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hab&#237;an alcanzado los niveles objetivo de hemoglobina A1c &#40;HbA1c&#41; recomendados por la <span class="elsevierStyleItalic">American Diabetes Association</span><a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">3</span></a>&#46; El empleo intensivo de la insulina predispone a los individuos a padecer hipoglucemia&#44; grandes variaciones en los niveles de glucosa y aumento de peso&#44; lo que puede aumentar las posibles complicaciones cardiovasculares<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">4-6</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">La metformina&#44; un f&#225;rmaco cl&#225;sico&#44; se ha empleado normalmente durante m&#225;s de medio siglo como un agente biguanida en el tratamiento de la diabetes mellitus tipo<span class="elsevierStyleHsp" style=""></span>2 &#40;DM2&#41;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46; La metformina act&#250;a principalmente inhibiendo la producci&#243;n de glucosa hep&#225;tica&#44; mejorando la absorci&#243;n muscular de glucosa y reduciendo la absorci&#243;n intestinal de glucosa&#46; Los datos disponibles han puesto de manifiesto que esta terapia de metformina adyuvante se asocia a p&#233;rdida de peso&#44; mejora del perfil lip&#237;dico y disminuci&#243;n de la dosis de insulina en los pacientes con DM1<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">8&#44;9</span></a>&#46; Los inhibidores del cotransportador-2 de sodio-glucosa &#40;SGLT2&#41;&#44; una nueva y prometedora modalidad terap&#233;utica para la DM2&#44; act&#250;an principalmente inhibiendo la reabsorci&#243;n de glucosa en el t&#250;bulo renal proximal y&#44; como consecuencia&#44; disminuyen los valores de glucosa en sangre mediante la excreci&#243;n de glucosa en orina<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">10</span></a>&#46; Los inhibidores del SGLT2&#44; seg&#250;n los datos disponibles&#44; han proporcionado numerosos beneficios&#44; incluyendo menores niveles de HbA1c&#44; p&#233;rdida de peso y reducci&#243;n de las necesidades de insulina de los pacientes con DM1<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">11-13</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Sin embargo&#44; hasta la fecha&#44; &#250;nicamente un ensayo directo <span class="elsevierStyleItalic">&#40;head-to-head&#41;</span> ha comparado a los inhibidores del SGLT2 y la metformina en t&#233;rminos de eficacia en la DM1&#46; Sin embargo&#44; cuando las comparaciones son escasas&#44; el metaan&#225;lisis en red permite la s&#237;ntesis y la comparaci&#243;n de tratamientos a trav&#233;s de la evidencia disponible para estimar comparaciones directas e indirectas de inter&#233;s<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">14&#44;15</span></a>&#46; Nuestro objetivo fue&#44; mediante el uso del metaan&#225;lisis en red&#44; comparar la eficacia y la seguridad de la metformina y los inhibidores de SGLT2 como complemento de la terapia de insulina est&#225;ndar en adultos con DM1&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material y m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Estrategia de investigaci&#243;n</span><p id="par0020" class="elsevierStylePara elsevierViewall">Mediante b&#250;squedas inform&#225;ticas exhaustivas en PubMed&#44; EMBASE&#44; Biblioteca Cochrane y Web of Knowledge se identificaron todos los ensayos cl&#237;nicos aleatorizados &#40;ECA&#41; que investigaban la seguridad y la eficacia de la metformina o de los inhibidores del SGLT2 en adultos con DM1 y que se hab&#237;an publicado hasta febrero de 2019&#44; sin restricciones de idioma&#46; La b&#250;squeda se llev&#243; a cabo empleando diferentes combinaciones de palabras clave&#44; como &#171;&#40;canagliflozina O dapagliflozina O sotagliflozina O LX4211 O empagliflozina O metformina&#41;&#187; y &#171;&#40;diabetes mellitus&#44; tipo 1&#41; O &#40;tipo 1 diabetes&#41; O &#40;diabetes insulino dependiente&#41;&#187;&#46; La b&#250;squeda exacta est&#225; disponible a trav&#233;s de petici&#243;n a los autores&#46; Tambi&#233;n se identificaron estudios adicionales mediante b&#250;squeda