La prescripcion de THS en EEUU disminuyo rapidamente despues de la publicacion de trabajos que cuestionaban su eficacia


Cover of the first issue of Journal of the Ame...
Image via Wikipedia

La prescripcion de THS en EEUU disminuyo rapidamente despues de la publicacion de trabajos que cuestionaban su eficacia

Hersh AL, Stefanick ML, Stafford RS. National Use of Postmenopausal Hormone Therapy. JAMA 2004; 291: 47-53.  TC (s) PDF (s)

Introducción

La prescripción de tratamiento hormonal sustitutivo (THS) ha aumentado de forma importante en las últimas dos décadas a medida que se iban publicando los trabajos observacionales que indicaban que podía tener un efecto beneficioso sobre la prevención de determinadas patologías, como la osteoporosis y la cardiopatía isquémica. En 1998 se publicaron los resultados del estudio HERS, el primer ensayo clínico sobre los efectos a largo plazo del THS, que demostró que el THS no era eficaz en la prevención secundaria de la cardiopatía isquémica. En 2002 se publicaron el estudio WHI, que demostró que el balance entre riesgos y beneficios del THS en prevención primaria no eran favorables al THS y el estudio HERSII.

Objetivo

Conocer si la publicación de los primeros estudios experimentales sobre los efectos del THS han modificado la prescripción de THS y las visitas relacionadas con el tema en los EEUU.

Perfil del estudio

Área del estudio: Tratamiento
Ámbito del estudio: Comunitario

Métodos

Las fuentes de datos fueron las siguientes:
  • Prescripciones: National Prescription Audit Plus (NPA). Incluye una muestra aleatoria de 20.000 farmacias. Los datos de las prescripciones se recogen diariamente y se vuelcan cada mes. Se tomaron los datos sobre el total de prescripciones y, a partir de éstos, se estimó el número de mujeres que estaban tomando THS.
  • Visitas: National Disease and Therapeutic Index (NDTI). Se trata de una base de datos que incluye una muestra representativa de 3.500 médicos que recogen los diagnósticos y los tratamientos de las visitas que realizan. Se recogieron los datos sobre las visitas en las que se había prescrito algún tipo de THS.

Resultados

Se pueden distinguir tres fases en la evolución de las prescripciones de THS (fugura): las prescripciones aumentaron desde 1995 a 1999 (el porcentaje de mujeres de 50-74 años en THS pasó del 33 al 42%), después permanecieron estables hasta el final del primer semestre de 2002 y después disminuyeron a partir de julio de 2002 (el porcentaje de mujeres en tratamiento pasó al 28%). El descenso fue más acusado para los medicamentos que combinaban un estrógeno y un gestágeno.
Figura. Número total de prescripciones de tratamiento hormonal sustitutivo (1995-2003)
En el número de visitas en las que se llevó a cabo alguna prescripción se apreció una evolución paralela. Aumentaron entre 1995 y junio de 2002 del 5% al 28%, para caer al 21% durante la primera mitad de 2003.

Conclusiones

Las prescripciones de THS en EEUU respondieron rápidamente a la publicación de los primeros ensayos clínicos en los que se cuestionó la eficacia del THS y el número de mujeres en tratamiento se redujo de forma significativa.

Conflictos de interés

Ninguno declarado.

Comentario

Los resultados de este estudio demuestran una rápida respuesta del sistema sanitario a la aparición de evidencias científicas relativas a un tratamiento de eficacia dudosa. Sin embargo, la historia del THS es un ejemplo de cómo no se deben incorporar prácticas científicas con un nivel de evidencia bajo, sobre todo en el campo de la prevención. Antes de la publicación de los estudios referenciados las recomendaciones de grupos de trabajo prestigiosos, como el US Preventive Services Task Force o el PAPPS eran muy cautas a la hora de recomendar la incorporación del THS. Es probable que esta prescripción inadecuada de THS haya sido responsable de un número considerable de episodios de cardiopatía isquémica y de cáncer de mama.
Afortunadamente en nuestro país (España) la prescripción de THS fue muy inferior a la de EEUU.

Bibliografía

  1. Hulley S, Grady D, Bush T, Furberg C, Herrington D Riggs B et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-613.  TC (s) PDF (s)
  2. Grady D. Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al. Cardiovascular diseaseoutcomes during 6.8 years of hormone therapy. JAMA 2002; 288: 49-57.  TC (s) PDF (s)
  3. Writing Group for the Women. Risk and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women. JAMA 2002; 288: 321-333.  TC (s) PDF (s)

Autor

Manuel Iglesias Rodal. Correo electrónico: mrodal@menta.net.

Enhanced by Zemanta

Estatinas para niños


Journal of the American Medical AssociationImage via Wikipedia
Fuente: Enrique Gavilan
Via: Lista MEDFAM-APS España
El JAMA acaba de publicar un artículo de análisis, que adjunto,
intentando discutir las consecuencias que puede tener el reciente
informe de expertos norteamericanos sobre detección precoz de
hipercolesterolemia en niños y adolescentes (éste:
http://www.nhlbi.nih.gov/guidelines/cvd_ped/summary.htm#chap9).

Sólo se salvan los bebés; a partir de los 2 añitos el sólo hecho de
que tengas un padre con un infarto antes de los 55 años hace que te
lleves como mínimo 2 pinchazos para medir la LDL. Y a partir de los 9
años, cribado universal…

La consecuencia lógica es que se prescriban estatinas a partir de la
conjunción de dos astros y unos LDL de entre 130-160. Me quedo frío.

Y todo ello, por la simple aplicación de, de nuevo, silogismos
fisiopatológicos y sin la más mínima evidencia, según el artículo del
JAMA, de que esta estrategia aporte más beneficios que riesgos. Salvo
por el uso indebido, una vez más, de variables surrogadas, como el
LDL.

Vale la pena leer el artículo, vale la pena…

Cuando sale este tema de los colesteroles en los niños siempre me
acuerdo de la anécdota que Petr Skranabek nos cuenta sobre la pequeña
Ariel y el helado furtivo. Vale la pena leerlo…

http://books.google.es/books?id=w_mdjxW5rjgC&printsec=frontcover&hl=es#v=onepage&q=helado&f=false

Universal Screening Treatment Lipids Childrenhttp://d1.scribdassets.com/ScribdViewer.swf?document_id=78668156&access_key=key-1386qn9jr0asu8rl5bx0&page=1&viewMode=list

Riesgo de padecer infección por virus herpes zoster en pacientes con artritis reumatoide tratados con anti-factor de necrosis tumoral α


