Causal association between lipid-lowering drugs and cancers: A drug target Mendelian randomization study.

Accumulating evidences have indicated that lipid-lowering drugs have effect for the treatment of cancers. However, causal associations between lipid-lowering drugs and the risk of cancers are still unclear. In our study, we utilized single nucleotide polymorphisms of proprotein convertase subtilis kexin 9 (PCSK9) inhibitors and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors and performed a drug target Mendelian randomization to explore the causal association between lipid-lowering drugs and the risk of cancers. Five regression methods were carried out, including inverse variance weighted (IVW) method, MR Egger, weighted median, simple mode and weighted mode methods, of which IVW method was considered as the main analysis. Our outcome dataset contained the risk of breast cancer (BC), colorectal cancer, endometrial cancer, gastric cancer (GC), hepatocellular carcinoma (HCC), lung cancer, esophageal cancer, prostate cancer (PC), and skin cancer (SC). Our results demonstrated that PCSK9 inhibitors were significant associated with a decreased effect of GC [IVW: OR = 0.482, 95% CI: 0.264-0.879, P = .017]. Besides, genetic inhibitions of HMGCR were significant correlated with an increased effect of BC [IVW: OR = 1.421, 95% CI: 1.056-1.911, P = .020], PC [IVW: OR = 1.617, 95% CI: 1.234-2.120, P = .0005] and SC [IVW: OR = 1.266, 95% CI: 1.022-1.569, P = .031]. For GC [IVW: OR = 0.559, 95% CI: 0.382-0.820, P = .0029] and HCC [IVW: OR = 0.241, 95% CI: 0.085-0.686, P = .0077], HMGCR inhibitors had a protective risk. Our method suggested that PCSK9 inhibitors were significant associated with a protective effect of GC. Genetic inhibitions of HMGCR were significant correlated with an increased effect of BC, PC and SC. Meanwhile, HMGCR inhibitors had a protective risk of GC and HCC. Subsequent studies still needed to assess potential effects between lipid-lowering drugs and the risk of cancers with clinical trials.

Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects.

BACKGROUND: Mechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 inhibitors can modulate inflammation. METHODS: Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level >70 mg/dL on maximum tolerated statin therapy received subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were change in circulating immune cell transcriptional response, lipoproteins and blood viscosity at 2 weeks and 12 weeks. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. RESULTS: All 41 randomized subjects completed the 2-week visit. Six subjects did not receive study medication consistently after the 2-week visit due to COVID-19 pandemic suspension of research activities. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by -68.8% (p < 0.0001) and -52.8% (p < 0.0001) at 2 and 12 weeks, respectively. There were no differences in blood viscosity at baseline nor at 2 and 12 weeks. RNA-seq was performed on peripheral blood mononuclear cells with and without TLR4 stimulation ("Stress" transcriptomics). "Stress" transcriptomics unmasked immune cell phenotypic differences between evolocumab and placebo groups at 2 and 12 weeks. CONCLUSIONS: This trial is the first to demonstrate that PCSK9 mAB with evolocumab can modulate circulating immune cell properties and highlights the importance of "stress" profiling of circulating immune cells that more clearly define immune contributions to ASCVD.

Leveraging Bidirectional Nature of Allostery To Inhibit Protein-Protein Interactions (PPIs): A Case Study of PCSK9-LDLR Interaction.

