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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., (© 2024. The Author(s).)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 μM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 μM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg -1 ·d -1 , i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE -/- mice (20, 60 mg·kg -1 ·d -1 , i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg -1 ·d -1 , i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Fatty liver disease (FLD) poses a significant global health concern worldwide, with its classification into nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) contingent upon the presence or absence of chronic and excessive alcohol consumption. The absence of specific therapeutic interventions tailored to FLD at various stages of the disease renders its treatment exceptionally arduous. Despite the fact that FLD and hyperlipidemia are intimately associated, there is still debate over how lipid-lowering medications affect FLD. Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) is a serine protease predominantly synthesized in the liver, which has a crucial impact on cholesterol homeostasis. Research has confirmed that PCSK9 inhibitors have prominent lipid-lowering properties and substantial clinical effectiveness, thereby justifying the need for additional exploration of their potential role in FLD., Purpose: Through a comprehensive literature search, this review is to identify the relationship and related mechanisms between PCSK9, lipid metabolism and FLD. Additionally, it will assess the pharmacological mechanism and applicability of PCSK9 inhibitors (including naturally occurring PCSK9 inhibitors, such as conventional herbal medicines) for the treatment of FLD and serve as a guide for updating the treatment protocol for such conditions., Methods: A comprehensive literature search was conducted using several electronic databases, including Pubmed, Medline, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the database to 30 Jan 2024. Key words used in the literature search were "fatty liver", "hepatic steatosis", "PCSK9", "traditional Chinese medicine", "herb medicine", "botanical medicine", "clinical trial", "vivo", "vitro", linked with AND/OR. Most of the included studies were within five years., Results: PCSK9 participates in the regulation of circulating lipids via both LDLR dependent and independent pathways, and there is a potential association with de novo lipogenesis. Major clinical studies have demonstrated a positive correlation between circulating PCSK9 levels and the severity of NAFLD, with elevated levels of circulating PCSK9 observed in individuals exposed to chronic alcohol. Numerous studies have demonstrated the potential of PCSK9 inhibitors to ameliorate non-alcoholic steatohepatitis (NASH), potentially completely alleviate liver steatosis, and diminish liver impairment. In animal experiments, PCSK9 inhibitors have exhibited efficacy in alleviating alcoholic induced liver lipid accumulation and hepatitis. Traditional Chinese medicine such as berberine, curcumin, resveratrol, piceatannol, sauchinone, lupin, quercetin, salidroside, ginkgolide, tanshinone, lunasin, Capsella bursa-pastoris, gypenosides, and Morus alba leaves are the main natural PCS9 inhibitors. Excitingly, by inhibiting transcription, reducing secretion, direct targeting and other pathways, traditional Chinese medicine exert inhibitory effects on PCSK9, thereby exerting potential FLD therapeutic effects., Conclusion: PCSK9 plays an important role in the development of FLD, and PCSK9 inhibitors have demonstrated beneficial effects on lipid regulation and FLD in both preclinical and clinical studies. In addition, some traditional Chinese medicines have improved the disease progression of FLD by inhibiting PCSK9 and anti-inflammatory and antioxidant effects. Consequently, the inhibition of PCSK9 appears to be a promising therapeutic strategy for FLD., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: END (Early Neurologic Deterioration) significantly elevates the risk of morbidity and mortality. While numerous studies have investigated END following hemorrhagic transformation post-thrombolysis in acute cerebral infarction research on END without hemorrhagic transformations in patients with acute cerebral infarction due to non-cardiogenic embolism remains scarce., Aim: This study aimed to elucidate the impact of PCSK9 inhibitors on early neurological deterioration (END) in patients with acute non-cardioembolism cerebral infarction without hemorrhagic transformation post-intravenous thrombolysis. Additionally it aimed to identify risk factors associated with END in patients suffering from this type of stroke., Objective: The objective of this study is to investigate the effect of PCSK9 inhibitors on early neurologic deterioration (END) in patients with acute non-cardiogenic cerebral infarction without hemorrhagic transformation after intravenous thrombolysis and identify associated risk factors for END in this patient population., Methods: In this retrospective case-control study the data of consecutive patients who underwent intravenous thrombolysis after AIS (acute ischemic stroke) without hemorrhagic transformation during hospitalization at the Stroke Center of The Fifth Affiliated Hospital of Sun Yat-sen University between January 2018 to February 2023 were retrieved and assessed. An increase of >2 in the National Institutes of Health Stroke Scale (NIHSS) within 7 days after admission was defined as END., Results: This study included 250 patients (56 males 22.4%) they were 63.344±12.901 years old. There were 41 patients in the END group and 209 in the non-END group. The usage rate of PCSK9 inhibitors was significantly different between the END group and non-END group (29.268% vs 58.852% P<0.001). The White blood cell count (WBC) and homocysteine levels showed a significant difference between the two groups (all P<0.05). Patients not using PCSK9 inhibitors (OR=0.282 95%CI: 0.127-0.593) and white blood cell count (OR=1.197, 95%CI: 1.085-1.325) were independently associated with END. Receiver-operating characteristic curve analysis suggested that the sensitivity specificity and area under the curve for PCSK9 inhibitors used for END were 88.9%, 80.7% and 0.648 respectively., Conclusion: The use of PCSK9 inhibitors can reduce the incidence of early neurological deterioration in patients with acute non-cardioembolism and non-hemorrhagic transformation after intravenous thrombolysis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Berberine is a natural product with a wide range of pharmacological effects. It has antimicrobial, anti-cancer, anti-inflammatory, anti-hyperlipidemic, neuroprotective, and cholesterollowering properties, among others. It has been used in traditional Chinese and Ayurvedic medicine