Riesgo de padecer infección por virus herpes zoster en pacientes con artritis reumatoide tratados con anti-factor de necrosis tumoral α
Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C et al.
Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF- α agents (Full Text)
JAMA 2009; 301: 737-44.
PREGUNTA CLÍNICA
¿Están relacionados los antifactores de necrosis tumoral alfa (anti-TNFα), como grupo farmacológico, como anticuerpos anti-TNFα específicos monoclonales (adalimubad, infliximab) o como proteína fusionada (etanercept), con un aumento de infecciones por virus herpes zóster en los pacientes con artritis reumatoide?
ANTECEDENTES
El empleo de los anti-TNFα ha aumentado, ya que se han mostrado efectivos en enfermedades como espondilitis anquilosante, artritis psoriásica y enfermedad inflamatoria intestinal, así como en artritis reumatoide.
El mayor riesgo de padecer infecciones bacterianas en los pacientes que son tratados con anti-TNFα ha sido estudiado en varios ensayos clínicos controlados, de distribución aleatoria y en estudios de cohortes, así como las infecciones oportunistas (1). Pero el riesgo de sufrir infecciones virales ha sido menos estudiado, en especial en las patologías donde se ha observado mayor riesgo, como artritis reumatoide, lupus eritematoso sistémico y patologías musculoesqueléticas no inflamatorias (2).
La infección por el virus herpes zoster (VHZ) es uno de los efectos adversos más estudiados en los ensayos clínicos realizados con anti-TNFα (3).
POBLACIÓN ESTUDIADA Y ÁMBITO DE ESTUDIO
Pacientes con artritis reumatoide que iniciaban tratamiento con un anti-TNFα (infliximab, etanercept, adalimumab o ankira) y los que empleaban otro fármaco modificador de la enfermedad (DMARD) por fallo de uno previo.
DISEÑO DEL ESTUDIO Y VALIDEZ
El estudio prospectivo de cohortes RABBIT, desarrollado en Alemania durante 67 meses, incluyó a 5.040 pacientes con artritis reumatoide. Realizó un seguimiento (a los 3, 6, 12, 18, 24, 30 y 36 meses), donde se recogían datos acerca de tratamiento, actividad de la enfermedad, comorbilidad y efectos adversos. Se incluyó en el análisis a todos los episodios de herpes zóster (multimetamérico, diseminado, ótico, oftálmico, iridociclitis y neurológica).
EFECTOS MÁS IMPORTANTES (RESULTADOS) MEDIDOS
Aumento de riesgo de infección por VHZ por el tratamiento con anti-TNF. Riesgo asociado al tratamiento con anticuerpos monoclonales (y en especial etanercept) comparado con DMARD.
RESULTADOS PRINCIPALES
Los pacientes tratados con anti-TNFα diferían del control en cuanto a que eran más jóvenes, con mayor tiempo de evolución y actividad de la enfermedad, más casos con factor reumatoide positivo, peor estado funcional y mayor número previo de DMARD.
Se recogieron 86 casos de infección herpética en 82 pacientes. Se encontró mayor incidencia de infección por VHZ en los pacientes tratados con anti-TNFα (p = 0,01), sobre todo en los tratados con anticuerpos monoclonales, donde se observaron mayor número de infección multimetamérica (3,8 con intevalo de confianza [IC] del 95% de 1 a 9,7 para infliximab y 3,6 con IC del 95% 1,7-6,9 para adalimumab). Hubo mayor número de casos en los pacientes más mayores y con mayor actividad de la enfermedad. En los pacientes tratados con glucocorticoides, y sobre todo con mayores dosis, se observó mayor riesgo de infección.
Se registró mayo riesgo en los pacientes tratado con infliximab y adalimumab (no así con etanercept).
Al comparar con los pacientes que recibieron tratamiento con DMARD, se observó mayor riesgo de VHZ en aquellos que recibían tratamiento con anti-TNFα, pero no fue estadísticamente significativo al comparar con etanercept.
CONFLICTOS DE INTERÉS
Los autores declaran no tener conflictos de interés.
La investigación fue financiada por los Essex pharma, Wyeth pharma, Amgen, Abbott, Hoffmann- La Roche y Bristol-Myers Squibb.
RECOMENDACIONES PARA LA PRÁCTICA
Conclusión
El empleo de infliximab y adalimumab se asoció con mayor riesgo de infección por VHZ, pero la muestra era pequeña y el seguimiento temporal corto. Se observó mayor riesgo en los pacientes más mayores y con mayor actividad de la enfermedad.
Comentario
A pesar de que se encontró una diferencia significativa entre los anticuerpos monoclonales y el tratamiento con DMARS, dicha significación no alcanzó el umbral de la significación clínica. Se decidió no realizar un análisis multivariante porque priorizaron la detección de un probable riesgo.
RECOMENDACIONES
Se necesita un mayor número de estudios con más pacientes para conocer si realmente el empleo de los anticuerpos monoclonales se asocia con mayor riesgo de infección por VHZ, pero es muy importante que los pacientes que lo están recibiendo estén bajo una vigilancia clínica estricta para evitar infecciones herpéticas complicadas.
BIBLIOGRAFÍA
1. Bongartz T, Sutton AK, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infection and malingnancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275-85.
2. Wolfe F, Michaud K, Chakravarty EF. Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders. Rheumatology (Oxford). 2006;45(11):1370-5.
3. Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA et al. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Care & Research. 2007;57(8):1431-8.
Revisado por Aránzazu López Villalvilla. Médica de Familia. C.S. Las Ciudades (Getafe) Madrid. Correo electrónico: arantxa.lopez.villalvilla@gmail.com
Fecha de publicación en C@P: 18/12/2009

Statins, Diabetes, and Attacking a Meta-Analysis


P-values from Fisher's meta analysis applied t...Image via Wikipedia

Source: Evidence Based Medicine

I’m a little late reading the June 19th 2010 Lancet, but was intrigued to find letters in response to the meta-analysis by Sattar et al. looking at whether statin therapy increases the risk of diabetes.

I had previously written about this well-performed meta-analysis, and also written about some unfair ways that people use to try to attack randomized trials, and these letters provide an interesting (at least to me) intersection between these posts.
Letters in academic scientific journals are sociologically revealing. There’s typically a polite veneer on even the most vicious attacks. Letters written to European medical journals have a somewhat different feel from those to American medical journals, and letters to the Lancet often seem to have a sneering tone that would be unusual to find in the NEJM or JAMA.
One letter about the meta-analysis objects that the results cease to be statistically significant when diabetes diagnosed only by physician report are excluded, and secondly that the results involved a post-hoc analysis of the data, with the warning that we might fall victim to the logical fallacy, “Post hoc ergo propter hoc“.
Are these fair objections?
Diagnosing diabetes by physician report rather than blood glucose measurement is likely to lead to misclassification: some patients will be classified as having diabetes who don’t, and some who have diabetes will be missed. In an RCT, though, misclassification like this will almost certainly be random as well, leading to random misclassification bias. Bias of this sort is toward the null hypothesis (no difference between the groups), as you can convince yourself of if you imagine that the classification is perfectly random such that there is no relation between the classification and diabetes. Under such perfect misclassification, the two groups would have equal numbers of patients classified as having diabetes and there would be no difference between treatment and control. In a meta-analysis that found higher rates of diabetes in patients receiving statins, misclassification bias can be expected to have somewhat reduced the true effect, not to have created an effect out of thin air.
The second objection might be called the “post-hoc-ergo-propter-hoc-fallacy fallacy”. The actual fallacy is, of course, a way of saying that just because B follows A, you should not conclude that A caused B. This question of causality is central to epidemiologic research and one of the primary reasons for performing randomized trials, which have particular strengths when arguing for causality. The fallacy has nothing to do with performing post hoc analyses of trials. (To be fair, it’s possible the letter writer understood this and was being humorous when writing of this fallacy.) The main problem with a post hoc analysis of a randomized trial is that it often involves multiple comparisons/data dredging, where statistical blips are likely to confuse the issue of what is a true effect. As discussed in my earlier post, a prime issue preceding this meta-analysis was whether JUPITER had found just such a random blip or detected a real problem. The meta-analysis’ reason for being performed was primarily to answer this question, and in such a setting there is nothing at all concerning about going back to previously conducted RCTs and performing post hoc analyses looking for diabetes effects. No data dredging was involved, and the analysis should not be looked at askance simply for being post hoc. Revealingly, the meta-analysis found an increased risk of diabetes even when data from JUPITER were excluded.
A second letter complained that the analysis would have been better had it been carried out using hazard ratios rather than odds ratios. While this would likely be true, such an analysis was not possible given the information available to the authors, and it is hard to imagine why an OR analysis would have shown statins to be causing diabetes if it were not true. The same letter also re-raised the possibility that statins appeared to be causing people to have more diabetes by keeping them alive longer to develop diabetes. However, the authors had already addressed this in their meta-analysis and reiterated in their response to the letters that differences in survival were much too small to produce such an effect.
A third letter mis-states the definition of a type I error on its way to arguing that the meta-analysis should have used 99% confidence intervals (p-value cutoff of 0.01) for some reason that was not made terribly clear, but seemed related to concerns that a very large meta-analysis would be more likely to detect a spurious result. It is true that given the enormous N in the analysis, it was possible to find a statistically significant difference in diabetes rates that is likely of little clinical significance, but this has nothing to do with the truth or falsehood of the result itself. The letter also argues that the result is biologically implausible, though it does not seem implausible that a medication could increase diabetes rates during the time of a randomized trial, if only by raising blood sugars in patients near the margin between insulin resistance and diabetes.
A fourth letter suggests that the “diabetes” found in the study might be different in terms of patient-important outcomes than the clinical condition we think of as diabetes. That is, statins might be raising blood sugars in a way that is harmless. While this is possible, it’s interesting that when a drug class raises blood sugar people are willing to argue it might be harmless, but when a drug class lowers  blood sugar there’s a tendency (at least for the manufacturer) to argue that blood sugar control is an excellent surrogate for clinical outcomes. The author of the letter suggests an analysis that might have been done to sort out this issue, which the authors of the meta-analysis correctly point out would not have answered the question.
There were a few other replies to the article, which I have not detailed. Overall, though, this is a fairly typical picture of what happens when someone publishes a trial that conflicts with conventional beliefs, such as “statins are good”. This occurs even when the conflict is quite minor — the meta-analysis merely shows a small increase in diabetes that would be heavily outweighed by cardiovascular benefit in anyone who would be appropriately treated with a statin.
There is no guarantee that the meta-analysis by Sattar et al. is correct about statins and diabetes, but none of the letters published by Lancet raise a sensible reason to think that the post-analysis state of knowledge should change: it is now far more likely than not that statins cause a small increase in diabetes risk. Our response to a meta-analysis like this should be to congratulate the authors on a job well done, while recognizing the possibilities for errors and chance to disrupt the conclusions. It should not be to search high and low for far-fetched flaws that would allow us to discard the inconvenient likelihood that a new statin side-effect has been detected.