The protein PCSK9 (proprotein convertase subtilisin/Kexin type 9) negatively regulates the recycling of LDLR (low-density lipoprotein receptor), leading to an elevated plasma level of LDL. Inhibition of PCSK9-LDLR interaction has emerged as a promising therapeutic strategy to manage hypercholesterolemia. However, the large interaction surface area between PCSK9 and LDLR makes it challenging to identify a small molecule competitive inhibitor. An alternative strategy would be to identify distal cryptic sites as targets for allosteric inhibitors that can remotely modulate PCSK9-LDLR interaction. Using several microseconds long molecular dynamics (MD) simulations, we demonstrate that on binding with LDLR, there is a significant conformational change (population shift) in a distal loop (residues 211-222) region of PCSK9. Consistent with the bidirectional nature of allostery, we establish a clear correlation between the loop conformation and the binding affinity with LDLR. Using a thermodynamic argument, we establish that the loop conformations predominantly present in the apo state of PCSK9 would have lower LDLR binding affinity, and they would be potential targets for designing allosteric inhibitors. We elucidate the molecular origin of the allosteric coupling between this loop and the LDLR binding interface in terms of the population shift in a set of salt bridges and hydrogen bonds. Overall, our work provides a general strategy toward identifying allosteric hotspots: compare the conformational ensemble of the receptor between the apo and bound states of the protein and identify distal conformational changes, if any. The inhibitors should be designed to bind and stabilize the apo-specific conformations.

Estimating the effect of lipid-lowering agents on novel subtypes of adult-onset diabetes.

AIMS: The aims of the present study were to assess the effects of lipid-lowering drugs [HMG-CoA reductase inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors] on novel subtypes of adult-onset diabetes through a Mendelian randomisation study. MATERIALS AND METHODS: We first inferred causal associations between lipid-related traits [including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoproteins A-I, and apolipoproteins B] and novel subtypes of adult-onset diabetes. The expression quantitative trait loci of drug target genes for three classes of lipid-lowering drugs, as well as genetic variants within or nearby drug target genes associated with LDL-C, were then utilised as proxies for the exposure of lipid-lowering drugs. Mendelian randomisation analysis was performed using summary data from genome-wide association studies of LDL-C, severe autoimmune diabetes, severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes. RESULTS: There was an association between HMGCR-mediated LDL-C and the risk of SIRD [odds ratio (OR) = 0.305, 95% confidence interval (CI) = 0.129-0.723; p = 0.007], and there was an association of PCSK9-mediated LDL-C with the risk of SIDD (OR = 0.253, 95% CI = 0.120-0.532; p < 0.001) and MOD (OR = 0.345, 95% CI = 0.171-0.696; p = 0.003). Moreover, NPC1L1-mediated LDL-C (OR = 0.109, 95% CI = 0.019-0.613; p = 0.012) and the increased expression of NPC1L1 gene in blood (OR = 0.727, 95% CI = 0.541-0.977; p = 0.034) both showed a significant association with SIRD. These results were further confirmed by sensitivity analyses. CONCLUSIONS: In summary, the different lipid-lowering medications have a specific effect on the increased risk of different novel subtypes of adult-onset diabetes.

Association between Lipid-Lowering Drugs and Traumatic Subdural Hemorrhage: A Mendelian Randomization Study.

BACKGROUND: There are current clinical observations that atorvastatin may promote subdural hematoma resorption. We aimed to assess the causal effects of lipid-lowering agents 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, Proproteinconvertase subtilisin/kexin type 9 (PCSK9) inhibitors and Niemann-Pick C1-like protein 1 (NPC1L1) inhibitors on traumatic subdural hematomas. METHODS: We used genetic instruments to proxy lipid-lowering drug exposure, with genetic instruments being genetic variants within or near low-density lipoprotein (LDL cholesterol)-associated drug target genes. These were analyzed by using a two-sample Mendelian randomization (MR) study. RESULTS: A causal relationship was found between HMGCR inhibitors and traumatic subdural hematoma (Inverse variance weighted (ß = -0.7593341 (Odds Ratio (OR) = 0.4679779), p = 0.008366947 < 0.05)). However, no causal relationship was found between PCSK9 inhibitors and NPC1L1 inhibitors and traumatic subdural hematoma (PCSK9 inhibitors: Inverse variance weighted (ß = 0.23897796 (OR = 1.2699505), p = 0.1126327), NPC1L1 inhibitors: Inverse variance weighted (ß = -0.02118558 (OR = 0.9790373), p = 0.9701686)). Sensitivity analysis of the data revealed good stability of the results. CONCLUSIONS: This two-sample MR study suggests a potential causal relationship between HMGCR inhibition (atorvastatin) and traumatic subdural hemorrhage.