for 3000 years and is generally well-tolerated with few side effects. Its main drawback is low oral bioavailability, which has hindered widespread clinical use. However, recent interest has surged with the emergence of evidence that berberine is effective in treating cancer, diabetes, Alzheimer's disease, and cardiovascular disease via multiple mechanisms. It enhances insulin sensitivity and secretion by pancreatic β-cells in Type 2 Diabetes Mellitus in addition to reducing pro-inflammatory cytokines such as IL-6, IL-1β, TLR4 and TNF-α. These cytokines are elevated in Alzheimer's disease, cardiovascular disease, and diabetes. Reductions in pro-inflammatory cytokine levels are associated with positive outcomes such as improved cognition, reduced cardiovascular events, and improved glucose metabolism and insulin sensitivity. Berberine is a natural PCSK9 inhibitor, which contributes to its hypolipidemic effects. It also increases low-density lipoprotein receptor expression, reduces intestinal cholesterol absorption, and promotes cholesterol excretion from the liver to the bile. This translates into a notable decrease in LDL cholesterol levels. High LDL cholesterol levels are associated with increased cardiovascular disease risk. Novel synthetic berberine derivatives are currently being developed that optimize LDL reduction, bioavailability, and other pharmacokinetic properties., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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., (© 2023 International Federation for Cell Biology.)

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively decrease low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events in patients at very high cardiovascular risk. Recent short-term studies suggest a partially LDL-C independent beneficial effect of PCSK9 inhibitor (PCSK9i) therapy on endothelial function and arterial stiffness, whereas it is unknown if this effect persists and what the effect is on microcirculation., Objective: To investigate the effects of PCSK9i therapy on vascular parameters beyond its lipid lowering effect., Methods: In this prospective trial, 32 patients at very high cardiovascular risk and indication for PCSK9i therapy were included. Measurements were performed at baseline and after 6 months of PCSK9i treatment. Endothelial function was assessed as flow-mediated dilation (FMD). Arterial stiffness was measured as pulse wave velocity (PWV) and aortic augmentation index (AIx). Peripheral tissue oxygenation (StO 2 ) as a marker of microvascular function was assessed at the distal extremities using near-infrared spectroscopy camera., Results: Six months of PCSK9i therapy decreased LDL-C levels from 141 ± 54 to 60 ± 30 mg/dl (-56 ± 21 %, p < 0.001), FMD significantly increased from 5.4 ± 1.7 % to 6.4 ± 1.9 % (+19 ± 10 %, p < 0.001), PWV decreased in male patients significantly from 8.9 ± 2.1 to 7.9 ± 1.5 m/s (-12 ± 9 %, p = 0.025). AIx decreased from 27.1 ± 10.4 % to 23.0 ± 9.7 % (-16 ± 14 %, p < 0.001), StO 2 significantly increased from 67 ± 12 % to 71 ± 11 % (+7 ± 6 %, p = 0.012). Brachial and aortic blood pressure showed no significant changes after six months. There was no correlation between LDL-C reduction and changes in vascular parameters., Conclusions: Chronic PCSK9i therapy is associated with sustained improvements in endothelial function, arterial stiffness, and microvascular function independent from lipid lowering., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Injectable medicines are increasingly used to manage risk factors for cardiovascular (CV) events, such as dyslipidaemia and diabetes. These include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Little is known about perceptions of injectable therapies among CV healthcare professionals (HCPs). This study explores their views to identify relevant facilitators and barriers to the use of injectables with CV benefit., Methods and Results: A 22-question survey was distributed internationally via online channels. In total, 192 anonymous responses were received (43.7% physicians, 32.6% nurses, 16.8% pharmacists, 6.8% others). Among respondents with experience of these medicines, 69.1% had used an injectable PCSK9 inhibitor and 67.0% had used an injectable GLP-1 receptor agonist. Commonly raised issues were resource problems (36.5%), lack of knowledge among colleagues (32.3%), paperwork (32.3%), and lack of patient knowledge (28.1%). Key barriers respondents felt made patients decline these treatments were fear of injection (56.6%), lack of awareness or education (26.4%), and administration issues (15.1%); potential reasons for discontinuation included side effects (46.4%), perceived lack of benefit (28.6%), and local reactions (21.4%). The main topics around injectables requiring further support included managing non-adherent patients (16.2%), troubleshooting with patients (16.2%), and educating colleagues about injectables (12.2%). Preferred educational methods to support HCPs were face-to-face training (43.5%) and online learning (26.1%); favoured formats were based on role playing and case studies., Conclusion: Healthcare professionals highlighted various potential barriers to initiation, continuation, and adherence with injectable therapies in CV medicine. Although some require healthcare system changes, many could be addressed through simple measures based primarily on enhanced training and support for patients and HCPs., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: There are concerns that Asian patients respond differently to some medications. This study evaluated the efficacy and safety of evolocumab among Asian vs. other subjects in the FOURIER trial, which randomized stable atherosclerosis patients to receive either evolocumab or placebo., Methods and results: Effects of adding evolocumab vs. placebo to background statin therapy on low-density lipoprotein cholesterol (LDL-C) reductions, cardiovascular outcomes, and adverse events were compared among 27,564 participants with atherosclerotic disease, according to self-reported Asian (n=2,723) vs. other (n=24,841) races followed for a median of 2.2 years in the FOURIER trial. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. At randomization, Asians had slightly lower LDL-C (median 89 [IQR 78-104] mg/dL vs. 92 [80-109] mg/dL; P<0.001) and were much less likely to be on a high-intensity statin (33.3% vs. 73.3%; P<0.001). Evolocumab lowered LDL-C more in Asians than in others (66% vs. 58%; P<0.001). The effect of evolocumab on the primary endpoint was similar in Asians (HR, 0.79; 95% CI, 0.61-1.03) and others (HR, 0.86; 95% CI, 0.79-0.93; P interaction=0.55). There was no excess of serious adverse events with evolocumab among Asians over others., Conclusions: Use of evolocumab robustly lowers LDL-C and is equally efficacious in lowering the risk of cardiovascular events and safe in Asians as it is in others.