IBP y Clopidogrel


La combinación de un IBP con clopidogrel podría reducir los efectos de este sobre la función plaquetaria y ser el origen de resultados clínicos pobres en pacientes con prevención secundaria de enfermedades cardiovasculares.
De nuevo, un estudio observacional publicado en JAMA encuentra mayor riesgo de resultados clínicos adversos en una cohorte de pacientes con síndrome coronario agudo tratados al alta con clopidogrel, cuando se les prescribe concomitantemente un IBP.
En la base de datos de Veterans Affairs localizaron un total de 8.205 pacientes a los que se les habían prescrito clopidogrel al alta
, tras un ingreso por IM o angina inestable; de ellos, al 63,9% se les prescribió un IBP simultáneamente o en algún momento durante el seguimiento (521 días de media).
Tras ajustar por factores de confusión mediante análisis multivariante, el empleo concomitante de IBPs se asoció a un mayor riesgo de muerte por cualquier causa o reingreso por síndrome coronario agudo (OR: 1,25 IC95% 1,11-1,41). Los resultados fueron consistentes cuando se analizó por subgrupos o se verificó mediante un estudio de casos y controles (OR: 1,32 IC95% 1,14-1,54).
Los autores concluyen que el uso concomitante de un IBP en pacientes que toman clopidogrel fue frecuente y se asoció con desenlaces peores a largo plazo. Lo que significa que el número absoluto de eventos podría ser considerable. Recomiendan el uso de IBP en pacientes que toman clopidogrel sólo cuando exista una indicación clara y no como profilaxis de rutina.

IBP y Clopidogrel


La combinación de un IBP con clopidogrel podría reducir los efectos de este sobre la función plaquetaria y ser el origen de resultados clínicos pobres en pacientes con prevención secundaria de enfermedades cardiovasculares.
De nuevo, un estudio observacional publicado en JAMA encuentra mayor riesgo de resultados clínicos adversos en una cohorte de pacientes con síndrome coronario agudo tratados al alta con clopidogrel, cuando se les prescribe concomitantemente un IBP.
En la base de datos de Veterans Affairs localizaron un total de 8.205 pacientes a los que se les habían prescrito clopidogrel al alta
, tras un ingreso por IM o angina inestable; de ellos, al 63,9% se les prescribió un IBP simultáneamente o en algún momento durante el seguimiento (521 días de media).
Tras ajustar por factores de confusión mediante análisis multivariante, el empleo concomitante de IBPs se asoció a un mayor riesgo de muerte por cualquier causa o reingreso por síndrome coronario agudo (OR: 1,25 IC95% 1,11-1,41). Los resultados fueron consistentes cuando se analizó por subgrupos o se verificó mediante un estudio de casos y controles (OR: 1,32 IC95% 1,14-1,54).
Los autores concluyen que el uso concomitante de un IBP en pacientes que toman clopidogrel fue frecuente y se asoció con desenlaces peores a largo plazo. Lo que significa que el número absoluto de eventos podría ser considerable. Recomiendan el uso de IBP en pacientes que toman clopidogrel sólo cuando exista una indicación clara y no como profilaxis de rutina.

El finasteride no provoca efectos oseos a largo plazo


Aunque se ha sugerido que la disminución de los niveles plasmáticos de la dihidrotestosterona que se produce en los pacientes tratados con finasterida podría traducirse a largo plazo en alteraciones óseas, los estudios realizados hasta la fecha, no han mostrado efectos en la densidad mineral ósea o los marcadores de formación y de resorción ósea.
Según un estudio de casos y controles publicado en JAMA no se ha encontrado que finasterida, utilizada en la hiperplasia benigna de próstata, incremente el riesgo de fractura de cadera (OR 0.77, IC95% 0.29-1.00, p=0.04). Se incluyeron 7076 casos (varones mayores de 45 años y con fractura de cadera) y un número igual de controles emparejados por edad y centro médico.
El estudio mostró un riesgo superior de fractura de cadera entre los pacientes con una prescripción reciente de alfa-bloqueantes (en los primeros 30 días: OR 2.04; IC95% 1.19-3.49) que los autores atribuyen al efecto adverso de hipotensión ortostática causado por estos fármacos al inicio del tratamiento.
Fuente: Hemos leido.

Rosiglitazona y Riesgo Cardiovascular


Long-term Risk of Cardiovascular Events With Rosiglitazone

A Meta-analysis

Sonal Singh, MDYoon K. Loke, MBBS, MDCurt D. Furberg, MD, PhD 

JAMA. 2007;298:1189-1195.

Context  Recent reports of serious adverse events with rosiglitazone use have raised questions about whether the evidence of harm justifies its use for treatment of type 2 diabetes.

Objective  To systematically review the long-term cardiovascular risks of rosiglitazone, including myocardial infarction, heart failure, and cardiovascular mortality.

Data Sources  We searched MEDLINE, the GlaxoSmithKline clinical trials register, the US Food and Drug Administration Web site, and product information sheets for randomized controlled trials, systematic reviews, and meta-analyses published in English through May 2007.

Study Selection  Studies were selected for inclusion if they were randomized controlled trials of rosiglitazone for prevention or treatment of type 2 diabetes, had at least 12months of follow-up, and monitored cardiovascular adverse events and provided numerical data on all adverse events. Four studies were included after detailed screening of 140 trials for cardiovascular events.

Data Extraction  Relative risks (RRs) of myocardial infarction, heart failure, and cardiovascular mortality were estimated using a fixed-effects meta-analysis of 4 randomized controlled trials (n = 14 291, including 6421 receiving rosiglitazone and 7870 receiving control therapy, with a duration of follow-up of 1-4 years).

Results  Rosiglitazone significantly increased the risk of myocardial infarction (n = 94/6421 vs 83/7870; RR, 1.42; 95% confidence interval [CI], 1.06-1.91; P = .02) and heart failure (n = 102/6421 vs 62/7870; RR, 2.09;95% CI, 1.52-2.88; P < .001) without a significant increase in risk of cardiovascular mortality (n = 59/6421 vs 72/7870; RR, 0.90; 95% CI, 0.63-1.26; P = .53). There was no evidence of substantial heterogeneity among thetrials for these end points (I2 = 0% for myocardial infarction, 18% for heart failure, and 0% for cardiovascularmortality).

Conclusion  Among patients with impaired glucose tolerance or type 2 diabetes, rosiglitazone use for at least 12 months is associated with a significantly increased risk of myocardial infarction and heart failure, without a significantly increased risk of cardiovascular mortality.


Author Affiliations: Department of Medicine (Dr Singh) and Division of Public Health Sciences (Dr Furberg), Wake Forest University School of Medicine, Winston-Salem, North Carolina; and School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, England (Dr Loke).