manual en todas las bibliograf&#237;as de los art&#237;culos recuperados&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Elecci&#243;n de estudio</span><p id="par0025" class="elsevierStylePara elsevierViewall">Los ECA que cumpl&#237;an los siguientes criterios de inclusi&#243;n fueron incorporaron en este metan&#225;lisis&#58; 1&#41;<span class="elsevierStyleHsp" style=""></span>los ECA fueron ensayos controlados aleatorizados en humanos&#59; 2&#41;<span class="elsevierStyleHsp" style=""></span>los pacientes con DM1 eran mayores de 18<span class="elsevierStyleHsp" style=""></span>a&#241;os&#59; 3&#41;<span class="elsevierStyleHsp" style=""></span>los cambios en HbA1c&#44; peso&#44; dosificaci&#243;n de la insulina&#44; casos de hipoglucemia grave o de cetoacidosis diab&#233;tica &#40;CAD&#41; fueron registrados en los grupos de intervenci&#243;n y control&#46; No se tuvieron en cuenta ni los res&#250;menes ni los informes no publicados&#46; Se excluyeron los informes de casos&#44; los editoriales&#44; los art&#237;culos de revisi&#243;n y las cartas al editor&#46; Se excluyeron los art&#237;culos que no ten&#237;an poblaci&#243;n control&#46; Tambi&#233;n se descartaron los art&#237;culos de aquellos estudios en los que se empleaban farmacoterapias adyuvantes adem&#225;s de la metformina o de los inhibidores del SGLT2&#46; Este estudio ha sido llevado a cabo siguiendo la gu&#237;a PRISMA &#40;ver <a class="elsevierStyleCrossRef" href="#sec0085">Anexo&#44; material adicional</a>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Extracci&#243;n de datos</span><p id="par0030" class="elsevierStylePara elsevierViewall">Dos investigadores &#40;Zhang QQ y Wu YC&#41; llevaron a cabo&#44; de manera independiente&#44; una revisi&#243;n preliminar de los estudios&#46; La fase siguiente consisti&#243; en la revisi&#243;n&#44; desde el punto de vista de los criterios de elecci&#243;n&#44; de los res&#250;menes&#44; y en el examen del texto completo&#46; La selecci&#243;n final de los art&#237;culos se realiz&#243; por consenso de los dos revisores&#46; De cada estudio se extrajeron las siguientes caracter&#237;sticas&#58; el primer autor&#44; el a&#241;o de publicaci&#243;n&#44; el dise&#241;o del estudio&#44; la duraci&#243;n del estudio&#44; la dosis diaria de inhibidor del SGLT2 o de la metformina&#44; la hipoglucemia grave&#44; la CAD&#44; las medidas basales y los cambios de los niveles basales de HbAc1&#44; dosis de insulina total o peso corporal tanto en el grupo de intervenci&#243;n como en el control&#46; Mientras tanto&#44; para la inclusi&#243;n en nuestro metaan&#225;lisis no definimos una cantidad m&#237;nima ni de intervenciones ni de controles&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Evaluaci&#243;n de la calidad del estudio y el riesgo de sesgo</span><p id="par0035" class="elsevierStylePara elsevierViewall">Para evaluar el riesgo de sesgo de todos los estudios incluidos se emple&#243; la Herramienta de Colaboraci&#243;n Cochrane para evaluaci&#243;n de riesgo de sesgo en ensayos aleatorizados<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">16</span></a>&#46; La tabla S1 &#40;ver <a class="elsevierStyleCrossRef" href="#sec0085">Anexo&#44; material adicional</a>&#41; muestra el riego de sesgo de todos los art&#237;culos incluidos&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">An&#225;lisis estad&#237;stico</span><p id="par0040" class="elsevierStylePara elsevierViewall">Inicialmente el metaan&#225;lisis por pares de efecto aleatorio se realiz&#243; dentro de cada comparaci&#243;n de tratamiento directo antes del metaan&#225;lisis de red&#44; para lo que se utiliz&#243; el STATA 11&#46;0 &#40;Stata&#44; College Station&#44; TX&#41;&#46; Para evaluar la heterogeneidad se usaron los valores I<span class="elsevierStyleSup">2</span>&#46; Se realiz&#243; un metaan&#225;lisis de red utilizando el marco bayesiano por simulaci&#243;n de Markov Chain Monte Carlo para evaluar la seguridad y la eficacia de la metformina y de los inhibidores del SGLT2 en adultos con DM1&#46; Para calcular el metaan&#225;lisis de red se us&#243; el Aggregate Data Drug Information System &#40;versi&#243;n 1&#46;17&#46;6&#41;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">17</span></a>&#46; La convergencia se logr&#243; utilizando los gr&#225;ficos de Brooks-Gelman-Rubin y los factores de reducci&#243;n de escala potencial &#40;PSRF&#41; &#40;1<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>1&#44;5&#41;&#46; La <span class="elsevierStyleItalic">run-length</span> se aumentaba en consonancia para mejorar el modelo de convergencia si el PSRF era superior a 1&#44;05&#46; Los valores dicot&#243;micos &#40;hipoglucemia grave o CAD&#41; se analizaron empleando la odds ratio &#40;OR&#41; con un intervalo de confianza &#40;IC&#41; del 95&#37;&#46; Las variables continuas &#40;HbA1c&#44; peso corporal y dosis total de insulina&#41; se analizaron utilizando la diferencia de media ponderada &#40;DMP&#41; con un IC del 95&#37;&#46; Se construyeron gr&#225;ficos de red para cada variable de resultado&#46; La t&#233;cnica de divisi&#243;n de nodos se us&#243; para comprobar la inconsistencia de la red de metaan&#225;lisis cuando esta presentaba bucles cerrados &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 revela inconsistencias significativas en la red&#41;&#46; Se realizaron an&#225;lisis de subgrupos para evaluar las diferencias en la seguridad y la eficacia de los inhibidores de SGLT2 en adultos con DM1&#46; Se calcul&#243; el rango de probabilidad para cada uno de los tratamientos con el fin mostrar los mejores resultados&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Resultados</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Caracter&#237;sticas de los estudios incluidos</span><p id="par0045" class="elsevierStylePara elsevierViewall">Se identificaron un total de 1&#46;280 registros&#44; de los cuales 1&#46;316 fueron excluidos por estar duplicados&#46; Adem&#225;s&#44; tras la revisi&#243;n de los t&#237;tulos y res&#250;menes se eliminaron 874 art&#237;culos&#46; Otros 46 art&#237;culos fueron descartados al no cumplir con los criterios de inclusi&#243;n&#46; En la <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> se muestra de forma detallada el diagrama de flujo seguido en el proceso de selecci&#243;n en el metaan&#225;lisis&#46; Finalmente se escogieron un total de 20 estudios con 5&#46;868 participantes&#44; que inclu&#237;an un art&#237;culo sobre canagliflozina<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a>&#44; 5 de dapagliflozina &#40;2 art&#237;culos en un ECA&#41;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">18-21</span></a>&#44; 3 de empagliflozina<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">22-24</span></a>&#44; 4 de sotagliflozina<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">25-28</span></a>&#44; 6 de metformina<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">25-31</span></a> y uno que directamente comparaba la metformina con la empagliflozina<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">32</span></a>&#46; De los estudios incluidos&#44; 19 eran ensayos aleatorizados de grupos paralelos y uno un ensayo cl&#237;nico controlado aleatorizado cruzado&#46; En la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> se muestran las caracter&#237;sticas de los ensayos incluidos&#46; Se equilibraron todos los par&#225;metros entre grupos&#46; Las definiciones de hipoglucemia grave fueron parecidas en todos los estudios y se basaron en los criterios de la <span class="elsevierStyleItalic">American Diabetes Association</span>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Resultado primario</span><p id="par0050" class="elsevierStylePara elsevierViewall">El metaan&#225;lisis por pares de 12 ensayos mostr&#243; que los inhibidores del SGLT2 daban lugar&#44; al compararlas con placebo&#44; a reducciones de la HbA1c &#40;0&#44;402&#37;&#41; significativamente mayores y con un grado de heterogeneidad elevado &#40;I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>70&#44;6&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#44; <a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46; El metaan&#225;lisis por pares de 6 ensayos revel&#243; que las diferencias en los niveles de la HbA1c entre