Background: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk., Objectives: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels., Methods: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL)., Results: In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (P interaction  = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with P interaction  = 0.43., Conclusions: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)., Competing Interests: Funding Support and Author Disclosures ODYSSEY Outcomes (NCT01663402) was funded by Sanofi and Regeneron Pharmaceuticals. Dr Schwartz has received research support to the University of Colorado from AstraZeneca, Resverlogix, Roche, Sanofi, and The Medicines Company; and is a coinventor on pending US patent 62/806,313 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado. Dr Szarek has served as a consultant or on advisory boards (or both) for CiVi, Resverlogix, Baxter, Esperion, Lexicon, Sanofi, and Regeneron Pharmaceuticals. Dr Bittner has received grant support from Sanofi, AstraZeneca, DalCor, Esperion, Bayer, The Medicines Company, and Amgen (all paid direct to her institution); and has received personal fees from Sanofi. Dr Diaz has received research grants from Sanofi, DalCor Pharmaceuticals, the Population Health Research Institute, the Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit; and has received personal fees, as a member of the executive steering committee, from Amgen and Cirius. Dr Goodman has received research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker and consulting honoraria (eg, advisory boards) from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, and Valeo Pharma; and has received salary support and honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, the Canadian Heart Research Centre and MD Primer, the Canadian VIGOUR Centre, the Cleveland Clinic Coordinating Centre for Clinical Research, the Duke Clinical Research Institute, the New York University Clinical Coordinating Centre, and the PERFUSE Research Institute. Dr Jukema has received research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme; and has received research support from Amgen, Astellas, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Dr Landmesser has received research grants from Novartis, Bayer, and Amgen; and has received lecture or advisory honorary fees from Amgen, Sanofi, Novartis, Bayer, Pfizer, and The Medicines Company. Dr López-Jaramillo has received honoraria for lectures from Menarini, Abbott, and Merck. Drs Manvelian and Pordy are employees of Regeneron Pharmaceuticals. Dr Scemama is an employee of Sanofi. Dr Sinnaeve has received institutional grants from the Flemish government, AstraZeneca, and Daiichi Sankyo; is a corecipient of a named chair supported by Bayer; and has received advisory and speaker fees (all institutional) from Sanofi, Amgen, Idorsia, Bristol Myers Squibb/Pfizer, AstraZeneca, and Abbott. Dr White has received grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY Outcomes trial from Sanofi and Regeneron Pharmaceuticals, for the ACCELERATE study from Eli Lilly, for the STRENGTH trial from Omthera Pharmaceuticals, for the SPIRE trial from Pfizer, for the HEART-FID study from American Regent, for the CAMELLIA-TIMI study from Eisai, for the dal-GenE study from DalCor Pharma UK, for the AEGIS-II study from CSL Behring, for the SCORED trial and the SOLOIST-WHF trial from Sanofi Australia, and for the CLEAR Outcomes study from Esperion Therapeutics. Dr White has served on advisory boards for Actelion, Sirtex, and Genentech (an affiliate of F. Hoffmann-La Roche; Lytics Post-PCI Advisory Board at the European Society of Cardiology); and has received lecture fees from AstraZeneca. Dr. Steg has received grants and nonfinancial support (cochair of the ODYSSEY Outcomes trial; as such, he received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (steering committee, MARINER, grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (cochair of the ODYSSEY Outcomes trial; cochair of the SCORED trial; consulting and speaking), Servier (chair of the CLARIFY registry; grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT trial; consulting); and has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Idorsia, Myokardia, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, and AstraZeneca. Dr Steg also has a European application number/patent number, issued on October 26, 2016 (15712241.7), for a method for reducing cardiovascular risk (all royalties assigned to Sanofi)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Although statin therapy is a primary treatment to prevent cardiac allograft vasculopathy (CAV), its use may be delayed due to pharmacologic interactions in the early post-transplant period among heart transplant (HT) recipients with hepatitis C virus positive (HCV+) donors. Further examination of the possible benefits of early, nonstatin lipid-lowering therapies (LLT), such as PCSK9 inhibitors (PCSK9i), among this specific subset of transplant recipients is therefore becoming increasingly important. We report a 60-year-old man who received a HT from a HCV+ donor for end-stage ischemic cardiomyopathy. In the early post-transplant period, there was concern for drug-drug interactions between statin, immunosuppressant, and direct acting antiviral (DAA) therapy. In addition, prior to transplant, he reported statin-associated muscle symptoms in response to multiple statins, which persisted despite attempts to re-challenge and use an every-other-day dosing strategy. Therefore, the patient was started on PCSK9i therapy after transplantation and while receiving curative DAA therapy for HCV. As the number of HT recipients of HCV+ donors continue to rise, investigation into the safety and benefits of early use of PCSK9i for the reduction of CAV and improved cardiovascular and mortality outcomes should be pursued., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021. Published by Elsevier Inc.)