RELATED ARTICLES

Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Trials
, , , and 
JAMA. ;298():1180-1188. 
FULL TEXT  

Cardiovascular Risk and the Thiazolidinediones: Deja Vu All Over Again?
and 
JAMA. ;298():1216-1218. 
FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Intensive Glucose Control in Type 2 Diabetes
Jenny-Avital et al.
NEJM 2008;359:1519-1521.
FULL TEXT  

Rosiglitazone and pioglitazone in the treatment of diabetes mellitus
Odom et al.
Am J Health Syst Pharm 2008;65:1846-1850.
FULL TEXT  

Rosiglitazone Treatment Reduces Diabetic Neuropathy in Streptozotocin-Treated DBA/2J Mice
Wiggin et al.
Endocrinology 2008;149:4928-4937.
ABSTRACT | FULL TEXT  

Thiazolidinediones in Type 2 Diabetes: A Cardiology Perspective
Khanderia et al.
The Annals of Pharmacotherapy 2008;42:1466-1474.
ABSTRACT | FULL TEXT  

The Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-{alpha}-Dependent Manner In Vitro and In Vivo in Mice
Orasanu et al.
J Am Coll Cardiol 2008;52:869-881.
ABSTRACT | FULL TEXT  

Pharmacological Differences of Glitazones: Does Peroxisome Proliferator-Activated Receptor-{alpha} Activation Make the Difference?
Kintscher
J Am Coll Cardiol 2008;52:882-884.
FULL TEXT  

Obese Mice Lacking Inducible Nitric Oxide Synthase Are Sensitized to the Metabolic Actions of Peroxisome Proliferator-Activated Receptor-{gamma} Agonism
Dallaire et al.
Diabetes 2008;57:1999-2011.
ABSTRACT | FULL TEXT  

Best Practices for Lowering the Risk of Cardiovascular Disease in Diabetes
Triplitt and Alvarez
Diabetes Spectr. 2008;21:177-189.
ABSTRACT | FULL TEXT  

Treating Elderly People with Diabetes and Stages 3 and 4 Chronic Kidney Disease
Abaterusso et al.
CJASN 2008;3:1185-1194.
ABSTRACT | FULL TEXT  

Patient-Important Outcomes in Registered Diabetes Trials
Gandhi et al.
JAMA 2008;299:2543-2549.
ABSTRACT | FULL TEXT  

Screening Adults for Type 2 Diabetes: A Review of the Evidence for the U.S. Preventive Services Task Force
Norris et al.
ANN INTERN MED 2008;148:855-868.
ABSTRACT | FULL TEXT  

Regulation of Macrophage Functions by PPAR-{alpha}, PPAR-{gamma}, and LXRs in Mice and Men
Rigamonti et al.
Arterioscler. Thromb. Vasc. Bio. 2008;28:1050-1059.
ABSTRACT | FULL TEXT  

Induction of CXCR2 Receptor by Peroxisome Proliferator-Activated Receptor {gamma} in Human Macrophages
Rigamonti et al.
Arterioscler. Thromb. Vasc. Bio. 2008;28:932-939.
ABSTRACT | FULL TEXT  

Diabetic retinopathy and risk of heart failure.
Cheung et al.
J Am Coll Cardiol 2008;51:1573-1578.
ABSTRACT | FULL TEXT  

PROactive: time for a critical appraisal
Betteridge et al.
Eur Heart J 2008;29:969-983.
ABSTRACT | FULL TEXT  

Glitazones in type 2 diabetes: an update
DTB 2008;46:25-29.
ABSTRACT | FULL TEXT  

Meta-analysis of rare events: an update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone
Dahabreh
Clin Trials 2008;5:116-120.
ABSTRACT  

The year in atherothrombosis.
Sanz et al.
J Am Coll Cardiol 2008;51:944-955.
FULL TEXT  

Peroxisome Proliferator-Activated Receptor-{gamma}-Mediated Effects in the Vasculature
Duan et al.
Circ. Res. 2008;102:283-294.
ABSTRACT | FULL TEXT  

Management of Type 2 Diabetes — Polling Results
Halperin et al.
NEJM 2008;358:e8-e8.
FULL TEXT  

Projecting future drug expenditures–2008
Hoffman et al.
Am J Health Syst Pharm 2008;65:234-253.
ABSTRACT | FULL TEXT  

New Drugs for the Treatment of Diabetes: Part II: Incretin-Based Therapy and Beyond
Inzucchi and McGuire
Circulation 2008;117:574-584.
ABSTRACT | FULL TEXT  

New Drugs for the Treatment of Diabetes Mellitus: Part I: Thiazolidinediones and Their Evolving Cardiovascular Implications
McGuire and Inzucchi
Circulation 2008;117:440-449.
FULL TEXT  

Glucose-lowering therapy after myocardial infarction: more questions than answers
Radke and Schunkert
Eur Heart J 2008;29:141-143.
FULL TEXT  

Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes 
Nathan et al.
Diabetes Care 2008;31:173-175.
FULL TEXT  

Standards of Medical Care in Diabetes–2008
American Diabetes Association
Diabetes Care 2008;31:S12-S54.
FULL TEXT  

Thiazolidinediones and Cardiovascular Outcomes in Older Patients With Diabetes
Lipscombe et al.
JAMA 2007;298:2634-2643.
ABSTRACT | FULL TEXT  

A Crash Course in Stats
Kirkman
DOC News 2007;4:2-2.
FULL TEXT  

Thiazolidinediones and Increased MI Risk: A Class Effect?
Journal Watch Cardiology 2007;2007:3-3.
FULL TEXT  

Cardiovascular Risk and the Thiazolidinediones: Deja Vu All Over Again?
Solomon and Winkelmayer
JAMA 2007;298:1216-1218.
FULL TEXT  

Thiazolidinediones and Heart Disease Risk
JWatch General 2007;2007:2-2.
FULL TEXT  


Rosiglitazona y Riesgo Cardiovascular


Long-term Risk of Cardiovascular Events With Rosiglitazone

A Meta-analysis

Sonal Singh, MDYoon K. Loke, MBBS, MDCurt D. Furberg, MD, PhD 

JAMA. 2007;298:1189-1195.

Context  Recent reports of serious adverse events with rosiglitazone use have raised questions about whether the evidence of harm justifies its use for treatment of type 2 diabetes.

Objective  To systematically review the long-term cardiovascular risks of rosiglitazone, including myocardial infarction, heart failure, and cardiovascular mortality.

Data Sources  We searched MEDLINE, the GlaxoSmithKline clinical trials register, the US Food and Drug Administration Web site, and product information sheets for randomized controlled trials, systematic reviews, and meta-analyses published in English through May 2007.

Study Selection  Studies were selected for inclusion if they were randomized controlled trials of rosiglitazone for prevention or treatment of type 2 diabetes, had at least 12months of follow-up, and monitored cardiovascular adverse events and provided numerical data on all adverse events. Four studies were included after detailed screening of 140 trials for cardiovascular events.

Data Extraction  Relative risks (RRs) of myocardial infarction, heart failure, and cardiovascular mortality were estimated using a fixed-effects meta-analysis of 4 randomized controlled trials (n = 14 291, including 6421 receiving rosiglitazone and 7870 receiving control therapy, with a duration of follow-up of 1-4 years).

Results  Rosiglitazone significantly increased the risk of myocardial infarction (n = 94/6421 vs 83/7870; RR, 1.42; 95% confidence interval [CI], 1.06-1.91; P = .02) and heart failure (n = 102/6421 vs 62/7870; RR, 2.09;95% CI, 1.52-2.88; P < .001) without a significant increase in risk of cardiovascular mortality (n = 59/6421 vs 72/7870; RR, 0.90; 95% CI, 0.63-1.26; P = .53). There was no evidence of substantial heterogeneity among thetrials for these end points (I2 = 0% for myocardial infarction, 18% for heart failure, and 0% for cardiovascularmortality).

Conclusion  Among patients with impaired glucose tolerance or type 2 diabetes, rosiglitazone use for at least 12 months is associated with a significantly increased risk of myocardial infarction and heart failure, without a significantly increased risk of cardiovascular mortality.


Author Affiliations: Department of Medicine (Dr Singh) and Division of Public Health Sciences (Dr Furberg), Wake Forest University School of Medicine, Winston-Salem, North Carolina; and School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, England (Dr Loke).

