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1.
Vasc Health Risk Manag ; 16: 403-418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116551

RESUMO

Cardiovascular (CV) disease remains the leading cause of morbidity and mortality worldwide and poses an ongoing challenge with the aging population. Elevated low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cardiovascular disease (ASCVD), and the expert consensus is the use of statin therapy (if tolerated) as first line for LDL-C reduction. However, patients with ASCVD may experience recurrent ischemic events despite receiving maximally tolerated statin therapy, including those whose on-treatment LDL-C remains ≥70 mg/dL, patients with familial hypercholesterolemia, high-risk subgroups with comorbidities such as diabetes mellitus, and those who have an intolerance to statin therapy. Optimal therapeutic strategies for this unmet need should deploy aggressive lipid lowering to minimize the contribution of dyslipidemia to their CV risk, particularly for very high-risk populations with additional risk factors beyond hypercholesterolemia and established ASCVD. To understand the current clinical climate and guidelines regarding ASCVD, we primarily searched PubMed for articles published in English regarding lipid-lowering therapies and CV risk reduction, including emerging therapies, and CV outcomes trials with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. This review discusses the findings of recent clinical trial evidence for CV risk reduction with cholesterol-lowering therapies, with a focus on CV outcomes trials with PCSK9 inhibitors, and considers the impact of the study results for secondary prevention and future strategies in patients with hypercholesterolemia and CV risk despite maximally tolerated statin therapy.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/epidemiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
2.
Cochrane Database Syst Rev ; 10: CD011748, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33078867

RESUMO

BACKGROUND: Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL-C and CVD risk. OBJECTIVES: Primary To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention. SEARCH METHODS: We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017. SELECTION CRITERIA: All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables. MAIN RESULTS: We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used  an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of -2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD -1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD -2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence). Compared to active treatment the alirocumab effects, for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was -1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence). Compared to placebo the evolocumab, for CVD, the RD was -2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was -1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than -1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence).  Compared to active treatment, the evolocumab effects, for any CVD event RD was less than -1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke.  AUTHORS' CONCLUSIONS: The evidence for the clinical endpoint effects of  evolocumab and alirocumab were graded as high. There is a strong evidence base to prescribe PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials.  The evidence base of PCSK9 inhibitors compared with active treatment is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies. Related, most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal. Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticolesterolemiantes/uso terapêutico , Causas de Morte , Antagonistas Colinérgicos/uso terapêutico , Ezetimiba/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Prevenção Primária/métodos , Pró-Proteína Convertase 9/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária/métodos , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo
3.
N Engl J Med ; 383(14): 1317-1327, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32865373

RESUMO

BACKGROUND: Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODS: We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTS: A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONS: In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Adolescente , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Criança , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Lipídeos/sangue , Masculino , Resultado do Tratamento
5.
Am J Cardiol ; 128: 163-167, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32650914

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that provide striking lowering of low-density lipoprotein cholesterol (LDL-C) when added to maximum tolerated therapy in patients with hypercholesterolemia. Ceramides, novel cardiac risk markers, have been associated with increased cardiovascular mortality, independent of traditional cardiovascular risk factors. The Ceramide Risk Score (CRS) predicts the likelihood of adverse cardiovascular events within 1 to 3 years in patients with coronary artery disease. The effect of PCSK9 inhibition on plasma ceramides is not well known. The study examines the effect of PCSK9 inhibitors on plasma ceramides and CRS in patients with clinical indication for this therapy. Retrospective chart review of consecutive patients with hypercholesterolemia on PCSK9 inhibitors was conducted (n = 24; Mayo Clinic 2015 to 2018). Plasma ceramides were measured before the initiation of PCSK9 inhibitors and 2 to 12 months after treatment. CRS was calculated before and after therapy based on individual plasma concentrations of 4 ceramides. Treatment with PCSK9 inhibitors was associated with significant reduction in mean CRS and individual ceramides levels (p <0.0001). CRS significantly improved with PCSK9 therapy. PCSK9 inhibitors significantly decreased LDL-C levels by 63% (p <0.0001). The absolute reduction in CRS did not correlate with the absolute reduction in LDL-C (r = 0.31; confidence interval -0.10 to 0.64), indicating that CRS may evaluate a different pathway for risk reduction beyond LDL-C lowering. In conclusion, treatment with PCSK9 inhibitors is associated with significant reduction in CRS and distinct ceramide levels.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Ceramidas/sangue , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Idoso , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Hipercolesterolemia/sangue , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
6.
High Blood Press Cardiovasc Prev ; 27(4): 331-338, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32651891

