RESUMO
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have represented an important change in the management of hypercholesterolemia, although, until now, they have barely been used. Without PCSK9i, many patients with atherosclerotic cardiovascular disease (CVD) or those at very high risk do not reach their therapeutic LDLc objectives. OBJECTIVE: The analysis aimed to examine the clinical and biochemical characteristics of subjects receiving PCSK9i treatment in the Dyslipidemia Registry of the Spanish Atherosclerosis Society. METHODS: All consecutive subjects aged ≥ 18 years from different Lipid Units included in the Dyslipidemia Registry of the SEA were analyzed. Inclusion criteria consisted of unrelated patients aged ≥ 18 at the time of inclusion with hypercholesterolemia (LDL-C ≥ 130 mg/dL or non-HDL-C ≥ 160 mg/dL after the exclusion of secondary causes) who were studied for at least two years after inclusion. Participants' baseline and final visit clinical and biochemical characteristics were analyzed based on whether they were on primary or secondary prevention and whether they were taking PCSK9i at the end of follow-up. RESULTS: Eight hundred twenty-nine patients were analyzed, 7014 patients in primary prevention and 1281 in secondary prevention at baseline. 4127 subjects completed the required follow-up for the final analysis. The median follow-up duration was 7 years (IQR 3.0-10.0). Five hundred patients (12.1%) were taking PCSK9i at the end of the follow-up. The percentage of PCSK9i use reached 35.6% (n = 201) and 8.7% (n = 318) in subjects with and without CVD, respectively. Subjects on PCSK9i and oral lipid-lowering agents with and without CVD achieved LDLc reductions of 80.3% and 75.1%, respectively, concerning concentrations without lipid-lowering drugs. Factors associated with PCSK9i use included increasing age, LDLc without lipid-lowering drugs and the Dutch Lipid Clinic Network (DLCN) score. However, hypertension, diabetes, smoking, and LDLc after oral lipid-lowering drugs were not independent factors associated with PCSK9i prescription. In subjects with CVD, the use of PCSK9i was higher in men than in women (an odds ratio of 1.613, P = 0.048). CONCLUSIONS: Approximately one-third of CVD patients received PCSK9i at the end of follow-up. The use of PCSK9i was more focused on baseline LDLc concentrations rather than on CVD risk. Women received less PCSK9i in secondary prevention compared to men.
Assuntos
Doenças Cardiovasculares , LDL-Colesterol , Inibidores de PCSK9 , Prevenção Secundária , Humanos , Inibidores de PCSK9/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Prevenção Secundária/métodos , Idoso , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/sangue , Prevenção Primária/métodos , Anticolesterolemiantes/uso terapêutico , Sistema de Registros , Pró-Proteína Convertase 9/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
BACKGROUND: India has the highest burden of cardiovascular disease (CVD) among developing nations. Data from international studies show significant underimplementation of recommended aggressive lipid-lowering strategies for achieving low-density lipoprotein cholesterol (LDL-C) goals, especially after percutaneous coronary intervention (PCI), a pattern also observed in India. Moreover, ethnic variation in response to statin therapy has prompted clinicians to adopt lower doses of statin therapy in Asians to achieve comparable LDL-C lowering. OBJECTIVE: To document the dose of statin ± ezetimibe required to achieve the European Society of Cardiology (ESC) goals of LDL-C <55 mg/dL in Indian patients with established atherosclerotic cardiovascular disease (ASCVD). MATERIALS AND METHODS: This retrospective single-center, cross-sectional, observational, all-comers study in Mumbai evaluated the dose of atorvastatin (A)/rosuvastatin (R) ± ezetimibe (E) treatment at which patients with established ASCVD (n = 542), irrespective of their baseline level, achieved LDL-C goals (<55 mg/dL). Those with LDL-C levels >55 mg/dL on current therapy were switched to R 40 mg ± E 10 mg daily. The final data set (n = 340) included those who achieved LDL-C goals at the initial visit and those at follow-up. The primary and secondary outcomes assessed the impact of R 40 mg ± E 10 mg (R40 ± E10) on LDL-C (<55 mg/dL) and non-high-density lipoprotein cholesterol [non-HDL-C (<85 mg/dL)] goal achievement, respectively. RESULTS: At the end of follow-up, LDL-C <55 mg/dL was observed in 42.16% of patients (n = 113) with R40 and in another 43.28% (n = 116) with R40 + E10. A few patients (n = 39; 14.6%) achieved this goal with other dosages. Similarly, non-HDL-C <85 mg/dL was observed in 39.3% of patients (n = 107) with R40 and in another 47.4% of patients (n = 129) with R40 + E10. Overall, around 20% of patients were unable to achieve their LDL-C and non-HDL-C goals despite being on high-intensity statin ± E therapy. CONCLUSION: In the first report of its kind in India, this study showed that suboptimal LDL-C goal achievement occurred in around 20% of high-risk ASCVD patients on dual therapy. This indicates that clinicians should consider the addition of other therapies [e.g., bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and inclisiran] to mitigate the residual risk. Several more trials are needed to determine the most suitable treatment regimen for this population.