RELATED ARTICLES

Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Trials
, , , and 
JAMA. ;298():1180-1188. 
FULL TEXT  

Cardiovascular Risk and the Thiazolidinediones: Deja Vu All Over Again?
and 
JAMA. ;298():1216-1218. 
FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Intensive Glucose Control in Type 2 Diabetes
Jenny-Avital et al.
NEJM 2008;359:1519-1521.
FULL TEXT  

Rosiglitazone and pioglitazone in the treatment of diabetes mellitus
Odom et al.
Am J Health Syst Pharm 2008;65:1846-1850.
FULL TEXT  

Rosiglitazone Treatment Reduces Diabetic Neuropathy in Streptozotocin-Treated DBA/2J Mice
Wiggin et al.
Endocrinology 2008;149:4928-4937.
ABSTRACT | FULL TEXT  

Thiazolidinediones in Type 2 Diabetes: A Cardiology Perspective
Khanderia et al.
The Annals of Pharmacotherapy 2008;42:1466-1474.
ABSTRACT | FULL TEXT  

The Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-{alpha}-Dependent Manner In Vitro and In Vivo in Mice
Orasanu et al.
J Am Coll Cardiol 2008;52:869-881.
ABSTRACT | FULL TEXT  

Pharmacological Differences of Glitazones: Does Peroxisome Proliferator-Activated Receptor-{alpha} Activation Make the Difference?
Kintscher
J Am Coll Cardiol 2008;52:882-884.
FULL TEXT  

Obese Mice Lacking Inducible Nitric Oxide Synthase Are Sensitized to the Metabolic Actions of Peroxisome Proliferator-Activated Receptor-{gamma} Agonism
Dallaire et al.
Diabetes 2008;57:1999-2011.
ABSTRACT | FULL TEXT  

Best Practices for Lowering the Risk of Cardiovascular Disease in Diabetes
Triplitt and Alvarez
Diabetes Spectr. 2008;21:177-189.
ABSTRACT | FULL TEXT  

Treating Elderly People with Diabetes and Stages 3 and 4 Chronic Kidney Disease
Abaterusso et al.
CJASN 2008;3:1185-1194.
ABSTRACT | FULL TEXT  

Patient-Important Outcomes in Registered Diabetes Trials
Gandhi et al.
JAMA 2008;299:2543-2549.
ABSTRACT | FULL TEXT  

Screening Adults for Type 2 Diabetes: A Review of the Evidence for the U.S. Preventive Services Task Force
Norris et al.
ANN INTERN MED 2008;148:855-868.
ABSTRACT | FULL TEXT  

Regulation of Macrophage Functions by PPAR-{alpha}, PPAR-{gamma}, and LXRs in Mice and Men
Rigamonti et al.
Arterioscler. Thromb. Vasc. Bio. 2008;28:1050-1059.
ABSTRACT | FULL TEXT  

Induction of CXCR2 Receptor by Peroxisome Proliferator-Activated Receptor {gamma} in Human Macrophages
Rigamonti et al.
Arterioscler. Thromb. Vasc. Bio. 2008;28:932-939.
ABSTRACT | FULL TEXT  

Diabetic retinopathy and risk of heart failure.
Cheung et al.
J Am Coll Cardiol 2008;51:1573-1578.
ABSTRACT | FULL TEXT  

PROactive: time for a critical appraisal
Betteridge et al.
Eur Heart J 2008;29:969-983.
ABSTRACT | FULL TEXT  

Glitazones in type 2 diabetes: an update
DTB 2008;46:25-29.
ABSTRACT | FULL TEXT  

Meta-analysis of rare events: an update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone
Dahabreh
Clin Trials 2008;5:116-120.
ABSTRACT  

The year in atherothrombosis.
Sanz et al.
J Am Coll Cardiol 2008;51:944-955.
FULL TEXT  

Peroxisome Proliferator-Activated Receptor-{gamma}-Mediated Effects in the Vasculature
Duan et al.
Circ. Res. 2008;102:283-294.
ABSTRACT | FULL TEXT  

Management of Type 2 Diabetes — Polling Results
Halperin et al.
NEJM 2008;358:e8-e8.
FULL TEXT  

Projecting future drug expenditures–2008
Hoffman et al.
Am J Health Syst Pharm 2008;65:234-253.
ABSTRACT | FULL TEXT  

New Drugs for the Treatment of Diabetes: Part II: Incretin-Based Therapy and Beyond
Inzucchi and McGuire
Circulation 2008;117:574-584.
ABSTRACT | FULL TEXT  

New Drugs for the Treatment of Diabetes Mellitus: Part I: Thiazolidinediones and Their Evolving Cardiovascular Implications
McGuire and Inzucchi
Circulation 2008;117:440-449.
FULL TEXT  

Glucose-lowering therapy after myocardial infarction: more questions than answers
Radke and Schunkert
Eur Heart J 2008;29:141-143.
FULL TEXT  

Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes 
Nathan et al.
Diabetes Care 2008;31:173-175.
FULL TEXT  

Standards of Medical Care in Diabetes–2008
American Diabetes Association
Diabetes Care 2008;31:S12-S54.
FULL TEXT  

Thiazolidinediones and Cardiovascular Outcomes in Older Patients With Diabetes
Lipscombe et al.
JAMA 2007;298:2634-2643.
ABSTRACT | FULL TEXT  

A Crash Course in Stats
Kirkman
DOC News 2007;4:2-2.
FULL TEXT  

Thiazolidinediones and Increased MI Risk: A Class Effect?
Journal Watch Cardiology 2007;2007:3-3.
FULL TEXT  

Cardiovascular Risk and the Thiazolidinediones: Deja Vu All Over Again?
Solomon and Winkelmayer
JAMA 2007;298:1216-1218.
FULL TEXT  

Thiazolidinediones and Heart Disease Risk
JWatch General 2007;2007:2-2.
FULL TEXT  


Anticolinergicos y eventos cardiovasculares


Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Department of Medicine, One Medical Center Blvd, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. sosingh@wfubmc.edu

CONTEXT: Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown. OBJECTIVE: To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke. DATA SOURCES: Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers’ trial registries with no date restrictions. STUDY SELECTION: Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events. DATA EXTRACTION: The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic. DATA SYNTHESIS: After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95% confidence interval {CI}, 1.21-2.06]; P 6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.36]; P < .001, I(2) = 0%). CONCLUSION: Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

Enlace a Pubmed

Anticolinergicos y eventos cardiovasculares


Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Department of Medicine, One Medical Center Blvd, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. sosingh@wfubmc.edu

CONTEXT: Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown. OBJECTIVE: To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke. DATA SOURCES: Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers’ trial registries with no date restrictions. STUDY SELECTION: Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events. DATA EXTRACTION: The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic. DATA SYNTHESIS: After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95% confidence interval {CI}, 1.21-2.06]; P 6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.36]; P < .001, I(2) = 0%). CONCLUSION: Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

Enlace a Pubmed

Tratamiento de EPOC y riesgo cardiovascular


Una revisión sistemática y meta-analisis en pacientes con EPOC, con los anticolinérgicos antiasmáticos por inhalación pulmonar, ipratropio (Atrovent) y tiotropio (Spiriva), en los cuales se detectó un incremento de riesgo CV del 58%  (muerte CV, IAM e ictus) en pacientes con un minimo de 30 dias de utilización, y mayor aún si han sido fumadores.

Los autores comentan datos en UK: en 2004 fallecieron 2.700 pacientes de EPOC y calculan que será la quinta causa de muerte en el mundo en 2020. Identifican un nivel de uso de 2 millones de prescripciones de estos inhaladores en UK en 2007 en pacientes asmáticos, muchos de ellos grandes fumadores y por lo tanto con alto riesgo CV.

En JAMA:
http://jama.ama-assn.org/cgi/content/short/300/12/1439

Las agencias reguladoras se manifestarán al respecto, como ya lo hizo la FDA en febrero 2008 con tiotropio e ictus (http://www.fda.gov/cder/drug/early_comm/tiotropium.htm)

Un abrazo,

Mariano Madurga Sanz
mmadurga@agemed.es


Fuente: lista de Medicina Familiar España. 

Tratamiento de EPOC y riesgo cardiovascular


Una revisión sistemática y meta-analisis en pacientes con EPOC, con los anticolinérgicos antiasmáticos por inhalación pulmonar, ipratropio (Atrovent) y tiotropio (Spiriva), en los cuales se detectó un incremento de riesgo CV del 58%  (muerte CV, IAM e ictus) en pacientes con un minimo de 30 dias de utilización, y mayor aún si han sido fumadores.

Los autores comentan datos en UK: en 2004 fallecieron 2.700 pacientes de EPOC y calculan que será la quinta causa de muerte en el mundo en 2020. Identifican un nivel de uso de 2 millones de prescripciones de estos inhaladores en UK en 2007 en pacientes asmáticos, muchos de ellos grandes fumadores y por lo tanto con alto riesgo CV.