RESUMO

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are proven to have profound lowering of low-density lipoprotein cholesterol (LDL-C) in patients with clinical atherosclerotic cardiovascular disease or familial hypercholesterolemia. AIM: The primary purpose of this study was to evaluate PCSK9i utilization in older adults, with a focus on efficacy outcomes within 6 months of initiation. Secondary outcomes included tolerability, out-of-pocket expenses (OPE), and barriers to initiation of therapy. METHODS: We conducted a retrospective chart review of patients ≥ 65 years prescribed PCSK9i therapy by a pharmacist-run lipid clinic within a cardiology practice. RESULTS: A total of 136 older adults were prescribed PCSK9i therapy for a Food and Drug Administration-approved indication between September 2015 and March 2019 with 98 patients included in the analyses. In terms of efficacy, 51 patients who took ≥ 3 doses of PCSK9i with baseline and follow-up lipid panels were assessed. On average, LDL-C reduced by 60% (169-67 mg/dL, p < 0.001). For tolerability, 15 patients reported treatment-emergent side effects, resulting in 10 therapy discontinuations. For the cost analysis, 72 patients reported anticipated OPE for 1 month of therapy. Ultimately 17 patients were approved for manufacturer patient assistance with $0 OPE and 31 patients utilized insurance coverage to obtain therapy reporting a median OPE of $9 United States Dollars ($0-$450). The main barrier to initiation was high OPE. CONCLUSIONS: PCSK9i are effective at lowering LDL-C in older adults. Tolerability was high among patients without a history of statin intolerance. PCSK9i remain high-cost medications to both insurance companies and patients in terms of cost-sharing responsibilities.


Assuntos
Anticolesterolemiantes/economia , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/economia , LDL-Colesterol/sangue , Custos de Medicamentos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/economia , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/economia , Inibidores de Serino Proteinase/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/diagnóstico , Biomarcadores/sangue , Regulação para Baixo , Feminino , Gastos em Saúde , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Seguro de Serviços Farmacêuticos/economia , Masculino , Pró-Proteína Convertase 9/metabolismo , Estudos Retrospectivos , Inibidores de Serino Proteinase/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
7.
Arterioscler Thromb Vasc Biol ; 40(9): 2084-2094, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673528

RESUMO

OBJECTIVE: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific Pcsk9-deficient (i-Pcsk9-/-) mouse model. PPL was measured in i-Pcsk9-/- as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9-/- mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr-/- mice. In contrast, i-Pcsk9-/- mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in Pcsk9+/+ but not in Pcsk9-/- mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated Pcsk9+/+ mice. CONCLUSIONS: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Hiperlipidemias/sangue , Intestinos/enzimologia , Lipídeos/sangue , Pró-Proteína Convertase 9/sangue , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Hiperlipidemias/enzimologia , Hiperlipidemias/genética , Hiperlipidemias/prevenção & controle , Hipolipemiantes/farmacologia , Intestinos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Período Pós-Prandial , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/deficiência , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo
8.
Arch Biochem Biophys ; 689: 108470, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32592802

