PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: a bayesian network meta-analysis

Cardiovascular Diabetology, Journal Year: 2022, Volume and Issue: 21(1)

Published: June 15, 2022

Abstract Background The Food and Drug Administration has approved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors for the treatment of dyslipidemia. However, evidence optimal PCSK9 agents targeting secondary prevention in patients with high-risk cardiovascular events is lacking. Therefore, this study was conducted to evaluate benefit safety different types inhibitors. Methods Several databases including Cochrane Central, Ovid Medline, Embase were searched from inception until March 30, 2022 without language restriction. Randomized controlled trials (RCTs) comparing administration placebo or ezetimibe statin-background therapy identified. primary efficacy outcome all-cause mortality. serious adverse events. Results Overall, nine totaling 54,311 Three evaluated. use alirocumab associated reductions mortality compared control (RR 0.83, 95% CrI 0.72–0.95). Moreover, evolocumab increased 1.26, 1.04–1.52). We also found decreased risk 0.94, 0.90–0.99). Conclusions In consideration fact that both monoclonal antibody inclisiran enable achieve recommended LDL-C target, findings meta-analysis suggest might provide benefits regarding relatively lower SAE risks, myocardial infarction Further head-to-head longer follow-up high methodologic quality are warranted help inform subsequent guidelines management these patients.

Language: Английский

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The relationship between statin therapy and adipocytokine/inflammatory mediators in dyslipidemic nondiabetic patients: A comparative study

Pharmacia, Journal Year: 2023, Volume and Issue: 70(3), P. 581 - 585

Published: Aug. 7, 2023

Background : Statins have emerged as a vital therapeutic option for dyslipidemia, effectively reducing morbidity and mortality in individuals with various medical conditions. Recent research has shed light on the intricate pathophysiology of atherosclerosis, which involves lipid accumulation inflammatory mediators. This was conducted to assess correlation between statin therapy adipocytokine mediator levels dyslipidemic nondiabetic patients. Methods A total 67 patients were enrolled, alongside 33 healthy controls. The participants categorized into three groups: Group (A), comprising undergoing (n = 34), (B), consisting not receiving 33); (C), controls 33). Results Patients exhibited significant profiles compared Levels cholesterol (TC), triglycerides (TG), very low-density lipoprotein (VLDL), (LDL) higher therapy. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) group than non-statin Additionally, PCSK9 treated rosuvastatin those atorvastatin. Conversely, retinol-binding protein 4 (RBP4) lower Although no difference RBP4 atorvastatin users found, displayed values. study also revealed C-reactive (CRP) group, primarily subgroup, group. Conclusion Statin increased levels, more pronounced rise observed proved protective by CRP

Language: Английский

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Drug development advances in human genetics‐based targets

MedComm, Journal Year: 2024, Volume and Issue: 5(2)

Published: Feb. 1, 2024

Drug development is a long and costly process, with high degree of uncertainty from the identification drug target to its market launch. Targeted drugs supported by human genetic evidence are expected enter phase II/III clinical trials or be approved for marketing more quickly, speeding up process. Currently, data technologies such as genome-wide association studies (GWAS), whole-exome sequencing (WES), whole-genome (WGS) have identified validated many potential molecular targets associated diseases. This review describes structure, biology, genetics-based beneficial loss-of-function (LOF) mutation (target mutations that reduce disease incidence) over past decade. The feasibility eight LOF (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, INHBE) discovery mainly emphasized, their research prospects challenges discussed. In conclusion, we expect this will inspire researchers use genetics genomics support novel therapeutic direction development, which contribute new repurposing.

