ABSTRACT
Los anticuerpos monoclonales proproteína convertasa subtilisina/kexina tipo 9 mejoran el reciclaje de los receptores de lipoproteínas de baja densidad, y reducen la concentración plasmática de estas lipoproteínas alrededor de un 50-60%. Además, reducen la concentración de lipoproteína (a) y aumentan la de lipoproteínas de alta densidad, entre otros beneficios en el metabolismo lipídico. En clínica, estos medicamentos disminuyen la incidencia de eventos cardiovasculares en pacientes con ateroesclerosis crônica y después de un sindrome coronario agudo reciente. Además, en esta poblaciôn, el uso de alirocumab se ha asociado con una menor mortalidad total. Los pacientes que obtienen mayor beneficio clínico son aquellos con ateroesclerosis extensa, diabetes o concentraciones de lipoproteínas de baja densidad ≥ 100 mg/dl. En general estos medicamentos son seguros y parecen ser una excelente herramienta adicional para tratar la dislipemia. Ahora, es nuestra tarea implementar su uso para pacientes con trastornos cardiovasculares para mejorar su pronóstico
Monoclonal antibodies that target proprotein convertase subtilisin/kexin type 9 (PCSK9) increase recycling of low-density lipoprotein receptors, and reduce plasma levels of these lipoproteins by 50-60%. Moreover, these agents also decrease lipoprotein(a) levels and increase high-density lipoprotein levels, as well as having other beneficial effects on lipid metabolism. clínically, these drugs decrease the incidence of cardiovascular events in patients with chronic atherosclerosis and in those who have recently experienced acute coronary syndrome. Furthermore, in these patients, the use of alirocumab has been associated with lower overall mortality. Patients with extensive atherosclerosis, diabetic patients and those with a low-density lipoprotein level >100 mg/dL achieve the greatest clínical benefits. In general, these drugs are safe and appear to offer an excellent additional tool for treating dyslipidemia. Today, the challenge is to promote the use of these agents in patients with cardiovascular disorders in order to improve their prognosis
Subject(s)
Humans , Proprotein Convertase 9/antagonists & inhibitors , Antibodies, Monoclonal/therapeutic use , Atherosclerosis/drug therapy , Atherosclerosis/physiopathology , Evidence-Based Medicine , Clinical Trials as TopicABSTRACT
El uso de fármacos inhibidores de la proprotein convertase subtilisin/kexin type 9 (iPCSK9) ha supuesto un cambio en el tratamiento de la dislipidemia en sus efectos sobre los eventos cardiovasculares. Actualmente, disponemos de 2principios activos comercializados (evolocumab y alirocumab) que tienen indicación en los pacientes que no alcanzan unos valores de lipoproteína de baja densidad (LDL) inferior a 100mg/dl habiendo presentado un evento cardiovascular previo y con dosis máximas o intolerancia a las estatinas. Los ensayos clínicos con iPCSK9 han incluido a pacientes con enfermedad renal, aunque con límites en el filtrado glomerular de hasta 20ml/min/1,73 m2 en el menos restrictivo de ellos. Los subanálisis de estos ensayos clínicos han demostrado eficacia en los pacientes con insuficiencia renal, tanto en la mejoría del perfil lipídico como en la reducción de eventos cardiovasculares. Derivado de su intenso efecto en la reducción de colesterol LDL han surgido algunas dudas sobre su seguridad que actualmente están resueltas y que confieren a los iPCSK9 un evidente beneficio cardiovascular también pacientes con enfermedad renal
The use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has changed the clinical practice of dyslipidemia and their effects in cardiovascular events. Nowadays 2active principles have been commercialized (evolocumab and alircumab) with indication in patients with low-density lipoprotein (LDL) cholesterol over 100mg/dl, history of cardiovascular events and higher statins doses prescribed. Clinical trials with PCSK9i have included chronic kidney disease (CKD) patients, although glomerular filtration rate has been limited up to 20ml/min/1,73m2 or higher. The published sub-analysis of them have demonstrated at least the same efficacy (in reduction of LDL and cardiovascular events) and safety in patients with CKD. However, as these drugs are very powerful in reducing LDL cholesterol, some safety concerns appeared in the past. Once safety is probed, we conclude that PCSK9i are beneficial for CKD patients
Subject(s)
Humans , Proprotein Convertase 9/administration & dosage , Proprotein Convertase 9/antagonists & inhibitors , Dyslipidemias/therapy , Patient Safety , Treatment Outcome , Renal Insufficiency, Chronic/therapy , Proprotein Convertase 9/therapeutic use , Glomerular Filtration Rate/drug effects , Lipoproteins, LDL , Practice Guidelines as Topic/standards , Dyslipidemias/prevention & controlABSTRACT
La asociación epidemiológica entre los niveles de colesterol asociado a lipoproteínas de baja densidad (c-LDL) y el desarrollo de enfermedad vascular aterosclerosa ha sido ratificada mediante estudios de aleatorización mendeliana. Paradójicamente, el éxito de las estatinas condujo a minusvalorar otros tratamientos hipolipidemiantes e incluso la medición del c-LDL. Estudios recientes muestran que la reducción del c-LDL hasta niveles extraordinariamente bajos mediante inhibidores de la absorción y, de modo especialmente intenso, con los anticuerpos monoclonales anti proproteína convertasa subtilisina kexina 9 (PCSK9) continúa ofreciendo protección cardiovascular. Sin embargo, el elevado coste y la limitada experiencia con los inhibidores de PCSK-9 aconsejan un uso prudente de los mismos. Una selección adecuada de los pacientes que más se pueden beneficiar del tratamiento con inhibidores de vPCSK9 emerge como base de consenso de las guías internacionales: la combinación de un elevado riesgo vascular absoluto y un mayor beneficio esperable por los niveles de c-LDL de partida