Background: To assess the effects of proprotein convertase subtilisin/kexin type 9 inhibitor (evolocumab) on lipoprotein particles subfractions with Nuclear Magnetic Resonance spectroscopy in patients with acute coronary syndromes., Methods: A total of 99 consecutive patients with ACS were enrolled and assigned to either the experimental group (n = 54) or the control group (n = 45). The combination therapy of PCSK9 inhibitor (Repatha®, 140 mg, q2w) and moderate statin (Rosuvastatin, 10 mg, qn) was administered in the experimental group, with statin monotherapy (Rosuvastatin, 10 mg, qn) in the control group. The therapeutic effects on lipoprotein particle subfractions were assessed with NMR spectroscopy after 8 weeks treatment, and the achievement of LDL-C therapeutic target in both groups were analyzed., Results: In the experimental group, after 8 weeks of evolocumab combination treatment, the concentrations of blood lipids (TC, LDL-C and its subfractions [LDL-1 to 6], VLDL-C and its subfractions [VLDL-1 to 5], IDL-C, and HDL-C), lipoprotein particles, and their subfractions [VLDL-P, IDL-P, LDL-P, and its subfractions [LDL-P1 to 6], apoB, and LP(a)] demonstrated therapeutic benefits with statistical significance (P < 0.05). The decrease in total LDL-P concentrations was mainly due to a decreased concentration of small-sized LDL particles (LDL-P 5 + 6), which was significantly more prominent than the decrease in medium-sized LDL-P (LDL-P3 + 4) and large-sized LDL-P (LDL-P1 + 2) (P < 0.001). According to lipid control target recommended by the latest China Cholesterol Education Program Expert Consensus in 2019, after 8 weeks treatment, 96.3% patients in the experimental group and 13.3% in the control group had achieved the LDL-C therapeutic target (P < 0.01)., Conclusions: Evolocumab combination treatment for 8 weeks significantly improves the plasma lipid profiles in ACS patients, and significantly decrease the concentration of lipoprotein particles which might contribute to the pathonesis of atherosclerosis.

Long-term high-fat diet consumption causes obese-insulin resistance and cardiac mitochondrial dysfunction, leading to impaired left ventricular (LV) function. Atorvastatin effectively improved lipid profiles in obese patients. However, inadequate reduction in low density lipoprotein cholesterol (LDL-C) level was found. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor effectively reduced LDL-C levels. We hypothesized that this PCSK9 inhibitor has a greater efficacy in attenuating cardiometabolic impairments than atorvastatin in obese-insulin resistant rats. Female rats were fed with either a high fat or normal diet for 12 weeks. High fat diet fed rats (HFD) were then divided into 3 groups and were given vehicle, atorvastatin (40 mg/kg/day; s.c.), or PCSK9 inhibitor (4 mg/kg/day; s.c.) for additional 3 weeks. The metabolic parameters, cardiac and mitochondrial function and [Ca 2+ ] i transients were determined. HFD rats developed obese-insulin resistance as indicated by increased plasma insulin and HOMA index. Although high-fat diet fed rats treated with vehicle (HFV) rats had markedly impaired LV function as indicated by reduced %LVFS, impaired cardiac mitochondrial function, and [Ca 2+ ] i transient regulation, these impairments were attenuated in high-fat diet fed rats treated with atorvastatin (HFA) and high-fat diet fed rats treated with PCSK9 inhibitor (HFP) rats. However, these improvements were greater in HFP rats than HFA rats. Our findings indicated that the PCSK9 inhibitor exerted greater cardioprotection than atorvastatin through improved mitochondrial function in obese-insulin resistant rats., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The accumulation of lipid as a result of long-term consumption of a high-fat diet (HFD) may lead to metabolic and brain dysfunction. Atorvastatin, a recommended first-line lipid-lowering agent, has shown beneficial effects on metabolic and brain functions in several models. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effective therapeutic drug for dyslipidemia patients. However, few studies have reported on the effect of this PCSK9 inhibitor on brain function. In addition, the comparative efficacy on the improvement of metabolic and brain functions between PCSK9 inhibitor and atorvastatin in obese models have not been elucidated. We hypothesized that PCSK9 inhibitor improves metabolic and brain functions in an obese model to a greater extent than atorvastatin. Thirty-two female rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline and HFD rats were given either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. Oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity, apoptosis, amyloid proteins production in the hippocampus and cognitive decline were found in HFD-fed rats. Atorvastatin and PCSK9 inhibitor therapies equally attenuated hippocampal apoptosis and amyloid protein production in HFD-fed rats. Interestingly, PCSK9 inhibitor had the greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity in the hippocampus and cognitive decline. These findings suggest that PCSK9 inhibitor may be another drug of choice for improving brain function in the obese condition with discontinued statin therapy., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Post-menopausal women have a higher risk of developing cardiometabolic dysfunction. Atorvastatin attenuates dyslipidaemia and cardiac dysfunction but it can have undesirable effects including increased risk of diabetes and myalgia. Currently, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor efficiently reduces low-density lipoprotein cholesterol (LDL-C) levels more effectively than atorvastatin. We have been suggested that PCSK9 inhibitor attenuated cardiometabolic impairment more effectively than atorvastatin in ovariectomized prediabetic rats. Female Wistar