revision sistematica riesgo de acidosis con tratamiento metformina
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Revision sistematica riesgo de acidosis con tratamiento metforminaTRANSCRIPT
Riesgo de acidosis láctica fatal y no fatal con el uso de metforminapara la diabetes mellitus tipo 2
Salpeter S, Greyber E, Pasternak G, Salpeter E
Reproducción de una revisión Cochrane, traducida y publicada en La Biblioteca Cochrane Plus, 2008, Número 2
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Usado con permiso de John Wiley & Sons, Ltd. © John Wiley & Sons, Ltd.Ningún apartado de esta revisión puede ser reproducido o publicado sin la autorización de Update Software Ltd.Ni la Colaboración Cochrane, ni los autores, ni John Wiley & Sons, Ltd. son responsables de los errores generadosa partir de la traducción, ni de ninguna consecuencia derivada de la aplicación de la información de esta Revisión,ni dan grantía alguna, implícita o explícitamente, respecto al contenido de esta publicación.El copyright de las Revisiones Cochrane es de John Wiley & Sons, Ltd.El texto original de cada Revisión (en inglés) está disponible en www.thecochranelibrary.com.
ÍNDICE DE MATERIAS
RESUMEN...................................................................................................................................................................1
RESUMEN EN TÉRMINOS SENCILLOS....................................................................................................................2
ANTECEDENTES........................................................................................................................................................2
OBJETIVOS.................................................................................................................................................................4
CRITERIOS PARA LA VALORACIÓN DE LOS ESTUDIOS DE ESTA REVISIÓN......................................................4
ESTRATEGIA DE BÚSQUEDA PARA LA IDENTIFICACIÓN DE LOS ESTUDIOS....................................................4
MÉTODOS DE LA REVISIÓN.....................................................................................................................................5
DESCRIPCIÓN DE LOS ESTUDIOS..........................................................................................................................7
CALIDAD METODOLÓGICA.......................................................................................................................................8
RESULTADOS.............................................................................................................................................................8
DISCUSIÓN.................................................................................................................................................................9
CONCLUSIONES DE LOS AUTORES......................................................................................................................10
POTENCIAL CONFLICTO DE INTERÉS...................................................................................................................10
FUENTES DE FINANCIACIÓN..................................................................................................................................11
REFERENCIAS.........................................................................................................................................................11
TABLAS......................................................................................................................................................................23
Characteristics of included studies.....................................................................................................................23
Characteristics of excluded studies....................................................................................................................96
CARÁTULA................................................................................................................................................................98
RESUMEN DEL METANÁLISIS.................................................................................................................................99
GRÁFICOS Y OTRAS TABLAS................................................................................................................................100
01 Fatal/nonfatal lactic acidosis........................................................................................................................100
01 Incidencia de acidosis láctica por paciente por año (metformina menos sin metformina)....................100
02 Niveles del lactato sanguíneo......................................................................................................................101
01 Efecto neto del tratamiento, niveles de lactato (mmol/L)......................................................................101
02 Niveles medios de lactato con el tratamiento (mmol/L)........................................................................102
03 Niveles pico de lactato estimulado (mmol/L)........................................................................................103
Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2 i
Copyright © John Wiley & Sons Ltd. Usado con permiso de John Wiley & Sons, Ltd.
Riesgo de acidosis láctica fatal y no fatal con el uso de metforminapara la diabetes mellitus tipo 2
Salpeter S, Greyber E, Pasternak G, Salpeter E
Esta revisión debería citarse como:Salpeter S, Greyber E, Pasternak G, Salpeter E. Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetesmellitus tipo 2 (Revisión Cochrane traducida). En: La Biblioteca Cochrane Plus, 2008 Número 2. Oxford: Update Software Ltd.Disponible en: http://www.update-software.com. (Traducida de The Cochrane Library, 2008 Issue 2. Chichester, UK: John Wiley& Sons, Ltd.).Fecha de la modificación más reciente: 16 de noviembre de 2005Fecha de la modificación significativa más reciente: 16 de noviembre de 2005
RESUMEN
AntecedentesLa metformina es un agente oral hipoglucemiante que se utiliza en el tratamiento de la diabetes mellitus tipo 2. Los resultadosdel UK Prospective Diabetes Study (Estudio prospectivo de diabetes del Reino Unido) indican que el tratamiento con metforminase asocia a una reducción en la mortalidad total en comparación con otros tratamientos hipoglucemiantes. Sin embargo, se creeque la metformina aumenta el riesgo de acidosis láctica y se la considera contraindicada para muchas enfermedades hipoxémicascrónicas que se pueden asociar con la acidosis láctica, como la enfermedad cardiovascular, renal, hepática y pulmonar, y la edadavanzada.
ObjetivosEvaluar la incidencia de la acidosis láctica fatal y no fatal con el uso de la metformina en comparación con el placebo y otrostratamientos que reducen la glucosa en pacientes con diabetes mellitus tipo 2. Un objetivo secundario fue evaluar los niveles delactato sanguíneo para aquellas personas tratadas con metformina en comparación con placebo o tratamientos sin metformina.
Estrategia de búsquedaSe realizó una búsqueda en The Cochrane Library (hasta 8/2005), MEDLINE (hasta 8/2005), EMBASE (hasta 11/2000), OLDMEDLINE y REACTIONS (hasta 8/2005) para identificar todos los estudios de tratamiento con metformina desde 1966 hastaagosto de 2005. Se utilizó el Cumulated Index Medicus para buscar artículos pertinentes desde 1959 hasta 1965. La búsqueda seamplió mediante el examen de las referencias de los artículos identificados y el contacto con los principales investigadores. Fechade la última búsqueda: agosto 2005.
Criterios de selecciónLos ensayos prospectivos en pacientes con diabetes tipo 2 que duraron más de un mes se incluyeron si evaluaban la metformina,sola o en combinación con otros tratamientos, en comparación con el placebo o cualquier otro tratamiento que reduzca la glucosa.También se incluyeron estudios observacionales de cohortes del tratamiento con metformina que duraron más de un mes.
Recopilación y análisis de datosDos revisores seleccionaron de forma independiente los ensayos para ser incluidos, evaluaron la calidad de los estudios y extrajeronlos datos. La incidencia de la acidosis láctica fatal y no fatal se registró como casos por pacientes tratados por año, para eltratamiento con metformina y para el placebo u otros tratamientos. Se calculó el límite superior para la verdadera incidencia delos casos en los grupos con metformina y sin metformina mediante las estadísticas de Poisson. En un segundo análisis, se midieronlos niveles de lactato como un cambio neto desde el valor inicial o como valores medios del tratamiento (basales y estimuladosmediante alimentos o ejercicios) para los grupos de tratamiento y comparación. Los resultados agrupados se registraron comodiferencia de medias ponderada (DMP) en mmol/L, mediante el modelo de efectos fijos para los datos continuos.
Resultados principalesLos datos combinados de los 206 ensayos comparativos y los estudios de cohortes no revelaron casos de acidosis láctica fatal ono fatal en 47 846 pacientes tratados por año con metformina o en 38 221 pacientes tratados por año en el grupo sin metformina.
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Mediante el uso de las estadísticas de Poisson con intervalos de confianza del 95%, el límite superior para la verdadera incidenciade la acidosis láctica asociada a la metformina fue 6,3 casos por cada 100 000 pacientes tratados por año y el límite superior parala verdadera incidencia de la acidosis láctica en el grupo sin metformina fue de 7,8 casos por cada 100 000 pacientes tratados poraño. No hubo diferencia alguna en los niveles de lactato, ya sea en los niveles promedios del tratamiento o en un cambio netodesde el valor inicial, para la metformina en comparación con el placebo u otros tratamientos sin biguanidas. Los niveles promediode lactato fueron ligeramente inferiores en el tratamiento con metformina que en el de fenformina (DMP -0,75 mmol/L; IC del95%: -0,86; -0,15).
Conclusiones de los autoresNo hay pruebas en los ensayos comparativos prospectivos o en los estudios observacionales de cohortes de que la metforminase asocie con un mayor riesgo de acidosis láctica o un aumento en los niveles del lactato, en comparación con otros tratamientoshipoglucemiantes si se prescribe en las condiciones del estudio.
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RESUMEN EN TÉRMINOS SENCILLOS
El uso de la metformina probablemente no está vinculado al riesgo de la acidosis lácticaDurante mucho tiempo, se ha creído que la metformina, una medicación usada para reducir los niveles de glucosa en pacientescon diabetes mellitus, aumenta el riesgo de un trastorno metabólico conocido como acidosis láctica. Esta revisión resumió losdatos de todos los estudios comparativos y observacionales conocidos que duraron más de un mes y no encontró casos de acidosisláctica fatal o no fatal en 47 846 pacientes tratados por año con metformina o en 38 221 pacientes tratados por año sin metformina.Los niveles promedio de lactato medidos durante el tratamiento con metformina no fueron diferentes que para el placebo o paraotros medicamentos usados para tratar la diabetes. En resumen, no hay pruebas en la actualidad, de la asociación de la metforminaa un mayor riesgo de acidosis láctica si se prescribe bajo las condiciones del estudio.
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ANTECEDENTES
La diabetes mellitus es un trastorno metabólico que resulta deun defecto en la secreción de insulina, la acción de la insulinao en ambos (DeFronzo 1999). Una consecuencia de esto es lahiperglucemia crónica con trastornos en el metabolismo decarbohidratos, grasas y proteínas. Entre las complicaciones alargo plazo de la diabetes mellitus se encuentran la retinopatía,la nefropatía, la neuropatía y un mayor riesgo de enfermedadescardiovasculares. Para obtener un resumen detallado de ladiabetes mellitus, ver título "Información adicional" en el GrupoCochrane de Trastornos Metabólicos y Endocrinos (Metabolicand Endocrine Disorders Group) en la Cochrane Library (ver"Acerca de la Colaboración Cochrane", "Grupos Colaboradoresde Revisión [Collaborative Review Groups]). Para obtener unaexplicación de los términos metodológicos, ver el glosarioprincipal en The Cochrane Library.
La metformina es un agente hipoglucemiante que se ha usadocon mayor frecuencia durante los últimos años, en especial enpacientes obesos con diabetes tipo 2 en la que los niveles deglucemia no se pueden controlar de otra manera que a travésde medios farmacológicos. Sin embargo, todavía debenabordarse tres preguntas principales. Primero, ¿cómo afecta elfármaco a la mortalidad total y al desarrollo de complicacionesa largo plazo relacionadas con la diabetes? y ¿son estos efectossimilares en todos los grupos de pacientes con diabetes tipo 2?
En segundo lugar, ¿cuál es el efecto en los factores de riesgocardiovascular como la obesidad, dislipidemia y la hipertensión?y ¿se asocia este efecto con los cambios en la morbilidad y lamortalidad cardiovascular? La tercera pregunta aborda lasinquietudes por la seguridad del fármaco; específicamente ¿cuáles el riesgo de acidosis láctica fatal y no fatal asociada con eluso de metformina? Estas tres preguntas se tratarán en tresrevisiones separadas. Esta revisión evalúa el riesgo de laacidosis láctica atribuida al uso de metformina en comparacióncon el placebo y otros agentes usados para el control glucémicoen pacientes con diabetes tipo 2. Se actualizarán las revisionesde forma continua para incluir estudios relevantes nuevos.
MetforminaEl clorhidrato de metformina es una biguanida que ha sido deuso clínico durante más de 45 años (DeFronzo 1999; Sterne1959). A diferencia de las sulfonilureas, las biguanidas no tienenun efecto hipoglucemiante en las personas sanas y no estimulanla liberación de insulina (Cusi 1996). A través de su efectohipoglucemiante, la metformina reduce los niveles de glucemiaen ayunas y posprandiales en pacientes con diabetes tipo 2.Aunque no se ha establecido completamente el mecanismopreciso de este efecto, las pruebas indican que el fármaco mejorala sensibilidad tanto periférica como hepática a la insulina,reduce la producción de glucosa hepática basal y aumenta lacaptación estimulada por la insulina y utilización de la glucosapor los tejidos periféricos (AHFS 1999). La metformina, aun
Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
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en dosis excesivas, normalmente no reduce las concentracionesde glucosa por debajo de la euglucemia. La metformina seacumula en la pared del intestino pero no parece tener efectosclínicamente importantes en la absorción de la glucosa.
Además de su influencia en el metabolismo de carbohidratos,se cree que la metformina tiene otros efectos positivosrelacionados a la diabetes tipo 2 y su pronóstico a largo plazo.Es posible que haya una mejoría moderada en los lípidos séricos,especialmente una reducción de los triglicéridos séricos enayunas así como en las concentraciones de colesterol total yLDL (LDL = lipoproteína de baja densidad). Además, eltratamiento con metformina puede asociarse con la pérdida depeso o una estabilización en el aumento de peso. Entre losmecanismos sugeridos para este efecto se encuentran la ausenciade un efecto hiperinsulinémico (que de estar presente puedeaumentar el apetito o la lipogénesis) y la ingesta dietéticareducida causada por los efectos adversos gastrointestinales dela metformina. Actualmente, no hay pruebas concluyentes sobreel efecto de la metformina en el sistema fibrinolítico y laagregación plaquetaria que tienen una función en el desarrollode la trombosis en las arterias coronarias (Palumbo 1998).
Estudios de la metforminaSe han publicado diversos ensayos que usan la metformina solao en combinación con otros fármacos en pacientes con diabetesmellitus tipo 2. El UK Prospective Diabetes Study (UKPDS)fue el primer ensayo grande que evaluó los resultados clínicosa largo plazo en relación al tratamiento con metformina enpersonas que presentaban una diabetes tipo 2. El estudio incluyópacientes con sobrepeso con una diabetes tipo 2 diagnosticadarecientemente, con un promedio de 53 años de edad, que nopresentaban una coronariopatía o una contraindicación altratamiento. Los resultados indicaron que la monoterapia conmetformina producía una reducción en las variables deevaluación relacionadas con la diabetes y también en lamortalidad relacionada con la diabetes y en la mortalidad total,comparada con la insulina, el tratamiento con sulfonilureas osólo la dieta (UKPDS-34 1998). No hubo casos de acidosisláctica en ninguno de los grupos.
Recientemente se han publicado tres metanálisis que evaluaronel efecto de la metformina en la regulación de la glucosa y elpeso en comparación con el placebo o las sulfonilureas.(Campbell 1995; Johansen 1999; Guthrie 1997). El metanálisisde Campbell indicó que la metformina tuvo un efectocomparativo hipoglucemiante con relación a las sulfonilureas,pero hubo una mayor reducción de peso en el grupo demetformina. En los metanálisis similares de Johansen y Guthrie,la metformina y la sulfonilurea reducían la glucemia y lahemoglobina glucosilada de forma significativa en comparacióncon el placebo, pero el peso corporal fue significativamenteinferior en el grupo de metformina comparado con el desulfonilurea. Estos estudios no evaluaron la mortalidad, loscriterios de valoración relacionados con la diabetes o los efectosadversos del tratamiento.
Efectos adversos de la metforminaSe informa que los efectos adversos, principalmentegastrointestinales, ocurren en el 20% al 30% de los pacientesque reciben un tratamiento con metformina y se debeinterrumpir la administración del fármaco en menos del 5% delos pacientes (DeFronzo 1999). La diarrea, las náuseas, losvómitos, la distensión abdominal, los calambres o doloresabdominales, la flatulencia y la anorexia son los síntomasgastrointestinales más comunes asociados al tratamiento conmetformina. Otros efectos adversos que se informaron son lacefalea, la agitación, el mareo y el cansancio.
La acidosis láctica es una enfermedad rara, metabólica ypotencialmente fatal que puede ocurrir siempre que exista unahipoperfusión tisular substancial y una hipoxia (Kreisberg 1980;Olivia 1970). La acidosis láctica se caracteriza por la elevadaconcentración de lactato sanguíneo (que excede los 45 mg/dlo los 5,0 mEq/L), un pH sanguíneo reducido (menor que 7,35)y trastornos de electrólitos con una mayor insuficiencia deaniones. La mortalidad en los casos informados esaproximadamente del 42% al 50% (Bailey 1996; Misbin 1998).Se cree que las biguanidas reducen la gluconeogénesis de laalanina, el piruvato y el lactato y es posible que los niveles delácido láctico se acumulen en ciertas circunstancias (Stang 1999).Una biguanida anterior, la fenformina, se retiró del mercadoporque se asociaba con una tasa informada de acidosis lácticade 40 a 64 casos cada 100 000 pacientes tratados por año(DeFronzo 1999; Stang 1999). La metformina difiere de lafenformina en la estructura molecular y en la farmacocinética(Sulkin 1997). Se piensa que la metformina, a diferencia de lafenformina, mejora la oxidación de la glucosa sin afectar demanera significativa la producción de lactato en ayunas de lostejidos periféricos (Cusi 1996).
Se desconoce la verdadera incidencia de la acidosis lácticainducida por metformina. La Food and Drug Administrationha calculado que la tasa de acidosis láctica fatal o no fatal esde cinco casos cada 100 000 personas tratadas en el curso deun año (Misbin 1998). Los estudios basados en la poblaciónhan calculado una tasa de dos a nueve casos de acidosis lácticaen usuarios de metformina cada 100 000 personas por año(Campbell 1985; Stang 1999; Wilholm 1993). Sin embargo, lamayoría de los casos informados se presentaron en pacientescon enfermedades agudas graves, como la insuficiencia renal,que podrían haber sido la causa de la acidosis láctica (Brown1998; Misbin 1998). Para calcular el riesgo específicamenteatribuible a la metformina, se debe evaluar la tasa deantecedentes de la acidosis láctica en pacientes con diabetestipo 2 que no han recibido un tratamiento con metformina. Coneste fin, se utilizó una base de datos para medir las tasas deincidencia en los pacientes con diabetes tipo 2 en los EstadosUnidos antes de que se introdujera la metformina y se encontróuna tasa de nueve casos cada 100 000 personas por año (Brown1998). Esto plantea la cuestión de si los pacientes con diabetestipo 2 corren un mayor riesgo de desarrollar acidosis láctica
Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
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mediante el uso de metformina en comparación con otrostratamientos que reducen la glucosa.
Los datos disponibles indican que el uso de la metformina enpacientes obesos con diabetes mellitus tipo 2 se asocia a unareducción en la morbilidad y mortalidad cardiovascularcomparado con la insulina, la sulfonilurea o sólo la dieta(UKPDS-34 1998). Sin embargo, actualmente el uso de lametformina se considera contraindicado en muchasenfermedades crónicas que puedan aumentar el riesgo de laanoxia tisular (falta de oxígeno) y el desarrollo de la acidosisláctica, como las enfermedades cardiovasculares, renales,pulmonares y hepáticas. Estas restricciones reducen de manerasignificativa el número de pacientes que podrían beneficiarsedel tratamiento con metformina. Esta revisión evalúa el riesgode la acidosis láctica fatal y no fatal asociada con la metformina.Otros efectos adversos asociados con el uso de la metforminase evalúan en otra revisión.
OBJETIVOS
Evaluar el riesgo de la acidosis láctica fatal y no fatal asociadaal uso de la metformina en personas con diabetes mellitus tipo2, en comparación con el placebo u otros tratamientos parareducir la glucosa. Un objetivo secundario fue evaluar losniveles del lactato sanguíneo, medidos al inicio y durante eltratamiento, para comparar la metformina con el placebo u otrostratamientos hipoglucemiantes.
CRITERIOS PARA LA VALORACIÓN DE LOSESTUDIOS DE ESTA REVISIÓN
Tipos de estudios
Se incluyeron los ensayos clínicos prospectivos en pacientescon diabetes mellitus tipo 2 si evaluaban la metformina, sola oen combinación con otros tratamientos, en comparación con elplacebo u otro tratamiento hipoglucemiante, y si duraban almenos un mes. Se incluyeron los ensayos clínicos aunque noestuvieran asignados al azar o cegados. Además, se incluyeronen el análisis todos los estudios observacionales de cohortesque evaluaron durante al menos un mes el uso de la metformina,siempre que proporcionaran el número de pacientes y laduración del tratamiento. Se evaluaron por separado los ensayosexcluidos que duraron menos de un mes para ver si había algúncaso de acidosis láctica.
Tipos de participantes
Los participantes estudiados fueron adultos con diabetes mellitustipo 2. Para ser coherentes con los cambios en los criterios declasificación y diagnóstico de la diabetes mellitus tipo 2 con elpaso de los años, se debería establecer el diagnóstico mediantelos criterios estándar en el momento del ensayo.
Tipos de intervención
Metformina, sola o en combinación con otros tratamientos,versus el placebo o una de las siguientes intervenciones usadascon la intención de disminuir los niveles de la glucosasanguínea:
1. Placebo2. Sulfonilurea (por ejemplo, glibenclamida)3. Tiazolidinediona (por ejemplo, rosiglitazona)4. Meglitinida (por ejemplo, repaglinida)5. Inhibidor de la alfa glucosidasa (por ejemplo, acarbosa ymiglitol)6. Insulina7. Intervención no farmacológica (por ejemplo, dietas)8. Cualquier combinación de las anteriores
Los datos sobre los participantes tratados con fenformina no seincluyeron en el análisis para la acidosis láctica, pero sí seincluyeron en las mediciones de los niveles de lactato.
Tipos de medidas de resultado
Medidas de resultados primarias1. Muerte descrita como consecuencia de acidosis láctica2. Casos informados de acidosis láctica no fatal, definidos porel investigador
Medidas de resultadosecundarias1. Niveles del lactato sanguíneo para la metformina encomparación con el placebo u otros tratamientos sin biguanidasy comparado con la fenformina.
Modificadores del efectoCasos informados de insuficiencia renal o del cambio encualquier enfermedad concomitante hipóxica (p.ej.,enfermedades pulmonares). Si se tenían que identificar casosde acidosis láctica, se evaluaba su asociación con la enfermedadconcomitante.
ESTRATEGIA DE BÚSQUEDA PARA LAIDENTIFICACIÓN DE LOS ESTUDIOS
Dos investigadores (SS, EG) desarrollaron de forma conjuntaestrategias de búsqueda con la ayuda de un bibliotecario delservicio de información y el coordinador de búsqueda deensayos del Grupo Cochrane de Trastornos Metabólicos yEndocrinos (Cochrane Metabolic and Endocrine DisordersGroup).
Búsquedas electrónicasSe realizó una búsqueda exhaustiva de las siguientes bases dedatos para identificar ensayos clínicos en humanos o metanálisisrelevantes: The Cochrane Library (incluyendo el RegistroCochrane de Ensayos Controlados [Cochrane Controlled TrialsRegister] (CENTRAL) y la Database of Abstracts of Reviewsof Effectiveness (DARE)) (8/2005), MEDLINE (1966-8/2005),OLD MEDLINE, Reactions (1983-8/2005), y EMBASE
Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
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(1974-11/2000). La siguiente estrategia de búsqueda paraMedline se adaptó para buscar otras bases de datos médicas:
NOTAS: a menos que se mencione lo contrario, los términosde búsqueda son términos de texto libre; MeSH: Medical subjectheading (título de tema médico) (término índice médico deMEDLINE); un asterisco (*) significa cualquier carácter(es)"
Diabetes mellitus tipo 21. Diabetes mellitus, non-insulin-dependent [MeSH, allsubheadings and categories included]2. NIDDM3. (Non insulin* dep*) OR (Noninsulin* dep*) OR (Non insulindep*)4. (Typ* II diabet*) OR (Typ* 2 diabet*) OR (diabet* typ* 2)OR (diabet* typ* II)5. #1 OR #2 OR #3 OR #4
Metformin6. Biguanides [MeSH, all subheadings and categories included]7. Biguanid*8. Metformin [MeSH, all subheadings and categories included]9. Glucophag*10. Metformin*11. #6 or #7 or #8 or #9 or #10
TYPE 2 DIABETES AND METFORMIN12. #5 AND #11
Búsqueda manualLa búsqueda se amplió aún más después de la investigación delas referencias de los artículos o revisiones identificadas, y delos resúmenes de un simposio clínico, que se informó en larevista Diabetologia, volumen 43, suplemento 1, 2000. Se utilizóel Cumulated Index Medicus para buscar artículos pertinentesdesde 1959 hasta 1965.
Otras búsquedasAdemás, se intentó establecer contacto con los autores de losestudios identificados para obtener referencias adicionales,ensayos no publicados, ensayos en curso o datos que faltabanno informados en los ensayos originales. De igual manera, seestableció contacto con el fabricante de la metformina,Bristol-Myers Squibb Company, para obtener información sobrelos ensayos, publicados o no publicados, acerca de lametformina.
Se incluyeron estudios publicados en cualquier idioma. No seidentificaron palabras clave adicionales de relevancia duranteninguna de las búsquedas electrónicas o las demás búsquedas.Si, en búsquedas futuras, se encuentran palabras claveadicionales, se modificarán las estrategias de la búsquedaelectrónica para incorporar estos términos. La fecha de labúsqueda más reciente fue agosto 2005.
MÉTODOS DE LA REVISIÓN
Selección de ensayos
Dos revisores (GP, SS), de forma independiente, examinaronlos títulos, los resúmenes y las palabras clave de cada registroencontrado en la búsqueda. Se obtuvieron artículos completospara una evaluación posterior cuando la información dadasugería que el estudio evaluaba el uso de la metformina enpacientes con diabetes mellitus. En caso de dudas con respectoa estos criterios, derivadas de la información proporcionada enel título y el resumen, se recuperó el artículo completo paraaclararlas. Además, se obtuvo cualquier ensayo clínicopotencialmente relevante encontrado al explorar las referenciasde artículos identificados o revisiones.
Dos investigadores (SS, EG) evaluaron de forma independientelos estudios obtenidos para su inclusión, y se logró el consensoen los casos de controversias. El acuerdo del porcentajeobservado entre los evaluadores de la inclusión antes delconsenso se midió a través de la estadística kappa (Fleiss 1981).
Evaluación de la calidad de los ensayosLa calidad metodológica de cada estudio se evaluó según loscriterios de calidad modificados a partir de Schulz, Jadad yStroup (Jadad 1996; Schulz 1995; Stroup 2000). Se dividieronlos estudios en cinco categorías.
Para los ensayos controlados aleatorios, se estudiaron lossiguientes factores:1. Minimización del sesgo de selección - a) ¿fue elprocedimiento de asignación al azar adecuado? b) ¿fue elocultamiento de la asignación adecuado?2. Minimización del sesgo de ejecución: ¿estaban losparticipantes y las personas que administraban el tratamientocegados a la intervención?2. Reducción del sesgo de deserción - a) ¿fueron los retiros ylos abandonos: completamente descritos? b) ¿se realizó elanálisis por intención de tratar (intention-to-treat analysis)?4. Minimización del sesgo de detección - ¿estaban losevaluadores de resultado cegados a la intervención?
Según estos criterios, los ensayos se subdividieron ampliamenteen estas tres categorías:A - se cumplieron todos los criterios de calidad: bajo riesgo desesgo.B - uno o más de los criterios de calidad se cumplieron sóloparcialmente: riesgo moderado de sesgo.C - no cumple con uno o más criterios: alto riesgo de sesgo.