Assuntos
Anticolesterolemiantes , LDL-Colesterol , Ezetimiba , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Ezetimiba/uso terapêutico , Estudos Transversais , Masculino , Índia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Estudos Retrospectivos , Pessoa de Meia-Idade , LDL-Colesterol/sangue , Feminino , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Atorvastatina/uso terapêutico , Quimioterapia Combinada , Idoso , Rosuvastatina Cálcica/uso terapêutico , Rosuvastatina Cálcica/administração & dosagemRESUMO
Visceral cestodiases, like cysticercoses and echinococcoses, are caused by cystic larvae from parasites of the Cestoda class and are endemic or hyperendemic in many areas of the world. Current therapeutic approaches for these diseases are complex and present limitations and risks. Therefore, new safer and more effective treatments are urgently needed. The Niemann-Pick C1 (NPC1) protein is a cholesterol transporter that, based on genomic data, would be the solely responsible for cholesterol uptake in cestodes. Considering that human NPC1L1 is a known target of ezetimibe, used in the treatment of hypercholesterolemia, it has the potential for repurposing for the treatment of visceral cestodiases. Here, phylogenetic, selective pressure and structural in silico analyses were carried out to assess NPC1 evolutive and structural conservation, especially between cestode and human orthologs. Two NPC1 orthologs were identified in cestode species (NPC1A and NPC1B), which likely underwent functional divergence, leading to the loss of cholesterol transport capacity in NPC1A. Comparative interaction analyses performed by molecular docking of ezetimibe with human NPC1L1 and cestode NPC1B pointed out to similarities that consolidate the idea of cestode NPC1B as a target for the repurposing of ezetimibe as a drug for the treatment of visceral cestodiases.
Assuntos
Cestoides , Ezetimiba , Proteína C1 de Niemann-Pick , Ezetimiba/farmacologia , Ezetimiba/uso terapêutico , Humanos , Animais , Proteína C1 de Niemann-Pick/metabolismo , Cestoides/metabolismo , Cestoides/efeitos dos fármacos , Cestoides/genética , Filogenia , Simulação de Acoplamento Molecular , Reposicionamento de Medicamentos/métodos , Simulação por Computador , Colesterol/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/química , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêuticoRESUMO
Proprotein Convertase Subtilisin/Kexin type-9 (PCSK-9) inhibitors have recently used in the management of different cardiac complications. Several clinical trials demonstrated their effectiveness in patients with hypercholesterolemia. However, the effectiveness of these medications in patients with heart diseases is still controversial. To review and summarize the clinical trials pertaining to the use and effectiveness of PCSK-9 inhibitors in heart diseases and to discuss the pharmacotherapy of these agents. A review was conducted of all clinical trials with PCSK-9 inhibitors for heart diseases registered at ClinicalTrials.gov since inception up to and including January 19th, 2024. These trials were retrieved. Data from these trials were extracted manually, categorized and analyzed. The number of identified clinical trials was 25,371. After screening and excluding irrelevant studies, 12 studies met the search criteria. The majority of these studies were conducted in the US. The total number of patients in these studies was 27,700. Alirocumab and Evolocumab were the most frequently used PCSK-9 inhibitors. This review identified only a few clinical trials on PCSK-9 inhibitors in heart disease patients. Therefore, it is recommended to conduct more randomized controlled clinical trials on PCSK-9 inhibitors in this patient population.