The epidemiological association of cholesterol associated with low density lipoproteins (LDL-c) levels and the development of atherosclerotic vascular disease has been ratified by mendelian randomization studies. Paradoxically, the success of statins led to the underestimation of other lipid-lowering therapies and even the measurement of LDL-c. Recent studies show that the reduction of LDL-c to extraordinarily low levels through absorption inhibition, and, in a particularly intensive manner, with monoclonal antibodies against pro-protein convertase subtilisine Kesine 9 (PCSK9) continues to offer cardiovascular protection. However, the high cost and limited experience with PCSK-9 inhibitors advised a prudent use of them. An appropriate selection of patients most likely to benefit from treatment with PCSK9 inhibitors emerges as the basis for a consensus of international guidelines: the combination of a high absolute vascular risk and a greater expected benefit by the starting LDL-c levels
Subject(s)
Humans , Cholesterol, LDL/analysis , Cardiovascular Diseases/prevention & control , Anticholesteremic Agents/therapeutic use , Proprotein Convertase 9/antagonists & inhibitors , Antibodies, Monoclonal/therapeutic use , Practice Guidelines as Topic , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Ezetimibe/therapeutic useABSTRACT
No disponible
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Hypercholesterolemia/drug therapy , Anticholesteremic Agents/therapeutic use , Proprotein Convertase 9/antagonists & inhibitors , Atherosclerosis/drug therapy , Drug Monitoring/methods , Treatment Adherence and ComplianceABSTRACT
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
Subject(s)
Humans , Male , Aged , Ischemic Attack, Transient/chemically induced , Dose-Response Relationship, Drug , Hyperlipoproteinemia Type II/drug therapy , Antibodies, Monoclonal/therapeutic use , Proprotein Convertase 9/antagonists & inhibitors , Ischemic Attack, Transient/metabolism , Cardiovascular Diseases/drug therapy , Proprotein Convertase 9/metabolism , Lipoproteins, LDL/drug effectsABSTRACT
La incidencia de las enfermedades arterioscleróticas ha aumentado en los países desarrollados. La dislipemia es un factor de riesgo cardiovascular mayor y el descenso del cLDL es el objetivo terapéutico. Hay que individualizar los objetivos en cada paciente y las estatinas han demostrado ser un tratamiento coste-efectivo tanto en prevención primaria como en secundaria. La aparición de los inhibidores de PSCK9, más potentes y por tanto consiguiendo un mayor descenso de las cifras de cLDL, son un avance en el tratamiento de la enfermedad cardiovascular. La publicación en 2019 de las guías de dislipemias (Sociedad Europea de Cardiología/Sociedad Europea de Arteriosclerosis), con el nivel de evidencia y fuerza de recomendación, pueden ayudar en la toma de decisiones y beneficios para nuestros pacientes en la práctica clínica diaria
The incidence of atherosclerotic cardiovascular disease has increased in the developed countries. Dyslipidemia is a primary major risk factor for atherosclerotic cardiovascular disease and LDL lowering is one of the main objectives. Although treatment goals for dyslipidemias should be personalized in every patient, statins are cost-effective in primary and secondary prevention of atherosclerotic cardiovascular disease. New treatments with higher power and greater decreases in LDL, PSCK9 inhibitors, have made a new breakthrough in atherosclerotic cardiovascular disease treatment. The 2019 guidelines for de management of dyslipidemias: lipid modification to reduce cardiovascular risk (European Society of Cardiology/European Atherosclerosis Society) with the level of evidence and the strength of the recommendations can facilitate the best decisions and benefits to our patients in clinical practice
Subject(s)
Humans , Adult , Middle Aged , Aged , Cholesterol, LDL/therapeutic use , Cardiovascular Diseases/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Arteriosclerosis/drug therapy , Proprotein Convertase 9/antagonists & inhibitors , Risk Factors , Primary Prevention , Health Status Indicators , Lipids/analysis , Life StyleABSTRACT
La disminución del colesterol de las lipoproteínas de baja densidad (c-LDL) se asocia a un descenso de la morbilidad y la mortalidad cardiovascular. Se ha demostrado que no existe un valor de c-LDL por debajo del cual deje de obtenerse un beneficio preventivo con su disminución, y tampoco se ha observado una mayor incidencia de efectos secundarios asociada a las concentraciones más bajas de c-LDL. Disponemos de un amplio arsenal terapéutico hipolipidemiante, sin embargo, en un elevado porcentaje de pacientes no se alcanzan los objetivos de c-LDL. Las estatinas de alta potencia disminuyen el c-LDL por encima del 50%, y al asociar ezetimiba se consigue un descenso adicional del c-LDL de un 15-30% y puede doblar el porcentaje de pacientes que alcanzan los objetivos. Dicha combinación se ha mostrado segura y eficaz en prevención primaria y secundaria de la enfermedad cardiovascular. Otra opción es la combinación de estatinas con resinas de intercambio, aunque requiere un manejo algo más complejo. La inhibición de la proteína PCSK9 con anticuerpos monoclonales disminuye el c-LDL por encima del 60% y es eficaz en la prevención de la enfermedad cardiovascular. Sin embargo, debido a su coste, su uso queda restringido a los pacientes isquémicos o con hipercolesterolemia familiar que no alcanzan los objetivos con los fármacos convencionales. La base de evidencias sobre el beneficio y la seguridad de lograr los objetivos de control del c-LDL es muy amplia y va en aumento. En los próximos años va a ser necesario adecuar la intensidad del tratamiento de la hipercolesterolemia al grado de riesgo vascular de los pacientes y al grado de descenso necesario para lograr los objetivos terapéuticos. Ello redundará en una prevención cardiovascular más eficaz y en una mayor calidad de vida, en particular en el amplio colectivo de pacientes de mayor riesgo vascular