Para los ensayos no aleatorios, se utilizaron los siguientescriterios:D - Ensayos controlados abiertos no aleatoriosE - Estudios observacionales de cohortes
Dos revisores (SS, EG) evaluaron de forma independiente cadaensayo y se logró el consenso en los casos de desacuerdo. Secalculó el acuerdo entre evaluadores antes del consenso a travésde la estadística kappa. Sin embargo, debido a que no seencontraron eventos en los resultados, no se realizaron análisisde sensibilidad mediante las evaluaciones de calidad.
Extracción de los datos
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Dos revisores (SS, EG) extrajeron de forma independiente losdatos sobre detalles de la población del estudio, la intervencióny los resultados mediante un formulario de extracción de datosestándar. El formulario de extracción de datos incluía lossiguientes ítems:
1. Información general: publicado/ no publicado, título, autores,dirección de contacto, idioma de publicación, año depublicación, publicaciones duplicadas, patrocinador, contexto.2. Características del ensayo: diseño, duración, asignación alazar (y método), cegamiento (simple, doble y triple), métodoy verificación del cegamiento.3. Intervención(es): placebo incluido, intervenciones (dosis,vía, tiempo), intervenciones de comparación (dosis, vía, tiempo),fármacos (dosis, vía, tiempo).4. Pacientes: criterios de inclusión y exclusión, número total ynúmero de participantes en los grupos de comparación, sexo,edad, características seleccionadas al inicio del estudio, criteriosde diagnóstico, semejanza entre los grupos al inicio del estudio(con inclusión de cualquier comorbilidad), retiros o pérdidasdurante el seguimiento (descripción), subgrupos.5. Resultados: muertes atribuidas a la acidosis láctica, acidosisláctica no fatal, niveles de lactato, insuficiencia renal,empeoramiento de las enfermedades hipoxémicasconcomitantes, duración de seguimiento, calidad de lanotificación de los resultados.
Las diferencias en la extracción de datos se resolvieron medianteel consenso y la consulta del artículo original. Los casos deacidosis láctica se tabulaban según el informe del investigador.Además, se buscó la información de los autores de los estudiosprincipales.
Análisis de los datosPara expresar el efecto del tratamiento sobre la acidosis lácticafatal y no fatal como diferencia de riesgo, se consideró laincidencia de eventos del uso de metformina, sola o encombinación con otros tratamientos, y luego se restó laincidencia de eventos del uso del placebo o los tratamientosalternativos. Cuando se encontraban eventos no fatales, elprimer evento se consideraba para cualquier paciente. Se habíapropuesto combinar los resultados mediante el modelo deefectos fijos para datos dicotómicos. A continuación, ladiferencia de riesgo se convertía en el número necesario paradañar (NND). Además, los resultados se podrían expresar comoel riesgo relativo de la acidosis láctica asociada con el uso demetformina en comparación con el placebo o el tratamiento sinmetformina. Sin embargo, cuando no se encontraron casos deacidosis láctica en alguno de los grupos de tratamiento, el límitesuperior para la verdadera incidencia de la acidosis láctica enel grupo de metformina y en el grupo sin metformina se calculópor separado a través de las estadísticas de Poisson.
Se probó la heterogeneidad entre estudios al utilizar laestadística de Ji cuadrado para presuponer la homogeneidad,con una significación estadística establecida en p < 0,1. Lasposibles fuentes de heterogeneidad se evaluaron mediante
análisis de sensibilidad y de subgrupos, como se describe acontinuación. Esto no se realizó debido a que no se encontraroncasos de acidosis láctica. Se probó el sesgo del estudio pequeñomediante la técnica del gráfico de embudo (funnel plot). Elanálisis se realizó mediante MetaView 4.1 (Cochrane Software).
Una vez que los resultados agrupados no revelaron casos deacidosis láctica, se decidió informar sobre ensayos que midieranlos niveles del lactato sanguíneo para la metformina, comparadocon el placebo o los tratamientos sin biguanidas, y también encomparación con la fenformina. Se analizaron tres resultadospara el grupo de metformina en contraste con los grupos decomparación: (1) el cambio en los niveles de lactato desde elinicio hasta el tratamiento, (2) la media de los niveles de lactatoregistrados durante el tratamiento, y (3) el cambio en los nivelesde lactato del tratamiento desde un estado basal hasta laestimulación máxima, ya sea con alimentos o ejercicios. Losresultados se registraron como diferencia de medias ponderada(DMP), en mmol/L, y se agruparon mediante el uso del modelode efectos fijos para los datos continuos.
Análisis de subgruposSe planificó realizar análisis de subgrupos a fin de investigarla asociación de la acidosis láctica con los siguientes factores:
1. Pacientes con enfermedades concomitantes hipoxémicas,p.ej., insuficiencia renal crónica (creatinina > 1,5 mg/dl) oinsuficiencia renal, insuficiencia cardíaca congestiva,enfermedad hepática, enfermedades pulmonares y arteriopatíaperiférica.2. Edad superior a los 65 años.3. Uso de metformina administrada como monoterapia o encombinación con otros fármacos.4. Diferentes intervenciones de comparación.
Estos análisis no se realizaron debido a que no había casos paraestudiar. En cambio, se obtuvo información acerca de cuántospacientes eran mayores de 65 años o cuántos se considerabaque presentaban enfermedades hipoxémicas concomitantes.
Análisis de sensibilidadSe planificaron análisis de sensibilidad para investigar lainfluencia de los siguientes factores en el tamaño del efecto:
1. Repetición del análisis con exclusión de los estudios nopublicados, ensayos no aleatorios y ensayos sin cegamiento.2. Repetición del análisis según la calidad del estudio, como seespecificó anteriormente.3. Repetición del análisis con exclusión de estudios muy largoso de gran tamaño para establecer cuánto dominan los resultados.4. Repetición del análisis con exclusión de estudios financiadospor patrocinadores industriales.
La solidez de los resultados también se comprobó mediante larepetición de los análisis que utilizaban diferentes medidas detamaño del efecto (diferencia de riesgo, riesgo relativo, etc.) ydiferentes modelos estadísticos (modelos de efectos fijos yaleatorios). Debido a que no se encontraron casos de acidosisláctica, no se realizaron los análisis de sensibilidad.
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DESCRIPCIÓN DE LOS ESTUDIOS
Ensayos identificadosLa búsqueda en las bases de datos electrónicas identificó 1192artículos, y de éstos, 192 eran estudios potencialmenterelevantes acerca del uso de la metformina en pacientes condiabetes tipo 2 (181 de MEDLINE y 11 artículos adicionalesde EMBASE). Después de revisar los artículos y lasbibliografías, el Cumulated Index Medicus y los resúmenes deun simposio clínico, se identificaron 70 estudios adicionales.De estos 262 estudios, 205 cumplieron con los criterios deinclusión. No se encontraron otros artículos a través de lacorrespondencia con los autores, pero se recibió del Dr. EvertineAbbink información de un ensayo no publicado adicional.
Acuerdo entre evaluadoresLa puntuación kappa para el acuerdo entre evaluadores en laselección de ensayos fue 0,88 (IC: 0,78 a 0,98) lo que indicabuen acuerdo. Se alcanzó el consenso sobre los demás ensayosal verificar de forma conjunta el artículo.
Datos faltantesSe intentó establecer contacto con 102 de los autores para losensayos comparativos a través de la dirección decorrespondencia mencionada y se recibieron 30 respuestas. Los30 que respondieron declararon no conocer caso alguno deacidosis láctica en cualquiera de sus 34 ensayos. Además, elfabricante de la metformina, Bristol-Myers Squibb Company,respondió y declaró que no tenía ensayos no publicados parainformar. Proporcionaron una lista de ensayos relacionados conla metformina, pero todos se habían analizado a través de labúsqueda.
Estudios excluidosLos estudios fueron excluidos por las siguientes razones: doseran estudios de cohorte retrospectivos que no suministraroninformación sobre el número de pacientes o la duración detratamiento (Debry 1966a; Debry 1966b), 12 eran estudios decohorte prospectivos que no suministraron información sobreel número de pacientes o duración de tratamiento (Bernard1965; Carpentier 1975; Chow 1995; Clauson 1996; Debry 1964;Messens 1965; Messens 1966; Muntoni 1965; Nauck 1993;Rambert 1961; Sugawara 1962; Teitelbaum 1963), 33 ensayoscomparativos prospectivos tuvieron una duración inferior a unmes (Bonfigli 1999; Bruneder 1978; Cacciapuoti 1991; Fery1997; Galuska 1994; Gibson 1995; Gin 1982; Gin 1985; Gin1989; Giugliano 1979; Isnard 1991; Isnard 1996; Irsigler 1978;Ismail 1978; Jansson 1996; Leslie 1987; Lim 1970; Orlikowska1966; Panahloo 1995; Perriello 1994; Pilger 1978; Prager 1983;Rigas 1968; Rizkalla 1986; Sambol 1996; Scarpello 1998;Schaffalitzky 1979; Signore 1996; Slama 1984; Sum 1992;Trischitta 1983; Turner 1995; Zapecka-Dubno 1999), y diezfueron análisis o revisiones retrospectivos (Aguilar 1992b;Connolly 1996; Daniel 1997; Guthrie 1997; Johansen 1999;Lalau 1994; Lalau 1995; Nauck 1997; O'Connor 1998; Selby1999).
Estudios Incluidos
Estudios y participantesDe los 206 estudios analizados, 148 fueron ensayoscomparativos prospectivos, 46 fueron estudios de cohortesprospectivos y 12 fueron estudios de cohortes retrospectivos.Se realizó el seguimiento de un total de 47 096 participantesde 86 067 pacientes tratados por año, con 30 294 participantes(47 846 pacientes tratados por año) en el grupo de metforminay 16 782 participantes (38 221 pacientes tratados por año) enel grupo sin metformina. La edad media de los participantesdel grupo de metformina fue 57,1 (+/- 8,9) años y un 61% eranhombres. En el grupo sin metformina, la media de edad fue57,2 (+/ - 9,1) años y un 61% eran hombres. De los datosdisponibles se calculó que un 24% de los participantes eranmayores de 65 años, que tuvieron un seguimiento de hastaaproximadamente 20 650 pacientes tratados por año. Laduración media del ensayo fue 2,1 años, con un rango de 0,08a 10,7 años. El tamaño medio del estudio en el grupo demetformina fue de 147 participantes con un rango de 6 a 7,227.El tamaño promedio del estudio en el grupo sin metformina fuede 81 participantes con un rango de 8 a 2 796. La tasa deabandono se estimó en un 9,2%.
Criterios de exclusión de los estudiosDe los 194 estudios prospectivos, la insuficiencia renal semencionó como criterio de exclusión en 105 (54%), lasenfermedades cardiovasculares en 76 (39%), las enfermedadeshepáticas en 104 (54%), las enfermedades pulmonares en 33(17%) y la edad superó los 65 en 34 (18%).
IntervencionesSe administró la metformina en dosis diarias de 1 a 3 gramos,con ajustes clínicos de la dosis. Los tratamientos decomparación incluían placebo, dieta, insulina, gliburida,gliclazida, glipizida, glibenclamida, clorpropramida,tolbutamida, acarbosa, nateglinida, repaglinida, miglitol,troglitazona, pioglitazona y la goma de guar.
Medidas de resultadoLos resultados midieron el control glucémico incluido (glucosaurinaria y sanguínea, HbA1, HbA1c, insulina y nivelesc-péptido), la sensibilidad de la insulina mediante un bolo deglucosa, el peso, el consumo de energía, los lípidos, laslipoproteínas, la fructosamina, los ácidos grasos libres, elfibrinógeno, el inhibidor del activador de plasminógeno, lafrecuencia cardíaca, la presión arterial, los niveles de lactato,el bicarbonato, las cetonas, la microalbuminuria, las pruebasde la función renal y hepática, la tasa bruta de mortalidad, lamortalidad relacionada con el tiempo y la diabetes relacionadacon los criterios de valoración (muerte súbita, muerte por hipero hipoglucemia, infarto del miocárdico, accidentecerebrovascular, insuficiencia renal y la enfermedad oculardiabética).
Sólo 19 ensayos estaban diseñados específicamente para evaluarla incidencia de la acidosis láctica, aunque en casi todos losensayos se describieron los efectos secundarios o los eventos
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adversos. Se realizaron intentos para establecer contacto conlos autores de los ensayos y 30 investigadores contestaron, todosconfirmaron que no había casos de acidosis fatal o no fatalconocidos en ninguno de sus 34 ensayos. El bicarbonato séricoo los niveles de lactato se midieron en 99 de los estudiosincluidos (48%). En los ensayos comparativos, 25 midieron losniveles de lactato durante los tratamientos con o sin metformina(Bjorntorp 1978; Botha 1977; Campbell 1994; Cavallo-Perin1989; Cryer 2005; Cusi 1996; Damsbo 1998; De Silva 1979;DeFronzo 1995; Fritsche 2000; Gregorio 1989; Gregorio 1990;Hother-Nielsen 1989; Inzucchi 1998; Jackson 1987; Josephkutty1990; Klein 1991; McAlpine 1988; Nattrass 1977; Pedersen1989; Rachmani 2002; Raptis 1996; Teupe 1991; Velussi 1992;Wu 1990).
CALIDAD METODOLÓGICA
Se asignaron las puntuaciones de calidad metodológica de losestudios mediante los criterios descritos con anterioridad. Paradeterminar una puntuación de calidad se utilizó sólo lainformación publicada en los ensayos. La puntuación kappapara el acuerdo entre los evaluadores fue 0,84 (intervalo deconfianza [IC] del 95%: 0,77 a 0,91) lo que indica buen acuerdo.Después que se logró el consenso en los ensayos restantes, sieteensayos recibieron una puntuación de A; 58 ensayos recibieronuna puntuación de B; otros 58 una puntuación de C; 25 ensayosuna puntuación de D; y 58 estudios más una puntuación de E.De los estudios analizados, 65 eran ensayos controladosaleatorios a doble ciego (siete describieron el método deasignación al azar y el ocultamiento de la asignación). Otros83 fueron ensayos comparativos de simple ciego o abiertos (58aleatorios y 25 no aleatorios). Los 58 estudios de cohortesfueron todos abiertos y observacionales. La tasa de abandonopromedio fue del 9,2%.
RESULTADOS
Incidencia de la acidosis lácticaCuando se combinaron los datos de los estudios de cohortescon los ensayos comparativos prospectivos, no se informóningún caso de acidosis láctica fatal o no fatal en el grupo demetformina, con un total de 47 846 pacientes tratados por añoy ningún caso en el grupo sin metformina, que representaban38 221 pacientes tratados por año. Mediante el uso de lasestadísticas de Poisson con un intervalo de confianza del 95%,el límite superior para la verdadera incidencia de la acidosisláctica asociada a la metformina fue de 6,3 casos por cada 100000 pacientes tratados por año y el límite superior para laincidencia de la acidosis láctica en el grupo sin metformina fuede 7,8 casos por cada 100 000 pacientes tratados por año.Cuando se combinaron los datos de los grupos de metforminay sin metformina, el límite superior para la verdadera incidenciade la acidosis láctica en todos los pacientes con diabetes tipo 2fue 3,5 casos cada 100 000 pacientes tratados por año.
Asociación con enfermedades hipoxémicas concomitantesOtro resultado que se evaluó fue el número de participantes quemostraron un empeoramiento en sus enfermedadesconcomitantes hipoxémicas durante el ensayo. No fue posiblerealizar una evaluación exacta de la incidencia de lainsuficiencia renal o el empeoramiento de otras enfermedadesporque dos de los ensayos grandes no proporcionaron datosadecuados (Fisman 2001; UKPDS-34 1998). No se pudoproporcionar esta información a través de la correspondenciacon los autores de estos ensayos.
No hubo información suficiente para calcular el número departicipantes estudiados que presentaban enfermedadeshipoxémicas concomitantes como la insuficiencia renal, lasenfermedades cardiovasculares, hepáticas o pulmonares. Encambio, cada uno de los ensayos incluidos en este análisis secaracterizó en cuanto a si alguna de estas enfermedades semencionaba como criterio de exclusión. Si los pacientes seenumeraron como saludables o con el uso de contraindicacionesestándar, se supuso que todas estas condiciones fueronexcluidas. La insuficiencia renal se definió normalmente comoun nivel de creatinina de más de 1,5 mg/dl. De los 194 estudiosprospectivos, 89 (46%) permitieron la inclusión de lainsuficiencia renal, según 28 244 pacientes por año de uso dela metformina y 186 (96%) permitieron la inclusión de al menosuna de las contraindicaciones mencionadas anteriormente. Delos datos disponibles, se calculó que el 24% de los participantesen los estudios tenían una edad superior a los 65 años, yrecibieron un seguimiento de hasta aproximadamente 11 483pacientes por año de uso de metformina.
Niveles del lactato sanguíneoPara aquellos ensayos que proporcionaron los datos, el nivelde lactato inicial medido antes del tratamiento con metforminafue de 1,13 +/-0, 25 mmol/L. No hubo diferencias en el cambioneto de los niveles de lactato desde el inicio del estudio para lametformina en comparación con el placebo o con lostratamientos sin biguanidas, con una diferencia de mediasponderada (DMP) de 0,12 mmol/L (intervalo de confianza [IC]del 95% -0,01; 0,25). El nivel de lactato promedio durante eltratamiento con metformina fue de 1,24 +/-0,31 mmol/L, elcual no fue significativamente diferente de las comparacionessin biguanidas (DMP 0,04 mmol/L; IC del 95%: 0,00 a 0,13,P = 0,07) y fue de 0,75 mmol/L más bajo que con la fenformina(IC del 95%: -0,86 a -0,65). El nivel de lactato durante eltratamiento con metformina, medido antes y después de laestimulación (a través de una comida o ejercicios enérgicos)fue 2,3 +/- 1,7 mmol/L. Este resultado no fue significativamentediferente para la metformina en comparación con el grupo sinbiguanidas (DMP 0,09 mmol/L; IC del 95%: -0,03; 0,22) o conla fenformina (DMP -0,37 mmol/L; IC del 95%: -1,06; 0,32).Cuatro ensayos que midieron los niveles de lactato noproporcionaron datos para ser analizados, pero informaronniveles normales durante el tratamiento con metformina y sinmetformina (DeFronzo 1995; Fritsche 2000; Gregorio 1989;Raptis 1996).
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Se observó una posible heterogeneidad en los tres ensayos quemidieron los niveles de lactato después de la estimulación conalimentos o ejercicios durante el tratamiento con metforminao los tratamientos sin biguanidas, probablemente debido a quecada uno se realizó bajo distintas condiciones. Los resultadosno fueron significativamente diferentes cuando se utilizó elmodelo de efectos aleatorios (DMP 0,04 mmol/L; IC del 95%:-0,45; 0,53). Además, se observó cierta heterogeneidad en lostres ensayos que medían los niveles promedio de lactato parael tratamiento con metformina en comparación con el defenformina. Cuando se utilizó el modelo de efectos aleatorios,la diferencia ya no era estadísticamente significativa (-0,64mmol/L; IC del 95%: -1,63; 0,35).
Análisis del sesgo de publicaciónLos gráficos de embudo (funnel plots) del tamaño del efectoversus el error estándar se evaluaron para los ensayos incluidosen el análisis. El gráfico de embudo (funnel plot) utilizado parala incidencia de la acidosis láctica no pudo aportar pruebas afavor o en contra de la posibilidad del sesgo del estudiopequeño, debido a que en ninguno de los ensayos se encontraroncasos de acidosis láctica. Los gráficos de embudo (funnel plots)para medir los niveles de lactato no mostraron pruebas de unsesgo significativo del estudio pequeño.
DISCUSIÓN
ResumenPara evaluar el riesgo de la acidosis láctica atribuida al uso demetformina, se analizaron los datos agrupados de todos losensayos comparativos prospectivos y los estudiosobservacionales de cohortes conocidos que duraron más de unmes. No se encontraron casos en 206 ensayos con 47 846pacientes tratados por año con metformina. En realidad, en larevisión de 47 ensayos adicionales que se excluyeron del análisis(aquellos que duraron menos de un mes o tuvieron una duraciónincierta) no se encontraron casos de acidosis láctica. Ladiferencia de riesgo para el tratamiento con metformina encomparación con el tratamiento sin metformina, calculadomediante las estadísticas de Poisson fue de 0,00 cada 100 000pacientes tratados por año (IC del 95%: -7,8; + 6,3). Esto indicaque el límite superior para la verdadera incidencia de la acidosisláctica asociada con la metformina es de 6 casos cada 100 000pacientes tratados por año y el límite superior para la incidenciacon otros tratamientos sin biguanidas es de 8 cada 100 000pacientes tratados por año. En los ensayos que midieron losniveles del lactato sanguíneo, no hubo diferencias significativaspara la metformina en comparación con el placebo o con lostratamientos sin biguanidas; y fueron inferiores para lametformina que para la fenformina.
La duración media de los estudios incluidos en esta revisiónfue de 2,1 años con un amplio rango de un mes hasta 10,7 años.Debido a que no se encontraron casos de acidosis láctica enninguno de los ensayos, no se pudo evaluar la asociación de laacidosis láctica a la duración del tratamiento. Además, se
evaluaron los ensayos excluidos con menos de un mes deduración para ver si la acidosis láctica ocurría poco después delinicio del tratamiento, pero no se encontraron casos.
Actualmente, se considera que la metformina estácontraindicada en pacientes con insuficiencia renal crónica,anormalidades de la función hepática, insuficiencia cardíacacongestiva, vasculopatía periférica, enfermedades pulmonareso en pacientes mayores de 65 años de edad, debido a que estasenfermedades pueden aumentar el riesgo de la anoxia tisular y,por consiguiente, el desarrollo de la acidosis láctica. En estarevisión, 187 (96%) de los 194 estudios prospectivospermitieron la inclusión de pacientes con al menos una de estascontraindicaciones y se estimó que el 24% de todos losparticipantes eran mayores de 65 años, sin efectos adversosdetectados. Sin embargo, es incierta la cantidad de participantescon estas enfermedades que se incluyeron en los ensayos, demanera que no se puede evaluar la seguridad de la metforminaen presencia de estas contraindicaciones estándar. Un ensayo(Rachmani 2002) cuestionó las contraindicaciones estándar alestudiar a 393 pacientes, con al menos una contraindicaciónpara el uso de metformina, y no encontró ningún caso deacidosis láctica en más de cuatro años de duración del ensayo.Todos los pacientes de este ensayo tenían insuficiencia renal,con niveles de creatinina plasmática medios de 1,5 a 2,5 mg/dl(nivel medio 1,8 mg/dl).
Limitaciones de la revisiónEsta revisión tiene algunas limitaciones. Esencialmente todoslos datos incluidos en este análisis provenían de ensayospublicados y esto puede haber producido resultados sesgados.Un gráfico de embudo (funnel plot) del tamaño del efecto versusel error estándar no pudo aportar pruebas para el sesgo depublicación significativo, ya que no se encontraron casos enninguno de los ensayos. Es interesante observar que muchosde los ensayos comparativos incluidos en el análisis recibieronel patrocinio de compañías farmacéuticas que producíanfármacos hipoglucemiantes distintos a la metformina, en cuyocaso un sesgo sería publicar los efectos adversos para lametformina.
Otra de las dificultades es que para evaluar el riesgo de unaaparición rara como la acidosis láctica, es posible que seanecesario evaluar a más de 48 000 pacientes tratados por añocon metformina. Es especialmente difícil evaluar el riesgo dela acidosis láctica en presencia de contraindicaciones estándarcomo la insuficiencia renal o la hepática porque es incierto elnúmero exacto de participantes que presentaban estasenfermedades. Por ese motivo, no se pueden establecerconclusiones acerca de la seguridad del uso de la metforminaen presencia de estas enfermedades. A pesar de estaslimitaciones, la conclusión más importante de esta revisión esque, en la actualidad, no hay pruebas en los ensayoscomparativos prospectivos o los estudios observacionales decohortes que apoyen la hipótesis de la asociación de lametformina a un mayor riesgo de acidosis láctica.
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Generalización y aplicabilidad de los resultadosLa metformina es un medicamento hipoglucemiante de lafamilia de las biguanidas que se ha utilizado durante más de 45años (Sterne 1959). Se ha demostrado que el tratamiento conmetformina en pacientes con sobrepeso que presentan diabetestipo 2 reduce la mortalidad cardiovascular y total encomparación con la insulina, la sulfonilurea o sólo la dieta(UKPDS-34 1998). La preocupación respecto al riesgo deacidosis láctica ha dado lugar a recomendaciones acerca de lasuspensión de la metformina en personas con enfermedadescrónicas que en sí mismas puedan causar la acidosis láctica. Sise siguen estas recomendaciones, se reducirá el número depacientes aptos para recibir metformina a aproximadamente lamitad (Brown 1998). Se ha encontrado que en la práctica clínicaestas contraindicaciones estándar se desatienden en gran manera,ya que del 54% al 73% de los pacientes tratados con metforminapresentan al menos una contraindicación al tratamiento (Holstein1999; Sulkin 1997). En un estudio transversal, el 19% de lospacientes tratados con metformina que ingresaron a un hospitalpresentaron una insuficiencia renal concomitante (Holstein1999).
Se ha implicado a la metformina como causa de acidosis lácticadebido a que se había asociado una biguanida relacionada, lafenformina, a diversos casos de acidosis láctica, y se retiró delmercado de los EE.UU. en 1977 (Aguilar 1992b). A pesar desus semejanzas, la fenformina tiene una estructura químicasignificativamente diferente a la metformina. A diferencia dela metformina, la fenformina puede deteriorar la fosforilaciónoxidativa del hígado, y aumentar de esta manera la producciónde lactato a través de vías anaeróbicas (Cavallo-Perin 1989;Irsigler 1978; Pilger 1978; Sirtori 1994; Velussi 1992). Encambio, la metformina inhibe la gluconeogénesis hepática sinalterar el recambio de lactato o la oxidación de lactato (Cusi1996; Scheen 1996; Stacpoole 1998). Además de los ensayosanalizados en esta revisión, otros ensayos han confirmado queel tratamiento con metformina no eleva de forma significativalos niveles del lactato sanguíneo, aun en presencia de unadeficiencia renal o edad avanzada (Connolly 1996; Debry 1964;Giugliano 1993; Irsigler 1978; Lalau 1990; Menzies 1989;Pagano 1983; Pilger 1978; Trischitta 1983).
En la actualidad, las únicas pruebas que indican la asociacióndel uso de metformina con la acidosis láctica provienen deinformes de aproximadamente 330 casos que ocurrieron enpacientes durante el tratamiento con metformina (Bergman1978; Gan 1992; Lalau 1994; Luft 1978). La incidencia deacidosis láctica en pacientes tratados con metformina se hacalculado en estudios de población y va de 2 a 9 casos cada 100000 pacientes tratados por año (Misbin 1998; Stang 1999;Wilholm 1993). La mayoría de los casos informados se encontróen pacientes con enfermedades subyacentes graves que en símismas podrían haber causado la acidosis láctica.