la metformina y los grupos placebo no eran significativas&#44; con una homogeneidad elevada &#40;I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#44;1&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;306&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">La <a class="elsevierStyleCrossRef" href="#fig0015">figura 3</a> muestra la gr&#225;fica de la red para el an&#225;lisis de la eficacia y la seguridad de la metformina y de los inhibidores del SGLT2&#46; Los resultados del metaan&#225;lisis en red indicaron que los inhibidores del SGLT2 estaban asociados a mayores reducciones en la HbA1c cuando se los comparaba con la metformina &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;32&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;0&#44;47 a &#8722;0&#44;14&#41; y el placebo &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;40&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;0&#44;47 a &#8722;0&#44;32&#41;&#46; Sin embargo&#44; no se encontraron diferencias significativas entre la metformina y el placebo &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;08&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;0&#44;24 a 0&#44;06&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46; El resultado de la prueba de consistencia mostr&#243; que no hay indicios de inconsistencias entre evidencia directa e indirecta para la HbA1c &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;51&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Resultados secundarios</span><p id="par0060" class="elsevierStylePara elsevierViewall">En la <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a> tambi&#233;n se exponen los resultados del metaan&#225;lisis por pares para resultados secundarios&#46; Los resultados del metaan&#225;lisis de red revelaron que tanto la metformina &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;3&#44;88&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;7&#44;46 a &#8722;0&#44;59&#41; como los inhibidores del SGLT2 &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;6&#44;94&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;9&#44;55 a &#8722;4&#44;32&#41; proporcionaban reducciones significativamente mayores en la dosis de la insulina total que el placebo&#44; siendo mayores las disminuciones para la metformina &#40;92&#37; de probabilidad de ser el tratamiento m&#225;s eficaz&#41;&#44; si bien no se observaron diferencias entre la metformina y los inhibidores del SGLT2 &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#44;09&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;1&#44;53 a 7&#44;09&#41;&#46; Los resultados del metaan&#225;lisis de red indicaron que los inhibidores del SGLT2 se asociaban a mayores disminuciones del peso corporal cuando se comparaban con la metformina &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;1&#44;54&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;2&#44;93 a &#8722;0&#44;09&#41; y el placebo &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;3&#44;56&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;4&#44;17 a &#8722;2&#44;92&#41;&#46; En cuanto a la p&#233;rdida de peso corporal&#44; tambi&#233;n fue inferior con la metformina que con el placebo &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;2&#44;02&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;3&#44;29 a &#8722;0&#44;77&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Resultados de seguridad</span><p id="par0065" class="elsevierStylePara elsevierViewall">En la <a class="elsevierStyleCrossRef" href="#fig0020">figura 4</a> se muestran los resultados del metaan&#225;lisis por pares para los resultados de seguridad&#46; El metaan&#225;lisis de red mostr&#243; la no existencia de diferencias en cuanto a la hipoglucemia grave entre la metformina&#44; los inhibidores del SGLT2 y el placebo&#46; La CAD ten&#237;a lugar con m&#225;s frecuencia con los inhibidores del SGLT2 que con la metformina y el placebo&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">An&#225;lisis de subgrupos</span><p id="par0070" class="elsevierStylePara elsevierViewall">La <a class="elsevierStyleCrossRef" href="#fig0025">figura 