The reduction of low density lipoprotein-cholesterol (LDL-chol) has been associated with a decrease in cardiovascular morbidity and mortality. It has been demonstrated that there is no value of LDL-chol below which there ceases to be a preventive benefit with its reduction, and neither has it been observed that there is a higher incidence of secondary effects associated with lower concentrations of LDL-chol. Although there is a wide range of lipid-lowering drugs available, a high percentage of patients do not achieve the desired LDL-chol levels. The high-potency statins reduce the LDL-chol by 15-30%, and can double the percentage of patients that reach their desired level. This combination has shown to be safe and effective in the primary and secondary prevention of cardiovascular disease. Another option is the combination of statins with exchange resins, although this requires a more complex management. The inhibition of PCSK9 protein with monoclonal antibodies reduces the LDL-chol by more than 60%, and is effective in the prevention of cardiovascular disease. However, due to its cost, its use is restricted to patients with ischaemia or familial hypercholesterolaemia that do not achieve the desired levels with conventional drugs. The evidence base as regards the benefit and safety of achieving the desired levels of LDL-chol is very wide and is still increasing. In the next few years, it may be necessary to adjust the intensity of the hypercholesterolaemia treatment to the level of vascular risk of the patients, and to the level of reduction necessary to achieve the therapeutic targets. This will result in a more effective cardiovascular prevention and in a better quality of life, particularly in the large group of patients at higher vascular risk
Subject(s)
Humans , Cholesterol, LDL/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Proprotein Convertase 9/antagonists & inhibitors , Lipid Metabolism/drug effects , Hypercholesterolemia/drug therapy , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/prevention & control , Quality of Life , Hypolipidemic Agents/administration & dosage , Coronary Artery Disease/prevention & control , Ezetimibe/therapeutic use , Anion Exchange Resins/therapeutic useABSTRACT
Los grandes ensayos clínicos de prevención cardiovascular han demostrado que cuanto más se disminuye el colesterol aterogénico, mayor es el beneficio preventivo, sin que se haya observado un valor umbral por debajo del cual desparezca dicho efecto o se observen efectos negativos para la salud. Por ello, los objetivos de control de la hipercolesterolemia en los pacientes de alto riesgo cardiovascular son cada vez más estrictos. El hecho de que la mayoría de pacientes de alto riesgo no alcancen dichos objetivos hace necesario, entre otras medidas, un uso racional de los fármacos hipolipemiantes disponibles, incluyendo los anticuerpos monoclonales inhibidores de la proteína PCSK9 (iPCSK9). Los iPCSK9 actualmente autorizados para uso clínico, evolocumab y alirocumab, han demostrado una alta potencia para disminuir el colesterolLDL, que puede superar el 60%, y otros efectos favorables sobre el perfil lipídico, incluyendo una disminución también muy acusada del colesterol-noHDL y de la apolipoproteínaB. Así mismo, mediante ensayos clínicos a gran escala ambos fármacos han demostrado un efecto preventivo frente a las enfermedades cardiovasculares y un alto grado de seguridad. Además, en el caso del alirocumab se ha observado una disminución de la mortalidad por todas las causas. Sin embargo, el elevado coste de los iPCSK9 hace necesario ceñir sus indicaciones a los pacientes de mayor riesgo cardiovascular que no puedan controlarse con estatinas de alta potencia y ezetimiba. Es de esperar que las nuevas guías que serán emitidas en un futuro cercano por distintas sociedades científicas definan con mayor detalle en qué pacientes y en qué condiciones pueden utilizarse los iPCSK9, unos agentes que en este momento constituyen el avance más importante de la terapia hipocolesterolemiante de las últimas décadas
The large clinical trials on cardiovascular prevention have demonstrated that the more atherogenic cholesterol is reduced the greater the preventive benefit, and neither a threshold value below which that effect disappears nor negative effects on health have been observed. Therefore, the objectives of hypercholesterolaemia control in patients at high cardiovascular risk are becoming ever stricter. The fact that most high-risk patients do not achieve these objectives requires, among other measures, rational use of available lipid-lowering drugs, including monoclonal antibodies that inhibit the protein PCSK9 (PCSK9i). The PCSK9i that are currently licensed for clinical use, evolocumab and alirocumab, have shown high potency in lowering LDL-cholesterol, which can exceed 60%, and other favourable effects on lipid profiles, including a very marked reduction of non-HDL cholesterol and apolipoproteinB. Likewise, through large-scale clinical trials, both drugs have demonstrated a preventive effect against cardiovascular diseases, and a high degree of safety. In addition, in the case of alirocumab, a reduction in all-cause mortality has been observed. However, the high cost of the PCSK9i means that prescription is restricted to patients at highest cardiovascular risk who cannot be controlled with high-potency statins and ezetimibe. It is to be hoped that the new guidelines that are to be issued soon by various scientific societies will define in greater detail the patients and the conditions in which we can use PCSK9i, drugs which currently constitute the greatest advance in hypercholesterolaemia of recent decades
Subject(s)
Humans , Adult , Middle Aged , Aged , Aged, 80 and over , Hypercholesterolemia/drug therapy , Cholesterol, LDL/drug effects , Antibodies, Monoclonal/administration & dosage , Proprotein Convertase 9/antagonists & inhibitors , Antibodies, Monoclonal/pharmacology , Cardiovascular Diseases/prevention & control , Clinical Trials as TopicABSTRACT
Se trata de un paciente con hipercolesterolemia familiar heterocigota y antecedentes de infarto agudo de miocardio, que es remitido a la unidad de lípidos de nuestro centro para ajuste del tratamiento hipocolesterolemiante. Dado que no alcanza los objetivos terapéuticos con tratamiento oral, comienza tratamiento con sesiones quincenales de aféresis de colesterol LDL, que mantiene durante 8 años. Con la introducción y disponibilidad de los inhibidores de la PCSK9, se presenta una nueva opción de tratamiento para este paciente