También se ha encontrado acidosis láctica en pacientesdiabéticos no tratados con metformina, que habitualmentepresentan enfermedades con una hipoperfusión tisular
significativa o hipoxia (Aguilar 1992b). Para evaluar la tasa deacidosis láctica en pacientes diabéticos que recibierontratamientos distintos a la metformina, un estudio de poblaciónrealizó un seguimiento de pacientes con diabetes tipo 2 que setrataron en los EE.UU. antes de la aparición de la metforminay después del retiro de la fenformina (Brown 1998). Este estudiohalló que la tasa de acidosis láctica confirmada eraaproximadamente de 10 cada 100 000 pacientes tratados poraño, lo que equivale a la encontrada en el tratamiento conmetformina. Otro estudio evaluó todos los casos de acidosismetabólica no cetónica en pacientes con diabetes tipo 2 queocurrieron en 609 ingresos de emergencia en un hospitaluniversitario (Aguilar 1992b). Las tasas de acidosis no cetónicacada 1000 ingresos en urgencias fueron 29 para la sulfonilurea,32 para la sulfonilurea más la fenformina, 48 para la insulinay ningún caso para aquellos tratados con metformina. Todoslos casos de acidosis metabólica no cetónica encontrados seasociaron con enfermedades precipitantes graves que podríanhaber causado la acidosis láctica. Los investigadores llegarona la conclusión de que el determinante principal para laaparición de la acidosis láctica es la disfunción sistémicasubyacente y no el tratamiento en sí. Para apoyar esa conclusión,los resultados de esta revisión revelan que no hay pruebas deun mayor riesgo de acidosis láctica asociada con el uso demetformina si se prescribe en las enfermedades del estudio yse tienen en cuenta las contraindicaciones.
CONCLUSIONES DE LOS AUTORES
Implicaciones para la práctica
No hay pruebas en los ensayos comparativos prospectivos o enlos estudios observacionales de cohortes de que el tratamientocon metformina aumente la incidencia de la acidosis láctica sise prescribe en las enfermedades del estudio, y se tienen encuenta las contraindicaciones. Esta revisión no fue capaz deevaluar cuantitativamente la seguridad del tratamiento conmetformina en presencia de cada una de las enfermedadesconcomitantes hipóxicas.
Implicaciones para la investigación
Será necesario realizar grandes ensayos prospectivos ycomparativos en pacientes con diabetes mellitus tipo 2 quepresenten enfermedades que se consideran, en la actualidad,contraindicaciones para su uso. Por ejemplo, se podría realizarun ensayo de gran tamaño en pacientes que se sabe presentanuna insuficiencia renal crónica. Los resultados a seguir incluiríanla incidencia de la acidosis láctica así como las complicacionesrelacionadas con la diabetes y la mortalidad total.
POTENCIAL CONFLICTO DE INTERÉS
Ninguno conocido.
Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
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FUENTES DE FINANCIACIÓN
Recursos externos
• La información sobre los recursos de apoyo no está
disponible
Recursos internos
• Santa Clara Valley Medical Center USA
✦
REFERENCIAS
Referencias de los estudios incluidos en esta revisión
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Gregorio 1989 {published data only}Gregorio F, Ambrosi F, Angelici F, Cristallini S, Dini FL, Vespasiani G,et al. [Body mass index, blood lactate and therapeutic effectiveness ofmetformin in type II diabetes mellitus]. Medicina (Firenze) 1989;9(2):200-4.
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Hermann 1991a {published data only}Hermann LS, Bitzen PO, Kjellstrom T, Lindgarde F, Schersten B.Comparative efficacy of metformin and glibenclamide in patients withnon-insulin-dependent diabetes mellitus. Diabete & Metabolisme 1991;17(1Pt 2):201-8.
Hermann LS, Kjellstrom T, Nilsson-Ehle P. Effects of metformin andglibenclamide alone and in combination on serum lipids and lipoproteinsin patients with non-insulin-dependent diabetes mellitus. Diabete &Metabolisme 1991;17(1 Pt 2):174-9.
Hermann 1991b {published data only}Hermann LS, Karlsson JE, Sjostrand A. Prospective comparative study inNIDDM patients of metformin and glibenclamide with special referenceto lipid profiles. European Journal of Clinical Pharmacology1991;41(3):263-5.
Hermann 1994a {published data only}Hermann LS, Schersten B, Melander A. Antihyperglycaemic efficacy,response prediction and dose-response relations of treatment with metforminand sulphonylurea, alone and in primary combination. Diabete &Metabolisme 1994;11(10):953-60.
Hermann 1994b {published data only}Hermann LS, Schersten B, Bitzen PO, Kjellstrom T, Lindgarde F, MelanderA. Therapeutic comparison of metformin and sulfonylurea, alone and invarious combinations. A double-blind controlled study [see comments].Diabetes Care 1994;17(10):1100-9.
Higginbotham 1979 {published data only}Higginbotham L, Martin FIR. Double-blind trial of metformin in the therapyof non-ketotic diabetics. Medical Journal of Australia 1979;2(154-6).
Hirsch 1999 {published data only}Hirsch IB. Metformin added to insulin therapy in poorly controlled Type-IIDiabetes. Diabetes Care 1999;22(5):854.
Hoffmann 1997 {published data only}Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose,metformin, or placebo in dietary-treated NIDDM patients: the Essen-IIStudy. American Journal of Medicien 1997;103(6):483-90.
Hollenbeck 1991 {published data only}Hollenbeck CB, Johnston P, Varasteh BB, Chen YD, Reaven GM. Effectsof metformin on glucose, insulin and lipid metabolism in patients with mildhypertriglyceridaemia and non-insulin dependent diabetes by glucosetolerance test criteria. Diabete & Metabolisme 1991;17(5):483-9.
Holman 1987 {published data only}Holman RR, Steemson J, Turner RC. Sulphonylurea failure in Type 2Diabetes: Treatment with a basal insulin supplement. Diabete &Metabolisme 1987;4:457-62.
Horton 2000 {published data only}Horton ES, Clinkenbeard C, Gatlin M, Foley J, Mallows S, Shen S.Nateglinide alone and in combination with metformin improves glycemiccontrol by reducing mealtime glucose levels in type 2 diabetes. DiabetesCare 2000;23(11):1660-5.
Horton 2004 {published data only}Horton ES, Doley JE, Shen SG, Baron MA. Efficacy and tolerability ofinitial combination therapy with nateglinide and metformin intreatment-naive patients with thpe 2 diabetes. Current Medical Researchand Opinion 2004;20(6):883-9.
Hother-Nielsen 1989 {published data only}Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H, PedersenO. Metformin improves peripheral but not hepatic insulin action in obesepatients with type II diabetes. Acta Endocrinologica (Copenhagen)1989;120(3):257-65.
Imano 1998 {published data only}Imano E, Kanda T, Nakatani Y, Nishida T, Arai K, Motomura M, et al.Effect of troglitazone on microalbuminuria in patients with incipient diabeticnephropathy. Diabetes Care 1998;21(12):2135-9.
Inzucchi 1998 {published data only}Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, et al.Efficacy and metabolic effects of metformin and troglitazone in type IIdiabetes mellitus [see comments]. New England Journal of Medicine1998;338(13):867-72.
Jackson 1962 {published data only}Jackson WPU. Combined oral therapy in Diabetes. South African MedicalJournal 1962;36:727-9.
Jackson 1987 {published data only}Jackson RA, Hawa MI, Jaspan JB, Sim BM, Disilvio L, Featherbe D, et al.Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes1987;36(5):632-40.
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Jeppesen 1994 {published data only}Jeppesen J, Zhou M-Y, Chen Y-D I, Reaven GM. Effect of metformin onpostprandial lipemia in patients with fairly to poorly controlled NIDDM.Diabetes Care 1994;17(10):1093-9.
Johansen 1984 {published data only}Johansen K. Acarbose treatment of sulfonylurea-treated non-insulindependent diabetics. A double-blind cross-over comparison of analpha-glucosidase inhibitor with metformin. Diabete & Metabolisme1984;10(4):219-23.
Johnson 1993 {published data only}Johnson AB, Webster JM, Sum CF, Heseltine L, Argyraki M, Cooper BG,et al. The impact of metformin therapy on hepatic glucose production andskeletal muscle glycogen synthase activity in overweight type II diabeticpatients. Metabolism 1993;42(9):1217-22.
Johnson 1998 {published data only}Johnson M, Krosnick A, Carson P, McDade AM, Laraway K. Aretrospective chart review of uncontrolled use of metformin as an add-ontherapy in type 2 diabetes. Clinical Therapeutics 1998;20(4):691-8.
Jones 2000 b {published data only}Jones NP, Mather R, Owen S, Porter LE, Patwardhan R. Long-term efficacyof rosiglitazone as monotherapy or in combination with metformin.Diabetologia 2000;43(Suppl 1):A192.
Jones 2000a {published data only}Jones T, Jones NP, Sautter M. Addition of rosiglitazone to metformin iseffective in obese, insulin-resistant patients with Type 2 Diabetes.Diabetologia 2000;43(Suppl 1):A191.
Jones 2002 {published data only}Jones KL, Arslanian S, Peterokova VA, Park J-S, Tomlinson MJ. Effectof metformin in pediatric patients with type 2 diabetes: a randomizedcontrolled trial. Diabetes Care 2002;25:89-94.
Josephkutty 1990 {published data only}Josephkutty S, Potter JM. Comparison of tolbutamide and metformin inelderly diabetic patients. Diabete & Metabolisme 1990;7(6):510-4.
Josse 1995 {published data only}Josse RG. Acarbose for the treatment of type II diabetes: the results of aCanadian multi-centre trial [published erratum appears in Diabetes ResClin Pract 1995 Sep;29(3):215]. Diabetes Research and Clinical Practice1995;28(Suppl):S167-72.
Jung 2005 {published data only}Jung HS, Youhn B-S, Cho YM, Yu K-Y, Park HJ, Shin CS, Kim SY, LeeHK, Park KS. The effects of rosiglitazone and metformin on the plasmaconcentrations of resistin in patients with type 2 diabetes mellitus.Metabolism Clinical and Experimental 2005;54:314-20.
Karlsson 2005 {published data only}Karlsson HKR, Hallsten K, Bjornholm M, Tsuchida H, Chibalin AV,Virtanen KA, Heinonen OJ, Lonnqvist F, Nuutila P, Zierath JR. Effects ofmetformin anad rosiglitazone treatment on insulin signaling and glucoseuptake in patients with newly diagnosed type 2 diabetes. Diabetes2005;54:1459-67.
Kiayias 1999 {published data only}Kiayias JA, Vlachou ED, Papadodima EL. Metformin and Lipoprotein (a)levels. Diabetes Care 1999;22(4):859.
Kim 2002 {published data only}Kim Y-B, Ciaraldi TP, Kong A, Kim D, Chu N, Mohideen P, Mudaliar Su,Henry RR, Kahn BB. Troglitazone but not metformin restoresinsulin-stimulated phosphoinositide 3-kinase activity and increases p110betaprotein levels in skeletal muscle of type 2 diabetic subjects. Diabetes2002;51:443-8.
Kirk 1999 {published data only}Kirk JK, Pearce KA, Michielutte R, Summerson JH. Troglitazone ormetformin in combination with sulfonylureas for patients with type 2diabetes?. Journal of Family Practice 1999;48(11):879-82.
Klein 1975 {published data only}Klein W, Herrmann A. [Therapy of diabetes mellitus using metformin.Clinical study on 60 patients]. Medizinische Welt 1975;26(11):516-9.
Klein 1991 {published data only}Klein W. Sulfonylurea-metformin-combination versussulfonylurea-insulin-combination in secondary failures of sulfonylureamonotherapy. Results of a prospective randomized study in 50 patients.Diabete & Metabolisme 1991;17(1 Pt 2):235-40.
Lalau 1990 {published data only}Lalau JD, Vermersch A, Hary L, Andrejak M, Isnard F, Quichaud J. Type2 diabetes in the elderly: an assessment of metformin (metformin in theelderly). International Journal Clinical Pharmacocology Therapeutics andToxicology 1990;28(8):329-32.
Lalor 1990 {published data only}Lalor BC, Bhatnagar D, Winocour PH, Ishola M, Arrol S, Brading M, etal. Placebo-controlled trial of the effects of guar gum and metformin onfasting blood glucose and serum lipids in obese, type 2 diabetic patients.Diabete & Metabolisme 1990;7(3):242-5.
Lam 1998 {published data only}Lam KSL, Tiu SC, Tsang MW, Ip TP, Tam SCF. Acarbose in NIDDMpatients with poor control on conventional oral agents. Diabetes Care1998;21(7):1154-8.
Laurenti 1992 {published data only}Laurenti O, Bravi MC, Faldetta MC, De Mattia G. [Evaluation of theefficacy of metformin-glibenclamide treatment in overweight non-insulindependent diabetics]. La Clinica Terapeutica 1992;140(3):259-63.
Lawrence 2004 {published data only}Lawrence JM, Reid J, Taylor GJ, Stirling C, Reckless J. Favorable effectsof pioglitazone and metformin compared with glicazide on lipoproteinsubgractions in overweight patients with early type 2 diabetes. DiabetesCare 2004;27:41-6.
Lean 1983 {published data only}Lean ME, Borthwick LJ. Ciclazindol: an oral agent with weight reducingproperties and hypoglycaemic activity. European Journal of ClinicalPharmacology 1983;25(1):41-5.
Lee 1998 {published data only}Lee A, Morley JE. Metformin decreases food consumption and inducesweight loss in subjects with obesity with type II non-insulin-dependentdiabetes. Obesity Research 1998;6(1):47-53.
Lord 1983 {published data only}Lord JM, White SI, Bailey CJ, Atkins TW, Fletcher RF, Taylor KG. Effectof metformin on insulin receptor binding and glycaemic control in type IIdiabetes. British Medical Journal (Clinical Research Edition)1983;286(6368):830-1.
Lunetta 1996 {published data only}Lunetta M, DiMauro M. Different effect of acute and chronic oral metforminadministration on glucose and insulin response to bread and to pasta innon-insulin dependent diabetic patients. Diabetes Research and ClinicalPractice 1996;33(1):53-8.
Makimattila 1999 {published data only}Makimattila S, Nikkila K, Yki-Jarvinen H. Causes of weight gain duringinsulin therapy with and without metformin in patients with Type II diabetesmellitus. Diabetologia 1999;42(4):406-12.
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Manzella 2004 {published data only}Manzella D, Grella R, Esposito K, Giugliano D, Barbagallo M, PaolissoG. Blood pressure and cardiac auonomic nervous system in obese type 2diabetic patients: effect of metformin administration. American Journal ofHypertension 2004;17:223-7.
Marena 1994 {published data only}Marena S, Tagliaferro V, Montegrosso G, Pagano A, Scaglione L, PaganoG. Metabolic effects of metformin addition to chronic glibenclamidetreatment in type 2 diabetes [see comments]. Diabete & Metabolisme1994;20(1):15-9.
Marfella 1996 {published data only}Marfella R, Acampora R, Verrazzo G, Ziccardi P, De Rosa N, Giunta R,et al. Metformin improves hemodynamic and rheological responses toL-arginine in NIDDM patients. Diabetes Care 1996;19(9):934-9.
Marre 2002 {published data only}Marre M, Howlett H, Lehertt P, Allavoine T. Improved glycemic controlwith metformin-glibenclamide combined tabled therapy (Glucovance) intype 2 diabetic patients inadequately controlled on metformin. DiabeticMedicine 2002;19:673-80.
McAlpine 1988 {published data only}McAlpine LG, McAlpine CH, Waclawski ER, Storer AM, Kay JW, FrierBM. A comparison of treatment with metformin and gliclazide in patientswith non-insulin-dependent diabetes. European Journal of ClinicalPharmacology 1988;34(2):129-32.
McBain 1988 {published data only}McBain AM, Brown IR, Menzies DG, Campbell IW. Effects of improvedglycaemic control on calcium and magnesium homeostasis in type IIdiabetes. Journal of Clinical Pathology 1988;41(9):933-5.
McIntyre 1991 {published data only}McIntyre HD, Ma A, Bird DM, Paterson CA, Ravenscroft PJ, CameronDP. Metformin increases insulin sensitivity and basal glucose clearance intype 2 (non-insulin dependent) diabetes mellitus. Australian and NewZealand Journal of Medicine 1991;21(5):714-9.
Mehta 1963 {published data only}Mehta BJ, Vakil BJ, Narula DV, Vakil PR. Utility of Metformin as anon-hormonal agent in the treatment of Diabetes mellitus. Journal of theIndian Medical Association 1963;40:151-5.
Menzies 1989 {published data only}Menzies DG, Campbell IW, McBain A, Brown IR. Metformin efficacy andtolerance in obese non-insulin dependent diabetics: a comparison of twodosage schedules. Current Medical Research and Opinion 1989;11(5):273-8.
Moses 1999a {published data only}Moses R. Repaglinide in combination therapy with metformin in Type 2diabetes. Exp Clin Endocrinol Diabetes 1999;107(Suppl 4):S136-9.
Moses R, Slobodniuk R, Boyages S, Colagiuri S, Kidson W, Carter J, etal. Effect of repaglinide addition to metformin monotherapy on glycemiccontrol in patients with type 2 diabetes. Diabetes Care 1999;22(1):119-24.
Munk 1975 {published data only}Munk W. [Treatment of obese diabetic patients using glucophage retard].Zeltschrift fur Allgemeinmedzin 1975;51(14):681-3.
Nagi 1993 {published data only}Nagi DK, Ali VM, Yudkin JS. Effect of metformin on intact proinsulin anddes 31,32 proinsulin concentrations in subjects with non-insulin-dependent(type 2) diabetes mellitus. Diabete & Metabolisme 1996;13(8):753-7.
Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factorsfor cardiovascular disease, and plasminogen activator inhibitor in NIDDMsubjects. A study of two ethnic groups [see comments]. Diabetes Care1993;16(4):621-9.
Natali 2004 {published data only}Natali A, Baldeweg S, Toschi E, Capaldo B, Barbaro D, Gastaldelli AmYudkin JS, Ferrannini E. Vascular effects of improving metabolic controlwith metformin or rosiglitazone in type 2 diabetes. Diabetes Care2004;27:1349-57.
Nattrass 1977 {published data only}Nattrass M, Todd PG, Hinks L, Lloyd B, Alberti KG. Comparative effectsof phenformin, metformin and glibenclamide on metabolic rhythms inmaturity-onset diabetics. Diabetologia 1977;13(2):145-52.
Niazi 1998 {published data only}Niazi R, Muzaffar Z. Comparison of bedtime NPH insulin or metformincombined with glibenclamide in secondary sulphonylurea failure in obesetype II (NIDDM) patients. Journal of the Pakistani Medical Association1998;48(11):336-8.
Nosadini 1987 {published data only}Nosadini R, Avogaro A, Trevisan R, Tessari P, Duner E, Tiengo A, et al.Effect of metformin on insulin-stimulated glucose turnover and insulinbinding to receptors in Type 2 diabetes. Diabetes Care 1987;10:62-7.
Noury 1991 {published data only}Noury J, Nandeuil A. Comparative three-month study of the efficacies ofmetformin and gliclazide in the treatment of NIDD. Diabete & Metabolisme1991;17(1 Pt 2):209-12.
Ohnhaus 1983 {published data only}Ohnhaus EE, Berger W, Duckert F, Oesch F. The influence ofDimethylbiguanide on Phenprocoumon elimination and its mode of action.Klinische Wochenschrift 1983;61:851-8.
Pavo 2003 {published data only}Pavo I, Jermendy G, Varkonyi TT, Kerenyl Z, Gyimesi A, Shoustov S, etal. Effect of pioglitazone compared with metformin on glycemic controland indicators of insulin sensitivity in recently diagnosed patients with type2 diabetes. Journal of Clinical Endocrinology and Metabolism2003;88:1637-45.
Peacock 1984 {published data only}Peacock I, Tattersall RB. The difficult choice of treatment for poorlycontrolled maturity onset diabetes: tablets or insulin?. British MedicialJournal (Clinical Research Edition) 1984;288(6435):1956-9.
Peacock 1986 {published data only}Peacock I, Hawkins M, Heptinstall S. Platelet behaviour innon-insulin-dependent Diabetes - Influence of vascular complications,treatment and metabolic control. Thrombosis and heamostasis1986;55:361-5.
Pedersen 1965 {published data only}Pedersen J. The effect of Metformin on weight loss in obesity. ActaEndocrinologica 1965;49:479-86.
Pedersen 1989 {published data only}Pedersen O, Nielsen O, Bak J, Richelsen B, Beck-Nielsen H, Sorensen N.The effects of metformin on adipocyte insulin action and metabolic controlin obese subjects with type 2 diabetes. Diabete & Metabolisme1989;6(3):249-56.
Pirart 1961 {published data only}Pirart J, Rutman S. [A new oral antidiabetic medicine: N.N.Dimethylbiguanide. Clinical trial alternating a placebo with a sulfamide].Acta Clinica Belgica 1961;16:575-89.
Ponssen 2000 {published data only}Ponssen HH, Elte JW, Lehert P, Schouten JP, Bets D. Combined metforminand insulin therapy for patients with type 2 diabetes mellitus [In ProcessCitation]. Clinical Therapeutics 2000;22(6):709-18.
Prager 1986 {published data only}Prager R, Schernthaner G, Graf H. Effect of metformin on peripheral insulinsensitivity in non insulin dependent diabetes mellitus. Diabete &Metabolisme 1986;12(6):346-50.
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Puchegger 1964 {published data only}Puchegger R. [Experience with the biguanide Glucophage]. WienerKlinische Wechenschrift 1964;76:335-7.
Rachmani 2002 {published data only}Rachmani R, Slavachevski I, Levi Z, Zadok B-S, Kedar Y, Ravid M.Metformin in patients with type 2 diabetes mellitus: reconsideration oftraditional contraindications. Eur J Int Med 2002;13:428-433.
Rains 1988 {published data only}Rains SG, Wilson GA, Richmond W, Elkeles RS. The effect ofglibenclamide and metformin on serum lipoproteins in type 2 diabetes.Diabete & Metabolisme 1988;5(7):653-8.
Rains 1989 {published data only}Rains SG, Wilson GA, Richmond W, Elkeles RS. The reduction of lowdensity lipoprotein cholesterol by metformin is maintained with long-termtherapy. Journal of the Royal Society of Medicine 1989;82(2):93-4.
Raptis 1996 {published data only}Raptis AE, Tountas NB, Yalouris AG, Halvatsiotis PG, Raptis SA.Therapeutic effect of glibenclamide in a fixed combination with metforminor phenformin in NIDDM patients. Hormone and Metabolic Research1996;28(2):89-94.
Reaven 1992 {published data only}Reaven GM, Johnston P, Hollenbeck CB, Skowronski R, Zhang JC,Goldfine ID, et al. Combined metformin-sulfonylurea treatment of patientswith noninsulin-dependent diabetes in fair to poor glycemic control. Journalof Clinical Endocrinology and Metabolism 1992;74(5):1020-6.
Relimpio 1998 {published data only}Relimpio F, Pumar A, Losada F, Mangas MA, Acosta D, Astorga R. Addingmetformin versus insulin dose increase in insulin-treated but poorlycontrolled Type 2 diabetes mellitus: an open-label randomized trial. Diabete& Metabolisme 1998;15(12):997-1002.
Reyes 1969 {published data only}Reyes Larrasilla JM. [Chlorpropamide-dimethylbiguanide combination inthe control of diabetes mellitus with complications]. La Prensa MedicaMexicana 1969;34(9):378-81.
Riccio 1991 {published data only}Riccio A, Del Prato S, Vigili de Kretzenberg S, Tiengo A. Glucose andlipid metabolism in non-insulin-dependent diabetes, effect of metformin.Diabete & Metabolisme 1991;17(1 pt 2):180-4.
Robinson 1998 {published data only}Robinson AC, Burke J, Robinson S, Johnston DG, Elkeles RS. The effectsof metformin on glycemic control and serum lipids in insulin-treatedNIDDM patients with suboptimal metabolic control [see comments].Diabetes Care 1998;21(5):701-5.
Roden 2005 {published data only}Roden M, Laaksot M, Johns D, Widel M, Urquhart R, Richardson C, et al.Long-term effects of pioglitazone and metformin on insulin sensitivity inpatients with type 2 diabetes mellitus. Diabetic Medicine 2005;22:1101-6.
Rodger 1995 {published data only}Rodger NW, Chiasson JL, Josse RG, Hunt JA, Palmason C, Ross SA, etal. Clinical experience with acarbose: results of a Canadian multicentrestudy. Clinical Investigation in Medicine 1995;18(4):318-24.
Roger 1999 {published data only}Roger P, Auclair J, Drain P. Addition of benflouorex to biguanide improvesglycemic control in obese non-insulin-dependent diabets: a double-blindstudy versus placebo. Journal of Diabetes and its complications1999;13(2):62-7.
Rosenstock 1998 {published data only}Rosenstock J, Brown A, Fischer J, Jain A, Littlejohn T, Nadeau D, et al.Efficacy and safety of Acarbose in Metformin-treated patients with Type2 Diabetes. Diabetes Care 1998;21:2050-5.
Sanchez-Barba 1999 {published data only}Sanchez-Barba Izquierdo MI, Ibarra Rueda JM, Ruiz de Adana Perez T.[The combination of insulin and metformin in obese patients with type-2diabetes mellitus]. Atencion Primaria 1999;24(8):462-7.
Santos 1995 {published data only}Santos RF, Nomizo R, Wajhenberg BL, Reaven GM, Azhar S. Changes ininsulin receptor tyrosine kinase activity associated with metformin treatmentof type 2 diabetes. Diabete & Metabolisme 1995;21(4):274-80.
Schernthaner 2004 {published data only}Schernthaner G, Matthews DR, Charbonnel B, Hanefeld M, Brunetti P andthe Quarter Study Group. Efficacy and safety of pioglitazone versusmetformin in patients with type 2 diabetes mellitus: a double-blind,randomized trial. The Journal of Clinical Endocrinology & Metabolism2004;89:6-68-76.
Schneider 1990 {published data only}Schneider J, Erren T, Zofel P, Kaffarnik H. Metformin-induced changes inserum lipids, lipoproteins, and apoproteins in non-insulin-dependent diabetesmellitus. Atherosclerosis 1990;82(1-2):97-103.
Schulte 1973 {published data only}Schulte J, Garcia Viveros M, Rull J, Lozano-Castaneda O. [Long-term (3year) results of the treatment of stable diabetes with low doses ofchlopropamide-metformin]. La Prensa Medica Mexicana 1973;38(7):281-2.
Sieradzki 1999 {published data only}Siedradzki J, Soszynski P. [Assessment of efficacy and safety of acarbosein the treatment of diabetes mellitus. Observation study in the conditionsof general health care]. Przeglad Lekarski 1999;56(5):335-41.
Stades 2000 {published data only}Stades AM, Heikens JT, Holleman F, Hoekstra JB. Effect of metformin onglycaemic control in type 2 diabetes in daily practice: a retrospective study.Netherlands Journal of Medicine 2000;56(3):86-90.
Stalhammar 1991 {published data only}Stalhammer J, Bergman U, Boman K, Dahlen M. Metabolic control indiabetic subjects in three Swedish areas with high, medium and low salesof antidiabetic drugs. Diabetes Care 1991;14:12-19.