5</a> muestra la gr&#225;fica de red para el an&#225;lisis de subgrupos&#46; En la <a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a> se presentan los resultados comparativos de eficacia y seguridad de los tipos de inhibidores del SGLT2&#44; la metformina y el placebo&#46; La reducci&#243;n de los niveles de HbA1c obtenidos con la dapagliflozina&#44; la empagliflozina y la sotagliflozina fueron superiores a los alcanzados con la metformina y con el placebo&#46; No se observaron diferencias entre la canagloflozina&#44; la metformina y el placebo&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">En t&#233;rminos de p&#233;rdida de peso corporal&#44; los cuatro inhibidores del SGLT2 fueron superiores al placebo&#46; Sin embargo&#44; no se observaron diferencias entre los cuatro inhibidores del SGLT2 y entre los inhibidores del SGLT2 y la metformina&#46; Una vez clasificados los resultados de la eficacia&#44; la canagliflozina&#44; la dapagliflozina y la sotagliflozina destacaron en la p&#233;rdida de peso corporal&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">En relaci&#243;n con la reducci&#243;n de la dosis total de insulina&#44; la dapagliflozina&#44; la sotagliflozina y la metformina fueron superiores al placebo&#46; Sin embargo&#44; canagliflozina&#44; dapagliflozina y sotagliflozina fueron las tres terapias m&#225;s efectivas seg&#250;n el rango de probabilidades&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">En cuanto a la hipoglucemia grave&#44; no se identificaron diferencias entre tratamientos&#46; La canagliflozina y la sotagliflozina ten&#237;an mayor probabilidad de causar la CAD que el placebo&#46; Adem&#225;s&#44; la incidencia de CAD parec&#237;a ser m&#225;s alta con los 4 inhibidores del SGLT2 que con la metformina&#44; lo que era consistente con los resultados del rango de probabilidades&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discusi&#243;n</span><p id="par0090" class="elsevierStylePara elsevierViewall">Aunque son varios los ECA que han evaluado la seguridad y la eficacia de los inhibidores del SGLT2 y de la metformina en adultos con DM1&#44; hasta la fecha &#250;nicamente se ha dise&#241;ado un ECA comparativo de los efectos que tienen sobre los niveles de la HbA1c el tratamiento con empagliflozina y con metformina en pacientes con DM1<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">32</span></a>&#46; El presente estudio ha permitido consolidar las evidencias obtenidas en numerosos ECA en los que se comparaban los inhibidores del SGLT2 o la metformina con placebo&#44; con el objetivo de lograr una comparaci&#243;n indirecta de la seguridad y la eficacia global entre los inhibidores del SGLT2 y entre estos y la metformina&#44; empleando para ello un enfoque de metaan&#225;lisis de red&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">As&#237; pues&#44; nuestro metaan&#225;lisis de red mostr&#243; que los inhibidores del SGLT2 presentaban un 92&#37; m&#225;s de probabilidades de ser los f&#225;rmacos adyuvantes m&#225;s eficaces en la DM1 en cuanto a control gluc&#233;mico &#40;medido por los valores de la HbA1c&#41;&#44; p&#233;rdida de peso y reducci&#243;n total de la dosis de insulina&#44; sin que aumente el riesgo de padecer hipoglucemia grave&#46; Sin embargo&#44; los inhibidores del SGLT2 se asociaron a un mayor riesgo de CAD&#46; Un metaan&#225;lisis ha sugerido que los inhibidores del SGLT2 eran m&#225;s eficaces en el control de la glucemia&#44; en la reducci&#243;n de la dosis total de insulina y en la p&#233;rdida de peso en la DM1&#44; y a pesar de que no induc&#237;an hipoglucemias graves&#44; s&#237; aumentaban el riesgo de CAD<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">11</span></a>&#46; La cetoacidosis que aparece durante el tratamiento con inhibidores del SGLT2 se ha relacionado con una serie de mecanismos biol&#243;gicos&#46; Una de las posibles razones ser&#237;a la dificultad para reconocer los s&#237;ntomas tempranos&#44; dado que las concentraciones de glucosa permanecen muy pr&#243;ximos a los niveles objetivo&#46; Adem&#225;s&#44; la reducci&#243;n excesiva de la dosis de insulina disminuir&#237;a