Assuntos
Anticorpos Monoclonais Humanizados , Cardiopatias , Inibidores de PCSK9 , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Cardiopatias/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9RESUMO
Due to the growing evidence of clinical benefits conferred by the reduction of low-density lipoprotein cholesterol (LDL-C) levels, the availability of multiple effective lipid-lowering agents, and guideline recommendations, clinicians not infrequently have to manage patients with low or very low LDL-C levels. In clinical practice it is essential to consider that, when LDL-C plasma concentrations are low, the Friedewald formula commonly used for LDL-C level calculation is less accurate, hence risk assessment should be integrated by using different methods for LDL-C level quantification and other parameters, such as non-high-density lipoprotein cholesterol and, where possible, apolipoprotein B, should be measured. As regards the clinical impact of low LDL-C levels, genetically determined hypocholesterolemia forms provide reassuring data on the effects of this condition in the long term, except for the forms with extremely low or undetectable LDL-C levels. Evidence from clinical studies that used highly effective lipid-lowering drugs, such as proprotein convertase subtilisin/kexin type 9 inhibitors, goes in the same direction. In these studies, the incidence of non-cardiovascular adverse events in patients who reached very low LDL-C levels was similar to that in the placebo arm. Overall, the fear of adverse effects should not deter intensive lipid-lowering treatment when indicated to reduce the risk of cardiovascular events.
Assuntos
Anticolesterolemiantes , LDL-Colesterol , Hipercolesterolemia , Humanos , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Inibidores de PCSK9/uso terapêutico , Medição de RiscoRESUMO
Atherosclerosis (AS), as the main pathophysiological basis of coronary heart disease, can develop into carotid atherosclerotic plaque (CAP) through intimal inflammation, necrosis, fibrosis and calcification. However, there are few reports on the clinical drug selection of CAP. The aim of this study was to explore the effects of atorvastatin and ezetimibe on CD147, HIF-1, MMP-2 and VEGF in CAP under the guidance of IVUS, so as to provide basis for CAP of the best drug. 32 male New Zealand rabbits were divided into the control group, the model group, the atorvastatin group and the ezetimibe group randomly. The levels of serum LDL-C and MMP-2 have a significant decrease in atorvastatin group and ezetimibe group (P <0.05). The level of serum CD147 has a significant decrease in ezetimibe group (P <0.05). The average OD value of HIF-1 in atorvastatin group decreased significantly (P <0.05). The relative expression of CD147 and VEGF decreased significantly in atorvastatin group (P <0.05). There were different degrees of fibrous plaque and lipid plaque in model group, atorvastatin group and ezetimibe group. There exists a significant decline of CD147, HIF-1, MMP-2 and VEGF by atorvastatin in plaque, but the effect of ezetimibe is not obvious.