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Stratmann 1965 {published data only}Stratmann FW. [Experience with Dimethylbiguanide in late failrues of oraldiabetes therapy]. Medizinische Welt 1965;49:2743-6.
Strowig 2002 {published data only}Strowig SM, Aviles-Santa ML, Raskin P. Comparison of insulinmonotherapy and combination therapy with insulin and metformin or insulinand troglitazone in type 2 diabetes. Diabetes Care 2002;25:1691-8.
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Turner RC, Cull CA, Frighi V, Holman RR, and the UK ProspectiveDiabetes Study Group. Glycemic control with diet, sulfonylurea, metformin,or insulin in patients with type 2 diabetes mellitus: progressive requirementfor multiple therapies (UKPDS 49). UK Prospective Diabetes Study(UKPDS) Group. Journal of the American Medical Association1999;281(21):2005-12.
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U.K. Prospective Diabetes Study Group. United Kingdom ProspectiveDiabetes Study (UKPDS) 13: Relative efficacy of randomly allocated diet,sulphonylurea, insulin, or metformin in patients with newly diagnosednon-insulin dependent diabetes followed for three years [see comments].BMJ 1995;310(6972):83-8.
U.K. Prospective Diabetes Study Group. United Kingdom ProspectiveDiabetes Study 24: a 6-year, randomized, controlled trial comparingsulfonylurea, insulin, and metformin therapy in patients with newlydiagnosed type 2 diabetes that could not be controlled with diet therapy[see comments]. Annals of Internal Medicine 1998;128(3):165-75.
U.K. Prospective Diabetes Study Group. UKPDS 28: a randomized trial ofefficacy of early addition of metformin in sulfonylurea-treated type 2diabetes. Diabetes Care 1998;21(1):87-92.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensiveblood-glucose control with metformin on complications in overweightpatients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
Vannasaeng 1995 {published data only}Vannasaeng S, Ploybutr S, Nitiyanant W, Peerapatdit T, Vichayanrat A.Effects of alpha-glucosidase inhibitor (acarbose) combined with sulfonylureaor sulfonylurea and metformin in treatment of non-insulin-dependentdiabetes mellitus. Journal of the Medical Association of Thailand1995;78(11):578-85.
Velussi 1992 {published data only}Velussi M, Cernigoi AM, Viezzoli L, Caffau C. [Median-term (4 months)treatment with glibenclamide + metformin substituting for glibenclamide+ fenformin lowers the lacticemia levels in type-2 diabetics (NIDDM)]. LaClinical Terapeutica 1992;141(12):483-92.
Vigneri 1991 {published data only}Vigneri R, Trischitta V, Italia S, Mazzarino S, Rabuazzo MA, Squatrito S.Treatment of NIDDM patients with secondary failure to glyburide:comparison of the addition of either metformin or bed-time NPH insulinto glyburide. Diabete & Metabolisme 1991;17(1 Pt 2):232-4.
Willey 1992 {published data only}Willey KA, Moyneaux JE, Overland JE, Yue DK. The effects ofdexfenluramine on blood glucose control in patients with Type 2 Diabetes.Diabetic Medicine 1992;9:341-3.
Willey 1994 {published data only}Willey KA, Molyneaux LM, Yue DK. Obese patients with type 2 Diabetespoorly controlled by insulin and metformin: Effects of adjunctiveDexfenfluramine therapy on glycaemic control. Diabetic Medicine1994;11:701-4.
Willms 1999 {published data only}Willms B, Ruge D. Comparison of acarbose and metformin in patients withType 2 diabetes mellitus insufficiently controlled with diet andsulphonylureas: a randomized, placebo-controlled study. Diabetic Medicine1999;16(9):755-61.
Wilson 1989 {published data only}Wilson JA, Scott MM, Gray RS. A comparison of metformin versus guarin combination with sulphonylureas in the treatment of non insulindependent diabetes. Hormone and Metabolic Research 1989;21(6):317-9.
Wolever 1995 {published data only}Wolever TMS, Radmard R, Chiasson J-L, Hunt JA, Josse RG, PalmasonC, et al. One-year Acarbose treatment raises fasting serum acetate inDiabetic patients. Diabetic Medicine 1995;12:164-72.
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Wolever 2000 {published data only}Wolever TMS, Assiff L, Basu T, Chiasson J-L, Boctor M, Gerstein HC, etal. Miglitol, an alpha-glucosidase inhibitor, prevents the metformin-inducedfall in serum folate and vitamin B12 in subjects with type 2 diabetes.Nutrition Research 2000;20(10):1447-56.
Wu 1990 {published data only}Wu MS, Johnston P, Sheu WH, Hollenbeck CB, Jeng CY, Goldfine ID, etal. Effect of metformin on carbohydrate and lipoprotein metabolism inNIDDM patients. Diabetes Care 1990;13(1):1-8.
Wulffele 2000 {published data only}Wulffele MG, Kooy A, Ogterop C, Borger vd Burg B, Stehouwer CDA,Donker AJM. Metformin and insulin therapy decreases glycosylatedhemoglobin and insulin requirement in Type 2 Diabetes. Diabetologia2000;43(Suppl 1):A184.
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Referencias de los estudios excluidos de esta revisión
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Gin 1985Gin H, Messerchmitt C, Brottier E, Aubertin J. Metformin improved insulinresistance in type I, insulin-dependent, diabetic patients. Metabolism1985;34(10):923-5.
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Leslie 1987Leslie P, Jung RT, Isles TE, Baty J. Energy expenditure in non-insulindependent diabetic subjects on metformin or sulphonylurea therapy. ClinicalScience 1987;73(1):41-5.
Lim 1970Lim P, Khoo OT. Metformin compared with tolbutamide in the treatmentof maturity-onset diabetes mellitus. Medical Journal of Australia1970;1(6):271-3.
Messens 1965Messens Y, Margoulies M. [Treatment of 81 cases of diabetes mellitus withN.N. dimethyl-biguanide]. Revue Medicale de Liege 1965;20(22):607-13.
Messens 1966Messens Y, Margoulies M. [Treatment of diabetes mellitus with N.N.dimethy-biguanide]. Diabete 1966;14(2):74-9.
Muntoni 1965Muntoni S, Boero A, Corona M, Flores M. [Dimethyl-biguanide in thetreatment of diabetes mellitus]. La Clinica terapeutica 1965;35:227-51.
Nauck 1993Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W.Normalization of fasting hyperglycaemia by exogenous glucagon-likepeptide 1 (17-36 amide) in Type 2 (non-insulin-dependent) diabetic patients.Diabetologia 1993;36:741-4.
Nauck 1997Nauck MA, Holst JJ, Wilms B. Glucagon-like peptide 1 and its potentialin the treatment of non-insulin-dependent Diabetes mellitus. Hormone andMetabolic Research 1997;29:411-6.
O'Connor 1998O'Connor PJ, Spann SJ, Woolf SH. Care of adults with type 2 diabetesmellitus. A review of the evidence [see comments]. Journal of FamilyPractice 1998;47(5 Suppl):S13-22.
Orlikowska 1966Orlikowska W. [Influence of N.N. dimethyl biguandie on certain elementsof lipid metabolism in diabetic patients]. Le Diabete 1966;14:183-9.
Panahloo 1995Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries SE, YudkinJS. Determinants of plasminogin activatory inhibitor 1 activiry in treatedNIDDM and its relation to a polymorphosm in the Plasminogen ActivatorInhibitor 1 gene. Diabetes 1995;44(37-42).
Perriello 1994Perriello G, Misericordia P, Volpi E, Santucci A, Santucci C, Ferannini E,et al. Acute antihyperglycemic mechanisms of Metformin in NIDDM:Evidence for suppression of lipid oxidation and hepatic glucose production.Diabetes 1994;43:920-8.
Pilger 1978Pilger E, Schmid P, Goebel R. [Effect of biguanide therapy on lactatemetabolism during graded submaximal ergometric testing]. Acta MedicaAustriaca 1978;5(3):91-5.
Prager 1983Prager R, Schernthaner G. Insulin receptor binding to monocytes, insulinsecretion, and glucose tolerance following metformin treatment. Resultsof a double-blind cross-over study in type II diabetics. Diabetes1983;32(12):1083-6.
Rambert 1961Rambert P, Canivet J, Quichaud J, Spitz B. [Treatment of diabetes mellituswith NN-dimethyl-diguanide. Experience of 177 cases]. Semaine desHospitaux de Paris 1961;37:247-54.
Rigas 1968Rigas AN, Bittles AH, Hadden DR, Montgomery DA. Circadian variationof glucose, insulin, and free fatty acids during long-term use of oralhypoglycaemic agents in diabetes mellitus. British Medical Journal1968;3(622):25-8.
Rizkalla 1986Rizkalla SW, Elgrably F, Tchobroutsky G, Slama G. Effects of metformintreatment on erythrocyte insulin binding in normal weight subjects, in obesenon diabetic subjects, in type 1 and type 2 diabetic patients. Diabete &Metabolisme 1986;12(4):219-24.
Sambol 1996Sambol NC, Chiang J, O'Conner M, Liu CY, Lin ET, Goodman AM, et al.Pharmacokinetics and pharmacodynamics of metformin in healthy subjectsand patients with noninsulin-dependent diabetes mellitus. Journal of ClinicalPharmacology 1996;36(11):1012-21.
Scarpello 1998Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile saltcirculation and intestinal motility in type 2 diabetes mellitus. DiabeticMedicine 1998;15(8):651-6.
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Schaffalitzky 1979Schaffalitzky de Muckadell OB, Mortensen H, Lyngsoe J. Metabolic effectsof glucocorticoid and ethanol administration in phenformin- andmetformin-treated obese diabetics. Acta Medica Scandinavia1979;206(4):269-73.
Selby 1999Selby JV, Ettinger B, Swain BE, Brown JB. First 20 months' experiencewith use of metformin for type 2 diabetes in a large health maintenanceorganization. Diabetes Care 1999;22(1):38-44.
Signore 1996Signore A, Fiore V, Chianelli M, Procaccini E, Barone R, Ronga G, et al.The effect of metformin on liver blood flow in vivo in normal subjects andpatients with non insulin dependent diabetes. Diabetes Research andClinical Practice 1996;33(2):83-7.
Slama 1984Slama G, Jean-Joseph P, Goicolea I, Elgrably F, Haardt MJ, CostagliolaD, et al. Sucrose taken during mixed meal has no additional hypergycemicaction over isocaloric amounts of starch in well-controlled diabetics. Lancet1984;July 21:122-5.
Stefanovic 1999Stefanovic V, Antic S, Mitic-Zlatkovic M, Vlahovic P. Reversal of increasedlymphocyte PC-1 activity in patients with type 2 diabetes treated withmetformin. Diabetes/Metabolism Research Reviews 1999;15(6):400-4.
Sugawara 1962Sugawara Y, Nitmi T, Sato T, Nakai Y, Mivata K, Kano H, et al. [Clinicaltrial with DMBG (Melbin) in diabetes mellitus]. Naika hokan, Japanesearchives of Internal Medicine 1962;9:405-7.
Sum 1992Sum C-F, Webster JM, Johnson AB, Catalano C, Cooper BG, Taylor R.The effect of intravenous Metformin on glucose metabolism duringhyperglycemia in Type 2 Diabetes. Diabetic Medicine 1992;9:61-6.
Teitelbaum 1963Teitelbaum M, Le Marchant J-M. [Biguanides and sulfamides in smalldoses in the initial treatment of diabetes in obese patients]. Diabete1963;11:342-3.
Trischitta 1983Trischitta V, Gullo D, Pezzino V, Vigneri R. Metformin normalizes insulinbinding to monocytes from obese nondiabetic subjects and obese type IIdiabetic patients. Journal of Clinical Endocrinology and Metabolism1983;57(4):713-8.
Turner 1995Turner RC, Holman RR. Lessons from IK prospective diabetes study.Diabetes Research and Clinical Practice 1995;28(Suppl):S151-S157.
Zapecka-Dubno 1999Zapecka-Dubno B, Czyzyk A, Dworak A, Bak MI. Effect of oral antidiabeticagents on plasma amylin level in patients with non-insulin-dependentDiabetes mellitus (Type 2). Arzliche-Forschung/ Drug Research1999;49(1):330-4.
Referencias adicionales
AHFS 1999Metformin hydrochloride. American Hospital Formulary Service DrugInformation. Bethesda: American Society of Health-System Pharmacists,Inc, 1999:2755-63.
Bailey 1996Bailey CJ, Turner RC. Metformin. New England Journal of Medicine1996;334:574-9.
Bergman 1978Bergman U, Boman G, Wiholm B-E. Epidemiology of adverse drugreactions to phenformin and metformin. British Medicial Journal1978;2:464-6.
Berlin 1989Berlin JA, Laird NM, Sacks HS, Chalmers TC. A comparison of statisticalmethods for combining event rates from clinical trials. Statistics in Medicine1989;8:141-51.
Brown 1998Brown JB, Pedula K, Barzilay J, Herson MK, Latare P. Lactic acidosisrates in type 2 diabetes. Diabetes Care 1998;21:1659-63.
Campbell 1985Campbell IW. Metformin and the sulphonylureas: The comparative risk.Hormone and Metababolism Research Supplement 1985;15:105-11.
Campbell 1995Campbell IW, Howlett HCS. Worldwide experience of metformin as aneffective glucose-lowering agent: A meta-analysis. Diabetes MetabolismReviews 1995;11 (Suppl 1):S57-62.
DeFronzo 1993DeFronzo RA, Goodman A, and the Metformin Investigator Group.Combined metformin/glyburide treatment in NIDDM patients not optimallyresponding to maximum dose sulfonylurea: Results of a mutlicenter trial.Diabetes 1993;42(Suppl 1):146A (Abs 455).
DeFronzo 1999DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Annalsof Internal Medicine 1999;131:281-303.
Fleiss 1981Fleiss JL. Statistical methods for rates and proportions. 2nd Edition. NewYork: Wiley, 1981:217-34.
Gan 1992Gan SC, Barr J, Arieff AI, Pearl RG. Biguanide-assoicated lactic acidosis:case report and review of the literature. Archives of Internal Medicine1992;152:2333-6.
Holstein 1999Holstein A, Nahrwold D, Hinze S, Egbert E-H. Contra-indications tometformin therapy are largely disregarded. Diabetic Medicine1999;16:692-6.
Jadad 1996Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds DJM, GavaghanDJ, et al. Assessing the quality of reports of randomized clinical trials: Isblinding necessary?. Controlled Clinical Trials 1996;17:1-12.
Kreisberg 1980Kreisberg RA. Lactate homerostasis and lactic acidosis. Annals of InternalMedicine 1980;92(Part 1):227-37.
Luft 1978Luft D, Schmulling, Eggstein M. Lactic acidosis in biguanide-treateddiabetics: a review of 330 cases. Diabetologia 1978;14:75-87.
Misbin 1998Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA.Lacic acidosis in patients with diabetes treated with metformin. NewEngland Journal of Medicine 1998;338:265-6.
Olivia 1970Olivia PB. Lactic acidosis. American Journal of Medicine 1970;48:208-25.
Palumbo 1998Palumbo PJ. Metformin: Effects of cardiovascular risk factors in patientswith non-insulin-dependent diabetes mellitus. Journal of Diabetes and itsComplications 1998;12:110-9.
Scheen 1996Scheen AJ. Clinical pharmacokinetics of metformin. ClinicalPharmacokinetics 1996;30(5):359-71.
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Schulz 1995Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias:Dimensions of methodological quality associated with estimates of treatmenteffects in controlled trials. Journal of the American Medical Association1995;273:408-12.
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* El asterisco señala los documentos más importantes para este estudio
Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
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TABLAS
Characteristics of included studies
Aarsand 1998Study
TRIAL DESIGN: Retrospective cohort studyDURATION: at least one year, then 12 weeks.
Methods
COUNTRY: NorwaySETTING: Endocrinology center Treatment N: 28, with 14 on folate and 14 on placebo.Metformin + placebo AGE: 57+/-2.8. Metformin + folate AGE: 62+/-2.5. Metformin +placebo SEX: 79% men. Metformin + folate SEX: 71% men. INCLUSION: patients withtype 2 DM, treated with metformin for a minimum of 1 yearEXCLUSIONS: vitamin use that would interfere with the study.
Participants
TREATMENT: metformin, at least 1g/day. One-half of patients on folate 0.25 mg/day+ iron 60mg/day, and one-half on iron 60mg/day.COMPARISON: none.
Interventions
Fasting homocysteine, cysteine, cysteinylglycine, vitamin B12, and folate.Outcomes
Notes
DAllocation concealment
Abbasi 1997Study
TRIAL DESIGN: Randomised controlled trialDURATION: 3 months
Methods
COUNTRY: United StatesSETTING: research laboratory Treatment N: 15Control N: 8.Treatment AGE: 53 +/-3Control AGE: 51 +/-4Treatment SEX: 64% menControl SEX: 87% malesINCLUSION: Type 2 DMEXCLUSIONS: abnormal laboratory values, vascular disease
Participants
TREATMENT: metformin-blind versus open-label metformin, dosage adjused clinically.COMPARISON: placebo
Interventions
Fasting and postprandial glucose, insulin, and free fatty acids.Outcomes
Notes
CAllocation concealment
Abbasi 1998Study
TRIAL DESIGN: Prospective cohort studyDURATION: 6 months
Methods
COUNTRY: United StatesSETTING: outpatient and research centerTreatment N: 11Control N: 0AGE: not listedSEX: not listedINCLUSION: diet-treated type 2 DM EXCLUSIONS: laboratory abnormalities, diabeticvascular complications, or abnormal electrocardiogram
Participants
Página 23
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
INTERVENTION: metformin 1-2.5 g/day COMPARISON: noneInterventions
Plasma glucose, insulin, and free fatty acids.Outcomes
Notes
DAllocation concealment
Abbink 2001Study
TRIAL DESIGN: Double-blind randomised controlled trial - unpublishedDURATION: 2 months
Methods
COUNTRY: NetherlandsSETTING: outpatientTreatment N: 12Control N: 12AGE: unclearSEX: not listed.INCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 500 mg TID COMPARISON: GlibenclamideInterventions
Glucose, HbA1.Outcomes
Notes
BAllocation concealment
Abbink 2000Study
TRIAL DESIGN: Abstract of a double-blind randomised controlled trialDURATION: 2 months
Methods
COUNTRY: NetherlandsSETTING: outpatientTreatment N: 12Control N: 60AGE: unclearSEX: not listedINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, dosage adjusted clinically COMPARISON: glibenclamindeor glimerperide or acarbose
Interventions
Vasodilator responses to diazoxide.Outcomes
Notes
BAllocation concealment
Aguilar 1992aStudy
TRIAL DESIGN: Prospective cohort studyDURATION: 2 months
Methods
Country: Mexico. Setting: diabetes institute. Treatment N: 9. Control N: 0. Age: unclear.Sex: 26% men. Inclusion: type 2 DM with secondary failure to oral agents. Exclusions:insulin dependence.
Participants
TREATMENT: metformin 1200 mg/day, chlorpropamide 375 mg/day, and bedtimeinsulin 0.1 U/kg/day COMPARISON: none
Interventions
Página 24
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Fasting glucose, HbA1c, insulin dose, and glucose tolerance.Outcomes
Notes
DAllocation concealment
Allen 1961Study
TRIAL DESIGN: Prospective cohort studyDURATION: 12 months
Methods
COUNTRY: FranceSETTING: outpatientTreatment N: 57Control N: 0AGE: >40SEX: not listedINCLUSION: poorly controlled DM EXCLUSION: none listed
Participants
TREATMENT: metformin, dosage unclear COMPARISON: noneInterventions
GlycemiaOutcomes
Notes
DAllocation concealment
Andras 1962Study
TRIAL DESIGN: Prospective cohort studyDURATION: approximately 1 month
Methods
COUNTRY: unclearSETTING: outpatientTreatment N: 20Control N: 0AGE: not listedSEX: not listedINCLUSION: maturity-onset DM EXCLUSIONS: none listed
Participants
TREATMENT: metformin, dosage unclearCOMPARISON: none
Interventions
GlycemiaOutcomes
Notes
DAllocation concealment
Aviles-Santa 1999Study
TRIAL DESIGN: Randomised controlled trialDURATION: 6 months
Methods
Página 25
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: United StatesSETTING: University clinicTreatment N: 21Control N: 22Treatment AGE: 53 +/-4Control AGE: 54 +/-8Treatment SEX: 28% menControl SEX: 45% menINCLUSION: Poorly controlled Type 2 DM on insulinEXCLUSIONS: pregnancy, creatinine > 1.5, hepatic enzymes double normal, medicalconditions that could promote lactic acidosis.
Participants
TREATMENT: Metformin + insulinCOMPARISON: placebo + insulin
Interventions
Weight, HbA1, and lipids.Outcomes
Notes
BAllocation concealment
Azerad 1960Study
TRIAL DESIGN: Prospective cohort studyDURATION: average 24 months
Methods
COUNTRY: FranceSETTING: outpatientTreatment N: 200Control N: 0AGE: not listedSEX: not listedINCLUSION: DMEXCLUSIONS: none listed
Participants
TREATMENT: metformin, with goal of 3 g/day, maximum 5 g/day.COMPARISON: none
Interventions
Glycemia, and glucosuria.Outcomes
Notes
DAllocation concealment
Bacci 1961Study
TRIAL DESIGN: Retrospective cohort studyDURATION: 3-6 months, average 4.5 months
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 42Control N: 0AGE: not listedSEX: not listedINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: metformin, dosage adjusted clinically COMPARISON: noneInterventions
Glycemia and glucosuria.Outcomes
Página 26
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
Bayraktar 1996Study
TRIAL DESIGN: Crossover randomised controlled trialDURATION: 2 months
Methods
COUNTRY: TurkeySETTING: University clinic Treatment N: 36Control N: 36AGE: 30-63SEX: 100% menINCLUSION : Type 2 DM with poor controlEXCLUSIONS: microvascular or macrovascular complIcations, liver functionabnormalities.
Participants
TREATMENT: Metformin 500mg TIDCOMPARISON: acarbose
Interventions
Insulin , c-peptide, fibrinogen, lipids, HbA1.Outcomes
Notes
BAllocation concealment
Beisswenger 1999Study
TRIAL DESIGN: Retrospective cohort studyDURATION: 3 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 30Control N: 0AGE: 62+/-8SEX: 56% menINCLUSION: Type 2 DM, some on metformin treatment and some not EXCLUSIONS:renal or hepatic impairment or cardiac disease
Participants
TREATMENT: metformin 500-2500 mg/dayCOMPARISON: none
Interventions
HbA1c, methylglyoxal levels, D-lactate, and glucose.Outcomes
Notes
DAllocation concealment
Belcher 2005Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 12 months
Methods
COUTNRY: United Kingdom SETTING: outpatientTreatment N: 917Control N: 2796Age: 57 +/- 9Sex: 55% menInclusion: type 2 DMExlcusions: ALT levels greater than 2.5 times upper limit of normal
Participants
Página 27
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
TREATMENT: metformin 2500 mg/dayCOMPARISON: pioglitazone 45 mg/day
Interventions
liver enzyme levelsOutcomes
Notes
DAllocation concealment
Bell 1997Study
TRIAL DESIGN: Prospective cohort studyDURATION: 6 weeks
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 55Control N: 0AGE: 60.2+/-13SEX: 45% menINCLUSION: patients with non-insulin-dependent DM treated with insulinEXCLUSIONS: creatinine > 1.5 mg/dl, or c-peptide < 0.8 ng/ml
Participants
TREATMENT: metformin, 1-3 g/day, some with glyburide or insulin, dosage titratedclinically COMPARISON: none
Interventions
Insulin requirement, HbA1, BMI, and % successfully changed to oral therapy.Outcomes
Notes
DAllocation concealment
Beyer 1975Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: GermanySETTING: outpatientTreatment N: 24Control N: 0AGE: not listedSEX: 36% menINCLUSION: adult-onset DM EXCLUSION: none listed
Participants
TREATMENT: metformin, dosage titrated clinicallyCOMPARISON: none
Interventions
Glucose and weight.Outcomes
Notes
DAllocation concealment
Bingle 1964Study
TRIAL DESIGN: Blinded randomised controlled trial (unclear if double-blind)DURATION: 2 months
Methods
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: United KingdomSETTING: outpatientTreatment N: 22Control N: 22AGE: unclearSEX: not listedINCLUSION: Type 2 DM not controlled on sulfonylureas EXCLUSIONS: none listed
Participants
TREATMENT: Metformin 1-2 g/day + chlorpropamideCOMPARISON: placebo + chlorpropamide
Interventions
Plasma glucose and weight.Outcomes
Notes
BAllocation concealment
Bjorntorp 1978Study
TRIAL DESIGN: Prospective, cross-over comparative trial; not randomisedDURATION: 8 weeks
Methods
COUNTRY: SwedenSETTING: outpatientTreatment N: 21Control N: 21AGE: 58SEX: 52% menINCLUSION: Type 2 DM on long-term biguanide treatment EXCLUSIONS: abnormalrenal function or liver function
Participants
TREATMENT: Metformin, 1.5-3.0 g/dayCOMPARISON: phenformin, 50-100 mg/day (not analysed)
Interventions
Fasting glucose and fasting lactate levels.Outcomes
Notes
DAllocation concealment
Blonde 2002Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 4 months
Methods
COUNTRY: United States SETTING: outpatientTreatment N: 476Control N: 164Age: 55.6 +/- 9.4Sex: 57% menInclusion: type DM uncontrolled on sulfnylurea treatmentExclusions: hepatic or renal dysfunction, congestive heart failure
Participants
TREATMENT: metformin 1 g/day, with and without glyburideCOMPARISON: glybruide 20 mg/day
Interventions
HbA1, fasting glucoseOutcomes
Notes
DAllocation concealment
Página 29
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Boronat 2000Study
TRIAL DESIGN: Retrospective cohort studyDURATION: average of 12 months
Methods
COUNTRY: SpainSETTING: Endocrine centerTreatment N: 21Control N: 0AGE: unclearSEX: 5% menINCLUSION: obese insulin-treated patients with type 2 DM, also on metforminEXCLUSIONS: none listed
Participants
TREATMENT: Insulin and metformin, dose adjusted clinicallyCOMPARISON: none
Interventions
HbA1c, weight, and insulin requirement.Outcomes
Notes
DAllocation concealment
Botha 1977Study
TRIAL DESIGN: Open-label cross-over trial; not randomisedDURATION: 1 month
Methods
COUNTRY: South AfricaSETTING: general practiceTreatment N: 21Control N: 21AGE: unclearSEX: not listedINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, dose adjusted clinicallyCOMPARISON: phenformin, buformin (not analysed), and untreated controls.
