Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 1.235
Filter
1.
Brain Behav ; 14(6): e3543, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38837845

ABSTRACT

BACKGROUND: In addition to lowering cholesterol levels, the proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has a variety of effects, including anti-neuroapoptosis. However, the effects of PCSK9 inhibitors on neurodegenerative diseases are controversial. Therefore, we used drug-targeted Mendelian randomization (MR) analysis to investigate the effects of PCSK9 inhibitors on different neurodegenerative diseases. METHODS: We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published statistics of genome-wide association studies and performed drug target MR analyses to detect a causal relationship between PCSK9 inhibitors and the risk of neurodegenerative diseases. We utilized the effects of 3-Hydroxy -3- methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors (statin targets) for comparison with PCSK9 inhibitors. Coronary heart disease risk was used as a positive control, and primary outcomes included amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). RESULTS: PCSK9 inhibitors marginally reduced the risk of ALS (OR [95%] = 0.89 [0.77 to 1.00], p = 0.048), while they increased the risk of PD (OR [95%] = 1.417 [1.178 to 1.657], p = 0.004). However, HMGCR inhibitors increased the risk of PD (OR [95%] = 1.907 [1.502 to 2.312], p = 0.001). CONCLUSION: PCSK9 inhibitors significantly reduce the risk of ALS but increase the risk of PD. HMGCR inhibitors may be the risk factor for PD.


Subject(s)
Mendelian Randomization Analysis , Neurodegenerative Diseases , PCSK9 Inhibitors , Polymorphism, Single Nucleotide , Humans , Neurodegenerative Diseases/genetics , Parkinson Disease/genetics , Parkinson Disease/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Alzheimer Disease/genetics , Alzheimer Disease/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/epidemiology , Genome-Wide Association Study , Proprotein Convertase 9
2.
Int J Equity Health ; 23(1): 116, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38840134

ABSTRACT

BACKGROUND: PCSK9 inhibitors are a novel class of lipid-lowering drugs that have demonstrated favorable efficacy and safety. Evolocumab and alirocumab have been added to China's National Reimbursement Drug List through the National Drug Price Negotiation (NDPN) policy. This study aims to evaluate the impact of the NDPN policy on the utilization and accessibility of these two PCSK9 inhibitors. METHODS: The procurement data of evolocumab and alirocumab were collected from 1,519 hospitals between January 2021 and December 2022. We determined the monthly availability, utilization, cost per daily defined dose (DDDc), and affordability of the two medicines. Single-group interrupted time series (ITS) analysis was performed to assess the impact of the NDPN policy on each drug, and multiple-group ITS analysis was performed to compare the differences between them. RESULTS: The NDPN policy led to a significant and sudden increase in the availability and utilization of PCSK9 inhibitors, along with a decrease in their DDDc. In the year following the policy implementation, there was an increase in the availability, utilization, and spending, and the DDDc remained stable. The affordability of PCSK9 inhibitors in China have been significantly improved, with a 92.97% reduction in out-of-pocket costs. The availability of both PCSK9 inhibitors was similar, and the DDDc of alirocumab was only $0.23 higher after the intervention. The market share of evolocumab consistently exceeded that of alirocumab. Regional disparities in utilization were observed, with higher utilization in the eastern region and a correlation with per capita disposable income. CONCLUSIONS: The NDPN policy has successfully improved the accessibility and utilization of PCSK9 inhibitors in China. However, regional disparities in utilization indicate the need for further interventions to ensure equitable medicine access.


Subject(s)
Antibodies, Monoclonal, Humanized , Drug Costs , Interrupted Time Series Analysis , PCSK9 Inhibitors , Humans , China , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/economics , Health Services Accessibility/statistics & numerical data , Anticholesteremic Agents/therapeutic use , Anticholesteremic Agents/economics , Health Policy
3.
Medicine (Baltimore) ; 103(18): e38010, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38701318

ABSTRACT

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.


Subject(s)
Hydroxymethylglutaryl CoA Reductases , Mendelian Randomization Analysis , Neoplasms , Polymorphism, Single Nucleotide , Proprotein Convertase 9 , Humans , Neoplasms/genetics , Neoplasms/epidemiology , Hydroxymethylglutaryl CoA Reductases/genetics , Female , PCSK9 Inhibitors , Hypolipidemic Agents/therapeutic use , Male , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
5.
Respir Res ; 25(1): 213, 2024 May 18.
Article in English | MEDLINE | ID: mdl-38762465

ABSTRACT

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.