rats (n = 48) were fed a normal diet (ND) or high-fat diet (HFD) for 12 weeks. Then, HFD rats were assigned to a sham-operated (Sham) or ovariectomized (OVX) group. Six weeks after surgery, the OVX group was subdivided into 4 treatment groups: vehicle (HFOV), atorvastatin (HFOA) (40 mg/kg/day; s.c.), PCSK9 inhibitor (HFOP) (4 mg/kg/day; s.c.) and oestrogen (HFOE 2 ) (50 µg/kg/day; s.c.) for an additional 3 weeks. Metabolic parameters, cardiac and mitochondrial function, and [Ca 2+ ] i transients were evaluated. All HFD rats became obese-insulin resistant. HFS rats had significantly impaired left ventricular (LV) function, cardiac mitochondrial function and [Ca 2+ ] i transient dysregulation. Oestrogen deprivation (HFOV) aggravated all of these impairments. Our findings indicated that the atorvastatin, PCSK9 inhibitor and oestrogen shared similar efficacy in the attenuation in cardiometabolic impairment in ovariectomized prediabetic rats., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C)., Objective: This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients., Methods: HeFH patients (n = 42) who were aged 8-17 years, had body weight (BW) ≥25 kg, and had LDL-C ≥130 mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30 mg (<50 kg) or 50 mg (≥50 kg) every 2 weeks (Q2W), #2: 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W, #3: 75 mg (<50 kg) or 150 mg (≥50 kg) every 4 weeks (Q4W), #4: 150 mg (<50 kg) or 300 mg (≥50 kg) Q4W. Primary endpoint was LDL-C % change from baseline to week 8., Results: Mean age was 12.4 years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9 mg/dL and free PCSK9 was 186.4-201.7 ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2 ng/mL and 8.6 ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events., Conclusions: In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Purpose: The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has produced significant reductions in LDL-C at a dose of 300 mg q4w administered as 2 separate 150-mg injections via a 1-mL autoinjector (AI). A recently developed 2-mL device (SYDNEY) permits the administration of a single 300mg dose of alirocumab., Methods: We assessed the usability and product technical complaints (PTCs) reported by patients using the 2-mL SYDNEY device in unsupervised settings, adverse events, and effects on LDL-C, in a multicenter, randomized, open-label, 16-week study conducted in the United States. For their first dose, 69 patients with hypercholesterolemia despite receiving statin with or without other lipid-lowering therapy randomly received supervised, self-administered alirocumab 300 mg via 1 × 300 mg injection with the SYDNEY device (n = 35) or 2 × 150-mg injections with the currently approved AI (n = 34). All continuing patients subsequently received unsupervised, self-administered alirocumab 300 mg q4w using the SYDNEY device at weeks 4, 8, and 12. The primary end point was the proportion of SYDNEY device-associated PTCs related to the use of the unsupervised injections., Findings: Baseline characteristics between the study arms varied only in a higher percentage of males being randomized to the study arm using the SYDNEY device (74.3%) compared with the AI arm (44.1%). A single PTC was reported during the unsupervised injections (0.5%; 1 of 196 injections; 95% CI, 0.0%-3.2%). This event was classified as patient related as opposed to device related. No PTCs occurred during supervised injections. Mean LDL-C reductions from baseline at week 4 were 66.2% with SYDNEY and 51.2% with the AI; after adjustment for sex differences between groups, mean LDL-C reductions were 63.5% and 53.9%, respectively. LDL-C reductions persisted for 16 weeks. The most common adverse event was upper respiratory tract infection (3 with SYDNEY and 0 with the AI during weeks 0-4)., Implications: The SYDNEY device allowed for a single 2-mL injection of alirocumab 300 mg, providing substantial LDL-C reductions with no new product technical issues or no new safety concerns compared with the currently marketed 1-mL AI device. In conclusion, the 2-mL SYDNEY device provides patients with the possibility of injecting the 300-mg alirocumab dose as a single injection. ClinicalTrials.gov identifier: NCT03415178., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Gender disparities in access to healthcare have been documented, including disparities in access to care for cardiovascular diseases (CVDs). Disparities in access to cardiologists could disadvantage some patients to the newer lipid-lowering proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) antibodies, as utilization management criteria for PCSK9is often require step therapy with statins and/or ezetimibe and prescription by a cardiologist. To assess whether these utilization management criteria disproportionally limit access to patients with certain characteristics, we assessed the use of cardiologist care and receipt of statin and/or ezetimibe prescriptions from a cardiologist by gender and other patient demographic and clinical characteristics., Methods: This cross-sectional study used administrative claims data from Inovalon's Medical Outcomes Research for Effectiveness and Economics Registry (MORE 2 Registry ® ) for patients enrolled in commercial and Medicare Advantage healthcare plans from January 1, 2014, through December 31, 2014. Provider data from the registry were linked to individual demographic and administrative claims data. Logistic regression models were used to assess characteristics associated with outpatient visits to a cardiologist and receipt of a prescription for statin and/or ezetimibe from a cardiologist., Results: Data from 39,322 patients in commercial plans and 261,898 patients with Medicare Advantage were analyzed. Female gender (vs male) was associated with a significantly lower likelihood of visiting a cardiologist for patients in commercial plans (odds ratio [OR] 0.85; 95% confidence limit [CL] 0.81-0.88) and in Medicare Advantage plans (OR 0.82; 95% CL 0.81-0.83). Female gender was also associated with a lower likelihood of receiving a statin and/or ezetimibe prescription from a cardiologist for patients in commercial plans (OR 0.69; 95% CL 0.65-0.74) and in Medicare Advantage plans (OR 0.78; 95% CL 0.76-0.79)., Conclusions: Compared with men, women were less likely to visit a cardiologist and less likely to receive a prescription for a statin and/or ezetimibe from a cardiologist., Funding: Amgen Inc.