Interventions
Heart rate, blood lactate, and lactate/pyruvate ratios, at baseline and with exercise.Outcomes
Notes
DAllocation concealment
Boyd 1992Study
TRIAL DESIGN: Randomised controlled trialDURATION: 6 weeks
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 8Control N: 19Treatment AGE: 64+/-6.2Control AGE: 63.5+/-7.6Treatment SEX: 37% menControl SEX: 68% menINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
Página 30
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
TREATMENT: Metformin, dosage adjusted clinicallyCOMPARISON: glibenclamide or insulin
Interventions
Insulin sensitivity, HbA1, weight.Outcomes
Notes
DAllocation concealment
Brown 1999Study
TRIAL DESIGN: Retrospective cohort studyDURATION: average 11.6 months
Methods
COUNTRY: United StatesSETTING: patients in an HMO registryTreatment N: 3402Control N: 0AGE: > 30SEX: 53% menINCLUSION: Type 2 DM on metformin treatmentEXCLUSIONS: none listed
Participants
TREATMENT: metformin, 1000-2550 mg/day COMPARISON: noneInterventions
HbA1c, and fructosamine.Outcomes
Notes
DAllocation concealment
Cairns 1977Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 4 weeks
Methods
COUNTRY: United Kingdom SETTING: outpatientTreatment N: 39Control N: 67AGE: 57SEX: 21% menINCLUSION: Type 2 DMEXCLUSIONS: renal failure, congestive heart failure
Participants
TREATMENT: Metformin 850 mg BIDCOMPARISON: phenformin (not analysed)
Interventions
Fasting glucose, body weight, and lipidsOutcomes
Notes
DAllocation concealment
Calle-Pascual 1995Study
TRIAL DESIGN: Open-label comparative trial; not randomisedDURATION: 4 months
Methods
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: SpainSETTING: outpatientTreatment N: 12Control N: 24AGE: unclearSEX: 50% menINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 850 mg TIDCOMPARISON: insulin or acarbose
Interventions
Lipids, blood pressure, HbA1, body weight, insulin sensitivity.Outcomes
Notes
DAllocation concealment
Campbell 1988Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 12 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 38Control N: 24AGE: 54+/-6.1SEX: 64% menINCLUSION: Type 2 DM, diet failedEXCLUSIONS: congestive heart failure, renal failure, liver function abnormalities
Participants
TREATMENT: Metformin, dosage adjusted clinically. COMPARISON: glipizideInterventions
Blood pressure, heart rate, microalbuminuria.Outcomes
Notes
DAllocation concealment
Campbell 1994Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 52 weeks
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 24Control N: 24Treatment AGE: 57+/-10Control AGE: 57+/-9Treatment SEX: 33% menControl SEX: 33% menINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, 500 mg BID to 3,000 mg/day maximum.COMPARISON: glipizide, 5 mg/day to 39 mg/day maximum BID
Interventions
Glucose, HbA1, lipids, lactate levelsOutcomes
Página 32
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
Canivet 1962Study
TRIAL DESIGN: Retrospective cohort studyDURATION: average 66 months
Methods
COUNTRY: FranceSETTING: outpatientTreatment N: 180Control N: 0AGE: not listedSEX: not listedINCLUSION: DM, 180 treated with metforminEXCLUSIONS: none listed
Participants
TREATMENT: metformin, dose unclearCOMPARISON: some patients treated with other agents, not analysed
Interventions
Plasma glucoseOutcomes
Notes
DAllocation concealment
Carpentier 1975Study
TRIAL DESIGN: Prospective cohort studyDURATION: 6 months
Methods
COUNTRY: BelgiumSETTING: outpatientTreatment N: 11Control N: 0AGE: 58.8SEX: 45% menINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: metformin 1.5 g/day + arginine infusion 11.7 mg/kg/minCOMPARISON: none
Interventions
Blood glucose, free fatty acids, and glycagon.Outcomes
Notes
DAllocation concealment
Carter 2005Study
TRIAL DESIGN: Double-blind randomised controlled trial DURATION: 6 monthsMethods
COUNTRY: United Kingdom SETTING: outpatientTreatment N: 26Control N: 16Age: not statedSex: not statedInclusion: poorly controlled overweight patients with type 2 DMExlcusions: not stated
Participants
TREATMENT: metformin 1.5 to 3 g/day COMPARISON: placeboInterventions
Página 33
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
C-reactive proteitn, complement factor C3Outcomes
Notes
DAllocation concealment
Cavallo-Perin 1989Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 6 months
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 10Control N: 10AGE: 51+/-2.1SEX: 60% menINCLUSION: Type 2 DMEXCLUSIONS: liver or kidney disease, heart failure, other drugs, or chronic infection
Participants
TREATMENT: Metformin 850 mg BIDCONTROL: phenformin 50 mg BID (not analysed)
Interventions
Weight, glucose, HbA1, and blood lactate levels at different times of day.Outcomes
Notes
AAllocation concealment
Cefalu 2002Study
TRIAL DESIGN: Open-label randomised controlled trial DURATION: 4.5 monthsMethods
COUNTRY: United States SETTING: outpatientTreatment N: 91Control N: 91Age: 35-70Sex: not statedInclusion: type 2 DMExclusion: not stated
Participants
TREATMENT: metformin 850 mg TID with and without glipizideCONTROL: glipizide 20 mg/day
Interventions
Glycemic control, body weight, abdominal fat distribution, PAI-1 levelsOutcomes
Notes
DAllocation concealment
Chakrabarti 1965Study
TRIAL DESIGN: Single-blind crossover comparative trial; not randomisedDURATION: 2 months placebo, 4 months treatment
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 27Control N: 27AGE: 56.3SEX: 95% menINCLUSION: Type 2 DM with coronary artey disease, claudicationEXCLUSIONS: none listed
Participants
Página 34
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
TREATMENT: metformin 500 mg TIDCOMPARISON: placebo
Interventions
Cholesterol, plasma fibrinogen.Outcomes
Notes
DAllocation concealment
Chan 1993Study
TRIAL DESIGN: Crossover randomised controlled trialDURATION: 4 weeks
Methods
COUNTRY: Hong Kong and United KingdomSETTING: outpatientTreatment N: 24Control N: 24AGE: 48.5+/-2.4SEX: 50% menINCLUSION: Type 2 DMEXCLUSIONS: renal insufficiency, hypertension
Participants
TREATMENT: Metformin, dosage adjusted clinically COMPARISON: glybenclanideInterventions
Weight, body mass index (BMI), lipids, blood pressure, systemic vascular resistanceindex.
Outcomes
Notes
BAllocation concealment
Chiasson 1994Study
TRIAL DESIGN: Randomised controlled trial of acarbose versus placebo. Metforminin non-randomised treatment strata.DURATION: 1 year
Methods
COUNTRY: CanadaSETTING: multicenterTreatment N: 83Control N: 271Treatment AGE: 57.4+/-1.1Control AGE: 57+/-1.1Treatment SEX: 51% menControl SEX: 58% menINCLUSION: Type 2 DMEXCLUSIONS: gastrointestinal disease, various medications
Participants
TREATMENT: Main: acarbose versus placebo Treatment strata: metformin (dosageadjusted clinically), diet, sulfonylurea, insulin
Interventions
Postprandaial glucose, HbA1, lipds, c-peptide levels.Outcomes
Notes
CAllocation concealment
Chiasson 2001Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 36 weeks
Methods
Página 35
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: CanadaSETTING: multicenterTreatment N: 156Control N: 162Treatment AGE: 57.9+/-8.6Control AGE: 57.3+/-9Treatment SEX: 77% menControl SEX: 74% menINCLUSION: Type 2 DMEXCLUSIONS: cardiovascular events, gastrointestinal disease, history of lactic acidosis,major debilitating disease
Participants
TREATMENT: Metformin, dosage adjusted clinically, or metformin + miglitol.COMPARISON: miglitol or placebo
Interventions
Fasting and postprandial glucose, HbA1, insulin, weight.Outcomes
Notes
BAllocation concealment
Cho 1992Study
TRIAL DESIGN: Open-label comparative trial; not randomisedDURATION: 36 days
Methods
COUNTRY: KoreaSETTING: University centerTreatment N: 22Control N: 27AGE: unclearSEX: 47% menINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 0.5-1.5 g/dayCOMPARISON: insulin or sulfonylurea
Interventions
Plasma t-PA and PAI-1 antigenOutcomes
Notes
DAllocation concealment
Clarke 1965Study
TRIAL DESIGN: Prospective cohort studyDURATION: Average 21 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 108Control N: 0AGE: > 30 to < 60SEX: 38% menINCLUSION: DM, treatment failures with sulfonyureasEXCLUSIONS: ketonuria, bicarbonate < 17 mEq/L, or serious organic disease
Participants
TREATMENT: metformin, 1 g/dayCOMPARISON: none
Interventions
Página 36
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Glycemica, glycosuria, and weight.Outcomes
Notes
DAllocation concealment
Clarke 1968Study
TRIAL DESIGN: Crossover randomised controlled trialDURATION: 1 year
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 139Control N: 139Treatment AGE: 59Control AGE: 57SEX: not listedINCLUSION: Obese patients with Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 1-3 g/dayCOMPARISON: chlorpropamide
Interventions
Weight, blood glucose.Outcomes
Notes
BAllocation concealment
Clarke 1977Study
TRIAL DESIGN: randomised controlled trialDURATION: 1 year
Methods
COUNTRY: United Kingdom SETTING: outpatientTreatment N:131Control N: 146Treatment AGE: 60Control AGE: 60Treatment SEX: 31% menControl SEX: 31% menINCLUSION: Newly diagnosed Type 2 DMEXCLUSIONS: malignancy, congestive heart failure, obesity, other hypoglycemicmedications.
Participants
TREATMENT: Metformin, 1-3 g/dayCOMPARISON: chlorpropamide
Interventions
Blood glucose, weight.Outcomes
Notes
BAllocation concealment
Collier 1989Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 6 months
Methods
Página 37
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: ScotlandSETTING: outpatientTreatment N: 12Control N: 12Treatment AGE: 53.3Control AGE: 55.5SEX: 50% menINCLUSION: Type 2 DMEXCLUSIONS: abnormal renal function, smokers, aspirin.
Participants
TREATMENT: Metformin, dosage adjusted clinicallyCOMPARISON: gliclazide
Interventions
Platelet density profiles and aggregability studies.Outcomes
Notes
DAllocation concealment
Cryer 2005Study
TRIAL DESIGN: Open-label randomised controlled trial DURATION: 12 monthsMethods
COUNTRY: United StatesSETTING: outpatientTreatment N: 7227Control N: 1505Age: 58.5 +/- 13Sex: 37% menInclusion: type 2 DM suboptimally controlled on diet or sulfonylureaExclusions: standard
Participants
TREATMENT: metformin 2.6 g/dayCONTROL: usual care
Interventions
Serious adverse effects such as lactic acidosisOutcomes
Notes
DAllocation concealment
Cusi 1996Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 15 weeks
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 10Control N: 10.Treatment AGE: 51+/-3Control AGE: 54+/-3Treatment SEX: 40% menControl SEX: 60% menINCLUSION: Type 2 DM, with body weight stableEXCLUSION: sedentary or strenuous activities, renal disease, hepatic disease or othersignificant organ system disease
Participants
TREATMENT: Metformin 500 mg BID to 2500 mg/day maximum + glibenclamide, doseon clinical groundsCOMPARISON: glibenclamide + placebo
Interventions
Página 38
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Glucose, HbA1, lipids, blood lactate.Outcomes
Notes
BAllocation concealment
D'Argenzio 1996Study
TRIAL DESIGN: Open-label, nonrandomised comparative trialDURATION: 6 months
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 23Control N: 57AGE: 56SEX: 40% menINCLUSION: Poorly controlled Type 2 DMEXCLUSIONS: cardiac, liver or renal disease, contraindication to oral hypoglycemicmedications
Participants
TREATMENT: Metformin, dosage adjusted clinically + glibenclamideCOMPARISON: glibenclamide or diet
Interventions
Basal glucose, HbA1, renal and liver functions, lipids.Outcomes
Notes
DAllocation concealment
Damsbo 1998Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 3 months
Methods
COUNTRY: SwedenSETTING: outpatientTreatment N: 9Control N: 9Treatment AGE: 51Control AGE: 53Treatment SEX: 78% menControl SEX: 66% menINCLUSION: Obese patients with Type 2 DMEXCLUSIONS: abnormal renal, liver fucntion, or cardiac function
Participants
TREATMENT: Metformin 1-3 g/dayCOMPARISON: placebo
Interventions
Insulin sensitivity, plasma glucose, insulin, c-peptide, free fatty acids, lactate levels.Outcomes
Notes
BAllocation concealment
Davidson 2000Study
TRIAL DESIGN: Abstract; randomised controlled trial, placebo-controlled; unclear ifsingle-blind
Methods
Página 39
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: United StatesSETTING: outpatientTreatment N: 484Control N: 161AGE: not listedSEX: not listedINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, dosage adjusted clinically, versus metformin + glyburideCOMPARISON: glyburide or placebo
Interventions
HbA1Outcomes
Notes
BAllocation concealment
De Silva 1979Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 2 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 21Control N: 20AGE: 55SEX: 32% menINCLUSION: Type 2 DMEXCLUSIONS: renal or liver abnormalities
Participants
TREATMENT: Metformin 1.5 g/day + placeboCOMPARISON: clofibrate + placebo
Interventions
Fasting glucose, urinary glucose, lipids and fibrinogen.Outcomes
Notes
AAllocation concealment
DeFronzo 1991Study
TRIAL DESIGN: Open-label cross-over trialDURATION: 3 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 14Control N: 14AGE: 60+/-3SEX: 71% menINCLUSION: Obese and lean type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 1-2.5 g/dayCOMPARISON: no metformin
Interventions
Insulin sensitivity, glucose tolerance test, continuous indirect calorimetry, and lipids.Outcomes
Página 40
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
DeFronzo 1995Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 29 weeks
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 566Control N: 355Treatment AGE: 53+/-1Control AGE: 55+/-1Treatment SEX: 43% menControl SEX: 49% menINCLUSION: Obese patients with Type 2 DMEXCLUSIONS: creatinine > 1.4, abnormal liver functions, cardiovascular disease
Participants
TREATMENT: Metformin 850 mg TID or metformin + glyburideCOMPARISON: glyburide or placebo
Interventions
HbA1c, fasting and postprandial glucoseOutcomes
Notes
BAllocation concealment
Derosa 2003Study
TRIAL DESIGN: Open-label randomised trialDURATION: 12 months
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 56Control N: 56Age: 54 +/- 9Sex: 50% menInclusion: type 2 DMExclusion: hypertension, heart disease, abnormal renal function, or drugs that interactwith treatment
Participants
TREATMENT: metformin 2.5 g/dayCONTROL: repaglinide 4 mg/day
Interventions
Fasting plasma insulin, postprandial plasma insulin, lipid profile, homocysteineOutcomes
Notes
DAllocation concealment
Dies 1978Study
TRIAL DESIGN: Prospective cohort studyDURATION: at least 5 years
Methods
Página 41
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: MexicoSETTING: outpatientTreatment N: 25Control N: 0AGE: 56SEX: 35% menINCLUSION: adult-onset DMEXCLUSIONS: none listed
Participants
TREATMENT: metformin 560 mg/day + chlorpropamide 175 mg/dayCOMPARISON: none
Interventions
Fasting and postprandial glucose, glycosuria, and weight.Outcomes
Notes
DAllocation concealment
Donnelly 1960Study
TRIAL DESIGN: Prospective cohort studyDURATIONS: average 6 months
Methods
COUNTRY: IrelandSETTING: outpatientTreatment N: 25Control N: 0AGE: 21-77Sex: 22% menINCLUSION: type 2 DMEXCLUSION: ketonuria or infection
Participants
TREATMENT: metformin, dosage adjusted clinicallyCOMPARISON: none
Interventions
GlycosuriaOutcomes
Notes
DAllocation concealment
Dornan 1991Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 8 months
Methods
COUNTRY: United KingdomSETTING: university clinicTreatment N: 30Control N: 30Treatment AGE: 55+/-1Control AGE: 55+/-1Treatment SEX: 53% menControl SEX: 30% menINCLUSION: Diet-treated Type 2 DMEXCLUSIONS: ketonuria, renal or liver dysfunction, congestive heart failure
Participants
TREATMENT: Metformin 500 mg QD-TID COMPARISON: placeboInterventions
Glucose, BMI, c-peptide, blood pressure, lipids.Outcomes
Página 42
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
BAllocation concealment
Elkeles 1991Study
TRIAL DESIGN: 1) Open-label cross-over randomised controlled trial2) Single-blind crossover trialDURATION: 3 months, then 6 weeks
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 63Control N: 49AGE: < 70 yearsSEX: 64% menINCLUSION: Type 2 DMEXCLUSIONS: renal or liver disease
Participants
TREATMENT: 1) Metformin, dosage adjusted clinically 2) MetforminCOMPARISONS: 1) glibenclamide2) placebo
Interventions
Serum lipids, lipoproteins, glucose, HbA1.Outcomes
Notes
DAllocation concealment
Erle 1999Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION:
Methods
COUNTRY:SETTING:Treatment N:Control N:AGE:SEX:INCLUSION: Type 2 DMEXCLUSIONS:
Participants
TREATMENT: Metformin, dosage adjusted clinically, + glyburideCOMPARISON: placebo + glyburide
Interventions
Glycemic controlOutcomes
Notes
BAllocation concealment
Fanghanel 1996Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 3 months
Methods
Página 43
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: MexicoSETTING: outpatientTreatment N: 30Control N: 30Treatment AGE: 52.1+/- 8.8Control AGE: 51.2+/-8.5Treatment SEX: 40% menControl SEX: 30% menINCLUSION: Type 2 DM, obeseEXCLUSIONS: abnormal liver functions, cardiomyopathy, lung disease
Participants
TREATMENT: Metformin 850 mg BID-TIDCOMPARISON: insulin BID
Interventions
Lipids, HbA1, blood pressure, BMI.Outcomes
Notes
DAllocation concealment
Fanghanel 1998Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 12 weeks
Methods
COUNTRY: MexicoSETTING: outpatientTreatment N: 30Control N: 30AGE: 49+/-9.6SEX: 38% menINCLUSION: Type 2 DM with sulfonylurea failureEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 0.85-2.5 g/dayCOMPARISON: insulin
Interventions
Plasma glucose, fibrinogen, body mass index.Outcomes
Notes
DAllocation concealment
Ferner 1988Study
TRIAL DESIGN: Open-label nonrandomised comparative trialDURATION: 3 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 6Control N: 12Treatment AGE: 56Control AGE: 56Treatment SEX: 67% menControl SEX: 50% menINCLUSION: Type 2 DMEXCLUSIONS: other medication, ketosis, ketonuria
Participants
TREATMENT: Metformin, dose adjusted clilnicallyCOMPARISON: tolbutamide or diet
Interventions
Página 44
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Insulin sensitivity under euglycemic insulin clampOutcomes
Notes
DAllocation concealment
Fisman 2001Study
TRIAL DESIGN: Open-label nonrandomised comparative trialDURATION: 7.7 years
Methods
COUNTRY: IsraelSETTING: research instituteTreatment N: 332Control N: 1943Treatment AGE: 60.1+/-6.5Control AGE: 59.9+/-6.6Treatment SEX: 66% menControl SEX: 76% menINCLUSION: Type 2 DM with coronary artery diseaseEXCLUSIONS: pacemaker, cerebrovascular disease, malignant disease, estrogenreplacement, and insulin treatment
Participants
TREATMENT: Metformin or metformin + sulfonylurea, dose adjusted clinicallyCOMPARISON: sulfonylurea or diet
Interventions
Crude mortality rate, time-related mortality, and cause of deathOutcomes
Notes
DAllocation concealment
Fonseca 2000Study
TRIAL DESIGN: Prospective cohort study of metformin in a randomised controlled trialof rosiglitazoneDURATION: 6.5 months
Methods
COUNTRY: United StatesSETTING: mulitcenter outpatientTreatment N: 348Control N: 0AGE: 58+/-9SEX: 68% menINCLUSION: type 2 DMEXCLUSIONS: renal or hepatic disease, angina, congestive heart failure, abnormallaboratory result, or chronic use of insulin
Participants
TREATMENT: metformin 2.5 g/day + placebo, metformin + rosiglitazone 4 mg/day, ormetformin + rosiglitazone 8 mg/day.
Interventions
HbA1c, fasting glucose, insulin sensitivity, weight, and lipids.Outcomes
Notes
DAllocation concealment
Fritsche 2000Study
TRIAL DESIGN: Double-blind cross-over randomised controlled trialDURATION: 10 weeks
Methods
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Characteristics of included studies
COUNTRY: GermanySETTING: outpatientTreatment N: 26Control N: 26AGE: 51+/-9SEX: not listedINCLUSION: Severely obese type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, dosage adjusted clinically, + insulinCOMPARISON: placebo + insulin
Interventions
Glucose, insulin, c-peptide, HbA1c, lipids, weight, venous lactic acid.Outcomes
Notes
BAllocation concealment
Fujioka 2005Study
TRIAL DESIGN:2 double-blind randomised controlled trialsDURATION: 3 months and 4 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 663Control N: 202Age: 56 +/- 10Sex: 50% menInclusion: type 2 DM inadequately controlled on diet and exerciseExclusions: standard
Participants
TREATMENT: metformin XR 500 -2000 mg/dayCOMPARISON: placebo
Interventions
HbA1c, fasting glucose and insulin, lipid profilesOutcomes
Notes
DAllocation concealment
Galeone 1998Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: ItalySETTING: diabetes referral centerTreatment N: 57Control N: 0AGE: 61+/-3.4SEX: 54% menINCLUSION: type 2 DM for at least 5 yearsEXCLUSIONS: hepatic or liver abnormalities, neurological, psychological or cardiacdisease
Participants
TREATMENT: metformin 1500 mg/day and glicazide 120mg/dayCOMPARISON: none
Interventions
HbA1c, 24-hour glycosuria, and fasting and postprandial glucose.Outcomes
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Characteristics of included studies
Notes
DAllocation concealment
Garber 1997Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 11 weeks
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 222Control N: 229Treatment AGE: 57+/-10Control AGE: 55+/-11Treatment SEX: 62% menControl SEX: 56% menINCLUSION: Type 2 DM, not controlledEXCLUSIONS: significant disease or contraindication likely to affect diabetes
Participants
TREATMENT: Metformin, dosage adjusted clinicallyCOMPARISON: placebo
Interventions
Fasting glucose and HbA1.Outcomes
Notes
BAllocation concealment
Garber 2002Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 2 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 317Control N; 321Age: 56 +/- 10Sex: 53% menInclusion: type 2 DM that failed diet and exerciseExclusions: polyurea, weight loss, acidosis, insulin treatment
Participants
TREATMENT: metformin 500 mg BID with and without glyburideCONTROL: gluburide 2.5 mg BID or placebo
Interventions
HbA1, fasting and postprandial glucoseOutcomes
Notes
DAllocation concealment
Garcia 1971Study
TRIAL DESIGN: Prospective cohort studyDURATION: 2 years
Methods
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Characteristics of included studies
COUNTRY: MexicoSETTING: outpatientTreatment N: 23Control N: 0AGE: 53.6SEX: 26% menINCLUSION: DM, treated with sulfonylureasEXCLUSIONS: none listed
Participants
TREATMENT: metformin + chlorpropamide in combination, dosage titrated clinicallyCOMPARISON: none
Interventions
Fasting and postprandial glucose, glucosuria.Outcomes
Notes
DAllocation concealment
Giugliano 1993Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 6 months
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 27Control N:AGE: not listedSex: 23% menINCLUSION: Obese patients with Type 2 DMEXCLUSIONS: intercurrent illness, age > 70, creatinine > 1.2 mg/dl, ischemic or wastingdisease
Participants
TREATMENT: Metformin, dosage adjusted clinicallyCOMPARISON: placebo
Interventions
HbA1, lipids, c-peptide, blood pressure, and BMI.Outcomes
Notes
BAllocation concealment
Goldstein 2003Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 4.5 months
Methods
COUNTRY: United StatesSETTING: outpatient Treatment N: 163Control N: 84Inclusions: type 2 DM inadequately controlled on sulfonylureaExclusions: renal and hepatic dysfunction, cardiovascular diseaese, acidosis or long-terminsulin treatment
Participants
TREATMENT: metformin 2 g/day with or without glipizideCONTROL: glipizide 30 mg/day
Interventions
BMI, HbA1, fasting glucoseOutcomes
Notes
DAllocation concealment
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Characteristics of included studies
Gonzalez-Ortiz 2004Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 3 months
Methods
COUNTRY: MexicoSETTING: outpatientTreatment N: 67Control N: 37Age: 53 +/- 7Sex: 52% menInclusion: type 2 DM with secondary failure to monotherapy with glibenclamideExlcusions: cardiovascular, renal or hepatic dysfunction, insulin treatment, pregnancy
Participants
TREATMENT: metformin 1-2 gm/day with or without glimepiride 2-4 mg/dayCOMPARISON: Glimipiride 2-4 mg/day
Interventions
HbA1c, adverse eventsOutcomes
Notes
DAllocation concealment
Gottlieb 1962Study
TRIAL DESIGN: Prospective cohort studyDURATION: 6 months
Methods
COUNTRY: United Kingdom SETTING: inpatient then outpatientTreatment N: 39Control N: 0AGE: 21 - >80SEX: 58% menINCLUSION: patients with DM, poorly controlled on previous regimenEXCLUSIONS: none listed
Participants
TREATMENT: metformin 1-3 g/dayCOMPARISON: none
Interventions
Weight, and glycemiaOutcomes
Notes
DAllocation concealment
Grant 1991Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 6 weeks
Methods
COUNTRY: United KingdomSETTING:Treatment N: 21Control N: 17Treatment AGE: 59.5+/-9Control AGE: 63.2+/-9.6SEX: not listedINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, low and high doseCOMPARISON: placebo
Interventions
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Characteristics of included studies
Plasminogen activator inhibitor, BMI, glucose, HbA1, insulin, lipids.Outcomes
Notes
BAllocation concealment
Grant 1996Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 6 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 52Control N: 23AGE: not listedSEX: not listedINCLUSION: Obese patients with Type 2 DMEXCLUSIONS: insulin therapy, BMI < 25, fasting glucose < 6 mmol/L
Participants
TREATMENT: Metformin 3 g/dayCOMPARISON: placebo
Interventions
Lipids, HbA1, insulin, BMI, plasminogen activator inhibitor.Outcomes
Notes
BAllocation concealment
Grant 1998Study
TRIAL DESIGN: randomised controlled trialDURATION: 6 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 27Control N: 17AGE: not listedSEX: not listedINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 1.5 g/day or metformin 3 g/dayCOMPARISON: placebo
Interventions
Plasma insulin, glucose, lipids, and factor VII levels.Outcomes
Notes
BAllocation concealment
Gregorio 1989Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 5 weeks
Methods
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Characteristics of included studies
COUNTRY: ItalySETTING: outpatientTreatment N: 53Control N: 53AGE: not listedSEX: not listedINCLUSION: Type 2 DM, poor controlEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, dosage adjusted clinically, + sulfonylureaCOMPARISON: placebo + sulfonylurea
Interventions
Weight, lipids, insulin, HbA1, and lactate levels.Outcomes
Notes
BAllocation concealment
Gregorio 1990Study
TRIAL DESIGN: Single-blind comparative trial. Patients were their own controlsDURATION: 5 weeks
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 20Control N: 10AGE: 50-63Treatment SEX: 45% menControl SEX: 40% menINCLUSION: Type 2 DM with poor controlEXCLUSIONS: heptic, renal or vascular disease
Participants
TREATMENT: Metformin, dosage adjusted clinically, + sulfonylureaCOMPARISON: placebo + sulfonylurea
Interventions
Glucose, insulin, c-peptide, fructosamine, lipids, lactate, pyruvate, alanine, and glycerol.Outcomes
Notes
DAllocation concealment
Gregorio 1997Study
TRIAL DESIGN: Prospective cohort studyDURATION: 6 months
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 68Control N: 0AGE: 67+/-1.2SEX: 43% menINCLUSION: type 2 DMEXCLUSIONS: liver or renal abnormality, respiratory insufficiency or congestive heartfailure
Participants
TREATMENT: metformin 2350 mg/dayCOMPARISON: none
Interventions
Lactate, free fatty acids, lipids, insulin, c-peptide, plasma metformin, and glucose.Outcomes
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Characteristics of included studies
Notes
DAllocation concealment
Groop 1989Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 6 months
Methods
COUNTRY: FinlandSETTING: outpatientTreatment N: 12Control N: 12AGE: not listedSEX: not listedINCLUSION: Type 2 DMEXCLUSIONS: cardiac, renal, hepatic or endocrine disease, intercurrent illness
Participants
TREATMENT: Metformin 500 mg TID + glibenclamideCOMPARISON: insulin
Interventions
Glucose, lipids, weight, BMI, basal hepatic glucose productionOutcomes
Notes
DAllocation concealment
Groop 1991Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 6 months
Methods
COUNTRY: FinlandSETTING: outpatientTreatment N: 12Control N: 24Treatment AGE: 60+/-2Control AGE: 59+/-2Treatment SEX: 50% menControl SEX: 50% menINCLUSION: Type 2 DM with sulfonylurea failureEXCLUSIONS: intercurrent illness, hepatic, renal or cardiac disease
Participants
TREATMENT: Metformin 1.5 g/day + glibenclamide.COMPARISON: insulin
Interventions
Blood glucose, HbA1, lipids, energy expenditure, glucose and fat oxidation.Outcomes
Notes
DAllocation concealment
Guillausseau 1997Study
TRIAL DESIGN: Open-label, nonrandomised comparative trialDURATION: at least 3 months
Methods
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Characteristics of included studies
COUNTRY: FranceSETTING: outpatientTreatment N: 26Control N: 36Treatment AGE: 60+/-10Control AGE: 60+/-12.9Treatment SEX: 73% menControl SEX: 63% menINCLUSION: Type 2 DM on sulfonylureaEXCLUSIONS: none listed
Participants
TREATMENT: Metfomin, dosage adjusted clinically + gliclazideCOMPARISON: gliclazide
Interventions
Fasting and postprandial glucose, and HbA1.Outcomes
Notes
DAllocation concealment
Gursoy 2000Study
TRIAL DESIGN: Abstract of a prospective cohort studyDURATION: 3 months
Methods
COUNTRY: TurkeySETTING: outpatientTreatment N: 20Control N: 0AGE: 49+/-8SEX: 80% menINCLUSION: obese and nonobese patients with type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 2.5 g/dayCOMPARISON: none
Interventions
Insulin sensitivity, lipid profiles, lactate, and BMI.Outcomes
Notes
DAllocation concealment
Haupt 1991Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: GermanySETTING: multicenter outpatientTreatment N: 1823Control N: 0AGE: 64.8SEX: 39% menINCLUSION: type 2 DM, poorly controlledEXCLUSIONS: nephropathy, previous treatment with metformin, and insulin-dependence
Participants
TREATMENT: metformin 850-2550 mg/day + sulfonylurea, dosage titrated clinicallyCOMPARISON: none
Interventions
Postprandial glucose, HbA1, weight, blood pressure, and lipids.Outcomes
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Characteristics of included studies
Notes
DAllocation concealment
Herman 1961Study
TRIAL DESIGN: Prospective cohort studyDURATION: approximately 1 month
Methods
COUNTRY: South AfricaSETTING: outpatientTreatment N: 47Control N: 0AGE: not listedSEX: not listedINCLUSION: maturity-onset DM, juvenile-onset patients were studied but not analysedEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 1.5-3 g/dayCOMPARISON: none
Interventions
Fasting glucose and glucose tolerance.Outcomes
Notes
DAllocation concealment
Hermann 1991aStudy
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 6 months
Methods
COUNTRY: SwedenSETTING: outpatientTreatment N: 122Control N: 45AGE: 60SEX: 64% menINCLUSION: Type 2 DMEXCLUSIONS: cardiac, renal or hepatic disease, alcohol abuse, severe chronic disease
Participants
TREATMENT: Metformin 1 g BID or metformin + glibenclamideCOMPARISON: glibenclamide
Interventions
Fasting glucose, HbA1, weight.Outcomes
Notes
DAllocation concealment
Hermann 1991bStudy
TRIAL DESIGN: Open-label crossover randomised controlled trialDURATION: 1 year
Methods
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Characteristics of included studies
COUNTRY: SwedenSETTING: outpatientTreatment N: 22Control N: 22AGE: 59SEX: 72% menINCLUSION: Type 2 DMEXCLUSIONS: renal or liver dysfunction
Participants
TREATMENT: Metformin 0.5-3 g/dayCOMPARISON: glibenclamide
Interventions
Fasting glucose, lipds, c-peptide, HbA1.Outcomes
Notes
DAllocation concealment
Hermann 1994aStudy
TRIAL DESIGN: randomised controlled trialDURATION: 3 months.