Assuntos
Atorvastatina , Basigina , Ezetimiba , Metaloproteinase 2 da Matriz , Placa Aterosclerótica , Fator A de Crescimento do Endotélio Vascular , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Masculino , Placa Aterosclerótica/tratamento farmacológico , Metaloproteinase 2 da Matriz/metabolismo , Coelhos , Ezetimiba/farmacologia , Ezetimiba/uso terapêutico , Basigina/metabolismo , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Ultrassonografia de Intervenção , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/metabolismo , LDL-Colesterol/sangue , Modelos Animais de Doenças , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismoRESUMO
BACKGROUND: Because of concerns of cost-effectiveness and low utilization, in 2018, manufacturers initiated a 60% price reduction for PCSK9 inhibitors, reducing the list price from more than $14,000 to $5,850. The goal of the reduction was to increase access and lower patient cost sharing for PCSK9 inhibitors. OBJECTIVE: To determine whether list price reductions resulted in a statistically significant decrease in patient cost sharing for PCSK9 inhibitors. The secondary objective is to quantify the change in monthly out-of-pocket (OOP) cost in the years following the price reduction policies. METHODS: This analysis uses a cross-sectional quasi-experimental design, with 2 time periods, to estimate the change in monthly OOP cost. A 2-stage cost model was used to quantify the difference in mean monthly OOP cost between the preprice and postprice reduction periods. This analysis was completed using IQVIA PharMetrics Plus for Academics health plan claims for PSCK9 inhibitors between January 2016 and December 2021 for commercially insured individuals in the United States. The primary exposure of interest is a manufacturer-initiated list price reduction in October 2018. The primary outcome of interest is the difference in the predicted monthly OOP cost between the prereduction and postreduction periods. RESULTS: There was a 50% decrease in the predicted monthly OOP cost, from $235.22 (SD = $241) in the prereduction period to $116.75 (SD = $152) in the postreduction period. CONCLUSIONS: This claims level analysis used robust statistical modeling techniques to quantify the effect of manufacturer-initiated price reductions on monthly OOP cost. This unique manufacturer decision resulted in a statistically significant decrease in the monthly OOP cost for beneficiaries using PCSK9 inhibitors. Manufacturer-initiated price reductions could be a strategy to reduce the cost for other therapies with access and cost concerns. Further research is needed on the downstream patient-level effects of cost reductions, particularly among individuals who experience multiple barriers to care.
Assuntos
Custos de Medicamentos , Gastos em Saúde , Inibidores de PCSK9 , Humanos , Estudos Transversais , Estados Unidos , Análise Custo-Benefício , Indústria Farmacêutica/economia , Custo Compartilhado de Seguro , Anticolesterolemiantes/economia , Anticolesterolemiantes/uso terapêutico , Redução de Custos , Pró-Proteína Convertase 9RESUMO
PURPOSE OF REVIEW: To provide perspective on the current development status, and potential future role, of obicetrapib, a third-generation cholesterylester transfer protein (CETP) inhibitor. Obicetrapib has received recent attention following positive Phase II clinical trial data and initiation of Phase III trials for the treatment of dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS: The ROSE and ROSE2 trials are Phase II studies that examined the lipid lowering effects of obicetrapib in patients on pre-existing high-intensity statin therapy. Obicetrapib significantly reduced key dyslipidemia biomarkers including low density lipoprotein cholesterol (LDL-C), Apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) while increasing high-density lipoprotein cholesterol (HDL-C). Four phase III clinical trials, including a cardiovascular outcomes trial, are ongoing. Preliminary data for obicetrapib shows favorable effects on dyslipidemia, which could theoretically lead to a decrease in ASCVD clinical events. Short-term safety data in preliminary studies shows no significant safety signals.
Assuntos
Anticolesterolemiantes , Proteínas de Transferência de Ésteres de Colesterol , Humanos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Anticolesterolemiantes/uso terapêutico , Dislipidemias/tratamento farmacológico , Dislipidemias/sangue , Aterosclerose/tratamento farmacológicoRESUMO
PURPOSE OF REVIEW: Although the clinical benefit of reducing low-density lipoprotein cholesterol (LDLc) in patients with coronary artery disease (CAD) is well-established, the impact on plaque composition and stability is less clear. Our narrative review aimed to assess the clinical effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on coronary plaque characteristics specifically focusing from atheroma progression to regression and stabilization. RECENT FINDINGS: The combination of statin therapy and PCSK9 inhibitors (evolocumab and alirocumab) promotes plaque stability in patients following an acute coronary syndrome. The GLAGOV study highlighted the relationship between achieved LDLc levels and changes in percentage atheroma volume. Similarly, the PACMAN-AMI study concluded that the qualitative and quantitative changes in coronary plaque were associated with the levels of LDLc. Assessing the severity of coronary artery stenosis and the extent of atherosclerotic burden by means of imaging techniques (e.g., IVUS, OCT and near-infrared spectroscopic) have significantly advanced our understanding of the benefits from promoting plaque regression and achieving to features of plaque stabilization through increasingly intensive lipid-lowering strategies.