En JAMA:
http://jama.ama-assn.org/cgi/content/short/300/12/1439

Las agencias reguladoras se manifestarán al respecto, como ya lo hizo la FDA en febrero 2008 con tiotropio e ictus (http://www.fda.gov/cder/drug/early_comm/tiotropium.htm)

Un abrazo,

Mariano Madurga Sanz
mmadurga@agemed.es


Fuente: lista de Medicina Familiar España. 

La disminucion de homocisteina con complejo B después de angiografia no muestra beneficio


Disminuir los niveles de homocisteina después de una angiografía coronaria no mejora el resultado en los pacientes, reporta un estudio en JAMA.

Alrededor de 3100 adultos fueron aleatorizados para iniciar uno de cuatro tratamientos diarios después de una angiografía por sospecha de enfermedad coronaria o estenosis aórtica:

  • Ácido fólico y vitaminas B6 y B12
  • Ácido fólico y vitamina B12
  • Vitamina B6
  • Placebo

Los niveles de homocisteína disminuyeron significativamente en los grupos que recibían ácido fólico y vitamina B12, pero se mantuvieron en los otros dos grupos. Sin embargo, durante 3 años de seguimiento, la incidencia del resultado primario (mortalidad, infarto, hospitalización por angina inestable, embolia tromboembólica) no fue diferente en los usuarios de ácido fólico y vitamina B12.

Algunos médicos han notado que otros estudios han producido resultados similares. Sin embargo, muchos médicos siguen prescribiendo suplementos de complejo B a los pacientes cardiopatas, con un costo anual de miles de dólares, cuando esta práctica no debe estar justifcada.

La disminucion de homocisteina con complejo B después de angiografia no muestra beneficio


Disminuir los niveles de homocisteina después de una angiografía coronaria no mejora el resultado en los pacientes, reporta un estudio en JAMA.

Alrededor de 3100 adultos fueron aleatorizados para iniciar uno de cuatro tratamientos diarios después de una angiografía por sospecha de enfermedad coronaria o estenosis aórtica:

  • Ácido fólico y vitaminas B6 y B12
  • Ácido fólico y vitamina B12
  • Vitamina B6
  • Placebo

Los niveles de homocisteína disminuyeron significativamente en los grupos que recibían ácido fólico y vitamina B12, pero se mantuvieron en los otros dos grupos. Sin embargo, durante 3 años de seguimiento, la incidencia del resultado primario (mortalidad, infarto, hospitalización por angina inestable, embolia tromboembólica) no fue diferente en los usuarios de ácido fólico y vitamina B12.

Algunos médicos han notado que otros estudios han producido resultados similares. Sin embargo, muchos médicos siguen prescribiendo suplementos de complejo B a los pacientes cardiopatas, con un costo anual de miles de dólares, cuando esta práctica no debe estar justifcada.

Epigenetics at the epicenter of modern medicine


Epigenetics at the Epicenter of Modern Medicine Andrew P. Feinberg, MD, MPH
JAMA. 2008;299(11):1345-1350.

ABSTRACT

Epigenetics, the study of non-DNA sequence–related heredity, is at the epicenter of modern medicine because it can help to explain the relationship between an individual’s genetic background, the environment, aging, and disease. It can do so because the epigenetic state varies among tissues and during a lifetime, whereas the DNA sequence remains essentially the same. As cells adapt to a changing internal and external environment, epigenetic mechanisms can remember these changes in the normal programming and reprogramming of gene activity. The common disease genetic and epigenetic (CDGE) model provides an epidemiologic framework that can incorporate epigenetic with genetic variation in the context of age-related susceptibility to disease. Under CDGE, the epigenetic program can modify the effects of deleterious genes or may be influenced by an adverse environment. Thus, including epigenetics into epidemiologic studies of human disease may help explain the relationship between the genome and the environment and may provide new clues to modifying these effects in disease prevention and therapy.


What Is Epigenetics?

 Jump to Section
 • Top
 • What is epigenetics?
 • Author information
 • References


Although epigenetics is considered a relatively new area of medicine, the term is more than 60 years old. Waddington first used the term epigenetics to describe what is now called developmental biology, the idea that phenotype, or the morphologic and functional properties of an organism, arises sequentially under a program defined by the genome under the influence of the organism’s environment.1 The modern definition of epigenetics is modifications of the DNA or associated proteins, other than DNA sequence variation, that carry information content during cell division.2 The best understood example of epigenetic modification is DNA methylation, a covalent addition of a methyl (CH3) group to the nucleotide cytosine. DNA methylation is maintained during cell division in mammals only at dinucleotide C-G (CpG), by virtue of the enzyme DNA methyltransferase I. This occurs because during semiconservative DNA replication, a methylated CpG on the parent DNA strand is partnered with a newly synthesized unmethylated CpG on the daughter strand. DNA methyltransferase I searches out this hemimethylated DNA and places a new methyl group on the daughter CpG.2 An important environmental connection to epigenetics is that the source of methyl groups in this reaction is methionine, an essential amino acid, that is converted to a biologically active methyl donor state through a well-understood pathway that involves folic acid (Figure 1).3

Figure 1
View larger version (192K):
[in this window]
[in a new window]
[as a PowerPoint slide]
Figure 1. Types of Epigenetic Information and Epigenetic Inheritance A, Types of epigenetic information. The term epigenetics refers to modifications of DNA or associated factors—aside from variations in the primary DNA sequence—that carry information content and are maintained during cell division. Examples of epigenetic modifications are DNA methylation, histone modifications, occupancy of chromatin factors, and changes in chromatin structure. CTCF indicates CCCTC-binding factor. B, Inheritance of DNA methylation. In somatic cells, epigenetic information is replicated during mitosis along with the DNA sequence. The mechanism for replication of DNA methylation is well understood but the mechanism for replication of histone modifications is not.

A second well-studied example of epigenetic change is chromatin modification, specifically, covalent modifications of the histone proteins that make up the nucleosomes around which the DNA double helix is coiled, approximately 2 turns of 200 base pairs, including the linker DNA between each nucleosome. These chemical modifications also include methylation but in this case involve the amino acids arginine or lysine, as well as phosphorylation of serine, acetylation of lysine, and ubiquitinylation of lysine.4 Unlike DNA methylation, the mechanism of maintaining chromatin modifications during cell division is not well understood because no enzyme has yet been identified that recognizes chromatin modifications from the parent cell and reproduces them in the daughter cell.5 Other examples of epigenetic information are the density of nucleosome packing along the DNA, the complex of DNA and nucleosomes with specific proteins that recognize methylated DNA or modified histones, and the higher-order topologic organization of all these elements into complex structures that are only beginning to be recognized in the laboratory.4

What is the effect of these epigenetic changes? The simplest answer is that they regulate gene expression. For example, DNA methylation has traditionally been thought to be found with silenced genes. More than 100 specific chromatin modifications have been discovered, some of which exist in association with actively transcribed genes and others with silenced genes.4 The relaxation of condensed nucleosomes is important for gene activity, and a key insight published more than 10 years ago was that proteins that cooperate with transcription factors in activating or silencing genes act by acetylating or deacetylating histones, respectively.67 A more subtle change is that epigenetic modifications as a group may define a higher-order structure within the nucleus. Recent studies using new methods, such as chromatin conformation capture to identify long-distance DNA interactions, have revealed that groups of genes may change their physical relationship with one another, depending on their transcriptional state.89 Similarly, important differences in tissue-specific gene expression are controlled by enhancer sequences on the DNA, and the physical relationship between these enhancers and the promoters, ie, the elements to which the transcriptional machinery binds to activate gene expression, is controlled in part by the methylation of insulator sequences and the resultant folding of gene regions into loops of various sizes, depending on the state of the cell.10

Modern Epigenetics Is at the Heart of Developmental Biology

Perhaps the most important aspect of epigenetics is that the modern definition and Waddington’s definition have converged because the epigenetic state of an organism has a lifecycle, whereas the DNA sequence does not (Figure 2). Epigenetic marks distinguish most of the important developmental properties of tissues from one another. For example, stem cell biology has now achieved the point at which differentiated somatic cells can be restored to a pluripotent state, ie, induced progenitor stem cells.11 But clearly, the DNA in these cells has not changed, and without interference from the investigator, the pluripotency of DNA or lack of such capacity is relatively stable, ie, heritable during cell division. Thus, an epigenetic program must underlie these state changes.