Subject(s)
Diet, High-Fat , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Mice, Inbred C57BL , Mice, Transgenic , Obesity , Pulmonary Fibrosis , Animals , Male , Diet, High-Fat/adverse effects , Obesity/drug therapy , Obesity/metabolism , Mice , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Pulmonary Fibrosis/prevention & control , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/drug therapy , PCSK9 Inhibitors , Atorvastatin/pharmacology , Atorvastatin/therapeutic use , Mice, Obese , Proprotein Convertase 9/metabolism , Proprotein Convertase 9/genetics , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Bronchial Hyperreactivity/prevention & control , Bronchial Hyperreactivity/drug therapy , Bronchial Hyperreactivity/metabolism , Bronchial Hyperreactivity/physiopathology , Antibodies, Monoclonal, Humanized
6.
Adv Ther ; 41(6): 2399-2413, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38691317

ABSTRACT

INTRODUCTION: The cardiovascular disease risk reduction benefits of proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibodies (PCSK9i mAb) and ezetimibe are dependent on remaining on treatment and being persistent and adherent. We estimated the percentage of patients on therapy, persistent and adherent at 182 and 365 days among US adults with health insurance who initiated a PCSK9i mAb (n = 16,588) or ezetimibe (n = 83,086) between July 2015 and December 2019. METHODS: Using pharmacy fill claims, being on therapy was defined as having a day of medication supply in the last 60 of 182 and 365 days following treatment initiation, being persistent was defined as not having a gap of 60 days or more between the last day of supply from one prescription fill and the next fill, and being adherent was defined by having medication available to take on ≥ 80% of the 182 and 365 days following treatment initiation. We estimated multivariable-adjusted risk ratios for being persistent and adherent comparing patients initiating PCSK9i mAb versus ezetimibe using Poisson regression. RESULTS: At 182 days following initiation, 80% and 68% were on therapy and 76% and 64% were persistent among patients who initiated a PCSK9i mAb and ezetimibe, respectively. Among patients who were on therapy and persistent at 182 days following initiation, 88% and 81% of those who initiated a PCSK9i mAb and ezetimibe, respectively, were on therapy at 365 days. Among those on therapy and persistent at 182 days following initiation, being persistent and being adherent at 365 days were each more common among PCSK9i mAb versus ezetimibe initiators (persistent: 82% versus 76%, multivariable-adjusted risk ratio 1.07; 95% confidence interval [CI] 1.06-1.08; adherent: 74% versus 71%, multivariable-adjusted risk ratio 1.02; 95% CI 1.01-1.03). CONCLUSIONS: These data suggest approaches to increase persistence and adherence to PCSK9i mAb and ezetimibe should be implemented prior to or within 182 days following treatment initiation.


Subject(s)
Anticholesteremic Agents , Ezetimibe , Medication Adherence , PCSK9 Inhibitors , Ezetimibe/therapeutic use , Humans , Male , Middle Aged , Female , Anticholesteremic Agents/therapeutic use , Medication Adherence/statistics & numerical data , Aged , Adult , Antibodies, Monoclonal/therapeutic use , United States , Hypercholesterolemia/drug therapy , Proprotein Convertase 9
7.
Lipids Health Dis ; 23(1): 156, 2024 May 25.
Article in English | MEDLINE | ID: mdl-38796450

ABSTRACT

The degradation of low-density lipoprotein receptor (LDLR) is induced by proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in elevated plasma concentrations of LDL cholesterol. Therefore, inhibiting the interactions between PCSK9 and LDLR is a desirable therapeutic goal for managing hypercholesterolemia. Aptamers, which are RNA or single-stranded DNA sequences, can recognize their targets based on their secondary structure. Aptamers exhibit high selectivity and affinity for binding to target molecules. The systematic evolution of ligands by exponential enrichment (SELEX), a combination of biological approaches, is used to screen most aptamers in vitro. Due to their unique advantages, aptamers have garnered significant interest since their discovery and have found extensive applications in various fields. Aptamers have been increasingly utilized in the development of biosensors for sensitive detection of pathogens, analytes, toxins, drug residues, and malignant cells. Furthermore, similar to monoclonal antibodies, aptamers can serve as therapeutic tools. Unlike certain protein therapeutics, aptamers do not elicit antibody responses, and their modified sugars at the 2'-positions generally prevent toll-like receptor-mediated innate immune responses. The focus of this review is on aptamer-based targeting of PCSK9 and the application of aptamers both as biosensors and therapeutic agents.