RESUMO

The accumulation of lipid as a result of long-term consumption of a high-fat diet (HFD) may lead to metabolic and brain dysfunction. Atorvastatin, a recommended first-line lipid-lowering agent, has shown beneficial effects on metabolic and brain functions in several models. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effective therapeutic drug for dyslipidemia patients. However, few studies have reported on the effect of this PCSK9 inhibitor on brain function. In addition, the comparative efficacy on the improvement of metabolic and brain functions between PCSK9 inhibitor and atorvastatin in obese models have not been elucidated. We hypothesized that PCSK9 inhibitor improves metabolic and brain functions in an obese model to a greater extent than atorvastatin. Thirty-two female rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline and HFD rats were given either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. Oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity, apoptosis, amyloid proteins production in the hippocampus and cognitive decline were found in HFD-fed rats. Atorvastatin and PCSK9 inhibitor therapies equally attenuated hippocampal apoptosis and amyloid protein production in HFD-fed rats. Interestingly, PCSK9 inhibitor had the greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity in the hippocampus and cognitive decline. These findings suggest that PCSK9 inhibitor may be another drug of choice for improving brain function in the obese condition with discontinued statin therapy.


Assuntos
Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Obesidade/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Feminino , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Ratos
9.
J Cardiovasc Pharmacol Ther ; 25(5): 409-417, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32419478

RESUMO

BACKGROUND: Previous meta-analyses have shown that statins may cause incident diabetes. This article reviews randomized controlled trials using proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) or ezetimibe on the risk of new-onset diabetes. METHODS: Eight trials involving PCSK9i and 3 trials of ezetimibe were selected for review. PubMed, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov were thoroughly searched for relevant trials. Inclusion criteria included at least 100 patients per treatment arm, follow-up of at least 52 weeks, and at least double-blinded study design. Exclusion criteria included patients with previously diagnosed diabetes, nonrandomized, placebo-controlled, open-label, and crossover trials. The primary outcome was the number of incident diabetes cases. A random effects model was used. Heterogeneity in effect sizes was measured with I 2 parameter and the Q statistic was used to test for excessive between-study heterogeneity. RESULTS: A total of 52 214 participants for the PCSK9i and a total of 20 084 for the ezetimibe meta-analyses were included. Participants randomized to PCSK9i did not differ from the control patients in diabetes incidence (risk ratio [RR] = 0.99, P = .87, 95% CI = 0.92-1.07). Participants randomized to ezetimibe did not differ from the control patients in diabetes incidence (RR = 1.05, P = .37, 95% CI = 0.95-1.15). DISCUSSION: The use of PCSK9i and ezetimibe does not appear to impact the risk of incident diabetes mellitus when added to guideline-directed medical therapy.


Assuntos
Anticolesterolemiantes/uso terapêutico , Diabetes Mellitus/epidemiologia , Dislipidemias/tratamento farmacológico , Ezetimiba/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Diabetes Mellitus/diagnóstico , Método Duplo-Cego , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Ezetimiba/efeitos adversos , Humanos , Incidência , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
11.
J Cardiovasc Pharmacol ; 75(5): 410-420, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32379108

RESUMO

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is the primary cause of ASCVD and reducing LDL-C levels with statin therapy significantly reduces ASCVD risk; however, significant residual risk remains. Two monoclonal antibodies (mAbs), alirocumab and evolocumab, that target proprotein convertase subtilisin/kexin-type 9 (PCSK9), reduce LDL-C levels by up to 60% when used in combination with statins and significantly reduce the risk of recurrent ASCVD events in both stable secondary prevention and acute coronary syndrome populations. Prespecified analyses of recent randomized controlled trials have shed light on how best to prioritize these therapies to maximize their value in select high-risk groups. These data have also informed recent clinical practice guidelines and scientific statements resulting in an expanded role for PCSK9-mAbs compared with previous guidelines, albeit there are notable differences between these recommendations. Ongoing research is exploring the long-term safety of PCSK9-mAbs and their role in the acute setting and patients without prior myocardial infarction or stroke. Novel therapies that inhibit PCSK9 synthesis via small interfering RNA, such as inclisiran, are also in development and may reduce LDL-C levels similar to PCSK9-mAbs, but with less frequent administration. Nonetheless, the PCSK9-mAbs are a breakthrough therapy and warrant consideration in very high-risk patients who are most likely to benefit. Such a personalized approach can help to ensure cost-effectiveness and maximize their value.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Medicina de Precisão , Pró-Proteína Convertase 9/antagonistas & inibidores , Prevenção Secundária , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Tomada de Decisão Clínica , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Humanos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Recidiva , Medição de Risco , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
12.
Adv Exp Med Biol ; 1177: 297-339, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32246449