su efecto inhibitorio sobre la producci&#243;n de cetonas&#46; Es m&#225;s&#44; quiz&#225; podr&#237;a existir una relaci&#243;n directa entre el tratamiento con inhibidores del SGLT2 y la cetosis&#46; Estudios previos han mostrado que el SGLT2 se expresa en las c&#233;lulas-&#945; pancre&#225;ticas y que su inhibici&#243;n desencadena de manera directa la secreci&#243;n de glucag&#243;n<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">33</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Se han analizado con mayor profundidad las diferencias en cuanto a seguridad y eficacia de los inhibidores del SGLT2 en adultos con DM1&#46; De esta manera&#44; el metaan&#225;lisis de red revel&#243; que aunque la canagliflozina proporcionaba reducciones del peso corporal &#40;con un 60&#37; de probabilidades de ser el tratamiento m&#225;s eficaz&#41; no acompa&#241;adas de hipoglucemia&#44; esta aumentaba la tasa de CAD&#46; Sin embargo&#44; hay que tener en cuenta que los resultados anteriormente mencionados se basaban &#250;nicamente en un ECA&#46; Ensayos cl&#237;nicos de alta calidad&#44; sobre grandes muestras y con un seguimiento a largo plazo garantizar&#237;an los resultados de la investigaci&#243;n de la eficacia y la seguridad de la canagliflozina en pacientes con DM1&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Se ha comprobado que la sotagliflozina&#44; un nuevo inhibidor dual del SGLT1 y SGLT2&#44; reduce la absorci&#243;n de glucosa en el tracto gastrointestinal a trav&#233;s de la inhibici&#243;n del SGLT2 y la reabsorci&#243;n de glucosa renal mediante la inhibici&#243;n del SGLT2<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">34&#44;35</span></a>&#46; Nuestros resultados mostraron que el tratamiento con sotagliflozina se traduc&#237;a en un descenso significativo de los niveles de HbA1c&#44; del peso corporal y de la dosis de insulina&#44; aunque con un riesgo mayor de CAD cuando se lo comparaba con placebo&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Nuestro metaan&#225;lisis de red hall&#243; reducciones parecidas en la HbA1c y en el peso corporal para la dapagliflozina y la empagliflozina&#44; siendo considerados dos de los mejores f&#225;rmacos adyuvantes para la DM1 seg&#250;n el rango de probabilidad&#46; Es m&#225;s&#44; la dapagliflozina mostr&#243; un 46&#37; de probabilidades de ser el mejor tratamiento adyuvante en cuanto a la reducci&#243;n de la dosis total de insulina sin aumento del riesgo de hipoglucemia grave y CAD&#46; En cuanto al riesgo de hipoglucemia grave y CAD&#44; la empagliflozina mostr&#243; resultados similares a la dapagliflozina&#46; La raz&#243;n por la que la dapagliflozina se asoci&#243; a un menor riesgo de CAD podr&#237;a venir explicada por el estudio DEPICT-1<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">19&#44;20</span></a>&#44; en el que los participantes se sometieron a una monitorizaci&#243;n regular en el hogar mediante el uso de medidores de glucosa y cetonas en sangre y mantuvieron una comunicaci&#243;n directa con los m&#233;dicos cada 2 semanas a fin de identificar los factores de riesgo de CAD y detectar las primeras se&#241;ales de advertencia&#46; Mientras tanto&#44; los investigadores establecieron una regla simple y viable por la que las dosis de insulina se reducir&#237;an en no m&#225;s de un 20&#37; tras el uso de la medicaci&#243;n del estudio&#44; debi&#233;ndose ajustar posteriormente a la dosis inicial&#46; Esta regla result&#243; ser muy eficaz en la reducci&#243;n del riesgo de cetoacidosis&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">En general&#44; los inhibidores del SGLT2 podr&#237;an ser empleados en los adultos con DM1 siempre que est&#233;n sometidos a un control domiciliario regular y que posean un buen conocimiento en la detecci&#243;n de los signos tempranos de cetoacidosis&#46; Hasta la fecha no hay ning&#250;n estudio sobre la eficacia de los inhibidores del SGLT2 en pacientes con DM1 con un per&#237;odo de seguimiento de m&#225;s de un a&#241;o&#46; Por lo tanto&#44; son necesarios ensayos a m&#225;s largo plazo a fin de aclarar la eficacia y la seguridad de los