Subject(s)
Aptamers, Nucleotide , Biosensing Techniques , Lipid Metabolism , Proprotein Convertase 9 , Proprotein Convertase 9/metabolism , Proprotein Convertase 9/genetics , Proprotein Convertase 9/blood , Humans , Biosensing Techniques/methods , Receptors, LDL/metabolism , SELEX Aptamer Technique , Hypercholesterolemia/drug therapy , Hypercholesterolemia/diagnosis , Hypercholesterolemia/blood , Animals , PCSK9 Inhibitors
8.
Calcif Tissue Int ; 115(1): 53-62, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38789568

ABSTRACT

PCSK9 inhibitors have been shown to lower serum low density lipoprotein cholesterol (LDL-C) levels and are considered integral in the treatment of cardiovascular diseases. However, the potential association between PCSK9 inhibitors and osteoporosis is unclear now. In this study, drug-targeted mendelian randomization (MR) was utilized in conjunction with mediation analysis including bone mineral density (BMD), total 25-hydroxyvitamin D (T25(OH)D) levels and calcium supplementation to investigate the causal relationship between PCSK9 inhibitors and osteoporosis. The LDL-C level was chosen as the exposure variable in a sample size of 173,082 individuals. We conducted a MR analysis on the relationship between PCSK9 inhibitors and osteoporosis, elucidating the mediators involved. Utilizing the inverse variance weighted (IVW) method, we found the risk of osteoporosis was reduced by 0.6% in those who used PCSK9 inhibitors compared with non-users (OR: 0.994, 95%CI: 0.991-0.998, P < 0.001). In people aged 30-45 years, the risk of low BMD was 1.176 times higher among PCSK9 inhibitor users compared to non-users (OR: 1.176, 95%CI: 1.017-1.336, P = 0.045). Conversely, people aged 45-60 years who used PCSK9 inhibitors had a 14.9% lower risk of low BMD compared to non-users (OR: 0.851, 95%CI: 0.732-0.968, P = 0.007). Mediation analysis revealed that 43.33% of the impact of PCSK9 inhibitors on osteoporosis was mediated through BMD levels, with the remaining 56.67% being a direct effect. Effects of PCSK9 inhibitors on BMD levels varied in different ages. In addition, the risk of high serum T25(OH)D levels were 1.091 times among PCSK9 inhibitor users compared to non-users (OR: 1.091, 95%CI: 1.065-1.112, P < 0.001), providing valuable insights for clinicians.


Subject(s)
Bone Density , Mendelian Randomization Analysis , Osteoporosis , PCSK9 Inhibitors , Humans , Osteoporosis/epidemiology , Middle Aged , Bone Density/drug effects , Female , Male , Adult , Mediation Analysis , Cholesterol, LDL/blood , Proprotein Convertase 9
9.
Curr Probl Cardiol ; 49(7): 102637, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38735347

ABSTRACT

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Hyperlipidemia, particularly elevated low-density lipoprotein cholesterol (LDL-C) is one of the major risk factors for CVD. Major landmark cardiovascular outcome clinical trials demonstrated that LDL-C lowering medications reduce cardiovascular events, and the lower the LDL-C the better the outcome. This article discusses the evolution of LDL-C lowering medications starting from bile acid sequestrants (BAS), statin therapy, bempedoic acid, the proprotein convertase subtilisin kexin 9 (PCSK9) synthesis inhibitor, novel small interfering RNA-based therapy (inclisiran) to the most recent oral PCSK9 inhibitors (MK-0616) which is currently under phase 3 clinical trial studies.


Subject(s)
Cardiovascular Diseases , Cholesterol, LDL , Humans , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/drug therapy , Cholesterol, LDL/blood , Anticholesteremic Agents/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , PCSK9 Inhibitors , Dicarboxylic Acids , Fatty Acids , RNA, Small Interfering
10.
J Am Heart Assoc ; 13(11): e033669, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38818934

ABSTRACT

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. METHODS AND RESULTS: A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P<0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P<0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups. CONCLUSIONS: Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.