RESUMO

Cardiovascular disease is the number one cause of human morbidity and mortality worldwide. Although cholesterol-lowering drugs, including statins and recently approved PCSK9 inhibitors, together with antithrombotic drugs have been historically successful in reducing the occurrence of coronary artery disease (CAD), the high incidence of CAD remains imposing the largest disease burden on our healthcare systems. We reviewed cardiovascular drugs recently approved or under clinical development, with a particular focus on their pharmacology and limitations. New agents targeting cholesterol/triglyceride lowering bear promise of further cardiovascular risk reduction. Some new antidiabetic agents show cardiovascular benefit in patients with diabetes. Improved antithrombotic agents with diminished bleeding risk are in clinical development. The recent clinical success of the IL-1ß antibody in reducing atherothrombosis opens a new era of therapeutic discovery that targets inflammation. Chinese traditional medicine and cardiac regeneration are also discussed. Human genetics studies of CAD and further delineation of key determinants/pathways underlying the residual risk of CAD under current standard therapy will continue to fuel the pipeline of cardiovascular drug discovery.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Descoberta de Drogas , Doença da Artéria Coronariana/complicações , Diabetes Mellitus/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Fatores de Risco , Trombose/complicações , Trombose/tratamento farmacológico
13.
Metabolism ; 107: 154221, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32240727

RESUMO

BACKGROUND: Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition decreases Lp(a) and cardiovascular events, particularly in high risk patients with elevated Lp(a). We investigated the kinetic mechanism whereby alirocumab, a PCSK9 inhibitor, lowers Lp(a) in statin-treated patients with high Lp(a) and ASCVD. METHODS: The effects of 12-week alirocumab treatment (150 mg every 2 weeks) on apo(a) kinetics were studied in 21 patients with elevated Lp(a) concentration (>0.5 g/L). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. All patients were on long-term statin treatment. RESULTS: Alirocumab significantly decreased plasma concentrations of total cholesterol (-39%), LDL-cholesterol (-67%), apoB (-56%), apo(a) (-25%) and Lp(a) (-22%) (P< 0.001 for all). Alirocumab also significantly lowered plasma apo(a) pool size (-26%, P <0.001) and increased the FCR of apo(a) (+28%, P< 0.001), but did not alter apo(a) PR, which remained significantly higher relative to a reference group of patients on statins with normal Lp(a) (P< 0.001). CONCLUSIONS: In statin-treated patients, alirocumab lowers elevated plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. This may be consequent on marked upregulation of hepatic receptors (principally for LDL) and/or reduced competition between Lp(a) and LDL particles for these receptors; the mechanism could contribute to the benefit of PCSK9 inhibition with alirocumab on cardiovascular outcomes.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Lipoproteína(a)/metabolismo , Pró-Proteína Convertase 9/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Apoproteína(a)/sangue , Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Feminino , Humanos , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Cardiovasc Diabetol ; 19(1): 33, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169071

RESUMO

The proprotein convertase subtilisin/kexin type 9 (PCSK9) acts via a canonical pathway to regulate circulating low-density lipoprotein-cholesterol (LDL-C) via degradation of the LDL receptor (LDLR) on the liver cell surface. Published research has shown that PCSK9 is involved in atherosclerosis via a variety of non-classical mechanisms that involve lysosomal, inflammatory, apoptotic, mitochondrial, and immune pathways. In this review paper, we summarized these additional mechanisms and described how anti-PCSK9 therapy exerts effects through these mechanisms. These additional pathways further illustrate the regulatory role of PCSK9 in atherosclerosis and offer an in-depth interpretation of how the PCSK9 inhibitor exerts effects on the treatment of atherosclerosis.