Assuntos
Doença da Artéria Coronariana , Inibidores de PCSK9 , Placa Aterosclerótica , Pró-Proteína Convertase 9 , Humanos , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/diagnóstico por imagem , Doença da Artéria Coronariana/tratamento farmacológico , Pró-Proteína Convertase 9/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , LDL-Colesterol/efeitos dos fármacos , Anticolesterolemiantes/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêuticoRESUMO
Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450â¯mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150â¯mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95â¯%CI) in LDL-C from baseline to week 12 of Ebronucimab 450â¯mg Q4W and Ebronucimab 150â¯mg Q2W groups versus the placebo group was -59.13 (-64.103, -54.153) (Adjusted p<0.0001) and -60.43 (-65.450, -55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9â¯%, 4.8â¯% and 3.5â¯%). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450â¯mg Q4W or 150â¯mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients.
Assuntos
Anticorpos Monoclonais Humanizados , LDL-Colesterol , Hipercolesterolemia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/efeitos adversos , China , LDL-Colesterol/sangue , Método Duplo-Cego , População do Leste Asiático , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9 , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Individuals with or at high risk of cardiovascular disease (CVD) often receive long-term treatment with low-density lipoprotein cholesterol (LDL-C) lowering therapies, but whether the effects of LDL-C reduction remain stable over time is uncertain. This study aimed to establish the course of the effects of LDL-C reduction on cardiovascular risk over time. METHODS: Randomized controlled trials (RCTs) of LDL-C lowering therapies were identified through a search in MEDLINE and EMBASE (1966-January 2023). The primary analyses were restricted to statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, with other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the hazard ratio (HR) for major vascular events (cardiovascular death, myocardial infarction, unstable angina, coronary revascularization, or stroke) per 1 mmol/L LDL-C reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the HR for major vascular events per 1 mmol/L LDL-C reduction. Additionally, treatment-by-time interactions were evaluated in an individual participant data meta-analysis of six atorvastatin trials. RESULTS: A total of 60 RCTs were identified (408,959 participants, 51,425 major vascular events). The HR for major vascular events per 1 mmol/L LDL-C reduction was 0.78 (95 % confidence interval [CI] 0.75-0.81). Follow-up duration was not associated with a change in the HR for major vascular events (HR for change per year 0.994; 95 % CI 0.970-1.020; p = 0.66). The HR attenuated with increasing age in primary prevention (HR for change per 5 years 1.097; 95 % CI 1.031-1.168; p = 0.003), but not secondary prevention (HR for change per 5 years 0.987; 95 % CI 0.936-1.040; p = 0.63). Consistent results were found for statin trials only, and all trials combined. In the individual participant data meta-analysis (31,310 participants, 6734 major vascular events), the HR for major vascular events did not significantly change over follow-up time (HR for change per year 0.983; 95 % CI 0.943-1.025; p = 0.42), or age (HR for change per 5 years 1.022; 95 % CI 0.990-1.055; p = 0.18). CONCLUSIONS: Based on available RCT data with limited follow-up duration, the relative treatment effects of LDL-C reduction are stable over time in secondary prevention, but may attenuate with higher age in primary prevention.
Assuntos
Doenças Cardiovasculares , LDL-Colesterol , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , LDL-Colesterol/sangue , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Fatores de Tempo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Fatores de Risco de Doenças Cardíacas , Resultado do Tratamento , Pessoa de Meia-Idade , Masculino , Feminino , Medição de Risco , Idoso , Inibidores de PCSK9/uso terapêutico , Biomarcadores/sangueRESUMO
Drugs that lower plasma apolipoprotein B (ApoB)-containing lipoproteins are central to treating advanced atherosclerosis and provide partial protection against clinical events. Previous research showed that lowering ApoB-containing lipoproteins stops plaque inflammation, but how these drugs affect the heterogeneous population of plaque cells derived from smooth muscle cells (SMCs) is unknown. SMC-derived cells are the main cellular component of atherosclerotic lesions and the source of structural components that determine the size of plaques and their propensity to rupture and trigger thrombosis, the proximate cause of heart attack and stroke. Using lineage tracing and single-cell techniques to investigate the full SMC-derived cellular compartment in progressing and regressing plaques in mice, here we show that lowering ApoB-containing lipoproteins reduces nuclear factor kappa-light-chain-enhancer of activated B cells signaling in SMC-derived fibromyocytes and chondromyocytes and leads to depletion of these abundant cell types from plaques. These results uncover an important mechanism through which cholesterol-lowering drugs can achieve plaque regression.