Figure 2
View larger version (115K):
[in this window]
[in a new window]
[as a PowerPoint slide]
Figure 2. Life Cycle of the Epigenome Unlike the DNA sequence, the epigenetic code changes during one’s lifetime in ways specific to a given cell type. Shown here are a sperm, which is highly methylated, and an egg, which is not. After fertilization, there is a wave of demethylation that spares imprinted marks (dark brown). Tissue-specific methylation patterns emerge during later embryonic development. Age-related hypermethylation or hypomethylation could theoretically impair or enhance normal gene responsiveness to environmental signals.

Similarly, reprogramming of somatic cells and cancer cells by nuclear transplantation shows that information successfully transmitted during cell division for years or even decades can be erased and reprogrammed epigenetically.12 This difference between stem and somatic cells extends to individual cell types. After all, how can a liver cell know to divide to form 2 liver cells rather than brain cells or heart cells, without some embedded epigenetic memory? Recently, it was shown that stem cells carry “bivalent” chromatin marks, ie, both on and off, on some genes, which then commit to one or the other state in differentiated tissues.13 Understanding the epigenetic correlate of tissue-specific differentiation is one of the great challenges of modern developmental biology.

Epigenetics of Disease: Disruption of Normal Phenotypic Plasticity

The first example of a human disease with an epigenetic mechanism was cancer. In 1983, widespread loss of DNA methylation was observed in colorectal cancers compared with matched normal mucosa from the same patients.14 This hypomethylation has been shown to lead to abnormal activation of genes in cancer, as well as genetic instability and chromosomal rearrangements.2 Subsequently, hypermethylation of gene promoters was reported for a number of tumor suppressor genes in cancer.1517 Epigenetic activation and silencing of genes in cancer turn genes on that should be off and vice versa. In fact, each type of normal epigenetic mark described earlier is altered in cancers, including abnormal histone modifications; excess of chromatin factors such as trithorax group proteins that promote gene expression, such as ALL1 in acute lymphocytic leukemia; and polycomb group proteins that repress gene expression, such as EZH2 in metastatic cancers.2

Single gene disorders of the epigenetic machinery also impair normal gene expression. For example, Rett syndrome, which involves progressive loss of developmental milestones caused by abnormal gene expression in the brain, is caused by lack of a normal MeCP2 protein that recognizes methylated DNA and thus helps to repress gene expression.18 Immunodeficiency, centromeric instability, and facial anomalies syndrome is caused by loss of DNMT3B, a DNA de novo DNA methyltransferase that adds methyl groups to CpGs where they were not present before.19 Affected cells abnormally express genes involved in immune function, neural function, and development.19

The unifying theme of epigenetic disease is disruption of normal phenotypic plasticity. Just as epigenetic change is at the heart of normal development, so also do disruptions in epigenetic modification disturb normal developmental programs. Thus, single gene disorders such as Rett syndrome show abnormal brain reprogramming in development, and complex traits such as cancer involve disruptions of the normal commitment of differentiating cells in tumors to specific patterns of active and repressed genes.20

Age-Related Disease and the Common Disease Genetic and Epigenetic Hypothesis

Clinical medicine deals more with delaying and mitigating the effects of aging than reversing and eliminating disease, particularly as the baby boom generation grows older, because all organ systems function more poorly with time among individuals and among tissues within individuals. Dan L. Longo, MD, scientific director of the National Institute on Aging, defines aging as a loss of phenotypic plasticity over time (written communication, February 8, 2008). This loss of responsiveness to stress also exacerbates the effects of underlying genetic variant–associated disease, accounting at least in part for the age dependence of common disorders such as heart disease, diabetes, and acquired intellectual impairment. But what accounts for this loss of responsiveness? Could lack of responsiveness interact at the level of the DNA with disease-predisposing genetic variation?

Fallin, Bjornsson, and Feinberg21 have proposed a model that could provide an epigenetic explanation to these questions. The common disease genetic and epigenetic (CDGE) model overlies the genetic variant hypothesis of disease, with an epigenetic component interacting with it. This could occur in several ways, first by environmental factors modifying epigenetic marks on the DNA or chromatin. DNA methylation depends on dietary methionine and folate, both of which are affected by nutritional state. Studies in mice have shown that reduction of dietary methionine can affect coat color by altering DNA methylation of the agouti gene.22 Simply feeding rats a low-methionine diet causes them to develop liver cancer at high frequency through hypomethylation of their DNA.23 Continue reading Epigenetics at the epicenter of modern medicine

Paracentesis


Does This Patient Have Bacterial Peritonitis or Portal Hypertension? How Do I Perform a Paracentesis and Analyze the Results? Camilla L. Wong, MD, FRCPC; Jayna Holroyd-Leduc, MD, FRCPC; Kevin E. Thorpe, MMath; Sharon E. Straus, MD, MSc, FRCPC
JAMA. 2008;299(10):1166-1178.

Context Abdominal paracenteses are performed in patients with ascites, most commonly to assess for infection or portal hypertension and to manage refractory ascites.

Objectives To systematically review evidence for paracentesis methods that may decrease risk of adverse events or improve diagnostic yield and to determine the accuracy of ascitic fluid analysis for spontaneous bacterial peritonitis or portal hypertension.

Data Sources Relevant English-language studies from MEDLINE (1966-April 2007) and EMBASE (1980-April 2007).

Study Selection Paracentesis studies evaluating interventions (use of preprocedure coagulation parameters, needle type, insertion location, ultrasound guidance, bedside inoculation into blood culture bottles, and use of plasma expanders in therapeutic taps) for reducing adverse events or improving the diagnostic yield, and studies assessing the accuracy of ascitic fluid biochemical analyses for spontaneous bacterial peritonitis or portal hypertension.

Data Extraction For technique studies, data on intervention and outcome; and for diagnostic studies, data on parameters for diagnosing spontaneous bacterial peritonitis and portal hypertension (ie, ascitic fluid white blood cell and polymorphonuclear leukocyte [PMN] count, ascitic fluid pH, blood–ascitic fluid pH gradient, and serum-ascites albumin gradient).

Data Synthesis Thirty-seven studies met inclusion criteria: 2 showed that obtaining preprocedure coagulation was likely unnecessary prior to paracentesis; 1 showed the 15-gauge, 3.25-inch needle-cannula results in less multiple peritoneal punctures [P = .05] and termination due to poor fluid return [P = .02] vs a 14-gauge needle in therapeutic paracentesis; 1 showed immediate inoculation of culture bottles improves diagnostic yield vs delayed (from 77% to 100% [95% CI for the difference, 5.3%-40.0%]); 9 evaluated therapeutic paracentesis, performed with or without albumin or nonalbumin plasma expanders, and found no consistent effect on morbidity or mortality; 16 showed the accuracy of biochemical analysis of ascitic fluid in patients suspected of having spontaneous bacterial peritonitis to increase the likelihood of spontaneous bacterial peritonitis (PMN count >250 cells/µL [summary likelihood ratio {LR}, 6.4] 95% CI, 4.6-8.8; ascitic fluid leukocyte count >1000 cells/µL [summary LR, 9.1] 95% CI, 5.5-15.1; pH < 7.35 [summary LR, 9.0] 95% CI, 2.0-40.6; or a blood–ascitic fluid pH gradient ≥ 0.10 [LR, 11.3] 95% CI, 4.3-29.9) and other levels lowered the likelihood (PMN count ≤ 250 cells/µL [summary LR, 0.2] 95% CI, 0.11-0.37; or a blood–ascitic fluid pH gradient < 0.10 [summary LR, 0.12] 95% CI, 0.02-0.77); and 4 showed the diagnostic accuracy of the serum-ascites albumin gradient lowers the likelihood of portal hypertension (< 1.1 g/dL [summary LR, 0.06] 95% CI, 0.02-0.20).

Conclusions Ascitic fluid should be inoculated into blood culture bottles at the bedside. Spontaneous bacterial peritonitis is more likely at predescribed parameters of ascitic PMN count or blood–ascitic fluid pH, and portal hypertension is less likely below a predescribed serum-ascites albumin gradient.