Assuntos
Aterosclerose/enzimologia , LDL-Colesterol/sangue , Diabetes Mellitus/enzimologia , Dislipidemias/enzimologia , Inflamação/enzimologia , Pró-Proteína Convertase 9/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/patologia , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Humanos , Inflamação/sangue , Inflamação/patologia , Macrófagos/enzimologia , Macrófagos/patologia , Placa Aterosclerótica , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico
15.
Value Health ; 23(2): 209-216, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32113626

RESUMO

OBJECTIVES: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is)-innovative yet costly cholesterol-lowering agents-have been subject to substantial prior authorization (PA) requirements and low approval rates. We aimed to investigate trends in insurer approval and reasons for rejection for PCSK9i prescriptions as well as associations between patients' demographic, clinical, pharmacy, payer, and PCSK9i-specific plan/coverage factors and approval. METHODS: We examined trends in PCSK9i approval rates and reasons for rejection using medical and prescription claims from 2015 to 2017 for individuals who received a PCSK9i prescription. We used multinomial logistic regression to estimate quarterly risk-adjusted approval rates for initial PCSK9i prescriptions and approval for any PCSK9i prescription within 30, 90, and 180 days of the initial PCSK9i prescription. For a 2016 subsample for whom we had PCSK9i-specific plan policy data, we examined factors associated with approval including PCSK9i-specific plan formulary coverage, step therapy requirements, and number of PA criteria. RESULTS: The main sample included 12 309 patients (mean age 64.8 years [SD = 10.8], 52.1% female, 51.5% receiving Medicare) and was similar in characteristics to the 2016 subsample (n = 6091). Approval rates varied across quarters but remained low (initial prescription, 13%-23%; within 90 days, 28%-44%). Over time, rejections owing to a lack of formulary coverage decreased and rejections owing to PA requirements increased. Lack of formulary coverage and having ≥11 PA criteria in the plan policy were associated with lower odds of PCSK9i prescription approval. CONCLUSIONS: These findings confirm ongoing PCSK9i access issues and offer a baseline for comparison in future studies examining the impact of recent efforts to improve PCSK9i access.


Assuntos
Anticolesterolemiantes/uso terapêutico , Definição da Elegibilidade/tendências , Alocação de Recursos para a Atenção à Saúde/tendências , Cobertura do Seguro/tendências , Seguro de Serviços Farmacêuticos/tendências , Autorização Prévia/tendências , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Idoso , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/economia , Estudos Transversais , Bases de Dados Factuais , Custos de Medicamentos , Prescrições de Medicamentos , Definição da Elegibilidade/economia , Feminino , Formulários Farmacêuticos como Assunto , Alocação de Recursos para a Atenção à Saúde/economia , Acesso aos Serviços de Saúde/economia , Acesso aos Serviços de Saúde/tendências , Humanos , Cobertura do Seguro/economia , Seguro de Serviços Farmacêuticos/economia , Masculino , Medicare/economia , Medicare/tendências , Pessoa de Meia-Idade , Autorização Prévia/economia , Inibidores de Serino Proteinase/efeitos adversos , Inibidores de Serino Proteinase/economia , Fatores de Tempo , Estados Unidos
16.
N Engl J Med ; 382(16): 1507-1519, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32187462

RESUMO

BACKGROUND: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Doenças Cardiovasculares , Doença da Artéria Coronariana/complicações , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Injeções Subcutâneas/efeitos adversos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Fatores de Risco
17.
Cleve Clin J Med ; 87(2): 109-120, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32015064

RESUMO

Familial hypercholesterolemia is an autosomal dominant disorder that affects the metabolism of low-density lipo-protein cholesterol (LDL-C) through mutations in the gene for LDL receptor (LDLR), and less commonly in those for apolipoprotein B (APOB), proprotein convertase subtili-sin-kexin type 9 (PCSK9), and others. Patients with these mutations have elevated plasma levels of LDL-C and, as a result, an increased risk of atherosclerotic cardiovascular disease beginning in childhood, leading to significant risk of illness and death.