It is a patient with heterozygous familial hypercholesterolemia and a personal history of acute myocardial infarction, which is referred to our lipid unit for hypocholesterolemic treatment adjustment. Since he does not reach therapeutic goals with oral medication, he starts a treatment with fortnightly sessions of LDL-apheresis, which he keeps for 8 years. With the introduction and availability of PCSK9 inhibitors, a new treatment option is possible for this patient
Subject(s)
Humans , Male , Middle Aged , Proprotein Convertase 9/antagonists & inhibitors , Hyperlipoproteinemia Type II/diagnosis , Myocardial Infarction/complications , Antibodies, Monoclonal/pharmacology , Cholesterol, LDL/antagonists & inhibitors , Anticholesteremic Agents , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/genetics , Proprotein Convertase 9/administration & dosage , Proprotein Convertase 9/metabolism , Lipoproteins, LDL/drug effectsABSTRACT
La reducción del colesterol-LDL (C-LDL) es un objetivo primordial en prevención cardiovascular. Estudios recientes demostraron beneficio clínico al administrar inhibidores de la proprotein convertase subtilisin/kexin-9 (iPCSK9) a pacientes que no habían logrado la meta de C-LDL con estatinas de alta intensidad y ezetimibe, sin embargo el uso de estos fármacos está limitado por su costo. El American College of Cardiology, la Sociedad Argentina de Cardiología y la European Society of Cardiology recomiendan una meta de C-LDL menor a 70 mg/dl en prevención secundaria, determinando umbrales de C-LDL de 70, 100 o 140 mg/dl respectivamente, para iniciar el tratamiento con iPCSK9. Con el objetivo de evaluar el esquema hipolipemiante prescripto en internados por síndrome coronario agudo o revascularización coronaria y analizar la proporción de elegibles para ser tratados con iPCSK9 en un escenario real y simulado, realizamos un estudio que incluyó 351 pacientes con enfermedad coronaria, tomados de una base de datos electrónica de un hospital universitario. El 48.4% recibió estatinas de elevada intensidad, 11.4% ezetimibe y 54.7% no logró la meta de C-LDL menor a 70 mg/dl. Utilizando un modelo de simulación en el que todos serían medicados con estatinas de elevada intensidad y ezetimibe, la elegibilidad para prescribir iPCSK9 fue de 31.1%, 12.8% y 9.1% según los umbrales de C-LDL determinados por las tres sociedades científicas. Nuestro estudio demostró una brecha entre las recomendaciones de los consensos para reducir el colesterol y la práctica habitual que debería ser minimizada para optimizar la relación costo/efectividad en prevención secundaria.
LDL-cholesterol (LDL-C) lowering is a primary objective in cardiovascular prevention. Recent studies demonstrated clinical benefit when proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i) were added to the treatment in patients who had not achieved the LDL-C goal despite being treated with high intensity statins and ezetimibe, however the use of these drugs is limited by their cost. The American College of Cardiology, the Argentine Society of Cardiology and the European Society of Cardiology recommend an LDL-C goal less than 70 mg/dl in secondary prevention, determining thresholds of LDL-C to start treatment with PCSK9i of 70, 100 or 140 mg/dl respectively. In order to evaluate the lipid-lowering regimen prescribed in patients hospitalized for acute coronary syndrome or coronary revascularization and analyze the proportion of eligible to be treated with PCSK9i in a real and simulated scenario, we conducted a study that included 351 patients with coronary disease collected from an electronic database of a university hospital. The 48.4% received high intensity statins, 11.4% ezetimibe and 54.7% did not achieve the LDL-C goal of less than 70 mg/dL. Using a simulation model in which all would be treated with high intensity statins and ezetimibe, the eligibility to prescribe PCSK9i was 31.1%, 12.8% and 9.1% according to the C- LDL thresholds determined by the three scientific societies. Our study demonstrated a gap between the consensus recommendations for LDL-C lowering and the current practice that should be minimized to optimize the cost/effectiveness ratio in secondary prevention.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Proprotein Convertase 9/antagonists & inhibitors , Hypercholesterolemia/drug therapy , Anticholesteremic Agents/therapeutic use , Argentina , Societies, Scientific , Time Factors , Sex Factors , Cross-Sectional Studies , Age Factors , Treatment Outcome , Practice Guidelines as Topic , Statistics, Nonparametric , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Ezetimibe/therapeutic useABSTRACT
Abstract Coronary artery disease (CAD) is one of the leading causes of mortality. High circulating levels of low-density lipoprotein (LDL) in the blood are associated with cardiovascular mortality, whether through an etiological role or through its association with the progression of CAD per se. Randomized clinical trials have shown that, when LDL levels are reduced, cardiovascular risk is also reduced, which reinforces this association. The first major trial involving a hypolipidemic agent of the statin family, the Scandinavian Simvastatin Survival Study (4S), was published in 1994 and found a significant reduction in mortality in patients at high cardiovascular risk. However, even in subsequent studies with different statins, a residual risk persisted, and this seems not to have changed over time; it is speculated that this risk may be due to statin intolerance. In this scenario, the potential exists for novel hypolipidemic agents to drive a true revolution in the therapy of dyslipidemia. The recent discovery of PCSK9 inhibitors (PCSK9i), a class of hypolipidemic monoclonal antibodies, is extremely promising. PCSK9 inhibition is capable of promoting a mean LDL reduction of up to 60%, with potential for very significant clinical repercussions, as every 38 mg/dL reduction in LDL appears to be associated with a 22% reduction in cardiovascular risk. This review addresses a brief history of PCSK9i, major trials of these drugs, cardiovascular outcomes, and aspects related to their efficacy and safety. Finally, the molecular mechanisms and possible pleiotropic effects of PCSK9i are also discussed.