Author Affiliations: Division of Geriatric Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Wong); Knowledge Translation Program, Faculty of Medicine, University of Toronto and St Michael’s Hospital, Toronto, Ontario, Canada (Dr Holroyd-Leduc, Mr Thorpe, and Dr Straus); Department of Public Health Sciences, University of Toronto (Mr Thorpe); and Divisions of General Internal Medicine and Geriatrics, University of Calgary, Calgary, Alberta, Canada (Drs Holroyd-Leduc and Straus).

RELATED ARTICLES

This Week in JAMA
JAMA. 2008;299(10):1105.
FULL TEXT

Abdominal Paracentesis
John L. Zeller, Alison E. Burke, and Richard M. Glass
JAMA. 2008;299(10):1216.
EXTRACT | FULL TEXT

¿Los niveles de triglicéridos postprandiales son un factor de riesgo para la cardiopatía isquémica?


Nordestgaard BG, Benn M, Schnohr P, Tybjærg-Hansen A. Nonfasting Triglycerides and Risk of Myocardial Infarction, Ischemic Heart Disease, and Death in Men and Women. JAMA 2007; 298: 299-308.  R   TC (s)   PDF (s)

Introducción

La relación entre la hipertrigliceridemia y el riesgo cardiovascular es controvertida. Recientemente se ha propuesto que los remanentes de quilomicrones y de VLDL presentes en el suero postprandial podrían jugar un papel en el desarrollo de la aterosclerosis. Sin embargo, estas partículas no se reflejan en los análisis habituales, puesto que habitualmente se recomienda que estos se hagan en ayunas.

Objetivo

Someter a prueba a hipótesis de que los triglicéridos postprandiales predicen el riesgo de sufrir una cardiopatía isquémica.

Perfil del estudio

Tipo de estudio: Estudio de casos y controles

Área del estudio: Causa

Ámbito del estudio: Comunitario

Métodos

Para este estudio se utilizaron los datos del Copenhagen City Heart Study , un estudio prospectivo de base poblacional, que se inició en 1976 y que incluyó más de 14.000 personas de 20-80 años de edad. Al 72% de los participantes se les determinaron los triglicéridos en una muestra que no se recogió en ayunas. Los participantes han sido seguidos hasta 2004 en el 100% de los casos.;

La variable de resultado principal fue la presencia de un infarto de miocardio (IM) o de otras manifestaciones de cardiopatía isquémica (CI). Otras variables analizadas fueron la presencia de HTA, el tabaquismo, el consumo de alcohol, el ejercicio físico de tiempo libre, la menopausia y el consumo de tratamiento hormonal sustitutivo. En una submuestra de 66 pacientes se llevó a cabo una prueba de sobrecarga grasa.

Resultados

Se incluyeron en el estudio los datos de 13.981 participantes, que se dividieron en cuartiles en función de sus niveles de triglicéridos. El porcentaje de pacientes que tomaban hpolipemiantes no superó el 2%. Los que se encontraban en los cuartiles superiores tenían un mayor IMC, fumaban más, hacían menos ejercicio y tenían más HTA y diabetes. En la prueba de sobrecarga grasa se comprobó que los niveles máximos de triglicéridos se observaron a las 4 horas de la comida (fig. 1).

Se detectó una relación directa entre los niveles de triglicéridos postprandiales y los de las partículas remanentes (fig. 2).

En los dos sexos, la incidencia de infarto de miocardio, cardiopatía isquémica y muerte aumentó con los niveles de triglicéridos. En el análisis multivariante, la relación se mantuvo, aunque de forma algo más atenuada (fig. 3). La relación fue más fuerte para las personas <55 años y para las que bebían alcohol >2 veces/semana.

Conclusiones

Los autores concluyen que en esta cohorte de la población general, los niveles de triglicéridos postprandiales se relacionan con el riesgo de infarto de miocardio, cardiopatía isquémica y muerte.

Conflictos de interés

Uno de los autores ha recibido honorarios de varios laboratorios farmacéuticos. Financiado por la Danish Heart Foundation, el Danish Medical Research Council, la Research Fund at Rigshospitalet, el Copenhagen University Hospital y la Unión Europea.

Comentario

La relación entre la hipertrigliceridemia y el riesgo de padecer una cardiopatía isquémica es un tema controvertido. A pesar de que se ha encontrado una relación entre ellos, la frecuente relación entre los niveles de triglicéridos y otros factores de riesgo cardiovascular (colesterol HDL bajo, diabetes, obesidad, etc.) han oscurecido su contribución neta a la patogenia de la aterosclerosis. Otro factor que puede influir es el hecho de que la hipertrigliceridemia parece ser un cajón de sastre en el que coinciden varios cuadros clínicos que pueden tener diferentes riesgos cardiovasculares. En la actualidad se tiende a considerar que la hipertrigliceridemia es un factor de riesgo independiente, pero de una menor potencia que el colesterol LDL.

Otro factor que puede influir en la interpretación del valor de la hipertrigliceridemia como factor de riesgo cardiovascular es que la mayor parte de las determinaciones se llevan a cabo en ayunas, mientras que las personas pasan una parte muy importante del día en una situación postprandial. En concreto, se ha propuesto que los remanentes de VLDL y de los quilomicrones, partículas presentes en el suero postprandial, son fácilmente captadas por el endotelio vascular y por lo tanto pueden estar implicadas en la etiopatogenia de la aterosclerosis.

Los resultados de este estudio parecen ir en esta dirección. Se ha detectado una relación entre los niveles de triglicéridos (especialmente evidente para los niveles de triglicéridos más elevados y en mujeres) con el riesgo de desarrollar una cardiopatía isquémica que se mantenía en el análisis multivariante. En otro estudio llevado a cabo en mujeres publicado en el mismo número de la revista se llegaba a las mismas conclusiones, de forma que la asociación entre la CI y los triglicéridos que se apreciaba en el análisis crudo desaparecía en el análisis multivariante para los triglicéridos en ayunas, pero se mantenía para los triglicéridos postprandiales.

La trascendencia clínica de esta relación está pendiente de determinar. Por un lado, el hecho de que tenga que hacerse una determinación de triglicéridos postprandial complica su determinación y es posible que haya que establecer unas condiciones estándar para incorporarla a la práctica habitual. Además habrá que llevar a cabo estudios de intervención que demuestren que tratar estos pacientes produce una reducción de la cardiiopatía isquémica.

Bibliografía

  1. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 2007; 176: 1113-1120.  R   TC   PDF
  2. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting Compared With Nonfasting Triglycerides and Risk of Cardiovascular Events in Women. JAMA 2007; 298: 309-316.  R   TC (s)   PDF (s)
  3. McBride PE. Triglycerides and Risk for Coronary Heart Disease. JAMA 2007; 298: 336-338.   TC (s)   PDF (s)

Autor

Manuel Iglesias Rodal. Correo electrónico: mrodal@menta.net.

JAMA. The Journal of the American Medical Association. Vol. 298. Núm. 20


Originales

Mackey DC, Lui LY, Cawthon PM, Bauer DC, Nevitt MC, Cauley JA, for the Study of Osteoporotic Fractures (SOF) and Osteoporotic Fractures in Men Study (MrOS) Research GroupsHigh-Trauma Fractures and Low Bone Mineral Density in Older Women and Men. Págs. 2381-2388 R TC (s) PDF (s) 

Robbins J, Aragaki AK, Kooperberg C, Watts N, Wactawski-Wende J, Jackson RD et alFactors Associated With 5-Year Risk of Hip Fracture in Postmenopausal Women. Págs. 2389-2398 R TC (s) PDF (s) 

Editoriales

Khosla SHigh-Trauma Fractures and Bone Mineral Density. Págs. 2418-2419 TC (s) PDF (s) 

Comentario

Brayne C, Fox C, Boustan MDementia Screening in Primary Care: Is It Time?. Págs. 2409-2411 TC (s) PDF (s) 

Jaffe HW, Valdiserri RO, De Cock KMThe Reemerging HIV/AIDS Epidemic in Men Who Have Sex With Men. Págs. 2412-2414 TC (s) PDF (s) 

Páginas para los pacientes

Zeller JL, Lynm C, Glass RSHip Fractures. Págs. 2442 TC PDF