Subject(s)
Cholesterol, LDL , Dyslipidemias , Hypercholesterolemia , Humans , Male , Female , Middle Aged , Hypercholesterolemia/drug therapy , Hypercholesterolemia/blood , Hypercholesterolemia/diagnosis , Cholesterol, LDL/blood , China , Dyslipidemias/drug therapy , Dyslipidemias/blood , Dyslipidemias/diagnosis , Treatment Outcome , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Aged , Double-Blind Method , PCSK9 Inhibitors , Adult , Asian People , Proprotein Convertase 9/immunology , Proprotein Convertase 9/metabolism , Biomarkers/blood , Time Factors , Drug Therapy, Combination , Anticholesteremic Agents/therapeutic use , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/administration & dosage , East Asian People
11.
Int J Mol Med ; 53(6)2024 Jun.
Article in English | MEDLINE | ID: mdl-38757360

ABSTRACT

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low­density lipoprotein­cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti­PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.


Subject(s)
Hemostasis , Proprotein Convertase 9 , Thrombosis , Humans , Proprotein Convertase 9/metabolism , Hemostasis/drug effects , Thrombosis/metabolism , Thrombosis/drug therapy , Animals , Blood Platelets/metabolism , PCSK9 Inhibitors , Lipid Metabolism/drug effects
13.
J Integr Neurosci ; 23(4): 76, 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38682216

ABSTRACT

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.


Subject(s)
Hydroxymethylglutaryl CoA Reductases , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Mendelian Randomization Analysis , Proprotein Convertase 9 , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hematoma, Subdural , PCSK9 Inhibitors , Membrane Transport Proteins/genetics , Membrane Proteins/genetics , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/pharmacology , Atorvastatin/adverse effects , Atorvastatin/administration & dosage , Atorvastatin/pharmacology
14.
Atherosclerosis ; 392: 117529, 2024 May.
Article in English | MEDLINE | ID: mdl-38583289

ABSTRACT

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.


Subject(s)
Antibodies, Monoclonal, Humanized , Cholesterol, LDL , Monocytes , PCSK9 Inhibitors , Proprotein Convertase 9 , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Male , Female , Middle Aged , Double-Blind Method , Monocytes/drug effects , Monocytes/metabolism , Monocytes/immunology , Aged , Cholesterol, LDL/blood , Proprotein Convertase 9/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/immunology , Anticholesteremic Agents/therapeutic use , Lipoproteins/blood , Treatment Outcome , COVID-19/blood , COVID-19/immunology , Blood Viscosity/drug effects
15.
Fitoterapia ; 175: 105951, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38583637

ABSTRACT

Four undescribed amide alkaloids hongkongensines A-C and 1-(1-oxo-6-hydroxy-2E,4E-dodecadienyl)-piperidine, five known amide alkaloids, and three known neolignans were isolated from the aerial part of Piper hongkongense. The planar structures of these compounds were determined by detailed analyses of HR-ESI-MS and NMR data. The absolute configurations of hongkongensines A-C were elucidated by single-crystal X-ray diffraction analysis and ECD calculations. Moreover, the inhibitory activities of PCSK9 expression in vitro for all compounds were assessed by PCSK9 AlphaLISA screening. Kadsurenone (10) displayed a significant inhibitory activity at 5 µM with an inhibition rate of 51.98%, compared with 55.55% of berberine (BBR 5 µM).


Subject(s)
Alkaloids , Lignans , PCSK9 Inhibitors , Phytochemicals , Piper , Plant Components, Aerial , Piper/chemistry , Molecular Structure , Alkaloids/pharmacology , Alkaloids/isolation & purification , Alkaloids/chemistry , Lignans/pharmacology , Lignans/isolation & purification , Humans , Phytochemicals/pharmacology , Phytochemicals/isolation & purification , Plant Components, Aerial/chemistry , Amides/pharmacology , Amides/isolation & purification , Amides/chemistry , Proprotein Convertase 9/metabolism , China
16.
Circ Cardiovasc Qual Outcomes ; 17(5): e010335, 2024 May.
Article in English | MEDLINE | ID: mdl-38634282