Effects of alirocumab on endothelial function and coronary atherosclerosis in myocardial infarction: A PACMAN-AMI randomized clinical trial substudy.

BACKGROUND AND AIMS: The effects of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on endothelial function as assessed by flow-mediated dilation (FMD) in patients with acute myocardial infarction (AMI) are unknown. Therefore, we aimed to investigate the effects of the PCSK9 inhibitor alirocumab added to high-intensity statin on FMD, and its association with coronary atherosclerosis in non-infarct related arteries using intracoronary intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT). METHODS: This was a pre-specified substudy among patients recruited at Bern University Hospital, Switzerland, for the randomized-controlled, double-blind, PACMAN-AMI trial, which compared the effects of biweekly alirocumab 150 mg vs. placebo added to rosuvastatin. Brachial artery FMD was measured at 4 and 52 weeks, and intracoronary imaging at baseline and 52 weeks. RESULTS: 139/173 patients completed the substudy. There was no difference in FMD at 52 weeks in the alirocumab (n = 68, 5.44 ± 2.24%) versus placebo (n = 71, 5.45 ± 2.19%) group (difference = -0.21%, 95% CI -0.77 to 0.35, p = 0.47). FMD improved throughout 52 weeks in both groups similarly (p < 0.001). There was a significant association between 4 weeks FMD and baseline plaque burden (IVUS) (n = 139, slope = -1.00, p = 0.006), but not with lipid pool (NIRS) (n = 139, slope = -7.36, p = 0.32), or fibrous cap thickness (OCT) (n = 81, slope = -1.57, p = 0.62). CONCLUSIONS: Among patients with AMI, the addition of alirocumab did not result in further improvement of FMD as compared to 52 weeks secondary preventative medical therapy including high-intensity statin therapy. FMD was significantly associated with coronary plaque burden at baseline, but not with lipid pool or fibrous cap thickness.

Oral PCSK9 Inhibitors.

PURPOSE OF REVIEW: In this review, we will discuss the data from early clinical studies of MK-0616 and summarize clinical trials of other oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. RECENT FINDINGS: The success of PCSK9 inhibition with monoclonal antibody injections has fueled the development of additional therapies targeting PCSK9, including oral formulations, the most advanced of which is MK-0616. MK-0616 is a novel, orally administered macrocyclic peptide that binds to PCSK9 and inhibits binding of PCSK9 to the LDL receptor, thereby decreasing plasma levels of LDL-C. Clinical trial data on the safety and efficacy of MK-0616 are promising and report LDL-C-lowering efficacy comparable to that provided by injectable PCSK9 inhibitors. Ongoing and future studies of oral PCSK9 inhibitors in development will evaluate the safety, efficacy, and effectiveness of these agents and their potential role in preventing cardiovascular disease events.

Current and emerging monoclonal antibodies for treating familial hypercholesterolemia in children.

INTRODUCTION: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder caused by pathogenic variants in the LDL-C metabolism. Lifelong exposure to elevated LDL-C levels leads to a high risk of premature cardiovascular disease. To reduce that risk, children with HeFH should be identified and treated with lipid-lowering therapy. The cornerstone consists of statins and ezetimibe, but not in all patients this lowers the LDL-C levels to treatment targets. For these patients, more intensive lipid-lowering therapy is needed. AREAS COVERED: In this review, we provide an overview of the monoclonal antibodies which are currently available or being tested for treating HeFH in childhood. EXPERT OPINION: Monoclonal antibodies that inhibit PCSK9 are first in line lipid-lowering treatment options if oral statin and ezetimibe therapy are insufficient, due to intolerance or very high baseline LDL-C levels. Both evolocumab and alirocumab have been shown to be safe and effective in children with HeFH. For children, evolocumab has been registered from the age of 10 years old and alirocumab from the age of 8 years old. The costs of these new agents are much higher than oral therapy, which makes it important to only use them in a selected patient population.

Causal relationship between PCSK9 inhibitor and primary glomerular disease: a drug target Mendelian randomization study.