Resumo A doença arterial coronariana (DAC) é uma das principais causas de mortalidade. Níveis circulantes elevados de lipoproteína de baixa densidade (LDL) no sangue estão associados com mortalidade cardiovascular, seja por um papel etiológico ou por sua associação com a progressão da DAC em si. Estudos clínicos randomizados mostram que, quando os níveis de LDL são reduzidos, o risco cardiovascular também é reduzido, o que reforça tal associação. O primeiro ensaio importante envolvendo um agente hipolipemiante da família da estatina, o estudo Scandinavian Simvastatin Survival Study (4S), foi publicado em 1994 e encontrou uma redução significativa na mortalidade de pacientes com risco cardiovascular elevado. Contudo, mesmo em estudos subsequentes com diferentes estatinas, observou-se um risco residual persistente, o qual aparentemente não mudou ao longo dos anos. Especula-se que esse risco se deve à intolerância às estatinas. Nesse cenário, existe um potencial para novos agentes hipolipemiantes que levem a uma verdadeira revolução no tratamento das dislipidemias. A descoberta recente dos inibidores de PCSK9 (PCSK9i), uma classe de anticorpos monoclonais, é extremamente promissora. A inibição da PCSK9 é capaz de promover uma redução média nos níveis de LDL de até 60%, com potencial para repercussões clínicas muito significativas, já que para cada redução de 38 mg/dL, parece haver uma redução de 22% no risco cardiovascular. Esta revisão aborda uma breve história dos PCSK9i, os principais ensaios envolvendo esses medicamentos, desfechos cardiovasculares, e aspectos relacionados a sua eficácia e segurança. Finalmente, os mecanismos moleculares e possíveis efeitos pleiotrópicos dos PCSK9i são também discutidos.
Subject(s)
Humans , Cardiovascular Diseases/prevention & control , Proprotein Convertase 9/antagonists & inhibitors , Hypercholesterolemia/drug therapy , Cholesterol, LDL/drug effects , Anticholesteremic Agents/therapeutic use , Cardiovascular Diseases/etiology , Reproducibility of Results , Risk Factors , Risk Assessment , Diabetes Mellitus/physiopathology , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Hypercholesterolemia/complications , Cholesterol, LDL/blood , Anticholesteremic Agents/pharmacologyABSTRACT
Varón de 60 años con hiperlipidemia familiar combinada, cardiopatía isquémica y diabetes tipo 2. Desde la infancia, intolerancia al esfuerzo intenso. Se le diagnosticó enfermedad de McArdle a raíz de rabdomiólisis asociada a estatinas tras un infarto de miocardio. Desde entonces había seguido tratamiento con dieta, fibratos y ezetimiba con buena tolerancia, pero a pesar de ello las concentraciones de colesterol LDL (cLDL) eran > 180 mg/dl. Se asoció al tratamiento alirocumab 150 mg subcutáneos cada 14 días, con excelente respuesta clínica y descenso de cLDL a 15 mg/dl, manteniéndose estable desde entonces. Nuestro caso demuestra que los inhibidores de PCSK9 son eficaces y seguros en pacientes con enfermedades musculares que contraindican las estatinas y que son una alternativa terapéutica ideal para este tipo de pacientes
A 60-year-old male with familial combined hyperlipidemia, ischemic heart disease and type 2 diabetes. Since childhood, intolerance to intense exercise. The patient was diagnosed of McArdle's disease after an episode of rhabdomyolysis associated with statins as treatment after a myocardial infarction. Since then, he had been treated with diet, fibrates and ezetimibe with good tolerance, despite this, LDL cholesterol (cLDL) remained > 180 mg/dl. He started to be treated with alirocumab 150mg/sc every 14 days, with excellent clinical response and a decrease in cLDL to 15 mg/dl. Our case shows that PCSK9 inhibitors are effective and safe in patients with muscle diseases who have statin contraindication, and they are a good therapeutic tool for these patients
Subject(s)
Humans , Male , Middle Aged , Glycogen Storage Disease Type V/drug therapy , Proprotein Convertase 9/antagonists & inhibitors , Antibodies, Monoclonal/therapeutic useABSTRACT
No disponible
Subject(s)
Humans , Proprotein Convertase 9/antagonists & inhibitors , Hyperlipoproteinemia Type II/prevention & control , Cholesterol, LDL , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Patient Selection , Risk Factors , 50303ABSTRACT
Introducción y objetivos: Analizar la razón de coste-efectividad y el impacto presupuestario del tratamiento con evolocumab (inhibidor de la PCSK9) para pacientes en prevención secundaria en el Sistema Nacional de Salud español. Métodos: Se realizaron, desde la perspectiva del sistema sanitario público, análisis de impacto presupuestario, modelos de árbol de decisión y Markov, basándose en el único ensayo clínico con datos de morbimortalidad (FOURIER). Las alternativas comparadas fueron evolocumab frente a estatinas y un 5% ezetimiba conjuntamente. La medida de eficacia utilizada fue el número de eventos cardiovasculares evitados. Se realizaron análisis de sensibilidad univariable y probabilístico. Resultados: El coste sanitario promedio de los pacientes tratados a 26 meses con evolocumab fue de 11.134,78 euros y de 393,83 euros con el estándar (estatinas + ezetimiba). El coste-efectividad incremental superó los 600.000 euros por evento cardiovascular evitado en las 2 variables (primera: muerte cardiovascular, infarto de miocardio, accidente cerebrovascular, hospitalización por angina inestable o revascularización coronaria; segunda: incluye los 3 primeros eventos). A 10 años, el modelo de Markov mostró un coste promedio de 471.417,37 frente a 13.948,45 euros con evolocumab y estándar respectivamente. El tratamiento con evolocumab en hipercolesterolemia familiar supondría anualmente entre 3 y 6,1 millones de euros, lo que supone una diferencia de 2,5-5,1 millones de euros con el tratamiento estándar (2017). Para el año 2021, en hipercolesterolemia no familiar (prevención secundaria), la diferencia osciló entre 204,3 y 1.364,7 millones de euros. Conclusiones: El evolocumab se asocia con menor frecuencia de eventos cardiovasculares, pero resulta ineficiente para los pacientes susceptibles de recibirlo en el Sistema Nacional de Salud