ABSTRACT

BACKGROUND: Lipid-lowering therapy (LLT) is underutilized for very high-risk atherosclerotic cardiovascular disease. PROMPT-LIPID (PRagmatic Trial of Messaging to Providers about Treatment of HyperLIPIDemia) sought to determine whether electronic health record (EHR) alerts improve 90-day LLT intensification in patients with very high-risk atherosclerotic cardiovascular disease. METHODS: PROMPT-LIPID was a pragmatic trial in which cardiovascular and internal medicine clinicians within Yale New Haven Health (New Haven, CT) were cluster-randomized to receive an EHR alert with individualized LLT recommendations or no alert for outpatients with very high-risk atherosclerotic cardiovascular disease and LDL-C (low-density lipoprotein cholesterol), ≥70 mg/dL. The primary outcome was 90-day LLT intensification (change to high-intensity statin and addition of ezetimibe or PCSK9i [proprotein subtilisin/kexin type 9 inhibitors]). Secondary outcomes included LDL-C level, proportion of patients with LDL-C of <70 or < 55 mg/dL, rate of major adverse cardiovascular events, ED visit incidence, and 6-month mortality. Results were analyzed using logistic and linear regression clustered at the provider level. RESULTS: The no-alert group included 47 clinicians and 1370 patients (median age, 71 years; 50.1% female, median LDL-C, 93 mg/dL); the alert group included 49 clinicians and 1130 patients (median age, 72 years; 47% female, median LDL-C 91, mg/dL). The primary outcome was observed in 14.1% of patients in the alert group as compared with 10.4% in the no-alert group. There were no differences in any secondary outcomes at 6 months. Among 542 patients whose clinicians (n=46) did not dismiss the EHR alert recommendations, LLT intensification was significantly greater (21.2% versus 10.4%, odds ratio, 2.33 [95% CI, 1.48-3.66]). CONCLUSIONS: With a real-time, targeted, individualized EHR alert as compared with usual care, the proportion of patients with atherosclerotic cardiovascular disease with LLT intensification was numerically higher but not statistically significant. Among clinicians who did not dismiss the alert, there was a > 2-fold increase in LLT intensification. EHR alerts, coupled with strategies to reduce clinician dismissal, may help address persistent gaps in LDL-C management. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04394715, https://www.clinicaltrials.gov/ct2/show/study/NCT04394715.


Subject(s)
Biomarkers , Cholesterol, LDL , Electronic Health Records , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hyperlipidemias , PCSK9 Inhibitors , Humans , Female , Male , Aged , Hyperlipidemias/drug therapy , Hyperlipidemias/diagnosis , Hyperlipidemias/blood , Treatment Outcome , Middle Aged , Biomarkers/blood , Cholesterol, LDL/blood , Time Factors , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Ezetimibe/therapeutic use , Ezetimibe/adverse effects , Risk Assessment , Drug Therapy, Combination , Heart Disease Risk Factors , Anticholesteremic Agents/therapeutic use , Anticholesteremic Agents/adverse effects , Clinical Decision-Making , Practice Patterns, Physicians' , Proprotein Convertase 9
17.
Diabetes Metab Res Rev ; 40(4): e3793, 2024 May.
Article in English | MEDLINE | ID: mdl-38661109

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2 , Dyslipidemias , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypolipidemic Agents , PCSK9 Inhibitors , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Niemann-Pick C1 Protein/antagonists & inhibitors , PCSK9 Inhibitors/adverse effects , Hypolipidemic Agents/adverse effects , Genome-Wide Association Study , Mendelian Randomization Analysis , Dyslipidemias/drug therapy , Risk Assessment , Quantitative Trait Loci , Odds Ratio
18.
J Chem Inf Model ; 64(9): 3923-3932, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38615325

ABSTRACT

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.


Subject(s)
Molecular Dynamics Simulation , Proprotein Convertase 9 , Protein Binding , Receptors, LDL , Receptors, LDL/metabolism , Receptors, LDL/chemistry , Proprotein Convertase 9/metabolism , Proprotein Convertase 9/chemistry , Allosteric Regulation , Humans , Protein Conformation , Thermodynamics , PCSK9 Inhibitors
19.
Medicine (Baltimore) ; 103(12): e37637, 2024 Mar 22.
Article in English | MEDLINE | ID: mdl-38517999

ABSTRACT

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.


Subject(s)
Anticholesteremic Agents , Dyslipidemias , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Myocardial Infarction , Adult , Humans , Proprotein Convertase 9 , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , PCSK9 Inhibitors , Dyslipidemias/drug therapy , Dyslipidemias/diagnosis , Ezetimibe/therapeutic use , Myocardial Infarction/drug therapy , Myocardial Infarction/chemically induced , Cholesterol, LDL
SELECTION OF CITATIONS
SEARCH DETAIL
...