During acute cardiac ischaemia/reperfusion (I/R), an increased plasma proprotein convertase subtilisin/kexin 9 (PCSK9) level instigates inflammatory and oxidative processes within ventricular myocytes, resulting in cardiac dysfunction. Therefore, PCSK9 inhibitor (PCSK9i) might exert cardioprotection against I/R injury. However, the effects of PCSK9i on the heart during I/R injury have not been investigated. The effects of PCSK9i given at different time-points during I/R injury on left ventricular (LV) function were investigated. Male Wistar rats were subjected to cardiac I/R injury and divided into 3 treatment groups (n = 10/group): pre-ischaemia, during ischaemia and upon onset of reperfusion. The treatment groups received PCSK9i (Pep2-8, 10 μg/kg) intravenously. A control group (n = 10) received saline solution. During the I/R protocol, arrhythmia scores and LV function were determined. Then, the infarct size, mitochondrial function, mitochondrial dynamics and level of apoptosis were determined. PCSK9i given prior to ischaemia exerted cardioprotection through protection of cardiac mitochondrial function, decreased infarct size and improved LV function, compared with control. PCSK9i administered during ischaemia and upon the onset of reperfusion did not provide any of those benefits. PCSK9i administered before ischaemia exerts cardioprotection, as demonstrated by the attenuation of infarct size and cardiac arrhythmia during cardiac I/R injury. The attenuation is associated with improved mitochondrial function and connexin43 phosphorylation, leading to improved LV function., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

PCSK9 inhibitors are potent low-density lipoprotein cholesterol-lowering medications. There is a lack of data regarding safety and efficacy of PCSK9 inhibitors in cardiac transplant patients. In this case series, we provide data supporting the low-density lipoprotein-lowering efficacy and short-term safety of PCSK9 inhibitors in three cardiac transplant patients., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Trials have demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective as an adjunct to statin therapy, but access and cost issues have limited their use in community practice., Objective: The aim of the study was to better understand patients' experiences when trying to obtain, fill, and use PCSK9 inhibitor therapy in community practice., Methods: We conducted a patient survey to evaluate patient experiences with PCSK9 inhibitors including medication initiation, indication for treatment, insurance approval status, medication persistence, and reason for discontinuation. The survey was emailed to 4740 adults who used a patient access support program., Results: Overall, 1327 of 4740 adults completed the survey (28.0% response rate). Of those, 75.0% were aged >60 years, 52.8% were male, and 92.4% were White. At the time of PCSK9 inhibitor prescription, 70.2% were not on a statin (with 84.4% of those not on a statin reporting statin intolerance). Overall, 74.6% of patients found the drug approval process to be "somewhat" or "very" burdensome. Among n = 1216 patients who initiated treatment, 33.7% discontinued by the time of the survey, with 50.0% taking the drug for 1 to 6 months. Patient out-of-pocket costs were the leading reported reason for discontinuation., Conclusions: Most PCSK9 inhibitor users in community practice were not on a statin, presumably because of statin intolerance. The drug approval process and costs continue to be strong reasons for lower initiation of PCSK9 agents, as well as higher discontinuation rates., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to investigate the comparative cardiovascular benefits of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin treatments in secondary prevention patients., Methods and results: We selected 12 randomized controlled trials (n=131,978 patients) using PubMed and Embase (inception-June 1, 2018). Subgroup differences were explored by meta-regression and Cochran Q test. The relative effects of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin on major cardiovascular events (MACE), and revascularization were varied and decreased gradually, of which high-dose statin resulted in lower risk of MACE and revascularization than PCSK9 inhibitor-statin per 1 mmol/L reduction of low-density lipoprotein cholesterol (LDL-C): risk ratio (RR) for MACE, 0.86 (95% confidence interval (CI), 0.81-0.90) for high-dose statin, 0.90 (95% CI, 0.83-0.96) for ezetimibe-statin, and 0.94 (95% CI, 0.92-0.96) for PCSK9 inhibitor-statin; RR for revascularization, 0.84 (95% CI, 0.77-0.90) for high-dose statin, 0.91 (95% CI, 0.81-1.00) for ezetimibe-statin, and 0.94 (95% CI, 0.90-0.97) for PCSK9 inhibitor-statin. Similar relative effects of intensive lipid-lowering treatment were also observed in analyses of myocardial infarction and stroke, although no significant difference between groups was identified., Conclusions: In secondary prevention patients, the relative benefits of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin treatments were varied and decreased gradually, of which high-dose statin was significantly superior to PCSK9 inhibitor-statin for improving MACE and revascularization per 1 mmol/L reduction of LDL-C.