Language: Английский

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Alirocumab boosts antioxidant status and halts inflammation in rat model of sepsis-induced nephrotoxicity via modulation of Nrf2/HO-1, PCSK9/HMGB1/NF-ᴋB/NLRP3 and Fractalkine/CX3CR1 hubs

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 177, P. 116929 - 116929

Published: June 17, 2024

Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, study aimed elucidate antibacterial effect alirocumab against E. coli vitro. Additionally, evaluation potential nephroprotective effects LPS-induced AKI rats, highlighting underlying mechanisms involved these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; normal control group, whereas sepsis-mediated induced II III through single-dose intraperitoneal injection LPS on day 16. In group III, animals given alirocumab. The results revealed mitigated alirocumab, evidenced amelioration renal function tests (creatinine, cystatin C, KIM-1, NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, MDA); apoptotic markers histopathological findings. Besides, pronouncedly hindered LPS-mediated response, confirmed diminishing HMGB1, TNF-α, IL-1β, caspase-1 contents; gene expression RAGE, NF-ᴋB Fractalkine/CX3CR1, along mRNA TLR4, MYD88, NLRP3. Regarding actions, showed displayed anti-bacterial activity pathogenic gram-negative coli. conclusion, elicited activities via modulation Nrf2/HO-1, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 axes.

Language: Английский

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Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: May 26, 2022

Background Graft vascular disease (GVD), which limits the long-term survival of patients after solid-organ transplantation, is associated with both immune responses and nonimmune factors, including dyslipidemia. Recent studies have shown that inhibition proprotein convertase subtilisin/kexin type 9 (PCSK9), a U.S. Federal Drug Administration-approved treatment for hyperlipidemia, reduces cardiovascular events, regulates inflammatory responses, enhances efficacy checkpoint therapy in cancer through cholesterol-independent mechanism. However, whether targeting PCSK9 potential therapeutic strategy GVD remains unknown. Methods Serum samples grafts were harvested from male mice undergoing abdominal aortic transplantation. The pathological alterations detected by hematoxylin eosin staining, Verhoeff’s Van Gieson Masson staining. Inflammatory cell infiltration proinflammatory cytokine expression immunohistochemistry quantitative real-time polymerase chain reaction (qRT-PCR), respectively. regulatory effects on smooth muscle (VSMC) migration proliferation examined transwell, EdU, western blot assays. effect Evolocumab, inhibitor, humanized was also evaluated. Results upregulated serum, grafts, liver allograft group subjected to Pcsk9 knockout significantly reduced stenosis, intimal hyperplasia area collagen deposition. depletion inhibited macrophage recruitment mRNA cytokines grafts. Furthermore, suppressed VSMCs, related NLRP3 inflammasome activation. Meanwhile, Evolocumab ameliorated mice. Conclusion mouse model GVD, occlusion, suggesting may be promising target GVD.

Language: Английский

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Proprotein convertase subtilisn/kexin type 9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: A systematic review and meta-analysis

PLoS ONE, Journal Year: 2023, Volume and Issue: 18(12), P. e0295359 - e0295359

Published: Dec. 6, 2023

Background Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Atherosclerosis occurs due to accumulation low-density lipoprotein cholesterol (LDL-c) in arterial system. Thus, lipid lowering therapy essential for both primary and secondary prevention. Proprotein convertase subtilisn/kexin type 9 (PCSK9) inhibitors (Evolocumab, Alirocumab) small interfering RNA (siRNA) (Inclisiran) have been demonstrated lower LDL-c ASCVD events conjunction with maximally tolerated statin therapy. However, degree reduction impact on reducing major adverse cardiac events, including their mortality, remains unclear. Objective The purpose this study examine effects PCSK9 (MACE) by conducting a meta-analysis randomized controlled trials. Methods Using Pubmed, Embase, Cochrane Library clinicaltrials.gov until April 2023, we extracted trials (RCTs) siRNA risk MACE. random-effects models, pooled relative risks 95% CIs weighted least-squares mean difference levels. We estimated odds ratios among MACE subtypes all-cause mortality. Fixed-effect model was used, heterogeneity assessed using I 2 statistic. Results In all, 54 studies 87,669 participants (142,262 person-years) met criteria inclusion. percent change reported 47 (n = 62,634) evaluating two Of those, 21 41,361) included treatment Evolocumab (140mg), 22 11,751) Alirocumab (75mg), 4 9,522) Inclisiran (284mg 300mg). Compared placebo, after median 24 weeks (IQR 12–52), reduced -61.09% (95% CI: -64.81, -57.38, p<0.01) -46.35% -51.75, -41.13, p<0.01). 284mg -54.83% -59.04, -50.62, p 0.05) 300mg -43.11% -52.42, -33.80, 0.01). After 8 months 6–15), myocardial infarction (MI), OR 0.72 0.64, 0.81, p<0.01), coronary revascularization, 0.77 0.70, 0.84, stroke, 0.79 0.66, 0.94, 0.01) overall 0.85 0.80, 0.89, MI, 0.57 (0.38, 0.86, 0.01), 0.35 0.16, 0.77, 0.60 0.43, (0.16, Conclusion significantly >40% high-risk individuals. Additionally, MACE,

