Financiado en parte por Amgen, Pfizer, AstraZeneca, Bayer, Sanofi, Biogen, Regeneron Pharmaceuticals, Ionis Pharmaceuticals, Esperion Therapeutics, Daiichi Sankyo Europe
Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis
Burgess S, Ference BA, Staley JR, Freitag DF, Mason AM, Nielsen SF, Willeit P, Young R, Surendran P, Karthikeyan S, Bolton TR, Peters JE, Kamstrup PR, Tybjærg-Hansen A, Benn M, Langsted A, Schnohr P, Vedel-Krogh S, Kobylecki CJ, Ford I, Packard C, Trompet S, Jukema JW, Sattar N, Di Angelantonio E, Saleheen D, Howson JMM, Nordestgaard BG, Butterworth AS, Danesh J, European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium
JAMA cardiology · 547 citas
Etiquetas de revisión
Financiado por la industriaDatos neutrales que nuestra revisión registró sobre cómo se hizo este estudio. Describen el método, nunca si nos gusta el resultado.
Cómo se estudió
- Diseño
- Estudio de cohortes (indexado por PubMed)
- Estudiado en
- Personas
- Resultado principal
- Eventos clínicos como enfermedad o muerte
Quién lo pagó
- Financiación
- Financiado por la industria
- Empresa
- Amgen
- Empresa
- Pfizer
- Empresa
- AstraZeneca
- Empresa
- Bayer
- Empresa
- Sanofi
- Empresa
- Biogen
- Universidad u hospital
- University of Pennsylvania
- Gobierno
- NHS Blood and Transplant
- Empresa
- Regeneron Pharmaceuticals
- Organización sin fines de lucro
- Wellcome Trust
- Empresa
- Ionis Pharmaceuticals
- Gobierno
- National Institute for Health and Care Research
- Organización sin fines de lucro
- British Heart Foundation
- Gobierno
- European Commission
- Universidad u hospital
- Cardiff University
- Empresa
- Esperion Therapeutics
- Universidad u hospital
- Perelman School of Medicine, University of Pennsylvania
- Gobierno
- Medical Research Council
- Gobierno
- NIHR Cambridge Biomedical Research Centre
- Empresa
- Daiichi Sankyo Europe
- Gobierno
- FP7 Ideas: European Research Council
- Organización sin fines de lucro
- Health Data Research UK
- Gobierno
- European Research Council
- Gobierno
- National Institute for Health Research (NIHR)
- Subvenciones
- Wellcome Trust (204623/Z/16/Z); National Institute for Health and Care Research (NF-SI-0617-10113); National Institute for Health and Care Research (NF-SI-0512-10165); British Heart Foundation (G0800270); Medical Research Council (MR/L003120/1); British Heart Foundation (SP/09/002); British Heart Foundation (RG/08/014); Medical Research Council (MR/S003746/1); Medical Research Council (G0800270); European Commission (279233); Medical Research Council (MC_UU_12015/1); Wellcome Trust (204623); FP7 Ideas: European Research Council (268834); British Heart Foundation (RG/13/13/30194); Medical Research Council (MR/L003120); British Heart Foundation (RG/08/014/24067); National Institute for Health and Care Research (NF-SI-0512-10135); National Institute for Health and Care Research (NF-SI-0617-10149); Medical Research Council (MR/L003120/1)
Según 24 financiadores declarados.
Publicación
- Publicado
- 2018-06-20 · JAMA Cardiol · vol. 3 · número 7 · pág. 619
- Editorial
- American Medical Association
- Citado
- 684 citas · más que el 100% de estudios similares · 57.7× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 39 trabajos
- Acceso
- Acceso abierto (revista híbrida) · CC-BY
- Áreas de investigación
- Lipoproteins and Cardiovascular Health · Genetic Associations and Epidemiology · Paraoxonase enzyme and polymorphisms
- Palabras clave
- lipoprotein(a), coronary heart disease risk, LDL cholesterol, Lp(a)-lowering therapy, genetic score, cardiovascular risk reduction, individual patient data, Mendelian randomization, LDL-C lowering therapy, PCSK9 inhibitors
- MeSH
- humans, coronary disease, lipoprotein(a), prognosis, risk factors, follow-up studies, prospective studies, phenotype, polymorphism, single nucleotide, middle aged, female, male, cholesterol, ldl, genetic variation, mendelian randomization analysis, hypolipidemic agents, biomarkers
30 autores
- Stephen Burgess🇬🇧 · autor de correspondenciaUniversity of Cambridge; MRC Biostatistics Unit
- Brian A. Ference🇺🇸🇬🇧Wayne State University; University of Cambridge; University of Bristol
- James R Staley🇬🇧University of Cambridge; University of Bristol; MRC Integrative Epidemiology Unit
- Daniel F. Freitag🇬🇧University of Cambridge
- Amy M. Mason🇬🇧University of Cambridge
- Sune Fallgaard Nielsen🇩🇰University of Copenhagen; Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital
- Peter Willeit🇦🇹🇬🇧Innsbruck Medical University; University of Cambridge
- Robin Young🇬🇧University of Cambridge; University of Glasgow
- Praveen Surendran🇬🇧University of Cambridge
- Savita Karthikeyan🇬🇧University of Cambridge
- Thomas R Bolton🇬🇧University of Cambridge
- James E. Peters🇬🇧University of Cambridge
- Pia R. Kamstrup🇩🇰Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital
- Anne Tybjærg‐Hansen🇩🇰University of Copenhagen; Frederiksberg Hospital; Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital; Rigshospitalet
- Marianne Benn🇩🇰University of Copenhagen; Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital; Rigshospitalet
- Anne Langsted🇩🇰Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital
- Peter Schnohr🇩🇰Frederiksberg Hospital; Copenhagen University Hospital
- Signe Vedel‐Krogh🇩🇰University of Copenhagen; Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital
- Camilla Jannie Kobylecki🇩🇰University of Copenhagen; Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital
- Ian Ford🇬🇧University of Glasgow
- Chris J. Packard🇬🇧University of Glasgow
- Stella Trompet🇳🇱Leiden University; Leiden University Medical Center
- J. Wouter Jukema🇳🇱Leiden University; Leiden University Medical Center; Netherlands Heart Institute
- Naveed A. Sattar🇬🇧University of Glasgow
- Emanuele Di Angelantonio🇬🇧University of Cambridge; National Institute for Health and Care Research
- Danish Saleheen🇵🇰🇺🇸Center for Non-Communicable Diseases; University of Pennsylvania
- Joanna M. M. Howson🇬🇧University of Cambridge
- Børge Grønne Nordestgaard🇩🇰University of Copenhagen; Frederiksberg Hospital; Herlev Hospital; Copenhagen University Hospital; Gentofte Hospital
- Adam S. Butterworth🇬🇧University of Cambridge; National Institute for Health and Care Research
- John Danesh🇬🇧University of Cambridge; Wellcome Sanger Institute; National Institute for Health and Care Research
Resumen
El texto original del estudio, en el idioma en que se publicó.
Importance
Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.
Objective
To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.
Design, setting, and participants
A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.
Exposures
Genetic LPA score and plasma Lp(a) mass concentration.
Main outcomes and measures
Coronary heart disease.
Results
Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.
Conclusions and relevance
The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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