK9i. Individuals underwent monthly visits and repeat high-resolution MRI (HR-MRI) at week 12. The primary outcome was a change in HR-MRI after 12 weeks of treatment and the secondary outcome was major vascular events during follow-up. Results: Forty-nine individuals were studied (PCSK9i group: 26 individuals with 28 abnormal vascular regions; statin group: 23 with 27 regions). The PCSK9i group showed a significant reduction in the normalized wall index (0.83 vs. 0.86, p = 0.028) and stenosis degree (65.5 vs. 74.2%, p = 0.01). Similarly, a greater percentage of individuals with a good response to the efficacy of treatment were treated in the PCSK9i group than that in the statin group (75 vs. 44.4%, p = 0.021). The incidence of major vascular events was overall similar between the groups. The treatment options (OR = 8.441, p = 0.01) and prior diabetes (OR = 0.061, p = 0.001) were significantly associated with the efficacy of treatment. Discussion: Statin and PCSK9i combination treatment stabilized intracranial atherosclerotic plaques more often compared to statins alone, as documented by HR-MRI. Further study is warranted to determine if combination treatment improves clinical outcomes in ICAS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]