Methods
COUNTRY: SwedenSETTING: regional health centersTreatment N: 110Control N: 34AGE: 34-74SEX: 64% menINCLUSION: Type 2 DMEXCLUSIONS: contraindications to the medications, or insulin requirements
Participants
TREATMENT: Metformin or metformin, dosage adjusted clinically, + glibenclamideCOMPARISON: glibenclamide
Interventions
Fasting glucose, body weight, and c-peptide levels.Outcomes
Notes
BAllocation concealment
Hermann 1994bStudy
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 6 months
Methods
COUNTRY: SwedenSETTING: regional health centersTreatment N: 108Control N: 36AGE: 60SEX: 63% menINCLUSION: Type 2 DMEXCLUSIONS: insulin treatment, contraindications to the medications
Participants
TREATMENT: Metformin, dosage adjusted clinicallyCOMPARISON: glibenclamide
Interventions
Fasting glucose, c-peptide levels, HbA1, blood pressure.Outcomes
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Characteristics of included studies
Notes
AAllocation concealment
Higginbotham 1979Study
TRIAL DESIGN: Double-blind cross-over randomised controlled trialDURATION: 2 months
Methods
COUNTRY: AustraliaSETTING: outpatientTreatment N: 17Control N: 17AGE: 31-79SEX: 29% menINCLUSION: Type 2 DMEXCLUSIONS: renal or liver insufficiency, retinopathy
Participants
TREATMENT: Metformin, dosage unclearCOMPARISON: glibenclamide
Interventions
Fasting and postprandial glucose, weight, insulin and lactate levels.Outcomes
Notes
BAllocation concealment
Hirsch 1999Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 5 months
Methods
COUNTRY: United StatesSETTING: research centerTreatment N: 25Control N: 25AGE: not listedSEX: not listedINCLUSION: Type 2 DM with poor control on insulinEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 2.5 g/dayCOMPARISON: placebo
Interventions
Weight, HbA1, insulin, c-peptide, or insulin dose.Outcomes
Notes
BAllocation concealment
Hoffmann 1997Study
TRIAL DESIGN: randomised controlled trial. Single blind with respect to metformintreatmentDURATION: 6 months
Methods
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Characteristics of included studies
COUNTRY:SETTING: multicenterTreatment N: 31Control N: 63Treatment AGE: 55.9Control AGE: 59.2Treatment SEX: 45% menControl SEX: 28.5% menINCLUSION: Type 2 DM, previously on dietEXCLUSIONS: renal, liver or cardiovascular disease, malignancy, pregnancy, infection
Participants
TREATMENT: Metformin 850 mg BIDCOMPARISON: acarbose or placebo.
Interventions
Fasting and postprandial glucose, insulin, lipids, HbA1.Outcomes
Notes
BAllocation concealment
Hollenbeck 1991Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: United StatesSETTING: Veteran's Administration outpatientTreatment N: 9Control N: 0AGE: 63+/-3SEX: 89% menINCLUSION: Type 2 DM, with elevated triglyceridesEXCLUSIONS: significant diseases or medication that could interfere with carbohydratemetabolism
Participants
TREATMENT: Metformin 2.5 g/dayCOMPARISON: none
Interventions
HbA1c, plasma insulin, free fatty acids, triglyceride, and lipids.Outcomes
Notes
DAllocation concealment
Holman 1987Study
TRIAL DESIGN: crossover randomised controlled trialDURATION: 2 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 18Control N: 45AGE: 57+/-11SEX: 33% menINCLUSION: Type 2 DMEXCLUSIONS: cardiovascular disease
Participants
TREATMENT: Metformin, dosage adjusted clinically, or metformin + sulfonylureaCOMPARISON: sulfonylurea or sulfonylurea + insulin versus insulin
Interventions
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Characteristics of included studies
Fasting glucose, c-peptide, HbA1.Outcomes
Notes
BAllocation concealment
Horton 2000Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 6 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 350Control N: 351AGE: 56-59Treatment SEX: 58% menControl SEX: 61% menINCLUSION: Type 2 DMEXCLUSIONS: renal impairment, significant diabetic complications
Participants
TREATMENT: Metformin 500 mg TID or metformin + nateglinindeCOMPARISON: nateglinide or placebo
Interventions
Fasting glucose, HbA1.Outcomes
Notes
AAllocation concealment
Horton 2004Study
TRIAL DESIGN: Double-blind randomised controlled trial DURATION: 6 monthsMethods
COUNTRY: United States SETTING: outpatientTreatment N: 193Control N: 297Age: 57 +/- 1.1Sex: 60% menInclusion: type 2 DM, treatment naiveExclusions: renal dysfunction, diabetic complications
Participants
TREATMENT: metformin 500 mg TID with and without nateglinide COMPARISON:nateglinide 120 mg before meals
Interventions
HbA1, fasting and postprandial glucose, post-load insulinOutcomes
Notes
DAllocation concealment
Hother-Nielsen 1989Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 4 weeks
Methods
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Characteristics of included studies
COUNTRY: DenmarkSETTTING: outpatientTreatment N: 9Control N: 9AGE: not listedSEX: not listedINCLUSION: Obese patients with Type 2 DMEXCLUSIONS: renal or liver dysfunction
Participants
TREATMENT: Metformin 500 mg TIDCOMPARISON: placebo
Interventions
Insulin requirements, glucose, insulin, lactate levels.Outcomes
Notes
BAllocation concealment
Imano 1998Study
TRIAL DESIGN: randomised controlled trialDURATION: 3 months
Methods
COUNTRY: JapanSETTING: outpatientTreatment N: 13Control N: 17Treatment AGE: 66+/-8Control AGE: 62+/-13Treatment SEX: 23% menControl SEX: 29% menINCLUSION: Type 2 DM with microalbuminuriaEXCLUSIONS: abnormal liver function
Participants
TREATMENT: Metformin 500 mg TIDCOMPARISON: troglitazone
Interventions
Lipids, blood pressure, BMI, fasting and postprandial glucose, albumin-to-creatinineratio.
Outcomes
Notes
BAllocation concealment
Inzucchi 1998Study
TRIAL DESIGN: randomised controlled trialDURATION: 3 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 29Control N: 24Treatment AGE: 51+/-13Control AGE: 56+/-12Control SEX: 43% menTreatment SEX: 47% menINCLUSION: Type 2 DMEXCLUSIONS: abnormal renal or hepatic function, recent atherosclerotic event
Participants
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Characteristics of included studies
TREATMENT: Metformin 1g BIDCOMPARISON: troglitazone
Interventions
Postprandial glucose, HbA1, glucose tolerance, insulin, c-peptide.Outcomes
Notes
BAllocation concealment
Jackson 1962Study
TRIAL DESIGN: Retrospective cohort studyDURATION: approximately 1 month
Methods
COUNTRY: South AfricaSETTING: outpatientTreatment N: 26Control N: 0AGE: not listedSEX: not listedINCLUSION: mild, not-ketosis-prone DMEXCLUSIONS: ketosis
Participants
TREATMENT: Metformin 1-3 g/dayCOMPARISON: none.
Interventions
Glycemia, and dose of sulfonylurea.Outcomes
Notes
DAllocation concealment
Jackson 1987Study
TRIAL DESIGN: Single-blind cross-over trialDURATION: 4.9 months average
Methods
COUNTRY: United KingdomSETTING: general practiceTreatment N: 10Control N: 10AGE: 56.6+/-1.9SEX: 100% menINCLUSION: Type 2 DM, nonobeseEXCLUSIONS: excessive physical activity or a metabolic disorder
Participants
TREATMENT: Metformin, dose adjusted clinically COMPARISON: placeboInterventions
Plasma glucose, hepatic glucose output, forearm glucose uptake, and blood lactatelevels.
Outcomes
Notes
DAllocation concealment
Jeppesen 1994Study
TRIAL DESIGN: Open-label cross-over trialDURATION: 12 weeks glipizide and 8 weeks metformin added
Methods
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Characteristics of included studies
COUNTRY: United StatesSETTING: research centerTreatment N: 16Control N: 16AGE: 57+/-3SEX: 63% menINCLUSION: Type 2 DM, poorly controlledEXCLUSIONS: patients not "in good health".
Participants
TREATMENT: Metformin, dosage adjusted clinically + glipizideCOMPARISON: glipizide
Interventions
Postprandial and steady-state glucose, lipids, free fatty acids.Outcomes
Notes
DAllocation concealment
Johansen 1984Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 8 weeks
Methods
COUNTRY: DenmarkSETTING: outpatientTreatment N: 10Control N: 10AGE: 59SEX: 30% menINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin 500 mg/day + placebo/day. COMPARISON: acarbose +placebo
Interventions
Postprandial glucose, HbA1, urinary glucose.Outcomes
Notes
BAllocation concealment
Johnson 1993Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 3 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 8Control N: 12AGE: 58+/-8SEX: 62% menINCLUSION: Newly diagnosed obese untreated Type 2 DMEXCLUSIONS: renal or hepatic abnormalities
Participants
TREATMENT: Metformin 0.85-2.5 g/dayCOMPARISON: placebo
Interventions
Insulin sensitivity, HbA1, insulin, c-peptide, skeletal muscle biopsy, glucose synthetaseactivity.
Outcomes
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Characteristics of included studies
Notes
BAllocation concealment
Johnson 1998Study
TRIAL DESIGN: Retrospective cohort studyDURATION: average 9 months
Methods
COUNTRY: United StatesSETTING: Diabetes center chart reviewTreatment N: 124Control N: 0AGE: not listedSEX: not listedINCLUSION: patients with type 2 DM treated with metforminEXCLUSIONS: none listed
Participants
TREATMENT: metformin 500-2500 mg/day, with other medications as neededCOMPARISON: none.
Interventions
Insulin dose, BMI, and HbA1c.Outcomes
Notes
DAllocation concealment
Jones 2000 bStudy
TRIAL DESISN: Abstract: open-label extension study of a randomised controlled trial.DURATION: 30 months
Methods
COUNTRY: United States. SETTING: outpatient. Treatment N: Control N: Age: notlisted. Sex: not listed. Inclusion: Type 2 DM. Exclusions: none listed.
Participants
TREATMENT: Metformin, dosage adjusted clinically, + rosiglitazone. COMPARISON:rosiglitazone
Interventions
Lipds, HbA1c, beta-cell function.Outcomes
Notes
DAllocation concealment
Jones 2000aStudy
TRIAL DESIGN: Abstract of a prospective cohort trial. Some data reported in Fonseca2000. Remaining data analysedDURATION: 6 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 102Control N: 0AGE: not listedSEX: not listedINCLUSION: type 2 DM, poorly controlled on metforminEXCLUSIONS: none listed
Participants
TREATMENT: metformin, dosage adjusted clinically + placebo, or metformin +rositglitazone 4 mg/day, or metformin + rosiglitazone 8 mg/day
Interventions
Fasting glucose and BMI.Outcomes
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Characteristics of included studies
Notes
DAllocation concealment
Jones 2002Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 4 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 42Control N: 40Age: 14 +/- 1.8Sex: 30% menInclusion: pediatric patients age 10-16 with type 2 DMExclusions: creatinine > 76 mcmole/L, hepatic dysfunction
Participants
TREATMENT: metformin up to 2 g/dayCOMPARISON: placebo
Interventions
Fasting glucose, HbA1cOutcomes
Notes
DAllocation concealment
Josephkutty 1990Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 3 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 20Control N: 20Treatment AGE: 76.5Control AGE: 80.5Treatment SEX: 30% menControl SEX: 30% menINCLUSION: Type 2 DM patients, aged 65 or olderEXCLUSIONS: renal or liver function abnormalities, recent congestive heart failure
Participants
TREATMENT: Metformin 1g BIDCOMPARISON: tolbutamide
Interventions
Fasting insulin, glucose, lactate levels, lipids and weight.Outcomes
Notes
BAllocation concealment
Josse 1995Study
TRIAL DESIGN: randomised controlled trial of acarbose versus placebo. Metformin innonrandomised treatment strataDURATION: 12 months
Methods
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: CanadaSETTING: outpatientTreatment N: 83Control N: 271AGE: 57.4+/-1.1SEX: 64% menINCLUSION: Type 2 DMEXCLUSION: debilitating disease, gastrointestinal disease
Participants
TREATMENT: Main: acarbose versus placebo. Treatment strata: Metformin (dosageadjusted clinically), diet, sulfonylureas, insulin
Interventions
Postprandial glucose, HbA1.Outcomes
Notes
CAllocation concealment
Jung 2005Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 6 months
Methods
COUNTRY: South KoreaSETTING: outpatientTreatment N: 13Control N: 14Age: 57 +/- 10Sex: 45% menInclusion: type 2 DM on sulfonylueraExlcusions: standard
Participants
TREATMENT: metformin 1 g/dayCOMPARISON: rosiglitazone 4 mg/day
Interventions
Anthropometric parameters, fasting plasma glucose, HbA1, lipid profile, adiponectin,resistin
Outcomes
Notes
DAllocation concealment
Karlsson 2005Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 6 months
Methods
COUNTRY: FinlandSETTING: outpatientTreatment N: 9Control N: 21Age: 58 +/- 2.1Sex: 80% menInclusion: newly diagnosed type 2 DMExclusions: cardiovascular, renal or hepatic dysfunction, anemia
Participants
TREATMENT: 2 g/dayCOMPARISON: rosiglitazone 4 mg BID or placebo
Interventions
Euglycemic clamp measurements, skeletal muscle biopsies, insulin receptor substrateOutcomes
Página 64
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
Kiayias 1999Study
TRIAL DESIGN: Comparative trial; not randomisedDURATION: 3 months
Methods
COUNTRY: GreeceSETTING: outpatientTreatment N: 33Control N: 16AGE: 64.6+/-9.5SEX: 51% menINCLUSION: Poorly controlled type 2 DMEXCLUSIONS: proteinuria, smokers, various medications
Participants
TREATMENT: Metformin, dosage adjusted clinically, or metformin + sulfonylureaCOMPARISON: sulfonylurea
Interventions
Lipoprotein (a) levels, lipids, HbA1.Outcomes
Notes
BAllocation concealment
Kim 2002Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 4 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 7Control N: 7Age: 56 +/- 1Sex: 79% menInclusion: type 2 DMExlcusions: standard
Participants
TREATMENT: metformin 2.5 g/dayCOMPARISON: troglitazone 600 mg/day
Interventions
Glucose disposal rate, HbA1, fasting glucoseOutcomes
Notes
DAllocation concealment
Kirk 1999Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 14 weeks
Methods
Página 65
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: United StatesSETTING: outpatientTreatment N: 15Control N: 16Treatment AGE: 50.5Control AGE: 54.5Treatment SEX: 64% menControl SEX: 31% menINCLUSION: Type 2 DMEXCLUSIONS: women of childbearing potential, renal or hepatic disease, alcoholabuse, various medications
Participants
TREATMENT: Metformin 0.5-1 g BIDCOMPARISON: troglitazone 200-400 mg/day.
Interventions
HbA1, fasting glucose and C-peptide.Outcomes
Notes
DAllocation concealment
Klein 1975Study
TRIAL DESIGN: Prospective cohort studyDURATION: 4 months
Methods
COUNTRY: GermanySETTING: outpatientTreatment N: 60Control N: 0AGE: not listedSEX: 48% menINCLUSION: maturity-onset DM EXCLUSION: none listed
Participants
TREATMENT: Metformin, dosage titrated clinically, some with chlorpropamideCOMPARISON: none
Interventions
Glucose, weight, and lipids.Outcomes
Notes
DAllocation concealment
Klein 1991Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 1 year
Methods
COUNTRY: GermanySETTING: outpatientTreatment N: 16Control N: 19Treatment AGE: 68+/-10Control AGE: 66+/-11Treatment SEX: 27% malesControl SEX: 20% malesINCLUSION: Type 2 DM with failure with sulfonylureaEXCLUSIONS: renal insufficiency with creatinine > 1.2, acute or severe disease, variousmedications
Participants
Página 66
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
TREATMENT: Metformin, dosage adjusted clinically, + sulfonylureaCOMPARISON: insulin + sulfonylurea
Interventions
Weight, blood pressure, insulin, c-peptide, HbA1, lipids, liver and renal function, andlactate levels.
Outcomes
Notes
DAllocation concealment
Lalau 1990Study
TRIAL DESIGN: Prospective cohort studyDURATION: 2 months.
Methods
COUNTRY: FranceSETTING: outpatientTreatment N: 24Control N: 0AGE: 74+/-1.5SEX: 67% menINCLUSION: patients over the age of 70 with type 2 DMEXCLUSIONS: creatinine clearance < 30 ml/min
Participants
TREATMENT: metformin, 1770-2550 mg/day COMPARISON: noneInterventions
Creatinine clearance, lactate levels.Outcomes
Notes
DAllocation concealment
Lalor 1990Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 3 months
Methods
COUNTRY: United KingdomSETTING: hospital clinicTreatment N: 38Control N: 38AGE: 58SEX: 46% menINCLUSION: Obese patients with type 2 DMEXCLUSIONS: previous treatment with metformin or guar
Participants
TREATMENT: Metformin, dosage adjusted clinically, + placeboCOMPARISON: Guar + placebo
Interventions
Fasting glucose, weight, and lipids.Outcomes
Notes
BAllocation concealment
Lam 1998Study
TRIAL DESIGN: Prospective cohort trial with 91% on metforminDURATION: 6 months
Methods
Página 67
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: ChinaSETTING: three-center outpatientTreatment N: 90Comparison N: 0AGE: 35-70SEX: 45% menINCLUSION: Type 2 DM with poor control on oral hypoglycemicsEXCLUSIONS: abnormal liver and renal function, significant diseases or conditions,ketonuria,abnormal gutmotility, lactose intolerance, pregnancy and lactation
Participants
TREATMENT: 91% on metformin, dosage adjusted clinically, + acarbose, 150-300mg/day, or metformin + placeboCOMPARISON: 9% on other oral agents + acarbose or placebo. These patients notanalysed.
Interventions
Fasting and postprandial glucose, HbA1c, insulin levels, and lipids.Outcomes
Notes
DAllocation concealment
Laurenti 1992Study
TRIAL DESIGN: Open-label comparative trialDURATION: 6 months
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 30Control N: 30AGE: 38-63SEX: not listedINCLUSION: Type 2 DM with poor control on sulfonylureaEXCLUSIONS: congestive heart failure, nephropathy, liver function abnormalities
Participants
TREATMENT: Metformin, dosage adjusted clinically, + glibenclamideCOMPARISON: sulfonylurea alone
Interventions
Fasting and postprandial glucose, insulin, fructosamine, and BMI.Outcomes
Notes
DAllocation concealment
Lawrence 2004Study
TRIAL DESIGN: Open-label randomised controlled trial DURATION: 3 monthsMethods
COUNTRY: United KingdomSETTING: outpatient Treatment N: 20Control N: 10Age: 60 +/- 9Sex: 60% menInclusion: overweight type 2 DMExclusions: Creatinine > 150 mcmole/L, congestive heart failure, hepatic dysfunction
Participants
TREATMENT: metformin 500 mg BIDCOMPARISON: pioglitazone 30 mg/day or glicazine 80 mg.day
Interventions
HbA1, lipid profile, glucose, BMIOutcomes
Página 68
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
Lean 1983Study
TRIAL DESIGN: Prospective cohort study or metformin in a randomised controlled trialof ciclazindolDURATION: 2 months
Methods
COUNTRY: United Kingdom SETTING: outpatientTreatment N: 10Control N: 0AGE: 42-68SEX: 30% menINCLUSION: obese patients with type 2 DM, treated with metforminEXCLUSIONS: hepatic or renal impairment, heart disease, psychiatric or alcoholproblems
Participants
TREATMENT: metformin 500 mg BID + placebo or metformin + ciclazindol 25-75mg/dayCOMPARISON: none
Interventions
Plasma insulin, triglycerides, lactate pyruvate, and weight.Outcomes
Notes
DAllocation concealment
Lee 1998Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 24 weeks
Methods
COUNTRY: United StatesSETTING: University centerTreatment N: 24Control N: 120Treatment AGE: 59+/-3Control AGE: 61+/-2SEX: 0 menINCLUSION: Obese type 2 DMEXCLUSIONS: major illnes, cardiac, renal or hepatic disorder, medicine known to affectbody weight or cholesterol metabolism
Participants
TREATMENT: Metformin 850 mg BIDCOMPARISON: placebo
Interventions
Food consumption and weight lossOutcomes
Notes
BAllocation concealment
Lord 1983Study
TRIAL DESIGN: Open-label cross-over trial with untreated controlsDURATION: 4 weeks
Methods
Página 69
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: United KingdomSETTING: outpatientTreatment N: 8Control N: 8AGE: 61+/-5SEX: 38% menINCLUSION: Obese, type 2 DMEXCLUSIONS: abnormal renal or liver function
Participants
TREATMENT: Metformin 500 mg TIDCOMPARISON: no metformin
Interventions
Glucose tolerance test, urinary glucose, and HbA1.Outcomes
Notes
DAllocation concealment
Lunetta 1996Study
TRIAL DESIGN: Prospective cohort studyDURATION: 1 month
Methods
COUNTRY: ItalySETTING: outpatient clinicTreatment N: 12Control N: 0AGE: 55+/-5SEX: 50% menINCLUSION: Type 2 DM for at least one year, with good glycemic controlEXCLUSIONS: diabetic neuropathy, gastroparesis or diarrhea
Participants
TREATMENT: metformin 850 mg BID, then a single dose of metformin 850 mg orplaceboCOMPARISON: none
Interventions
Postprandial glucose.Outcomes
Notes
DAllocation concealment
Makimattila 1999Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 12 months
Methods
COUNTRY: FinlandSETTING: outpatientTreatment N: 13Control N: 39Treatment AGE: 54+/-2Control AGE: 58+/-3SEX: not listedINCLUSION: Type 2 DMEXCLUSIONS: congestive heart failure, cardiovascular disase, seizure, liver diseaseunrelated to DM
Participants
TREATMENT: Metformin 2 g/day + insulin NPH QHS COMPARISON: insulin BIDInterventions
Weight gain, urinary glucose, and HbA1.Outcomes
Página 70
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
Manzella 2004Study
TRIAL DESIGN: Blinded randomised controlled trial DURATION: 4 monthsMethods
COUNTRY: ItalySETTING: outpatientTreatment N: 60Control N: 60Age: 57 +/- 11Sex: 55% menInclusion: obese type 2 DMExclusions: coronary artery disease
Participants
TREATMENT: metformin 850 mg BIDCOMPARISON: placebo
Interventions
Fasting glucose, insulin, triglyceride, free fatty acids, insulin resistance by HOMAmethod
Outcomes
Notes
DAllocation concealment
Marena 1994Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 6 weeks
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 10Control N: 10AGE: 60.8+/-10.7SEX: 60% menINCLUSION: Type 2 DM with poor controlEXCLUSIONS: hepatic, renal, pulmonary or cardiac dysfunctions
Participants
TREATMENT: Metformin, dosage adjusted clinically, + glibenclamideCOMPARISON: placebo + glibenclamide
Interventions
Fasting glucose, HbA1, weight, insulin sensitivity.Outcomes
Notes
BAllocation concealment
Marfella 1996Study
TRIAL DESIGN: Prospective cohort studyDURATION: 2 months
Methods
Página 71
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: ItalySETTING: outpatientTreatment N: 10Control N: 0AGE: 47+/-0.8SEX: 50% menINCLUSION: newly diagnosed patients with type 2 DM, with mild hyperglycemiaEXCLUSIONS: evidence of microvascular or macrovascular complications
Participants
TREATMENT: Metformin 1700 mg/dayCOMPARISON: none
Interventions
Weight, glucose, HbA1, insulin, lipids, blood pressure, heart rate, platelet aggregation,blood viscosity, blood filterability, epinephrine, and norepinephrine.