Assuntos
Anticolesterolemiantes/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/genética , Anamnese , Guias de Prática Clínica como Assunto , Receptores de LDL/genética , Medição de Risco
19.
Clín. investig. arterioscler. (Ed. impr.) ; 32(1): 30-32, ene.-feb. 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-187005

RESUMO

Los inhibidores de la PCSK9, disponibles desde el año 2015, son capaces de reducir la concentración de colesterol transportado en las lipoproteínas de baja densidad entre un 40-70% y, por consiguiente, disminuir el riesgo cardiovascular. Presentamos un caso en el que un episodio cardiovascular grave apareció al espaciar la administración del tratamiento hipolipidemiante; discutiremos la importancia de mantener una concentración baja de colesterol, para conseguir un mayor beneficio clínico según los últimos estudios publicados


Inhibitors of the protein PCSK9, available since 2015, are capable of reducing the concentration of low density lipoprotein cholesterol by 40 to 70%, thus reducing the cardiovascular risk. The present case reports an adverse cardiovascular event that appeared when spacing out the administration of lipid-lowering treatment. A discussion will be presented on the importance of maintaining low cholesterol levels in order to achieve a greater benefit, according to the latest published clinical studies


Assuntos
Humanos , Masculino , Idoso , Ataque Isquêmico Transitório/induzido quimicamente , Relação Dose-Resposta a Droga , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Ataque Isquêmico Transitório/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Pró-Proteína Convertase 9/metabolismo , Lipoproteínas LDL/efeitos dos fármacos
20.
EBioMedicine ; 52: 102650, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32058941

RESUMO

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that down-regulates hepatic low-density lipoprotein receptor (LDLR) by binding and shuttling LDLR to lysosomes for degradation. The development of therapy that inhibits PCSK9 has attracted considerable attention for the management of cardiovascular disease risk. However, only monoclonal antibodies of PCSK9 have reached the clinic use. Oral administration of small-molecule transcriptional inhibitors has the potential to become a therapeutic option. METHODS: Here, we developed a cell-based small molecule screening platform to identify transcriptional inhibitors of PCSK9. Through high-throughput screening and a series of evaluation, we found several active compounds. After detailed investigation on the pharmacological effect and molecular mechanistic characterization, 7030B-C5 was identified as a potential small-molecule PCSK9 inhibitor. FINDINGS: Our data showed that 7030B-C5 down-regulated PCSK9 expression and increased the total cellular LDLR protein and its mediated LDL-C uptake by HepG2 cells. In both C57BL/6 J and ApoE KO mice, oral administration of 7030B-C5 reduced hepatic and plasma PCSK9 level and increased hepatic LDLR expression. Most importantly, 7030B-C5 inhibited lesions in en face aortas and aortic root in ApoE KO mice with a slight amelioration of lipid profiles. We further provide evidences suggesting that transcriptional regulation of PCSK9 by 7030B-C5 mostly depend on the transcriptional factor HNF1α and FoxO3. Furthermore, FoxO1 was found to play an important role in 7030B-C5 mediated integration of hepatic glucose and lipid metabolism. INTERPRETATION: 7030B-C5 with potential suppressive effect of PCSK9 expression may serve as a promising lead compound for drug development of cholesterol/glucose homeostasis and cardiovascular disease therapy. FUND: This work was supported by grants from the National Natural Science Foundation of China (81473214, 81402929, and 81621064), the Drug Innovation Major Project of China (2018ZX09711001-003-006, 2018ZX09711001-007 and 2018ZX09735001-002), CAMS Innovation Fund for Medical Sciences (2016-I2M-2-002, 2016-I2M-1-011 and 2017-I2M-1-008), Beijing Natural Science Foundation (7162129).


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O3/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/genética , Inibidores de Proteases/farmacologia , Animais , Apolipoproteínas E/genética , Aterosclerose/patologia , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Glucose/metabolismo , Células Hep G2 , Fator 1-alfa Nuclear de Hepatócito , Humanos , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Inibidores de Proteases/química
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