Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia

Navarese, Eliano Pio; Kołodziejczak, Michalina; Schulze, Volker; Gurbel, Paul A.; Tantry, Udaya S.; Lin, Yingfeng; Brockmeyer, Maximilian; Kandzari, David E.; Kubica, Julia Maria; D’Agostino, Ralph B.; Kubica, Jacek; Volpe, Massimo; Agewall, Stefan; Kereiakes, Dean J.; Kelm, Malte

doi:10.7326/m14-2957

Cited by 385 publications

(297 citation statements)

References 35 publications

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“…No statistically significant differences were identified in study‐level subgroup analyses including patients on or off treatment with a background statin and patients with FH. In contrast with a previous meta‐analysis from lipid‐lowering trials,47 we found no benefit in all‐cause mortality with PCSK9 inhibitor therapy. This finding may be attributable to the fact that our analysis included 2 large trials of populations with a baseline LDL‐C of <100 mg/dL,5, 20 contributing to an overall baseline LDL‐C of 106 mg/dL in our pooled sample.…”

Section: Discussioncontrasting

confidence: 99%

“…Until recently, the highest quality of evidence surrounding alirocumab and evolocumab stemmed from phase 2 and 3 lipid‐lowering trials and their meta‐analyses 46, 47. The encouraging results led to the 2015 US Food and Drug Administration fast‐track approval for use of PCSK9 inhibitors as adjuncts to diet and maximally tolerated statin for patients with FH and clinical ASCVD.…”

Section: Discussionmentioning

confidence: 99%

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Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Karatasakis

Danek

Karácsonyi

et al. 2017

JAHA

155

104

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BackgroundWe sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab.Methods and ResultsWe performed a systematic review and meta‐analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45 539 patients (mean follow‐up: 85.5 weeks) were included. Mean age was 61.0±2.8 years, and mean baseline low‐density lipoprotein cholesterol was 106±22 mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64–0.81]; P<0.001), stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67–0.96]; P=0.02), and coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71–0.86]; P<0.001). Overall, no significant change was observed in all‐cause mortality (OR: 0.71 [95% CI, 0.47–1.09]; P=0.12) or cardiovascular mortality (OR: 1.01 [95% CI, 0.85–1.19]; P=0.95). A significant association was observed between higher baseline low‐density lipoprotein cholesterol and benefit in all‐cause mortality (P=0.038). No significant change was observed in neurocognitive adverse events (OR: 1.12 [95% CI, 0.88–1.42]; P=0.37), myalgia (OR: 0.95 [95% CI, 0.75–1.20]; P=0.65), new onset or worsening of preexisting diabetes mellitus (OR: 1.05 [95% CI, 0.95–1.17]; P=0.32), and increase in levels of creatine kinase (OR: 0.84 [95% CI, 0.70–1.01]; P=0.06) or alanine or aspartate aminotransferase (OR: 0.96 [95% CI, 0.82–1.12]; P=0.61).ConclusionsTreatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all‐cause or cardiovascular mortality, such benefit may be achievable in patients with higher baseline low‐density lipoprotein cholesterol.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Karatasakis

Danek

Karácsonyi

et al. 2017

JAHA

155

104

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“…Currently, no treatment option has been established for high Lp(a) levels, other than experimental and observational regimes 27, 28, 29, 30, 31, 32, 33. Moreover, to date, no randomized controlled trials have directly evaluated the effect of lowering Lp(a) on cardiovascular outcomes including AS development.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Ljungberg

Holmgren

Bergdahl

et al. 2017

JAHA

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BackgroundAortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS.Methods and ResultsWe identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni‐ and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07‐1.55]), but not in 132 patients without CAD (1.04 [0.83‐1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16‐1.76]) but not in those without CAD (0.87 [0.69‐1.10]).ConclusionsHigh levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

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“…Los efectos adversos importantes no aumentaron con la administración de anticuerpos PCSK9, considerándose seguros y efectivos para los adultos con dislipidemia. La importante limitación de este metaanálisis es que los estudios que incluye no estaban diseñados para ver eventos y hay que esperar el desarrollo de nuevos estudios que están en desarrollo 10 .…”

Section: Anticuerpos Humanos Monoclonales Anti-pcsk9unclassified

Inhibición de la proproteína convertasa subtilisina/kexina tipo 9 en el tratamiento de la hipercolesterolemia

Ascaso

2016

Endocrinología y Nutrición

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EDITORIALInhibición de la proproteína convertasa subtilisina/kexina tipo 9 en el tratamiento de la hipercolesterolemia Inhibition of proprotein convertase subtilisin/kexin type 9 in the treatment of hypercholesterolemia Juan F. Ascaso Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, departamento de Medicina, Universitat de Valencia, INCLIVA, CIBERDEM, presidente de la Sociedad Española de ArteriosclerosisSegún datos de la Organización Mundial de la Salud, la enfermedad cardiovascular de origen isquémico o arterioscleroso (ECVA) es la primera causa de muerte en el mundo y especialmente en los países desarrollados 1 . La aterosclerosis es una enfermedad arterial multifactorial, en la que el depósito en el espacio subendotelial de las lipoproteínas que transportan apolipoproteína B y colesterol, principalmente las lipoproteínas de baja densidad (LDL), y los fenómenos inflamatorios y proliferativos que posteriormente se desarrollan son fundamentales en el desarrollo y en las manifestaciones clínicas de la ECVA. Por consiguiente, la aterosclerosis es una enfermedad «colesterol dependiente», iniciada por el depósito de colesterol en la íntima arterial 2 .La reducción de las concentraciones del colesterol de las LDL (cLDL) es el principal objetivo de las estrategias para prevenir o tratar la ECVA. El tratamiento con estatinas, inhibidores de la 3-hidroxi-3-metil-glutaril-CoA reductasa, capaces de reducir entre un 30-50% las concentraciones de cLDL, han demostrado beneficios en la reducción de la enfermedad cardiovascular y son consideradas por todas las sociedades científicas y todas las guías como el primer escalón terapéutico por su eficacia en la reducción de cLDL y el riesgo de ECVA, con una reducción de episodios cardiovasculares mayores de un 21% por cada 39 mg/dl de descenso en los valores de cLDL. Estos resultados son independientes del Correo electrónico: ascaso@uv.es valor basal de cLDL. Las estatinas tienen un perfil favorable de seguridad y de rentabilidad 3 . La asociación de estatinas a otros fármacos hipocolesterolemiantes como ezetimiba o resinas aumenta la reducción plasmática de cLDL y de la ECVA.Sin embargo, una proporción significativa de pacientes es incapaz de tolerar las estatinas en la dosis necesaria para lograr el control de las concentraciones de cLDL y otro subgrupo de población, fundamentalmente con hipercolesterolemias genéticas, es parcialmente resistente a la acción de las estatinas 4 .Por tanto, se han buscado nuevas formas de reducir el cLDL. El papel de la proproteína convertasa subtilisina/kexina tipo 9 (PCSK9) en el metabolismo del colesterol fue reconocido al identificar 2 familias francesas con el fenotipo clínico de hipercolesterolemia familiar autosómica dominante y mutaciones en el gen PCSK9 que codificaba dicha proteína PCSK9, hasta ese momento no relacionada con el metabolismo del colesterol. El interés de esta proteína PCSK9 se inicia con el descubrimiento y el hallazgo de que es un gen altamente polimórfico 5 . Así, mutaciones con ganancia...

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Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia

Abstract: CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG.

Cited by 385 publications

References 35 publications

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Inhibición de la proproteína convertasa subtilisina/kexina tipo 9 en el tratamiento de la hipercolesterolemia

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