Assuntos
Aterosclerose , Modelos Animais de Doenças , Miócitos de Músculo Liso , Placa Aterosclerótica , Animais , Placa Aterosclerótica/patologia , Placa Aterosclerótica/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/metabolismo , Aterosclerose/patologia , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Condrócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Masculino , Colesterol/metabolismo , Colesterol/sangue , Camundongos , Doenças da Aorta/patologia , Doenças da Aorta/metabolismo , Análise de Célula Única , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Músculo Liso Vascular/metabolismo , NF-kappa B/metabolismoRESUMO
BACKGROUND: It remains controversial whether adding ezetimibe to low/moderate-intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high-intensity statin regimens. HYPOTHESIS: A combination of low/moderate-intensity statins plus ezetimibe might be more effective and safer than high-intensity statin monotherapy. METHODS: We searched databases for randomized controlled trials comparing lipid profile alterations, drug-related adverse events, and MACE components between high-intensity statin monotherapy and low/moderate-intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random-effects model. RESULTS: Our comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels compared to monotherapy (MD = -6.6, 95% CI: -10.6 to -2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13-0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51-0.74). The occurrence of MACE was similar between the two treatment groups. CONCLUSIONS: Adding ezetimibe to low/moderate-intensity statins resulted in a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta-analysis, the observed reduction in LDL-C levels in the combination group did not correlate with a reduction in MACE compared to the high-intensity statin group.
Assuntos
Anticolesterolemiantes , LDL-Colesterol , Quimioterapia Combinada , Ezetimiba , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Ezetimiba/uso terapêutico , Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , LDL-Colesterol/sangue , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Resultado do Tratamento , Aterosclerose/tratamento farmacológico , Aterosclerose/sangue , Biomarcadores/sangueRESUMO
INTRODUCTION: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and confers a high risk of stroke recurrence, despite aggressive medical therapy. Asymptomatic ICAS (aICAS) is a frequent finding on neuroimaging, and it's an independent risk factor for future stroke. Alirocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and effectively lower low-density lipoprotein cholesterol levels. We hypothesize that extra alirocumab in addition to statin therapy (EAST) could stabilize intracranial plaques in patients with aICAS. METHODS AND ANALYSIS: In this prospective, randomized, open-label, blinded end-point study, we will use high-resolution vessel-wall magnetic resonance imaging (HR-vwMRI) to evaluate the efficacy and safety of alirocumab in patients with asymptomatic ICAS. Eighty patients with aICAS (50â¯%-99â¯%) caused by unstable plaques will be assigned to the arm of alirocumab plus statin therapy, or the arm of statin therapy in a 1:1 ratio. Patients will undergo HR-vwMRI at recruitment and after 6 months. The primary outcome is changes in plaque features evaluated by HR-vwMRI after 6 months' treatment. This trial is being conducted at the first affiliated hospital of Nanjing medical university, China. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University. Written informed consents will be obtained from all participants. Study results will be published as peer-reviewed articles. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, Identifier: NCT06080256.