Background: Successive observational studies have highlighted low-density lipoprotein cholesterol (LDL-C) as a standalone risk factor for the progression of chronic kidney disease (CKD) to end-stage renal disease. Lowering LDL-C levels significantly reduces the incidence of atherosclerotic events in patients with progressive CKD. Recent research indicates that proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors not only effectively lower LDL-C levels in CKD patients but also exhibit therapeutic potential for autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis. However, the role of PCSK9 inhibitors (PCSK9i) in treating CKD beyond lowering LDL-C levels remains uncertain. Therefore, this study employs drug-targeted Mendelian randomization (MR) to investigate the causal impact of PCSK9i on primary glomerular diseases such as IgA nephropathy (IgAN), membranous nephropathy (MN), and nephrotic syndrome (NS). Methods: Single-nucleotide polymorphisms (SNPs) linked to LDL-C were sourced from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Genes situated in proximity to 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and PCSK9 served as proxies for therapeutic inhibition of these targets. The causal link between PCSK9i and the risk of primary glomerular disorders was discovered using drug-target MR studies. The HMGCR inhibitor, a drug target of statins, was utilized for comparative analysis with PCSK9i. Primary outcomes included the risk assessment for IgAN, MN, and NS, using the risk of coronary heart disease as a positive control. Results: The inhibition of PCSK9, as proxied genetically, was found to significantly reduce the risk of IgAN [odds ratio, OR (95% confidence interval, CI) = 0.05 (-1.82 to 1.93), p = 2.10 × 10-3]. Conversely, this inhibition was associated with an increased risk of NS [OR (95% CI) = 1.78 (1.34-2.22), p = 0.01]. Similarly, HMGCR inhibitors (HMGCRi) demonstrated a potential reduction in the risk of IgAN [OR (95%CI) = 0.0032 (-3.58 to 3.59), p = 1.60 × 10-3). Conclusions: PCSK9i markedly decreased the risk of IgAN, suggesting a potential mechanism beyond their primary effect on LDL-C. However, these inhibitors were also associated with an increased risk of NS. On the other hand, HMGCRi appears to serve as a protective factor against IgAN. Conversely, PCSK9i may pose a risk factor for NS, suggesting the necessity for cautious application and further research into their impacts on various glomerular diseases.

The impact of the 2019 ESC/EAS dyslipidaemia guidelines on real-world initial lipid-lowering therapy in patients with acute myocardial infarction.

This study aimed to investigate the impact of the latest guidelines on the real-world clinical practice of initial lipid-lowering therapy, especially on the use of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in China. All adult patients diagnosed with acute myocardial infarction in our hospital between August 31, 2018, and August 31, 2020, were divided into the following 2 groups: those patients treated before the latest guideline release, and those patients treated after the release. A propensity score-matched method was used, and logistic regression was used to assess the association with intensive statin, ezetimibe and PCSK9 inhibitor usage together with treatment results between the 2 groups. A total of 325 patients were enrolled in this study, including 141 patients who were admitted before the release of the latest guideline and 184 patients who were admitted after the release. After a median follow-up time of 8.20 months, the mean low-density lipoprotein cholesterol was 1.87 ±â€…0.59 mmol/L (1.87 ±â€…0.55 in the before group vs 1.88 ±â€…0.62 in the after group, P = .829). After propensity score matching, the initial usage of intensive statin therapy was decreased after guideline release without statistical significance (17.00% vs 28.00%, P = .090), whereas the usage of ezetimibe and PCSK9 inhibitors was increased (19.00% vs 8.00%, P = .039; and 10.00% vs 3.00%, P = .085, respectively). In logistic regression models, the release of the guideline was associated with a statistically significantly increased use of ezetimibe (odds ratio [OR]: 1.91; 95% confidence interval [CI]: 1.21, 3.02; P = .005), a marginally decreased use of intensive statins (OR: 0.68; 95% CI: 0.45, 1.03; P = .069) and a marginally increased use of PCSK9 inhibitors (OR: 1.31; 95% CI: 0.98, 1.76; P = .068). In this single-center, real-world data analysis, after the release of the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines, an increasing number of patients with a recent acute myocardial infarction were initially receiving ezetimibe and PCSK9 inhibitors.