Introduction and objectives: To analyze the cost-effectiveness ratio and budget impact of treatment with evolocumab (PCSK9 inhibitor) for patients in secondary prevention in the Spanish National Health System. Methods: A budget impact analysis, decision tree and Markov models were designed under the public health system perspective, based on the only study with morbidity and mortality data (FOURIER). The alternatives compared were evolocumab vs statins, and dual therapy with ezetimibe in 5% of the population. The measure of effectiveness used was the number of cardiovascular events avoided. Univariate and probabilistic sensitivity analyses were performed. Results: The average annual cost of patients receiving evolocumab was 11 134.78€ and 393.83€ for standard treatment (statins plus ezetimibe). The incremental cost-effectiveness ratio was > 600 000 € per avoided cardiovascular event for both assessed outcomes (first: cardiovascular death, myocardial infarction, stroke, and hospitalization due to unstable angina or coronary revascularization; second: includes the first 3 events). To perform the 10-year Markov model, the average cost of standard treatment was 13 948.45€ vs 471 417.37€ with evolocumab. Treatment with evolocumab for patients with familial hypercholesterolemia would cost between 3 and 6.1 million euros, assuming a difference of 2.5 and 5.1 million euros with the standard treatment (2017). This difference would be between 204.3 and 1364.7 million euros (2021) for those with nonfamiliar hypercholesterolemia (secondary prevention). Conclusions: Treatment with evolocumab is associated with a lower frequency of cardiovascular events, but is inefficient for patients suitable to receive this drug in the Spanish National Health System
Subject(s)
Humans , Male , Female , Middle Aged , Hypercholesterolemia/drug therapy , Cardiovascular Diseases/prevention & control , Proprotein Convertase 9/antagonists & inhibitors , Anticholesteremic Agents/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , 50303 , Antibodies, Monoclonal/therapeutic use , Hypolipidemic Agents/economics , Anticholesteremic Agents/economicsABSTRACT
INTRODUÇÃO: hipercolesterolemia familiar homozigota é uma doença genética rara (estimativas de prevalência 1:300 mil a 1:1 milhão de pessoas) que caracteriza-se por níveis extremamente elevados de colesterol total (usualmente acima de 500 mg/dL) e morte cardíaca precoce. O tratamento atualmente disponível, além de medidas não farmacológicas é o uso de estatinas de alta potência. TECNOLOGIA: evolocumabe (Repatha®). PERGUNTA: eficácia clínica do tratamento com evolocumabe em pacientes com hiperlipidemia familiar homozigótica sem resposta adequada com estatinas de alta potência. EVIDÊNCIAS CIENTÍFICAS: os dados sobre a eficácia do tratamento com evolocumabe para HFHo são limitadas. Resumem-se a um estudo randomizado cegado e controlado por placebo mostrando eficácia na redução do colesterol total e um estudo de coorte mostrando segurança do tratamento em um seguimento médio de 1,9 ano. AVALIAÇÃO ECONÔMICA: foi realizada uma análise utilizando modelo de Markov com análises de coortes comparadas, da perspectiva do sistema de saúde público, com horizonte de análise por toda vida. O modelo baseia-se em equações de risco cardiovascular influenciadas por perfil lipídico da coorte. Utilizando estimativa de efetividade derivada do estudo acima descrito, observou-se uma RCEI de 502.666,00 reais por QALY ganho. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: considerando uma prevalência de 1:1.000.000 de indivíduos, estima-se o impacto orçamentário em 31,2 milhões de reais para os próximos cinco anos. RECOMENDAÇÃO PRELIMINAR: A evidência atualmente disponível sobre eficácia e segurança do evolocumabe para tratamento da hiperlipidemia familiar homozigota é baseada em um ensaio clínico e um estudo observacional de coorte, com nível de evidência "1b" e grau de recomendação "A" para redução de níveis de colesterol LDL. Não há dados comprovando o efeito dessa medicação em desfechos duros. A análise econômica depende diretamente da confiança nessa estimativa de efetividade, e demonstrou uma RCEI elevada, mesmo que considerando potencial viés conservador na aferição de custos. O impacto econômico dessa medicação parece incerto em função de uma prevalência desconhecida na população brasileira, podendo variar em até 3 vezes em relação ao estimado. Considerou-se que, os critérios utilizados para o diagnóstico clínico apresentavam aspectos subjetivos, que tornaria difícil selecionar de forma definitiva os indivíduos elegíveis para tratamento, segundo proposta do demandante. Assim, a CONITEC em sua 62ª reunião, recomendou a não incorporação no SUS do evolocumabe para tratamento de hipercolesterolemia familiar homozigótica. CONSULTA PÚBLICA: Foram recebidas 21 contribuições técnico-científicas e 34 contribuições de experiência ou opinião, sendo a maioria (94,5%) discordante com a recomendação preliminar da CONITEC. De maneira geral, as contribuições apontaram que a hipercolesterolemia familiar homozigótica acarreta importante morbidade e mortalidade aos portadores, e os objetivos terapêuticos não são atingidos pelos medicamentos atuamente disponíveis no SUS. Os contribuintes consideram que o Evolucumabe é eficaz no tratamento da doença e que sua adoção poderia trazer economia de recursos se contraposto ao atual gasto com medicações obtidas por via judicial. Como contribuição adicional, o fabricante do Repatha® apresentou uma nova proposta de preço para o produto, revisando as análises econômicas considerando o novo valor, comprometendo-se a financiar os custos excedentes àqueles previstos na análise de impacto orçamentário, caso o número de pacientes efetivamente tratados exceda o estimado no cenário avaliado. Entretanto, a CONITEC entendeu que não houve argumentação suficiente para alterar sua recomendação preliminar. RECOMENDAÇÃO FINAL: Os membros da CONITEC em 02/08/2018 deliberaram por unanimidade recomendar a não incorporação do evolocumabe para tratamento de hipercolesterolemia familiar homozigótica, no SUS. Foi assinado o Registro de Deliberação nº 363/2018. DECISÃO: Não incorporar o evolocumabe para tratamento de pacientes com hipercolesterolemia familiar homozigótica (HFHo), no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 73, publicada no DOU nº 239, seção 1, página 80, em 13 de dezembro de 2018.