Assuntos
Anticorpos Monoclonais Humanizados , Inibidores de Hidroximetilglutaril-CoA Redutases , Arteriosclerose Intracraniana , Humanos , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos Prospectivos , Pessoa de Meia-Idade , Masculino , Feminino , Imageamento por Ressonância Magnética , Idoso , Adulto , Constrição Patológica , Doenças Assintomáticas , Quimioterapia Combinada , Anticolesterolemiantes/uso terapêuticoRESUMO
Previous studies have found a possible causal relationship between triglycerides and lipid-lowering drugs and valvular disease. The aim of this study was to explore the potential causal relationship between triglycerides and lipid-lowering drugs and valvular disease using Mendelian randomization (MR) analysis. Data sets associated with triglycerides (441,016 participants and 12,321,875 single nucleotide polymorphisms [SNPs]) and cholesterol-lowering drugs (209,638 participants and 9851,867 SNPs) were retrieved from the Genome-Wide Association Study (GWAS) database. A total of 297 and 49 SNPs significantly associated with triglycerides and cholesterol-lowering drugs, respectively (Pâ <â 5â ×â 10-8), were identified. Similarly, data sets for non-rheumatic valve diseases (NVDs) (361,194 participants and 10,080,950 SNPs) were obtained from the GWAS database. Inverse variance weighting was used as the primary method for calculating the odds ratio (OR) and 95% confidence intervals (CI). The MR-Egger, weighted median, and weighted mode analyses were also used to test the robustness of the main results. The MR-Egger intercept test and the MR-PRESSO test were used to evaluate horizontal pleiotropy. Inverse variance weighted (IVW) results showed that both triglyceride and cholesterol-lowering medication were positively associated with NVDs (ORâ =â 1.001, 95% CI 1.000-1.0012, Pâ = 0.006; ORâ =â 1.007, 95% CI 1.003-1.010; Pâ = 0.002). This study suggests that both triglyceride and cholesterol-lowering medications are positively associated with NVDs, suggesting that lowering triglyceride levels or the use of cholesterol-lowering medications may reduce the incidence of NVDs. However, larger samples are required for further validation.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Triglicerídeos , Humanos , Triglicerídeos/sangue , Doenças das Valvas Cardíacas/genética , Anticolesterolemiantes/uso terapêuticoRESUMO
BACKGROUND AND AIMS: The criteria for the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) more restrictive than those approved were established in Catalonia by the Health System (CatSalut) to improve their efficiency, with different LDL-C values from which to start treatment according to risk factors. The aim of the study is to analyse adherence to these criteria and results. METHODS: A retrospective study of patients treated with PCSK9i at Vall d'Hebron University Hospital between 2016 and 2021 was performed using data from the Registry of Patients and Treatments and medical records. The degree of agreement with the CatSalut criteria, LDL-C-responders (decrease ≥30%), cardiovascular events and discontinuations were analysed. RESULTS: A total of 193 patients treated with PCSK9i were followed for a median of 27 months (IQR 23). The median age was 61 (IQR 15); 62.7% were men. Seventy percent of the patients had non-familial hypercholesterolemia. Treatment was for secondary prevention of cardiovascular disease in 82.4% of cases. The median LDL-C decreased from 139 (IQR 52) to 59 (IQR 45) mg/dL. The percentage of LDL-C reduction was 61.0% (IQR 30). In 72.5% of patients, all CatSalut criteria for starting treatment were met. The rate of responders was 85.4%. During follow-up, 19 patients (9.8%) had a cardiovascular event, and 15 (7.7%) discontinued treatment, in two cases due to toxicity. CONCLUSION: PCSK9i were used according to CatSalut criteria in three out of four cases. In this high-risk population, incidence of cardiovascular events was similar to that in clinical trials.
Assuntos
Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , Doenças Cardiovasculares , LDL-Colesterol , Hipercolesterolemia , Inibidores de PCSK9 , Humanos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/complicações , Idoso , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia , Inibidores de PCSK9/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Resultado do Tratamento , Fatores de Risco de Doenças Cardíacas , Pró-Proteína Convertase 9RESUMO
Importance: Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial. Objective: To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti-PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C-lowering treatment. Design, Setting, and Participants: This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg/dL or greater with CVD or 100 mg/dL or greater if at high risk of CVD were included. Interventions: Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo for 52 weeks. Main Outcomes and Measures: The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets. Results: Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C-lowering efficacy. Conclusions and Relevance: In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone. Trial Registration: ClinicalTrials.gov Identifier: NCT04806893.