Background: Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9-I) reduce low-density lipoprotein (LDL) cholesterol in human studies. Previous studies suggest that PCSK9-I may also affect very-low-density lipoproteins (VLDL). We therefore studied VLDL size and composition in a "real-world" study population with the use of β-quantification., Subjects and Methods: 350 patients (62 ± 11 years old, 58% men, 22% with diabetes mellitus) with different concomitant lipid lowering therapies, and in whom PCSK9-I treatment was indicated, received either evolocumab (140 mg) or alirocumab (75 or 150 mg). The major lipoprotein fractions were separated by β-quantification and lipid and apolipoprotein compositions were determined before and 4 weeks after initiation of PCSK9-I treatment., Results: After 4 weeks of PCSK9-I treatment, the ratio of triglycerides to apolipoprotein B in VLDL particles (VLDL-TG/apoB ratio) increased by 40% (p < .0001). VLDL-associated apolipoproteins E, CII, and CIII were reduced by 29.4%, 16.4%, and 12.4%, respectively (all p < .0001)., Conclusion: PCSK9-I treatment increased VLDL size (estimated by an increased VLDL-TG/apoB ratio) and reduced VLDL-associated apolipoproteins in a heterogeneous "real-world" study-population, reflecting a higher clearance of small atherogenic VLDL remnant particles by PCSK9-I. This may potentially lower cardiovascular risk in clinical routine patients beyond low-density cholesterol (LDL-C) reduction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Hyperlipidemia is an important risk factor for atherosclerotic cardiovascular disease. Many patients are intolerant to or have limited benefit from statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been approved for treating hyperlipidemia in these patients. We sought to investigate the impact of these medications in a real-world cardiology practice., Methods: This was a retrospective study of 17 patients with either heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) levels above the treatment target despite maximally tolerated statins. Baseline lipid profile was compared with a repeat lipid profile obtained 4 to 6 weeks after initiating treatment with a PCSK9 inhibitor., Results: The average duration of PCSK9 inhibitor treatment was 10.7 months. Lipid profile comparison showed that total cholesterol decreased from 243 ± 72 to 148 ± 39 (mg/dL) (39% reduction), triglycerides decreased from 185 ± 86 to 149 ± 62 (mg/dL) (19.5% reduction), high-density lipoprotein cholesterol increased from 56 ± 20 to 62 ± 26 (mg/dL) (10.7% increase), and LDL-C decreased from 154 ± 30 to 57 ± 32 (mg/dL) (63% reduction) from baseline., Conclusions: PCSK9 inhibitors as add-on therapy to maximally tolerated statins resulted in an approximately 63% reduction in LDL-C.

Statins are generally believed to have cardiovascular protective effects independent of low-density lipoprotein-cholesterol (LDL-C) lowering, such as antithrombotic effects characterized by a decrease in D-dimer levels. For the recently introduced Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors antithrombotic effects are yet unknown. We determined the effect of starting PCSK9 inhibitors on D-dimer and fibrinogen levels as most robust markers for thrombogenicity in statin-intolerant patients with familial hypercholesterolemia. We determined D-dimer and fibrinogen levels before and after start of evolocumab (n = 19) or alirocumab (n = 11). Baseline median D-dimer levels were 0.34 mg/L (IQR 0.24-0.59 mg/L) and baseline median fibrinogen levels 3.2 g/L (IQR 2.88-3.63 g/L). At follow-up D-dimer levels (median 0.31 mg/L (IQR 0.25-0.59 mg/L); p = 0.37), and fibrinogen levels (median 3.4 g/L (IQR 2.98-3.62 g/L); p = 0.38) did not change significantly. We therefore conclude PCSK9 inhibitors do not seem to have a profound antithrombotic effect, although a more subtle effect can not been excluded., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain., Methods: We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRP OT ) and LDL-C OT measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death., Results: At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was -60.5% (95% confidence interval [CI], -61.2 to -59.8; P <0.001; median change, -65.4%) as compared to 6.6% (95% CI, -1.0 to 14.1; P =0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRP OT <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81-1.66), and 1.62 (95% CI, 1.14-2.30) ( P -trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-C OT . Comparable adjusted hazard ratios for LDL-C OT (<30, 30-50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively ( P -trend=0.16). Relative risk reductions with bococizumab were similar across hsCRP OT groups ( P -interaction=0.87)., Conclusions: In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01975376, NCT01975389., (© 2018 American Heart Association, Inc.)