Language: Английский

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Whether and Why Do We Need a Vaccine Against Atherosclerosis? Can We Expect It Anytime Soon?

Current Atherosclerosis Reports, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 2, 2024

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of premature death. Lipid disorders, particularly elevated serum low-density lipoprotein cholesterol (LDL-C), contribute significantly to ASCVD. The risk developing ASCVD influenced by the duration exposure LDL-C concentrations (cholesterol-years concept). Implementing lipid-lowering treatments based on principles "the earlier better," lower and longer better" has been shown reduce extend lifespan. Despite availability numerous drugs, achieving satisfactory control lipid disorders remains very challenging. Therefore, there need for novel approaches improve treatment adherence.

Language: Английский

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The Current and Emerging Role of Statins in the Treatment of PCOS: The Evidence to Date

Medicina, Journal Year: 2024, Volume and Issue: 60(2), P. 244 - 244

Published: Jan. 30, 2024

Polycystic ovary syndrome (PCOS) manifests a multifactorial pathology characterized by polycystic ovaries, menstrual cycle disorders, varying degrees of hyperandrogenism, and an ad-verse metabolic risk profile. The position hyperandrogenism in this has been extensively studied. A multitude mechanisms place it the cause but also consequence; therefore, ongoing research efforts are focused on identifying medications that can effectively reduce levels androgens women with PCOS. Moreover, lipid abnormalities common population, up to 70% patients having dyslipidemia. Statins may have potential therapeutic benefits for PCOS, as they shown improve insulin resistance cardiovascular disease. In addition, their role accelerated steroidogenesis limiting one source cholesterol, influencing enzymatic activity, providing several other beneficial is widely investigated. This review aimed provide comprehensive overview pathogenesis androgen excess dyslipidemia well statins.

Language: Английский

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PCSK9 in T-cell function and the immune response

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Dec. 30, 2024

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) was first reported in 2003 and confirmed to be strongly associated with familial hypercholesterolemia. Small-molecule inhibitors targeting PCSK9 provide an effective safe method for managing hypercholesterolemia reducing the cardiovascular risk. In recent years, increasing evidence has indicated other important roles inflammation, tumors, even immune regulation. might attractive regulator of T-cell activation expansion. It mediate inflammation regulate types cells. this review, we summarize current advances field a narrative biological processes PCSK9. The relationships between different T cells were investigated depth. Finally, signaling pathways response are also summarized review.

Language: Английский

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The correlation between proprotein convertase subtilisin/kexin type 9 and adiponectin in the progression from prediabetes to type 2 diabetes mellitus

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 12, 2025

Data on the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) and adiponectin in prediabetes progression to 2 diabetes mellitus (T2DM) remains inconclusive. Therefore, this study investigated roles PCSK9 process. This included 1,528 participants with T2DM conducted correlation analyses investigate relationship between levels, pancreatic beta-cell function, insulin levels. Logistic regression analysis receiver operating characteristic (ROC) curves were used determine whether play protective from their potential as diagnostic biomarkers for T2DM. In prediabetic patients, levels [573.00 (412.35) ng/mL vs. 924.20 (673.38) ng/mL, p < 0.001] [4.50 (2.80) mg/mL 6.22 (4.51) mg/mL, significantly higher than those patients (r = 0.167, 0.001) 0.113, positively correlated cell homeostasis had effects against (PCSK9: OR 0.274, 95% CI 0.121–0.621, 0.002; adiponectin: 0.135, 0.057–0.320, 0.001). The combined value showed an area under curve 0.751 (95% 0.727–0.775). Prediabetes significant differences have T2DM, use is a biomarker transition

Language: Английский

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