Harnessing RNA Interference for Cholesterol Lowering: The Bench-to-Bedside Story of Inclisiran.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021, <20 years after the discovery of PCSK9, inclisiran became the first RNA interference therapeutic approved in the United States for LDL-C lowering in patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and has since been approved for use in patients with primary hyperlipidemia. This article reviews the journey of inclisiran from bench to bedside, including early development, the clinical trial program, key characteristics of inclisiran, and practical points for its use in the clinic.

Potential use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and prevention method in viral infection.

Cellular lipid membranes serve as the primary barrier preventing viral infection of the host cell and provide viruses with a critical initial point of contact. Occasionally, viruses can utilize lipids as viral receptors. Viruses depend significantly on lipid rafts for infection at virtually every stage of their life cycle. The pivotal role that proprotein convertase subtilisin/kexin Type 9 (PCSK9) plays in cholesterol homeostasis and atherosclerosis, primarily by post-transcriptionally regulating hepatic low-density lipoprotein receptor (LDLR) and promoting its lysosomal degradation, has garnered increasing interest. Conversely, using therapeutic, fully humanized antibodies to block PCSK9 leads to a significant reduction in high LDL cholesterol (LDL-C) levels. The Food and Drug Administration (FDA) has approved PCSK9 inhibitors, including inclisiran (Leqvio®), alirocumab (Praluent), and evolocumab (Repatha). At present, active immunization strategies targeting PCSK9 present a compelling substitute for passive immunization through the administration of antibodies. In addition to the current inquiry into the potential therapeutic application of PCSK9 inhibition in human immunodeficiency virus (HIV)-infected patients for hyperlipidemia associated with HIV and antiretroviral therapy (ART), preclinical research suggests that PCSK9 may also play a role in inhibiting hepatitis C virus (HCV) replication. Furthermore, PCSK9 inhibition has been suggested to protect against dengue virus (DENV) potentially and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses. Recent evidence regarding the impact of PCSK9 on a variety of viral infections, including HCV, HIV, DENV, and SARS-CoV-2, is examined in this article. As a result, PCSK9 inhibitors and vaccines may serve as viable host therapies for viral infections, as our research indicates that PCSK9 is significantly involved in the pathogenesis of viral infections.

In-hospital initiation of a PCSK9 inhibitor in patients with acute coronary syndrome: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to be effective and safe in patients with stable angina and previous myocardial infarction. However, evidence for initiating their use in patients hospitalized with acute coronary syndrome (ACS) is limited. This systematic review and meta-analysis was performed to provide more clinical evidence. METHODS: PubMed, Embase, OVID, Cochrane Library and ClinicalTrials.gov were systematically searched for eligible randomized controlled trials up to March 20, 2023. The risk ratios, standardized mean differences and 95% confidence intervals were calculated for primary and secondary outcomes. The bias risk of the included studies was assessed using the Cochrane RoB 2 criteria. RESULTS: About 8 randomized controlled trials involving 1255 inpatients with ACS were included. PCSK9 inhibitor treatment significantly reduced low-density lipoprotein cholesterol (LDL-C) (SMD -1.28, 95% CI -1.76 to -0.8, P = .001), triglycerides (TG) (SMD -0.93, 95% CI -1.82 to -0.05, P = .03), total cholesterol (SMD -1.36, 95% CI -2.01 to -0.71, P = .001), and apolipoprotein B (Apo B) (SMD -0.81, 95% CI -1.09 to -0.52, P = .001) within approximately 1 month. PCSK9 inhibitor treatment significantly reduced the total atheroma volume (TAV) (SMD -0.33, 95% CI -0.59 to -0.07, P = .012). It also significantly increased minimum fibrous cap thickness (FCT) (SMD 0.41, 95% CI 0.22-0.59, P = .001) in long-term follow-up (>6 months). PCSK9 inhibitor treatment significantly reduced the risk of readmission for unstable angina (RR 0.32, 95% CI 0.12-0.91, P = .032) in short-term follow-up (<6 months). There were no significant differences in all-cause mortality, cardiovascular death, myocardial infarction, ischemic stroke, coronary revascularization or heart failure. Only nasopharyngitis (RR 1.71, 95% CI 1.01-2.91, P = .047) adverse events were significantly observed in the PCSK9 inhibitor group. CONCLUSION: Application of a PCSK9 inhibitor in hospitalized patients with ACS reduced lipid profiles and plaque burdens and was well tolerated with few adverse events.

Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

BACKGROUND: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. METHODS: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. RESULTS: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. CONCLUSIONS: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

A promising therapy for fatty liver disease: PCSK9 inhibitors.

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.

An update on inclisiran for the treatment of elevated LDL cholesterol.

INTRODUCTION: The burden of atherosclerotic cardiovascular disease (ASCVD) persists globally, demanding innovative therapeutic strategies. This manuscript provides an expert opinion on the significance of managing low-density lipoprotein cholesterol in ASCVD prevention and introduces inclisiran, a novel small interfering RNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). AREAS COVERED: This work delves into the intricate mechanism of inclisiran, highlighting its unique approach of hepatic intracellular PCSK9 inhibition, its precision and low off-target effects risk. Pharmacodynamic and pharmacokinetic distinctions from PCSK9 monoclonal antibodies are explored, underlining inclisiran's efficiency, extended duration, and clearance. Clinical trials, including pivotal phase-III placebo-controlled studies (ORION-9, -10, -11), the open-label ORION-3 and pooled safety analysis of these trails including the open-label phase of ORION-8, as well as real-word data are discussed to provide a comprehensive evaluation of inclisiran's efficacy and safety. EXPERT OPINION: Inclisiran stands as a first-in-class breakthrough in lipid-lowering therapies, showing potential in alleviating the global burden of ASCVD and is supported by multiple global regulatory approvals. To optimize inclisiran's utilization and comprehend its long-term effects, future directions include pediatric studies, cardiovascular outcome trials, and extended-duration investigations. Overall, inclisiran emerges as a precise and effective therapeutic option, offering significant promise for preserving cardiovascular health.

A retrospective nationwide analysis of evolocumab use in Sweden and its effect on low-density lipoprotein cholesterol levels.

Background: Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduces low-density lipoprotein cholesterol (LDL-C) levels and decreases the incidence of major ischaemic events in clinical trials. However, less is known about the efficacy of PCSK9 inhibition in clinical practice. This study aimed to describe the change in LDL-C levels over time and LDL-C goal achievement in patients with/without atherosclerotic cardiovascular disease (ASCVD), who were prescribed evolocumab in clinical practice, and to describe adherence to and persistence with treatment. Methods: Patients in Sweden with at least one evolocumab prescription filled between July 2015 and May 2020 were included. Medical history and lipid-lowering therapy (LLT) were sourced from national registries. LDL-C levels before and after treatment initiation were assessed using medical records. Persistence with and adherence to evolocumab and oral LLT were assessed up to 12 months after treatment initiation using the refill-gap method and proportion of days covered, respectively. Results: Of the 2,360 patients with at least one prescription for evolocumab, 2,341 were included; 1,858 had ASCVD. Persistence with (76%) and adherence to (86%) evolocumab were high throughout the 12 months following initiation. Mean LDL-C levels decreased by 53% (95% confidence interval [CI]: 51-55%) in patients adherent to evolocumab (n = 567) and 59% (95% CI: 55-63%) in patients adherent to evolocumab and oral LLT (n = 186). Similar reductions in LDL-C were observed in patients with/without ASCVD. Reduced LDL-C levels remained stable during follow-up. Amongst patients adherent to evolocumab and those adherent to evolocumab and oral LLT, 23 and 55% achieved the LDL-C goal of <1.4 mmol/L, respectively. Conclusions: The evolocumab LDL-C-lowering effect observed in clinical trials was confirmed in clinical practice in Sweden, particularly in patients also treated with oral LLT. During follow-up, adherence to and persistence with evolocumab were high, with stable reduced levels of LDL-C during observation.