Epidemiology and the results of large-scale outcome trials indicate that the association of LDL with atherosclerotic cardiovascular disease is causal, and continuous not only across levels seen in the general population but also down to sub-physiological values. There is no scientific basis, therefore, to set a target or 'floor' for LDL cholesterol lowering, and this presents a clinical and conceptual dilemma for prescribers, patients, and payers. With the advent of powerful agents such as proprotein convertase/subtilisin kexin type 9 (PCSK9) inhibitors, LDL cholesterol can be lowered profoundly but health economic constraints mandate that this therapeutic approach needs to be selective. Based on the need to maximize the absolute risk reduction when prescribing combination lipid-lowering therapy, it is appropriate to prioritize patients with the highest risk (aggressive and established CVD) who will obtain the highest benefit, that is, those with elevated LDL cholesterol on optimized statin therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) is associated with significant morbidity and mortality worldwide. Increased serum levels of low-density lipoprotein cholesterol (LDL-C) are an independent risk factor for ASCVD, and clinical trial data have shown that lowering LDL-C generally reduces cardiovascular risk. Until recently, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been the main therapy for lowering LDL-C. However, some statin-treated patients have persistently elevated residual cardiovascular risk due to inadequate lowering of LDL-C levels or non-LDL-related dyslipidemia. In addition, adverse effects of statins may limit their tolerability and therefore the ability to attain effective doses in some patients. A new class of drugs that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed to treat hyperlipidemia. This review discusses the history and mechanism of action of PCSK9 inhibitors, their metabolic effects, and clinical outcomes associated with these medications, highlighting recent large cardiovascular outcome trials investigating these therapies.

Background: Efficacy-safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO), have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in 69 patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated LDLC therapy, we assessed efficacy and safety of ALI and EVO., Methods: Post-commercially, we started 29 patients on ALI 75 mg, 18 on ALI 150 mg, and 22 on EVO 140 mg every 2 weeks added to a maximally tolerated LDLC-lowering regimen. Since LDLC lowering did not differ between ALI 150 and EVO 140 mg, ALI 150-EVO 140 data were pooled (ALI-EVO). Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed., Results: Of the 69 patients, 25 had HeFH, 25 CVD, and 19 had both. At entry, 23 (33%) took statins and 46 (67%) were statin-intolerant. Mean ± SD and median follow-up were 49 ± 13 and 49 weeks on ALI 75 mg, and 37 ± 12 and 33 weeks on ALI-EVO. In the ALI-EVO group (n = 40), median LDLC fell from 165 mg/dl at entry to 70 mg/dl (median - 59%, p < .0001). AHA 10-year calculated CVD risk fell from 10.2 to 5.5% (median - 28%, p < .0001), and by the NIH calculator from 14.2 to 3.6% (median - 78%, p < .0001). In the ALI 75 mg group (n = 29), entry LDLC fell from 115 to 68 mg/dl (median - 39%, p < .0001). AHA 10-year calculated CVD risk fell from 11.5 to 7.3% (median - 20%, p = .004), and NIH 10-year risk from 12.9 to 5.1% (median 67%, p < .0001). Absolute and percent change in LDLC was independent of statin use. There were flu-like symptoms in 14% of patients. Adverse events did not differ (p > 0.05) between ALI 75 mg and ALI-EVO., Conclusion: In patients with HeFH and/or CVD, LDLC decreased from 115 to 68 mg/dl (39%) on ALI 75 mg with mean follow-up of 49 weeks, and from 165 to 70 mg/dl (59%) on ALI-EVO over 37 weeks, p < .0001 for both. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering.

After maximizing statin and lifestyle adherence, some patients may benefit from additional low-density lipoprotein cholesterol (LDL-C) lowering. The potential for net benefit from added therapy can inform nonstatin decision-making. Considering patient risk and the LDL-C level on statin, the additional potential cardiovascular disease (CVD) risk reduction benefit from further lowering LDL-C depends on the magnitude of LDL-C lowering from the nonstatin. Ezetimibe is the only nonstatin shown to reduce atherosclerotic CVD events added to a statin, albeit modestly, since it modestly reduces LDL-C by about 20%. Proprotein Convertase Subtilisin-Like/Kexin Type 9 mononclonal antibodies lower LDL-Cby 45-65%, but definitive CVD outcomes and safety trials are pending. Niacin and fenofibrate do not clearly reduce CVD events in statin-treated patients, and may increase adverse events. Bile acid sequestrants have not been evaluated in CVD outcome trials in statin-treated patients, and have an excess of adverse effects. Cost also plays a role in access to nonstatin therapy. These considerations may inform shared decision-making., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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]