Subject(s)
Humans , Proprotein Convertase 9/antagonists & inhibitors , Hyperlipoproteinemia Type II/drug therapy , Technology Assessment, Biomedical , Health Evaluation/economics , Unified Health System , Brazil , Cost-Benefit Analysis/economicsSubject(s)
Humans , Male , Female , Middle Aged , Aged , Cardiovascular Diseases/drug therapy , Proprotein Convertase 9/antagonists & inhibitors , Hypercholesterolemia/drug therapy , Cholesterol, LDL/blood , Antibodies, Monoclonal/therapeutic use , Anticholesteremic Agents/therapeutic use , Arteriosclerosis/drug therapy , Cardiovascular Diseases/complications , Cardiovascular Diseases/mortality , Cardiovascular Diseases/epidemiology , Least-Squares Analysis , Double-Blind Method , Follow-Up Studies , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/complications , Antibodies, Monoclonal/adverse effects , Anticholesteremic Agents/adverse effectsABSTRACT
El descubrimiento de la proproteína convertasa de subtilisina/kexina tipo 9 (PCSK9) en el año 2003 en familias con hipercolesterolemia familiar (HF) generó posteriormente el desarrollo de estrategias farmacológicas a fin de inhibir esta proteína. Doce años después de este descubrimiento, se logró la aprobación de los 2 primeros compuestos biológicos (anticuerpos monoclonales) que han demostrado disminuir en forma sustancial el cLDL y otras subfracciones lipídicas. El objetivo del presente artículo es repasar la historia del descubrimiento de la PCSK9, de su fisiología y fisiopatología, y del posterior desarrollo farmacológico. Se plantean los objetivos y las metas alcanzados a la fecha y las cuestiones pendientes en cuanto a la eficacia y la seguridad de su uso clínico
The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) in 2003 in families with familial hypercholesterolemia (HF) later generated the development of pharmacological strategies in order to inhibit this protein. Twelve years after this discovery, the first two biological compounds (monoclonal antibodies) were approved, which have been shown to substantially decrease LDL-C and other lipid subfractions. The objective of the present article is to review the history of the discovery of PCSK9, its physiology and pathophysiology and subsequent pharmacological development. The objectives and goals reached to date and the pending questions regarding the efficacy and safety of its clinical use are presented
Subject(s)
Humans , Proprotein Convertase 9/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , Proprotein Convertase 9/antagonists & inhibitors , Low Density Lipoprotein Receptor-Related Protein-1/therapeutic use , Proprotein Convertase 9/pharmacology , Antibodies, Monoclonal/classificationABSTRACT
TECNOLOGIA: Alirocumabe (Praluent®). INDICAÇÃO NA BULA: Indicado em adultos com hipercolesterolemia primária (familiar heterozigótica e não familiar) ou dislipidemia mista, como adjuvante à dieta: em pacientes incapazes de atingir os níveis alvos predefinidos da lipoproteína de baixa densidade (LDL-C) com o máximo de dose de estatina tolerada, em combinação à estatina ou à estatina associada a outras terapias hipolipemiantes ou, em pacientes intolerantes a estatina, seja como monoterapia ou em associação a outra terapia hipolipemiante. PERGUNTA: Alirocumabe é eficaz e seguro para o tratamento da dislipidemia? EVIDÊNCIAS: Foram incluídas uma revisão sistemática e uma meta-análise que avaliaram o uso de alirocumabe em comparação com placebo e ezetimibe no tratamento de diferentes tipos de dislipidemia. Não foram encontrados estudos de comparação direta com as estatinas. Uma revisão sistemática demonstrou que o uso de alirocumabe (75 mg a 150 mg por via subcutânea a cada 2 semanas) apresentou reduções significativamente maiores no colesterol de lipoproteínas de baixa densidade (LDL-C; -8% a -67%) em 12 a 24 semanas contra placebo ou ezetimibe em (a) pacientes com hipercolesterolemia familiar heterozigótica e (b) pacientes com risco cardiovascular (CV) elevado ou variado, que não alcançaram as metas de LDL-C em uso de terapia com estatina. A maior força de evidência foi para pacientes com alto risco CV. O alirocumabe também resultou em aumentos de colesterol de lipoproteínas de alta densidade (HDL-C) de 6 a 12%. Evidência de qualidade baixa a moderada para julgamento de eventos CV no período de 52 a 78 semanas não indicou nenhum benefício comparado a placebo ou ezetimibe. Evidência de qualidade baixa a moderada também não encontrou diferenças nos danos, exceto por mais reações no local da aplicação. Alirocumabe apresenta evidência de grande melhora nos níveis lipídicos. Estudos são necessários para confirmar os benefícios e segurança dos medicamentos à longo prazo. Uma meta-análise de ensaios clínicos randomizados de fase II e fase III avaliou a eficácia e a segurança dos inibidores da PCSK-9, alirocumabe e evolocumabe. Foram incluídos 25 estudos com um total de 12.200 pacientes. As taxas de eventos adversos comuns não mostraram diferença significativa entre anticorpos anti-PCSK9 e placebo (ou ezetimibe), exceto que o alirocumabe foi associado a taxas reduzidas de mortalidade (risco relativo (RR): 0,43, intervalo de confiança de 95% (IC): 0,19 a 0,96, P = 0,04) e uma taxa aumentada de reações no local da aplicação (RR: 1,48, IC 95%: 1,05 a 2,09, P = 0,02) comparado a placebo. Alirocumabe a cada duas semanas, na dose de 50 a 150 mg, reduziu o LDL-C em -52,6% contra placebo (IC 95%: -58,2 a -47,0%) e em -29,9% contra ezetimibe (IC 95%: -32,9 a -26,9%) e aumentou HDL-C em 8,0% contra placebo (IC 95%: 4,2 a 11,7%). Alirocumabe foi considerado seguro e bem tolerado e reduziu substancialmente o nível de LDL-C em mais de 50%, aumentou o nível de HDL-C e resultou em mudanças favoráveis em outros lipídios. CONCLUSÕES: Alirocumabe apresenta eficácia e segurança para o tratamento da dislipidemia comparado a placebo e ezetimibe. O medicamento é registrado na ANVISA, EMA e FDA. Nas agências canadense e britânica de tecnologias em saúde, alirocumabe apresenta indicações de uso para subgrupos específicos e condicionado a redução de preço por não ser considerado custo-efetivo.(AU)