Outcomes
Notes
DAllocation concealment
Marre 2002Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 4 months
Methods
COUNTRY: France, Belgium, Netherlands, Denmark, PortugalSETTING: outpatientTreatment N: 308Control N: 103Age: 58 +/- 11Sex: 60% menInclusion: type 2 DM inadequately controlled on metforminExclusions: creatinine 127 mcmole/L, hypoxic states, hepatic dysfunction
Participants
TREATMENT: metformin 2.5 g/day with and without glibenclamideCOMPARISON: glimenclamide 20 mg/day
Interventions
HbA1, fasting glucose, fructosamine, lipid profileOutcomes
Notes
DAllocation concealment
McAlpine 1988Study
TRIAL DESIGN: Open-label crossover trialDURATION: 3 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 27Control N: 27AGE: 58SEX: 57% menINCLUSION: Type 2 DMEXCLUSIONS: significant renal or hepatic impairment, various medications
Participants
TREATMENT: Metformin, dosage adjusted clinicallyCOMPARISON: glicazide
Interventions
Weight, fasting and postprandial glucose.Outcomes
Página 72
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
McBain 1988Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 6 months
Methods
COUNTRY: Scotland. SETTING: outpatient. Treatment N: 14. Control N: 20. Treatmentage: 56.5. Control age:56.3.Treatment sex: 36% men. Control sex: 35% men. Inclusion:Type 2 DM. Exclusions: low weight, Abnormal renal function, liver function.
Participants
TREATMENT: Metformin 500mgBID. COMPARISON: glipizide 5mg/day.Interventions
Calcium and magnesium levelsOutcomes
Notes
DAllocation concealment
McIntyre 1991Study
TRIAL DESIGN: Open-label cross-over trialDURATION: 6 weeks
Methods
COUNTRY: AustraliaSETTING: outpatientTreatment N: 9Control N: 9AGE: 48-75SEX: 44% menINCLUSION: Type 2 DMEXCLUSIONS: renal or liver abnormalities
Participants
TREATMENT: metformin 1.5-3 g/dayCOMPARISON: diet
Interventions
Postprandial glucose, total insulin, and c-peptide levels.Outcomes
Notes
DAllocation concealment
Mehta 1963Study
TRIAL DESIGN: Prospective cohort studyDURATION: approximately 1 month.
Methods
COUNTRY: IndiaSETTING: outpatientTreatment N: 41Control N: 0AGE: not listedSEX: not listedINCLUSIONS: patients with DM on medications other than metforminEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, dosage unclearCOMPARISON: none.
Interventions
Glycemia, glucosuria.Outcomes
Página 73
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
Menzies 1989Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: United KingdomSETTING: outpatientTreatment N: 64Control N: 0AGE: 64+/-9SEX: 41% menINCLUSION: obese patients with type 2 DMEXCLUSIONS: ketosis, or abnormal electrolytes or renal function
Participants
TREATMENT: Metformin 1.5-2 g/day or 2.5-3 g/day COMPARISON: noneInterventions
Plasma glucose, HbA1, and lactate.Outcomes
Notes
DAllocation concealment
Moses 1999aStudy
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 22 weeks
Methods
COUNTRY: AustraliaSETTING: outpatientTreatment N: 54Control N: 28Treatment AGE: 57.8Control AGE: 60.3Treatment SEX: 63% menControl SEX: 54% menINCLUSION: Type 2 DM with poor control on metforminEXCLUSIONS: clincally significant renal insufficiency, abnormal liver functions, cardiacdiasease, history of lactic acidosis
Participants
TREATMENT: Metformin, dosage adjusted clinically, + placebo; or metformin +repaglinideCOMPARISON: repaglinide + placebo
Interventions
Fasting glucose, and HbA1.Outcomes
Notes
DAllocation concealment
Munk 1975Study
TRIAL DESIGN: Open-label comparative trialTRIAL DURATION: 6 months
Methods
Página 74
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: GermanySETTING: outpatientTreatment N: 40Control N: 20AGE: unclearSEX: 55% malesINCLUSION: Type 2 DMEXCLUSIONS: none listed
Participants
TREATMENT: Metformin, dosage unclear, or metformin + insulin COMPARISON:Sulfonylurea
Interventions
Lipids, liver function studies, and glucose.Outcomes
Notes
DAllocation concealment
Nagi 1993Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 3 months
Methods
COUNTRY: United States.SETTING: outpatient. Treatment N: 27. Control N: 27. Age: 56.8 +/-8.9. Sex: not listed.Inclusion: Type 2 DM. Exclusions: cardiovascular disease, thromboembolic disease,renal or hepatic disease, retinopathy.
Participants
TREATMENT: Metformin, dosage adjusted clinically. COMPARISON: placeboInterventions
Fasting glucose, lipids, BMI, insulin, c-peptide, blood pressure, plasminogen activatorinhibitor, and other factors
Outcomes
Notes
BAllocation concealment
Natali 2004Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 4 months
Methods
COUNTRY: ItalySETTING: outpatient:Treatment N: 28Control N: 46Age: 58 +/- 9Sex: 70% menInclusion: type 2 DMExclusions: renal or hepatic dysfrunction, congestive heart failure
Participants
TREATMENT: Metformin 500 mg TIDCOMPARISON: placebo
Interventions
Insulin sensitivity by euglycemic clamp, fat-free mass, response to acetycholineOutcomes
Notes
DAllocation concealment
Página 75
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Nattrass 1977Study
TRIAL DESIGN: Open-label, cross-over comparative trialDURATION: 1 month
Methods
Country: United Kingdom. Setting: outpatient.Treatment N: 6. Control N: 6. Age: 50-57.Sex: 67% men. Inclusion: Type 2 DM longer than 3 years. Exclusions: hepatic or renaldisease.
Participants
TREATMENTt: Metformin 500mg TID. COMPARISON: intervention: phenformin 50mgBID (not analysed) or glibenclamide, 2.5-5mg/day.
Interventions
Blood glucose, lactate, pyruvate, 3-hydroxybutyrate, acetoacetate,ketones, lactatopyruvate ratios, and cyclic AMP.
Outcomes
Notes
DAllocation concealment
Niazi 1998Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 5 months
Methods
COUNTRY: Pakistan. SETTING: outpatient. Treatment N: 18. Control N: 36. Treatmentage: 50 +/-11. Control age: 48 +/-11. Treatment sex: 61% men. Control sex: 56% men.Inclusion: Type 2 DM with sulfonylurea failure. Exclusions: cardiomegaly, lung disease,malnutrition, infection, various medications.
Participants
TREATMENT: Metformin 0.5-3g/day. COMPARISON: insulinInterventions
Lipids, blood pressure, weight, and BMI.Outcomes
Notes
DAllocation concealment
Nosadini 1987Study
TRIAL DESIGN: Open-label trial with patients as own controlsDURATION: 1 month
Methods
COUNTRY: Italy. SETTING: outpatient. Treatment N: 7. Control N: 7. Age: 46 +/-5.Sex: 57% men. Inclusion: Type 2 DM. Exclusions: age > 65.
Participants
TREATMENT: Metformin 850mg TID. COMPARISON: dietInterventions
Glucose turnover and insulin bindingOutcomes
Notes
DAllocation concealment
Noury 1991Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 3 months
Methods
COUNTRY: France. SETTING: outpatient. Treatment N: 30. Control N: 27. Age: 55+/-9.1. Treatment sex: 53% men. Control sex: 44% men. Inclusion: Type 2 DM.Exclusions: renal or hepatic disease.
Participants
TREATMENT: Metformin 1700mg/day. COMPARISON: glicazideInterventions
Blood glucose, insulin levels, and weight lossOutcomes
Página 76
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
Ohnhaus 1983Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 1.5 months
Methods
COUNTRY: Switzerland. SETTING: outpatient. Treatment N: 12. Control N: 12. Age:not listed. Sex: not listed. Inclusion: Type 2 DM pts on phenprocoumon. Exclusions:none listed.
Participants
TREATMENT: Metformin 850mg TID. COMPARISON: dietInterventions
Phenprocoumon pharmacokineticOutcomes
Notes
DAllocation concealment
Pavo 2003Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 8 months
Methods
COUNTRY: RussiaSETTING: outpatientTreatment N: 100Control N: 105Age: 55 +/- 9Sex: 50% menInclusion: recently diagnosed type 2 DM naive to oral medicationsExclusions: hepatic and renal dysfunction, congestive heart failure
Participants
TREATMENT: metformin 2.5 g/dayCOMPARISON: pioglitazone 45 mg/day or placebo
Interventions
HbA1c, fasting glucose, insuliln resistance by HOMA methodOutcomes
Notes
DAllocation concealment
Peacock 1984Study
TRIAL DESIGN: Prospective cohort studyDURATION: at least 3 months
Methods
Country: United Kingdom. Setting: outpatient setting. Treatment N: 33. Control N: 0.Age: 58. Sex: 60% men. Inclusion: patients with type 2 DM, treated with high doses ororal hypoglycemics. Exclusions: history or ketosis or good control on oral agents.
Participants
TREATMENT: metformin, dosage unclear, + glibenclamide, dosage adjusted clinically.After 3 months, some were treated additionally with insulin. COMPARISON: none.
Interventions
Fasting glucose, HbA1, and fasting c-peptide.Outcomes
Notes
DAllocation concealment
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Peacock 1986Study
TRIAL DESIGN: Comparative trialDURATION: 6 months
Methods
Country: United Kingdom. Setting: outpatient.Treatment N: 27. Control N: 20.Treatmentage: 59.9 +/-2.1. Control age: 56.7 +/-2.1. Treatment sex: 59% men. Control sex: 66%men. Inclusion: Type 2 DM. Exclusions: none listed.
Participants
TREATMENT: Metformin, dosage unclear, + glibenclamide. COMPARISON: insulinInterventions
Platelet reactivity (ADP release, adrenaline release and NaAA threshold), and fastingglucose, HgA1.
Outcomes
Notes
CAllocation concealment
Pedersen 1965Study
TRIAL DESIGN: Prospective cohort studyDURATION: 18 months
Methods
Country: Denmark. Setting: inpatient and outpatient. Treatment N: 20. Control N: 0.Age: not listed. Sex: not listed. Inclusion: maturity-onset DM. Exclusions: none listed.
Participants
TREATMENT: metformin, dose titrated up clinically, 1-4g/day. COMPARISON: none.Interventions
Plasma glucoseOutcomes
Notes
DAllocation concealment
Pedersen 1989Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 1 month
Methods
Country: Denmark. Setting: outpatient. Treatment N: 10. Control N: 10. Age: 53 +/-9.Sex: 20% men. Inclusion: Obese pts with Type 2 DM. Exclusions: renal or liverdysfunction.
Participants
TREATMENT: Metformin 500mg TID. COMPARISON: placeboInterventions
Fasting and postprandial glucose, fructosamine, insulin, c-peptide, and adipocite insulinreceptor binding.
Outcomes
Notes
BAllocation concealment
Pirart 1961Study
TRIAL DESIGN: Retrospective cohort studyDURATION: 3 motnhs
Methods
Country: Belgium. Setting: outpatient. Treatment N: 107. Control N: 0. Age: not listed.Sex: not listed. Inclusion: type 2 DM, poorly controlled on a single agent. Exclusions:obesity.
Participants
TREATMENT: metformin, unclear dose. COMPARISON: some patients treated withother agents, not analysed.
Interventions
Glycemia, and glucosuria.Outcomes
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
DAllocation concealment
Ponssen 2000Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 5 months
Methods
Country: Netherlands. Setting: outpatient. Treatment N: 31. Control N: 62. Age: 62.+/-10. Sex: 77% men. Inclusion: Type 2 DM. Exclusions: renal insufficency withCreatinine clearance < 50 ml.min, hepatic disease, cardiovascular disease, alcoholabuse, various medications.
Participants
TREATMENT: Metformin, dosage unclear, + insulin COMPARISON: placebo + insulinInterventions
Glucose, fructosamine, insulin requirements, lipds, BMI, and HbA1.Outcomes
Notes
BAllocation concealment
Prager 1986Study
TRIAL DESIGN: Open-label trial, cross-over, with patients as their own controlsDURATION: 3 months control then 1 month metformin
Methods
Country: Austria. Setting: outpatient. Treatment N: 12. Control N: 12. Age: 35-62. Sex:16% men. Inclusion: Type 2 DM. Exclusions: vascular disease, renal failure, liverfunction abnormalities.
Participants
TREATMENT: Metformin 850mg TID. COMPARISON: dietInterventions
Insulin sensitivity, fasting glucose, and HbA1.Outcomes
Notes
DAllocation concealment
Puchegger 1964Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: Germany. SETTING: outpatient. Treatment N: 43. Control N: 0. Age:notlisted. Sex: 28% men. Inclusion: patients with DM. Exclusions: none listed.
Participants
TREATMENT: metformin, alone or in combination with insulin, dosage adjusted clinically.COMPARISON: none.
Interventions
Plasma glucose.Outcomes
Notes
DAllocation concealment
Rachmani 2002Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 48 months
Methods
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
COUNTRY: IsraelSETTING: outpatientTreatment N: 195Control N: 198Age: 64.5 +/- 4Sex: 60% nebInclusion: type 2 DM with at least one traditional contraindicationExclusions: liver cirrhosis, actue myocardial infarction or pulmonary edema withinprevious 30 days, CO2 narcosis, malginancy
Participants
TREATMENT: metformin, dose adjusted clinicallyCOMPARISON: no metformin
Interventions
Lactic acid levels, lactic acidosis, cardiovascular events, complicationsOutcomes
Notes
DAllocation concealment
Rains 1988Study
TRIAL DESIGN: Single-blind randomised controlled trialDURATION: 3 months
Methods
COUNTRY: United Kingdom/ SETTING: hospital clinic. Treatment N: 35. Control N:70. Age: not listed. Sex: not listed. Inclusion: Type 2 DM. Exclusions: age > 70, BUN> 6 mmol/L, abnormal liver functions.
Participants
TREATMENT: Metformin 1-3g/day. COMPARISON: placeboInterventions
Plasma glucose, lipoproteins, and HbA1.Outcomes
Notes
DAllocation concealment
Rains 1989Study
TRIAL DESIGN: Open-label cross-over randomised controlled trialDURATION: 1.5 months
Methods
Country: United Kingdom. Setting: diabetes clinic. Treatment N: 28. Control N: 14. Age:unclear. Sex: 64% men. Inclusion: Type 2 DM. Exclusions: none listed.
Participants
TREATMENT: Metformin, dosage unclear. COMPARISON: glibenclamideInterventions
Weight, lipds, glucose, and HbA1.Outcomes
Notes
DAllocation concealment
Raptis 1996Study
TRIAL DESIGN: Open-label crossover randomised controlled trialDURATION: 3 months
Methods
Country: Greece. Setting: University center. Treatment N: 30. Control N: 30. Age: 60+/-7.5. Sex: 57% men. Inclusion: Type 2 DM. Exclusions: cardiac, renal, hepatic failure,autoimmune disease.
Participants
TREATMENT: Metformin, dosage adjusted clinically, + glibenclanide. COMPARISON:phenformin + glibenclanide
Interventions
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Characteristics of included studies
Postprandial glucose, HgA1c, lipids, and blood lactate levels.Outcomes
Notes
DAllocation concealment
Reaven 1992Study
TRIAL DESIGN: Nonrandomised open-label trialDURATION: 3 months
Methods
Country: United States. Setting: research center. Treatment N: 13. Control N: 13. Age:57 +/-2. Sex: 77% men. Inclusion: Type 2 DM with poor control on sulfonylureas.Exclusions: Other drugs that effect lipids.
Participants
TREATMENT: Metformin 0.5-2.5g/day. COMPARISON: glipizide.Interventions
Insulin sensitivity, glucose, and HbA1.Outcomes
Notes
DAllocation concealment
Relimpio 1998Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 4 months
Methods
Country: Spain. Setting: outpatient. Treatment N: 31. Control N: 29. Treatment age:65 +/-8. Control age: 66 +/-6.Treatment sex: 21% men. Control sex: 40% men. Inclusion:Poorly controlled insulin-treated Type 2 DM. Exclusions: life-threatening condition,common contraindication to treatment, renal insufficiency.
Participants
TREATMENT: Metformin, dosage adjusted clilnically, + insulin. COMPARISON: insulinincrease.
Interventions
Lipids, HbA1, and fasting glucose.Outcomes
Notes
DAllocation concealment
Reyes 1969Study
TRIAL DESIGN: Prospective cohort studyDURATION: 1 month
Methods
Country: Mexico. Setting: outpatient. Treatment N: 53. Control N: 0. Age: not listed.Sex: 28% men. Inclusion: DM, poorly controlled on sulonylureas. Exclusions: nonelisted
Participants
TREATMENT: metformin, 1600-2400mg/day + chlorpropamide 500-750mg/day.COMPARISON: none
Interventions
Glycemia, and glucosuria.Outcomes
Notes
DAllocation concealment
Riccio 1991Study
TRIAL DESIGN: Prospective comparative trial, with control group for less than 1 month.Metformin data analysedDURATION: 4 weeks
Methods
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Characteristics of included studies
Country: Italy. Setting: medical center. Treatment N: 6. Control N: 0. Treatment age:48+/-2. Sex: not listed. Inclusion: non-insulin-dependent type DM. Exclusion: nonelisted.
Participants
TREATMENT: metformin 850mg BID. COMPARISON: none.Interventions
Basal and insulin-mediated glucose, free-fatty acid metabolism, and lipds.Outcomes
Notes
DAllocation concealment
Robinson 1998Study
TRIAL DESIGN: Double-blind crossover randomised controlled trialDURATION: 3 months
Methods
Country: United Kingdom. Setting: teaching hospital clinic. Treatment N: 35. ControlN: 35. Treatment age: 61.3. Control age: 56.1. Treatment sex: 37% men. Control sex:21% men. Inclusion: Insulin-treated Type 2 DM. Exclusions: childbearing age, anotheranihyperglycemic medication, renal insufficiency with creatinine > 125.
Participants
TREATMENT: Metformin 1-2 g/day. COMPARISON: placeboInterventions
Fasting glucose, HbA1, lipids, weight, and blood pressure.Outcomes
Notes
BAllocation concealment
Roden 2005Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 3 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 917Control N: 916Age: 57 +/- 8.5Sex: 55% menInclusion: type 2 DM naive to metformin pioglitazoneExlcusions: not stated
Participants
TREATMENT: metformin 2.5 g/dayCOMPARISON: pioglitazone 45 mg/day
Interventions
Insulin sensitivity, fasting serum glucose and insulinOutcomes
Notes
DAllocation concealment
Rodger 1995Study
TRIAL DESIGN: randomised controlled trial of acarbose vs placebo. Metformin innon-randomised treatment strataDURATION: 12 months
Methods
COUNTRY: Canada. SETTING: outpatient. Treatment N: 74. Control N: 242. Age:unclear. Sex: not listed. Inclusion: Type 2 DM. Exclusions: lactose intolerance,debilitating disease, gastrointestinal disease, various medications.
Participants
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Characteristics of included studies
TREATMENT: Main: acarbose vs placebo.Treatment strata: metformin (dosage adjustedclinically), diet, sulfonylurea, insulin.
Interventions
Postprandial glucose, HbA1, insulin, and c-peptide.Outcomes
Notes
CAllocation concealment
Roger 1999Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: France. SETTING: community-based multi-center study. Treatment N:127, with 63 on metformin + benflurex and 64 on metformin + placebo. Control N: 0.Age: not listed. Sex: not listed. Inclusion: obese patients with uncontrolled type 2 DM,treated with metformin. Exclusions: young patients, severe inervurrent illnes, kidneyor liver failure, severehypertension, chronic pancreatitis,and alcoholism.
Participants
TREATMENT: metformin 850mg BID + benflurex 150mg TID or metformin + placebo.COMPARISON: none.
Interventions
Basal and stimulated insulin, HgA1, and body weight.Outcomes
Notes
DAllocation concealment
Rosenstock 1998Study
TRIAL DESIGN: Prospective cohort study of metformin in a randomised controlled trialof acarboseDURATION: 6 months
Methods
COUNTRY: United States. SETTING: multicenter outpatient.Treatment N: 148. ControlN: 0. Age: 56.7. Sex: 74% men. Inclusion: metformin-treated patients with type 2 DM.Exclusions: acute or chronic acidosis, persistent ketonuria, or a history of ketoacidosis.
Participants
TREATMENT: metformin 2-2.5g/day + placebo or metformin +acarbosis 75-300mg/day.COMPARISON: none.
Interventions
HbA1c, glucose, insulin, triglycerides, and plasma metformin levels.Outcomes
Notes
DAllocation concealment
Sanchez-Barba 1999Study
TRIAL DESIGN: Prospective cohort studyDURATION: 30 months
Methods
COUNTRY: Spain. SETIING: outpatient. Treatment N: 30. Control N: 0. Age: not listed.Sex: not listed. Inclusion: type 2 DM. Exclusions: none listed
Participants
TREATMENT: metformin, dosage adjusted clinically + insulin, dosage adjusted clinically.COMPARISON: none
Interventions
HgA1c, and plasma glucose.Outcomes
Notes
DAllocation concealment
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Characteristics of included studies
Santos 1995Study
TRIAL DESIGN: Prospective cohort studyDURATION: 2.5 months
Methods
COUNTRY: Brazil. SETTING: metabolic laboratory. Treatment N: 14. Control N: 0.Age: 44+/-2. Sex: 36% men. Inclusions: type 2 DM, on no medications. Exclusions:prior insulin treatment.
Participants
TREATMENT: metformin 850mg BID. COMPARISON: none.Interventions
Fasting glucose, HbA1, fasting insuling, lipids, and insuling receptor tyrosine kinaseactivity.
Outcomes
Notes
DAllocation concealment
Schernthaner 2004Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 12 months
Methods
COUNTRY: 12 European countriesSETTING: outpatientTreatment N: 597Control N; 597Age: 57 +/- 9Sex: 60% menInclusion: poorly controlled type 2 DMExlcusions: standard
Participants
TREATMENT: metformin850 mg TIDCOMPARISON: pioglitazone 45 mg/day
Interventions
HbA1c, fasting glucose and insulin, lipid profilesOutcomes
Notes
DAllocation concealment
Schneider 1990Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 3 months
Methods
COUNTRY: Germany. SETTING: outpatient. Treatment N: 18. Control N: 18. Treatmentage: 60.4, Control age: 61.5.Treatment sex: 44% men. Control sex: 56% men. Inclusion:Patients with Type 2 DM and hyperlipoproteinemia. Exclusions: cardiovascular disease,pulmonary disease, hepatic or gastrointestinal diseaes, malignancy or psychiatricdisorder.
Participants
TREATMEN: Metformin, dosage adjusted clinically. COMPARISON: placeboInterventions
Lipids, and lipoproteins.Outcomes
Notes
BAllocation concealment
Schulte 1973Study
TRIAL DESIGN: Prospective cohort studyDURATION: 36 months
Methods
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Characteristics of included studies
COUNTRY: Mexico. SETTING: outpatient. Treatment N: 53. Control N: 0. Age: 57.Sex: 33% men. Inclusion: adult-onset DM. Exclusions: none listed.
Participants
TREATMENT: metformin + chlorpropamide, dose adjusted clinically. COMPARISON:none.
Interventions
Fasting and postprandial glucose, weight, and glycosuria.Outcomes
Notes
DAllocation concealment
Sieradzki 1999Study
TRIAL DESIGN: Acarbose trial. Metformin in nonrandomised treatment strataDURATION: 2 motnhs
Methods
COUNTRY: Poland. SETTING: outpatient. Treatment N: 106. Control N: 374. Age:31-88. Sex: 44% men. Inclusion: Type 2 DM. Exclusions: none listed.
Participants
TREATMENT: Metformin, dosage adjusted clinically, +/- sulfonylurea + acarbose.COMPARISON: sulfonyurea + acarbose or acarbose
Interventions
Fasting and posprandial glucose, urinary glucose, and lipids.Outcomes
Notes
DAllocation concealment
Stades 2000Study
TRIAL DESIGN: Retrospective cohort studyMethods
Country: Netherlands. Setting: outpatient clinic. Treatment N: 65. Control N: 0. Age:64.5. Sex: not listed. Inclusion: patients with type 2 DM on metformin treatment for atleast 6 months. Exclusions: insufficient follow-up time, or no HgA1c on record.
Participants
Study duration: median 32 months. Treatment: metformin, dosage adjusted clinically.Comparison: none.
Interventions
HbA1c and body weight.Outcomes
Notes
DAllocation concealment
Stalhammar 1991Study
TRIAL DESIGN: Retrospective cohort studyDURATION: 35 months
Methods
COUNTRY: Sweden. SETTING: Swedish population study. Treatment N: 81. ControlN: 0. Age: 50-74 years. Sex: 51% men. Inclusion: Patients with type 2 DM receivingmetformin. Exclusions: none listed
Participants
TREATMENT: metformin, dosage adjusted clinically. COMPARISON: none.Interventions
HbA1c and BMI.Outcomes
Notes
DAllocation concealment
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Characteristics of included studies
Sterne 1963Study
TRIAL DESIGN: Prospective cohort studyDURATION: 60 motnhs
Methods
COUNTRY: Germany. SETTING: outpatient. Age: not listed. Sex: not listed. Inclusions:maturity-onset DM. Exclusions: none listed.