Subject(s)
Humans , Antibodies, Monoclonal/therapeutic use , Dyslipidemias/drug therapy , Ezetimibe/therapeutic use , Proprotein Convertase 9/antagonists & inhibitors , Brazil , Cost-Benefit Analysis , Technology Assessment, BiomedicalABSTRACT
El grado de control de las dislipemias en los pacientes con manifestaciones clínicas de enfermedad arteriosclerótica es aún muy deficiente. La disponibilidad de nuevos agentes, como los anticuerpos monoclonales anti-PCSK9, puede suponer un notable avance para cubrir este déficit. En un amplio programa de ensayos clínicos se ha demostrado que estos agentes disminuyen el colesterol unido a lipoproteínas de baja densidad (cLDL) por encima de un 60% y disminuyen también la apolipoproteína B y la lipoproteína (a), mostrando un excelente perfil de tolerancia y seguridad. Por otro lado, en los análisis post-hoc de los ensayos de fase II y III se ha observado que cuando estos agentes se asocian al tratamiento hipolipemiante convencional disminuyen el riesgo cardiovascular (RCV). Este hecho ha sido recientemente confirmado en el estudio FOURIER, que claramente ha demostrado que la inhibición de PCSK9 con evolocumab en pacientes de alto RCV tratados con estatinas reduce los valores de cLDL a cifras medias de 30 mg/dl y el riesgo de nuevos eventos cardiovasculares en un 20% a los 2,2 años. Estos resultados demuestran que los pacientes con manifestaciones clínicas de enfermedad arteriosclerótica se benefician de la reducción de los valores de cLDL por debajo de los objetivos marcados en la actualidad. Es esperable que los resultados del estudio FOURIER puedan y deban ser implementados en las guías internacionales de consenso del tratamiento de las hiperlipemias en pacientes de alto RCV (AU)
Dyslipidemia control in patients with clinical manifestations of arteriosclerotic disease remains deficient. The availability of new agents, such as anti-PCSK9 antibodies, could represent a significant advance in filling this gap. A wide programme of clinical trials has shown that these agents reduce low-density lipoprotein cholesterol by more than 60% and also reduce apolipoprotein B and lipoprotein(a), showing an excellent safety and tolerability profile. In addition, post hoc analyses of phase II and III trials showed that the association of these agents with conventional lipid-lowering treatment reduced cardiovascular risk (CVR) by around 50%. This finding has recently been confirmed in the FOURIER trial, which has clearly demonstrated that PCSK9 inhibition with evolocumab in patients with high CVR treated with statins reduces LCL-c levels to mean values of 30 ml/dl and the risk of new cardiovascular events by 20% at 2.2 years. These results show that patients with clinical manifestations of arteriosclerotic disease benefit from a reduction of LDLc values below current targets. It is expected that the results of the FOURIER study can and should be included in the international consensus guidelines for the treatment of hyperlipidemia in patients with high CVR (AU)
Subject(s)
Humans , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/prevention & control , Proprotein Convertase 9/therapeutic use , Evidence-Based Medicine/methods , Proprotein Convertase 9/antagonists & inhibitors , Lipoproteins, LDL/therapeutic use , Hypercholesterolemia/drug therapy , Antibodies, Monoclonal/therapeutic use , Hyperlipidemias/drug therapy , Hyperlipidemias/prevention & control , Hypercholesterolemia/prevention & control , Secondary Prevention/trendsABSTRACT
Los anticuerpos son glucoproteínas con alta especificidad de unión a múltiples antígenos gracias al gran número de conformaciones estructurales de sus cadenas variables. La tecnología de los hibridomas (fusión de células de mieloma no secretor con linfocitos productores de inmunoglobulinas) ha permitido la síntesis de grandes cantidades de anticuerpos únicos (monoclonales [mAb]). Los mAb iniciales eran murinos, posteriormente se desarrollaron mAb quiméricos, humanizados y finalmente humanos. La alta selectividad y buena tolerancia de los mAb humanos permite su administración terapéutica para el bloqueo de determinadas moléculas (endógenas o exógenas). Recientemente se han desarrollado mAb humanos selectivos para la zona catalítica de PCSK9 (proproteína convertasa subtilisina/kexina tipo 9). Estos anticuerpos bloquean la PCSK9, favorecen el reciclaje del receptor de lipoproteínas de baja densidad y reducen de modo notable el colesterol circulante. Estudios preliminares indican que la reducción del colesterol mediante anticuerpos anti-PCSK9 puede implicar importantes reducciones en las complicaciones cardiovasculares de la arteriosclerosis
Antibodies are glycoproteins with high specificity binding to multiple antigens due to the large number of structural conformations of the variable chains. Hybridoma technology (fusion of myeloma cells with immunoglobulin-producing lymphocytes) has allowed the synthesis of large quantities of unique antibodies (monoclonal [mAb]). mAbs were initially murine. Subsequently, chimeric mAbs were developed, followed by humanized mAbs and finally human mAbs. The high selectivity and good tolerance of human mAbs allows their therapeutic administration to block specific exogenous or endogenous molecules. Selective human mAbs to the catalytic domain of PCSK9 have recently been developed. These antibodies block PCSK9, favour low-density lipoprotein receptor recycling and markedly reduce circulating cholesterol. Preliminary studies indicate that lowering cholesterol through anti-PCSK9 antibodies may significantly reduce the cardiovascular complications of arteriosclerosis