Participants
TREATMENT: metformin, dosage titrated clinically, alone or in combination with insulinor sulfonyrureas. COMPARISON: none
Interventions
Glycemia, side effects.Outcomes
Notes
DAllocation concealment
Stratmann 1965Study
TRIAL DESIGN: Prospective cohort studyDURATION: 8 months
Methods
COUNTRY: Germany. SETTING: outpatient. Treatment N: 92. Control N: 0. Age: notlisted. Sex: not listed. Inclusion: patients with DM, who have failed oral sulfonylureas.Exclusions: none listed.
Participants
TREATMENT: metformin, dosage adjusted clinically. COMPARISON: none.Interventions
Level of glycemic control.mOutcomes
Notes
DAllocation concealment
Strowig 2002Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 4 months
Methods
COUNTRY: United StatesSETTING: outpatientTreatment N: 27Control N: 61Age: 52 +/- 9Sex: 50% menInclusion: type 2 DM inadequately treated on insulinExclusions: renal or hepatic dysfunction
Participants
TREATMENT: metformin 2 g/day + insulinCOMPARISON: insulin with or without troglitazone 600 mg/day
Interventions
HbA1c, body weight, lipid profileOutcomes
Notes
DAllocation concealment
Stumvoll 1995Study
TRIAL DESIGN: Prospective comparative trial, with controlDURATION: 4 monthsgroup studied for less than 1 month. Metformin data analysed
Methods
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Characteristics of included studies
Country: United States. Setting: outpatient. Treatment N: 10. Control N: 0. Age: 58+/-9.Sex: 60% men. Inclusion: healthy obese type 2 DM. Exclusions: none listed, but allwere described as healthy.
Participants
Study duration: 4 months. Treatment intervention: metfomin 800-2550mg/day.Comparison intervention: none.
Interventions
HbA1, fasting glucose, weight, plasma glucose turnover, and lactate conversion toglucose.
Outcomes
Notes
DAllocation concealment
Sundaresan 1997Study
TRIAL DESIGN: Double-blind randomised controlled trialMethods
COUNTRY: Australia. SETTING: outpatient. Treatment N: 14. Control N: 14. Age:40-73. Sex: 64% men. Inclusion: Type 2 DM. Exclusions: BMI > 40 different from idealbody weight, vascular disease, microvscular disease.
Participants
TREATMENT: Metformin 1-2g/day. COMPARISON: glibenclamicdeInterventions
Norepinephrine levels, blood pressure, and forearm vascular resistance.Outcomes
Notes
BAllocation concealment
Swislocki 1999Study
TRIAL DESIGN: Retrospective cohort studyDURATION: 5 motnhs
Methods
COUNTRY: United States. SETTING: Veteran's Administration Health Care system.Treatment N: 251. Comparison: 0. Age: mot listed. Sex: not listed. Inclusion: patientswith type 2 DM receiving metformin. Exclusions: none listed.
Participants
TREATMENT: metformin, doses adjusted clinically. COMPARISON: none.Interventions
HbA1c, weight and blood pressure.Outcomes
Notes
DAllocation concealment
Szanto 1964Study
TRIAL DESIGN: Open-label comparative trialDURATION: 9 months
Methods
COUNTRY: Ireland. SETTING: diabetes clinic. Treatment N: 10. Control N: 9. Age:51-76. Sex: 45% men. Inclusion:Type 2 DM not controlled on sulfonylueas. Exclusions:hypoglycemia.
Participants
TREATMENT: Metformin, dosage unclear. COMPARISON: phenformin (not analyses).Then acetohexamide-biguanide combination was given.
Interventions
Weight, blood glucose, and insulin dose.Outcomes
Notes
DAllocation concealment
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Characteristics of included studies
Taylor 1982Study
TRIAL DESIGN: Nonrandomised open-label trialDURATION: 12 months
Methods
COUNTRY: United Kingdom. SETTING: outpatient. Treatment N: 23. Control N: 71.Age: 51-52 years. Treatment sex: 43% men. Control sex: 77% male. Inclusion: Type2 DM, obese and nonobese. Exclusions: renal or hepatic disease.
Participants
TREATMENT: Metformin (obese) 500mg TID. COMPARISON: glibenclamice (nonobese)2.5-15mg/day.
Interventions
Lipids and apolipoproteinsOutcomes
Notes
DAllocation concealment
Tessari 1994Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 1 month
Methods
COUNTRY: Italy. SETTING: outpatient. Treatment N: 11. Control N: 6. Treatment age:53 +/-3. Control age: 60 +/-3> Treatment sex: 55% men. Control sex: 33% men.Inclusion: Diet-treated Type 2 DM. ExclusionsL cardiovascular, gastrointestinalpulmonary or renal disease.
Participants
TREATMENT: Metformin, dosage adjusted clinically. COMPARISON: placeboInterventions
Postprandial phenylalanine kinetics, weight, free fatty acids, BMI, and HbA1.Outcomes
Notes
BAllocation concealment
Tessier 1999Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 6 months
Methods
COUNTRY: Canada. SETTING: outpatient. Treatment N: 18 Control N: 18. Treatmentage: 59.1 +/- 7.1. Control age: 59.3 +/-7.3. Treatment sex: 16% men. Control sex: 44%men. Inclusion: Type 2 DM. Exclusions: acute cardiovascular or neurological events,malignancy, various medications.
Participants
TREATMENT: Metformin 0.75-2.5g/day. COMPARISON: gliclazideInterventions
HbA1, fructosamine, glucose tolerance test.Outcomes
Notes
DAllocation concealment
Testa 1996Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: Italy. SETTING: outpatient clinic and metabolic laboratory. Treatment N:80. Control N: 0. Age: 63+/-9.7. Sex: 63% men. Inclusion: type 2 DM with good glycemiccontrol on sulfonylureas for at least 2 years.. Exclusions: previous insulin treatment
Participants
TREATMENT: 1.2-1.7g/day. COMPARISON: none.Interventions
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Characteristics of included studies
Plasminogen activator inhibitor, lipoprotein(a), and BMI.Outcomes
Notes
DAllocation concealment
Teupe 1991Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 24 months
Methods
COUNTRY: Germany. SETTING: outpatient. Treatment N: 50. Control N: 50. Treatmentage: 51.5 +/-10. Control age: 56 +/-8. Treatment sex: 40% males. . Control sex: 40%males. Inclusion: Type 2 DM, poor control. Exclusions: age > 70, creatinine > 1.2, ivercirhosis, ischemia or wasting disease, sever acute disease.
Participants
TREATMENT: Metformin, dosage adjusted clinically, + diet. COMPARISON: dietInterventions
Weight, lipids, HbA1, c-peptide, and lactate levels.Outcomes
Notes
DAllocation concealment
Tikkainen 2004Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 4 months
Methods
COUNTRY: FinlandSETTING: outpatientTreatment N: 11Control N: 9Age: 30.6 +/- 3.5Sex: 35% menInclusion: type 2 DM treated with dietExclusions: cardiovascular or renal disease
Participants
TREATMENT: metformin 1 g BID + placeboCOMARISON: rosiglitazone 4 mg BID + placebo
Interventions
HbA1c, insulin, free fatty acid, body weight, adiponectinOutcomes
Notes
DAllocation concealment
Tosi 2003Study
TRIAL DESIGN: Double-blind randomised controlled cross-over trialDURATION: 6 months for each treatment armDURATION:
Methods
COUNTRY: ItalySETTING: outpatientTreatment N: 88Control N: 88Age: 57.3 +/- 7Sex: 70% menInclusion: type 2 DMExclusions: severe cardiovascular, renal or hepatic disease, insulin treatment,
Participants
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Characteristics of included studies
TREATMENT: metformin 3 g/day with or without glibenclamideCOMPARISON: glibenclamide 15 mg/day
Interventions
HbA1c, fasting glucoseOutcomes
Notes
DAllocation concealment
Trischitta 1992Study
TRIAL DESIGN: randomised controlled trial cross-overDURATIPN: 2 months for each arm
Methods
COUNTRY: Italy. SETTING: outpatient. Treatment N: 20. Control N: 20. Age: 53.6+/-2.1. Sex: not listed. Inclusion: Type 2 DM with sulfonylurea. Exclusions: renal, liver,cardiovascular or systemic disese.
Participants
TREATMENT: Metformin 500mg TID. COMPARISON: insulinInterventions
Fasting and postprandial glucose, c-peptide, HbA1, weight, and lipids.Outcomes
Notes
BAllocation concealment
Trischitta 1998Study
TRIAL DESIGN: randomised controlled trial cross-overDURATION: 2 months
Methods
COUNTRY: Italy. SETTING: outpatient. Treatment N: 50. Control N: 50. Age: 55.7+/-1.2. Sex: 24% men. Inclusion: Type 2 DM. Exclusions: none listed.
Participants
TREATMENT: Metformin 850mg TID + glibenclamide. COMPARISON: insulin +glibenclamide
Interventions
Fasting glucose, HbA1, c-peptide, and weight.Outcomes
Notes
BAllocation concealment
UKPDS-34 1998Study
TRIAL DESIGN: Open-label randomised controlled trial.Methods
Country: United Kingdom Setting: large multicenter.Treatment N: 683. Control N: 1631.Treatment age: 53 +/-8. Control age: 53 +/-8. Treatment sex: 46% men. Control sex:46% men. Inclusion: Type 2 DM. Exclusions: severe vascular disease, acceleratedhypertension, renalfailure with creatinine > 175 mmol/L, life thretening disease, severeasthma, myocardial infarction in past year, current angina, congestive heart failure.n = 1704
Participants
Trial duration: 6.6 - 10.7 years. Treatment: Metformin 850mg QD-TID. Comparison:diet, sulfonylurea, or insulin
Interventions
DM-related endpoint (sudden death, death for hyper- or hypoglycemia, myocardialinfarction, stroke, renal failure, amputation, eye problems), diabetes-related death,all-cause mortality, HgA1, microalbuminuria.
Outcomes
Notes
DAllocation concealment
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Characteristics of included studies
Vannasaeng 1995Study
TRIAL DESIGN: Open-label trial of acarbose. Metformin in nonrandomised treatmentstrataDURATION: 6 months
Methods
COUNTRY: Thailand. SETTING: Outpatient. Treatment N: 24. Control N: 12. Age: 50.4+/-1.5, Sex: 19% men. Inclusion: Type 2 DM. Exclusions: pregnancy, liver disorder,renal insufficiency with Creatinine > 2 mg/dl.
Participants
TREATMENT: Metformin, dosage adjusted clinically, + sulfonylurea + acarbose.COMPARISON: sulfonylurea + acarbose
Interventions
Fasting glucose, HbA1, lipids, insulin and c-peptide.Outcomes
Notes
DAllocation concealment
Velussi 1992Study
TRIAL DESIGN: Open-label cross-over nonrandomised comparative trialDURATION: 4 months
Methods
COUNTRY: Italy. SETTING: general practive. Treatment N: 60. Control N: 60. Age: 68+/- 3 Sex: 53% men. Inclusion: Type 2 DM with hypertension. Exclusions: none listed.
Participants
TREATMENT: Metformin, dosage adjusted clinically, + glibenclamide, doses on clinicalgrounds. COMPARISON: Phenformin + glibenclamide (not analysed).
Interventions
Fasting glucose, HbA1c, basal C-peptide, glucosuria, and lactate levels.Outcomes
Notes
DAllocation concealment
Vigneri 1991Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 2 months
Methods
COUNTRY: Italy. SETTING: outpatient. Treatment N: 12. Control N: 12. Age: 52.3+/-2.1 Sex: not listed. Inclusion: Type 2 DM with failure to sulfonylureas. Exclusions:none listed.
Participants
TREATMENT: Metformin, dosage adjusted clinically, + glyburide. COMPARISON:insulin + glyburide
Interventions
Fasting and postprandial glucose, and HbA1.Outcomes
Notes
DAllocation concealment
Willey 1992Study
TRIAL DESIGN: Prospective cohort studyMethods
Country: Australia. Setting: outpatient. Treatment N: 38. Control N: 0. Age: 54+/-1.7.Sex: 44% men. Inclusion: overweight patients with type 2 DM, and HbA1c >normal.Exclusions: none listed.
Participants
Trial duration: 3 months.Treatment intervention: metformin, 1-3g/day, + dexfenfluramineor metformin + placebo. Comparison: none.
Interventions
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Characteristics of included studies
Body weight, HbA1c, blood pressure, and fructosamine.Outcomes
Notes
DAllocation concealment
Willey 1994Study
TRIAL DESIGN: Prospective cohort studyDURATION: 3 months
Methods
COUNTRY: Australia. SETTING: diabetes center. Metformin treatment N: 20 (10 ondexfenfluramine, 10 on placebo). Age: 55+/-1.9. Sex: 30% men. Inclusion: Type 2 DM,overweight with poor control, on maximum dose metformin. Exclusions: none listed.
Participants
TREATMENT: Metformin, 1-3g/day, + dexfluramine or metformin + placebo.COMPARISON: none.
Interventions
Weight, BMI, and HbA1c.Outcomes
Notes
DAllocation concealment
Willms 1999Study
TRIAL DESIGN: randomised controlled trial. Single-blind for metformin versus other.DURATION: 3 months
Methods
COUNTRY: Germany. SETTING: outpatient. Treatment N: 29. Control N: 60. Treatmentate: 53.4. Control age: 59.2. Treatment sex: 48% males. Control sex: 48% males.Inclusion: Type 2 DM. Exclusions: Severe hepatic or renal abnormalities, respiratoryinsufficiency, conditions that predispose to tissue anoxia.
Participants
TREATMENT: MetfORmin 850mg BID. COMPARISON: acarbose or placeboInterventions
Body weight, and HbA1.Outcomes
Notes
CAllocation concealment
Wilson 1989Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 2 months
Methods
COUNTRY: United Kingdom. SETTING: outpatient. Treatment N: 15. Control N: 45.Age: 65 +/-2. Sex: 80% men. Inclusion: Type 2 DM on sulfonylureas. Exclusion: Nonelisted.
Participants
TREATMENT: Metformin 500mg TID. COMPARISON: guar 5gmTID.Interventions
Glucose, HbA1, and lipidsOutcomes
Notes
DAllocation concealment
Wolever 1995Study
TRIAL DESIGN: Double-blind randomised controlled trial of acarbose versus placebo.Metformin in 1 of 4 non-randomized treatment strata.DURATION: 11 years
Methods
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Characteristics of included studies
COUNTRY: Canada. SETTING: outpatient. Treatment N: 83. Control N: 271. Treatmentage: 55.8. Control age 57.6. Treatment sex: 44% men. Control sex: 57% males.Inclusion: Type 2 DM. Exclusions: renal or liver abnormalities.
Participants
TREATMENT: acarbos vs placebo. Treatment strata: Metformin (dosage adjustedclinically), diet, sulfonylurea, insulin
Interventions
Lipids, HbA1, and serum acetate levelsOutcomes
Notes
CAllocation concealment
Wolever 2000Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 9 months
Methods
COUNTRY: Canada. SETTING: outpatient. Treatment N: 109. Control N: 90. Treatmentage: 58.7 +/-1.1. Control age: 59.5 +/-1.1. Treatment sex: 80% men. Control sex: 69%men. Inclusion: Type 2 DM. Exclusions: insulin treatment, major debilitating disease,recent cardiovascular event or surgery, various medication, renal or liver idsease,emotional disorder.
Participants
TREATMENT: Metformin 500 mgTID or metformin + miglitol. COMPARISON: miglitolor placebo
Interventions
Serum folate and B12 levels, and HbA1.Outcomes
Notes
BAllocation concealment
Wu 1990Study
TRIAL DESIGN: Prospective cohort studyDURATION: 4 months
Methods
COUNTRY: United States. SETTING: inpatient and outpatient.Treatment N: 12. ControlN: 0. Age: 56+/-3. Sex: 58% men. Inclusion: type 2 DM. Exclusion: significant illness,or medication that could affect carbohydrate metabolism.
Participants
TREATMENT: metformin 2.5g/day. COMPARISON: none.Interventions
Fasting and postprandial glucose, HbA1c, insulin binding, lactate and lipids.Outcomes
Notes
DAllocation concealment
Wulffele 2000Study
TRIAL DESIGN: Abstract of randomised controlled trial, placebo-controlledDURATION: 4 months
Methods
COUNTRY: NetherlandsSETTING: outpatientTreatment N: 95Control N: 95AGE: not listedSEX: not listedINCLUSION: Type 2 DM treated with insulinEXCLUSIONS: none listed
Participants
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Characteristics of included studies
TREATMENT: Metformin, dosage unclear, + insulinCOMPARISON: placebo + insulin
Interventions
Daily dose insulin, and HbA1.Outcomes
Notes
BAllocation concealment
Wulffele 2002Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 48 months
Methods
COUNTRY: The NetherlandsSETTING: outpatientTreatment N: 171Control N: 182Age: 60 +/- 10Sex: 45% m4nInclusion: type 2 DM controlled with insulinExlcusions: renal insufficiency with GFR < 50, congestive heart failure
Participants
TREATMENT: metformin, dose adjusted clinically, + insulinCOMPARISON: placebo + insulin
Interventions
Insulin requirements, lipid profile, glycemic controlOutcomes
Notes
DAllocation concealment
Wulffele 2003Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 4 months
Methods
COUNTRY: The NetherlandsSETTING: outpatientTreatment N: 196Control N; 194Inclusion: type 2 DMExlcusions: renal insufficiency with GFR < 50, congestive heart failure, pregnancy
Participants
TREATMENT: metformin, dose adjusted clinicallyCOMPARISON: placebo
Interventions
Homocystein, folate, vitamin B12, body weight, glycemic controlOutcomes
Notes
DAllocation concealment
Wulffele 2005Study
TRIAL DESIGN: Double-blind randomised controlled trialDURATION: 4 months
Methods
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Characteristics of included studies
COUNTRY: THe NetherlandsSETTING: outpatientTreatment N: 89Control N: 93Age: 58 +/- 11Sex: 48% menInclusion: type 2 DMExclusions: congestive heart failure, serious illness, renal insufficiency with GFR < 50
Participants
TREATMENT: metformin 2.5 g/dayCOMPARISON: placebo
Interventions
Systolic, diastolic, mean blood pressure, 24-hour blood pressureOutcomes
Notes
DAllocation concealment
Yamanouchi 2005Study
TRIAL DESIGN: Open-label randomised controlled trialDURATION: 12 months
Methods
COUNTRY: JapanSETTING: outpatientTreatment N: 39Control N: 75Age: 55.4 +/- 9Sex: 55% menInclusion: newly diagnosed type 2 DMExclusions: standard
Participants
TREATMENT: metformin750 mg/dayCOMPARISON: pioglitazone 30-45 mg/day or glimepiride 1-2 mg/day
Interventions
Fasting glucose, free fatty acid, HbA1c, blood pressure, lipid profileOutcomes
Notes
DAllocation concealment
Yki-Jarvinen 1999Study
TRIAL DESIGN: randomised controlled trialDURATION: 1 year
Methods
COUNTRY: FinlandSETTING: multicenterTreatment N: 48Control N: 48AGE: 58+/-1SEX: not listedINCLUSION: Poorly controlled type 2 DMEXCLUSIONS: congestive heart failure, liver diseae, creatinine > 120
Participants
TREATMENT: Metformin, dosage adjusted clinically, + placebo or metformin + glyburideCOMPARISON: insulin + glyburide + placebo or BID insulin
Interventions
Weight, HbA1, plasma glucose, insulin, lipids.Outcomes
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of included studies
Notes
AAllocation concealment
Yu 1999Study
TRIAL DESIGN: randomised controlled trialDURATION: 4 weeks
Methods
COUNTRY: United StatesSETTING: research laboratoryTreatment N: 10Control N: 10Treatment AGE: 49+/-9Control AGE: 51+/-9Treatment SEX: 70% menControl SEX: 80% menINCLUSION: Type 2 DM with suboptimal contolEXCLUSIONS: renal or liver abnormalities
Participants
TREATMENT: Metformin 1-2.5 g/dayCOMPARISON: troglitazone
Interventions
Fasting glucose, insulin sensitivity.Outcomes
Notes
BAllocation concealment
Notas:BID= two times a day; BMI=body mass index; DM=diabetes mellitus; TID=three times a day
Characteristics of excluded studies
Reason for exclusionStudy
TRIAL DESIGN: Retrospective analysis studyAguilar 1992b
TRIAL DESIGN: Prospective cohort, with varying durations of treatmentBernard 1965
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthBonfigli 1999
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthBruneder 1978
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthCacciapuoti 1991
TRIAL DESIGN: Prospective cohort trial, that did not give length of treatmentChow 1995
TRIAL DESIGN: Prospective cohort trial, that did not give lenght of treatmentClauson 1996
TRIAL DESIGN: Retrospective analysis studyConnolly 1996
TRIAL DESIGN: Retrospective meta-analysisDaniel 1997
TRIAL DESIGN: Prospective cohort study, of varying durationsDebry 1964
TRIAL DESIGN: Retrospective cohort study, with no durations givenDebry 1966a
TRIAL DESIGN: Retrospective cohort study, with no durations givenDebry 1966b
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthFery 1997
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthGaluska 1994
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of excluded studies
TRIAL DESIGN: Prospective comparative trial, as part of another UKPDS trial, with patientsstudied less than 1 month
Gibson 1995
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthGin 1982
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthGin 1985
TRIAL DESIGN: Prospective cohort study, lasting less than 1 monthGin 1989
TRIAL DESIGN: Prospective cohort study, lasting less than 1 monthGiugliano 1979
TRIAL DESIGN: Retrospective meta-analysisGuthrie 1997
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthIrsigler 1978
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthIsmail 1978
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthIsnard 1991
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthIsnard 1996
TRIAL DESIGN: Prospective cohort study, lasting less than 1 monthJansson 1996
TRIAL DESIGN: Retrospective meta-analysisJohansen 1999
TRIAL DESIGN: Retrospective analysisLalau 1994
TRIAL DESIGN: Retrospective analysisLalau 1995
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthLeslie 1987
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthLim 1970
TRIAL DESIGN: Prospective cohort study of varying durationsMessens 1965
TRIAL DESIGN: Prospective cohort study of varying durationsMessens 1966
TRIAL DESIGN: Prospective cohort study, of varying durationsMuntoni 1965
TRIAL DESIGN: Prospective cohort study, of unclear durationNauck 1993
TRIAL DESIGN: Retrospective review of 4 trialsNauck 1997
TRIAL DESIGN: Retrospective meta-analysisO'Connor 1998
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthOrlikowska 1966
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthPanahloo 1995
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthPerriello 1994
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthPilger 1978
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthPrager 1983
TRIAL DESIGN: Prospective cohort study of varying durations.Rambert 1961
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthRigas 1968
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthRizkalla 1986
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthSambol 1996
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthScarpello 1998
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthSchaffalitzky 1979
TRIAL DESIGN: Retrospective analysisSelby 1999
TRIAL DESIGN: Prospective cohort study, lasting less than 1 monthSignore 1996
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Characteristics of excluded studies
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthSlama 1984
TRIAL DESIGN: Prospective cohort study, of unclear durationStefanovic 1999
TRIAL DESIGN: Prospective cohort study, of varying durationSugawara 1962
TRIAL DESIGN: Prospective cohort study, lasting less than 1 monthSum 1992
TRIAL DESIGN: Prospective cohort study, of unclear durationTeitelbaum 1963
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthTrischitta 1983
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthTurner 1995
TRIAL DESIGN: Prospective comparative trial, lasting less than 1 monthZapecka-Dubno 1999
CARÁTULA
Riesgo de acidosis láctica fatal y no fatal con el uso de metformina parala diabetes mellitus tipo 2
Titulo
Salpeter S, Greyber E, Pasternak G, Salpeter EAutor(es)
SHELLEY SALPETER : Desarrollo del protocolo, selección de ensayos,evaluación de la calidad de los ensayos, extracción de datos, análisis de datos,preparación del texto, manejo de las referencias.
Contribución de los autores
ELIZABETH GREYBER: Estrategia de búsqueda, evaluación de la calidad delos ensayos, extracción de los datos, preparación del manuscrito.
GARY PASTERNAK: Selección de los ensayos.
EDWIN SALPETER: Análisis de los datos, evaluación estadística.
2001/1Número de protocolo publicadoinicialmente
2002/2Número de revisión publicadainicialmente
16 noviembre 2005Fecha de la modificación másreciente"
16 noviembre 2005"Fecha de la modificaciónSIGNIFICATIVA más reciente
El autor no facilitó la informaciónCambios más recientes
El autor no facilitó la informaciónFecha de búsqueda de nuevosestudios no localizados
El autor no facilitó la informaciónFecha de localización de nuevosestudios aún noincluidos/excluidos
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
01 agosto 2005Fecha de localización de nuevosestudios incluidos/excluidos
El autor no facilitó la informaciónFecha de modificación de lasección conclusiones de losautores
Prof Edwin SalpeterCenter for Radiophysics and Space ResearchCornell University612 Space Sciences BuildingIthaca14853NYUSATélefono: +1 607 2554937E-mail: [email protected]: +1 607 2553433
Dirección de contacto
CD002967Número de la Cochrane Library
Cochrane Metabolic and Endocrine Disorders GroupGrupo editorial
HM-ENDOCCódigo del grupo editorial
RESUMEN DEL METANÁLISIS
01 Fatal/nonfatal lactic acidosis
Tamaño del efectoMétodo estadísticoNº departicipantes
Nº deestudios
Resultado
0.00 [0.00, 0.00]Diferencia de riesgo(efectos fijos) IC del 95%
6296014801 Incidencia de acidosis lácticapor paciente por año (metforminamenos sin metformina)
02 Niveles del lactato sanguíneo
Tamaño del efectoMétodo estadísticoNº departicipantes
Nº deestudios
Resultado
0.12 [-0.01, 0.25]Diferencia de mediasponderada (efectos fijos) ICdel 95%
222701 Efecto neto del tratamiento,niveles de lactato (mmol/L)
-0.09 [-0.13, -0.05]Diferencia de mediasponderada (efectos fijos) ICdel 95%
15471902 Niveles medios de lactato conel tratamiento (mmol/L)
0.08 [-0.05, 0.20]Diferencia de mediasponderada (efectos fijos) ICdel 95%
92403 Niveles pico de lactatoestimulado (mmol/L)
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
GRÁFICOS Y OTRAS TABLAS
Fig. 01 Fatal/nonfatal lactic acidosis
01.01 Incidencia de acidosis láctica por paciente por año (metformina menos sin metformina)
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
Fig. 02 Niveles del lactato sanguíneo
02.01 Efecto neto del tratamiento, niveles de lactato (mmol/L)
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02.02 Niveles medios de lactato con el tratamiento (mmol/L)
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2
02.03 Niveles pico de lactato estimulado (mmol/L)
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Riesgo de acidosis láctica fatal y no fatal con el uso de metformina para la diabetes mellitus tipo 2