inhibidores del SGLT2 como terapia adyuvante&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Aunque la metformina no es m&#225;s eficaz que los inhibidores del SGLT2&#44; la disminuci&#243;n del peso corporal y de la dosis de insulina es significativamente mayor a la producida por el grupo control&#46; El reciente estudio REMOVAL con metformina en la DM1 ha mostrado que las reducciones de peso corporal se mantuvieron durante al menos 3<span class="elsevierStyleHsp" style=""></span>a&#241;os<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a>&#46; Los estudios han demostrado que la metformina tambi&#233;n puede reducir el nivel de colesterol LDL&#44; importante factor de riesgo cardiovascular&#44; y que dichas reducciones se mantuvieron durante al menos 3<span class="elsevierStyleHsp" style=""></span>a&#241;os<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a>&#46; En cuanto a la seguridad&#44; el tratamiento con metformina no aument&#243; el riesgo de hipoglucemia grave y de CAD&#59; m&#225;s a&#250;n&#44; la metformina present&#243; un menor riego de CAD que el grupo control&#46; La metformina ser&#237;a un tratamiento fiable complementario a la insulina para pacientes con DM1 que necesitan una dosis total alta de insulina&#44; los que tienen un evidente aumento de peso corporal o los que tengan un alto riesgo cardiovascular&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Es necesario reconocer algunas limitaciones en este metaan&#225;lisis de red&#46; En primer lugar&#44; finalmente se incluyeron en el estudio &#250;nicamente 13 ensayos con inhibidores del SGLT2 y 6 con metformina&#44; siendo incluso menor el n&#250;mero de ECA empleados en el an&#225;lisis de subgrupos&#46; En segundo lugar&#44; existen ligeras diferencias en cuanto a las poblaciones de los ECA incluidos&#46; Hasta ahora&#44; los estudios han asumido que los pacientes con DM1 son un grupo homog&#233;neo de individuos con una respuesta similar a los tratamientos adyuvantes&#44; lo que es poco probable que ocurra&#46; En tercer lugar&#44; se estim&#243; alta heterogeneidad para HbA1c y dosis total de insulina para estudios relacionados con inhibidores del SGLT2&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; los inhibidores del SGLT2 proporcionan mayores disminuciones de los niveles de HbA1c y de peso corporal cuando se comparan con la metformina y el placebo&#46; Tanto los inhibidores del SGLT2 como la metformina produjeron mayores reducciones en la dosis de insulina que el placebo&#44; no observ&#225;ndose diferencias significativas entre los inhibidores del SGLT2 y la metformina&#46; Sin embargo&#44; el riesgo de inducci&#243;n de CAD era mayor con los inhibidores del SGLT2 que con la metformina y el placebo&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Financiaci&#243;n</span><p id="par0135" class="elsevierStylePara elsevierViewall">Este informe est&#225; respaldado por el proyecto hospitalario del Taizhou People&#39;s Hospital &#40;Proyecto n&#46;&#176; ZL201725&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflicto de intereses</span><p id="par0140" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Comparar la eficacia y la seguridad de los inhibidores del cotransportador-2 de sodio-glucosa &#40;SGLT2&#41; y de la metformina en adultos con diabetes mellitus tipo 1 &#40;DM1&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">M&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se buscaron en PubMed&#44; EMBASE&#44; Cochrane Library y Web of Science los ensayos cl&#237;nicos aleatorizados llevados a cabo hasta febrero de 2019 dise&#241;ados para evaluar la eficacia y la seguridad de los inhibidores del SGLT2&#47;metformina en adultos con DM1&#46; Los datos de seguridad y eficacia fueron recopilados empleando el metaan&#225;lisis en red bayesiana&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Veinte estudios&#44; con 5&#46;868 participantes&#44; fueron aptos para ser incluidos en el metaan&#225;lisis en red&#46; Los inhibidores del SGLT2 proporcionaron mayores reducciones en la HbA1c que el placebo &#40;diferencia de media ponderada &#91;DMP&#93; &#8722;0&#44;40&#59; intervalo de confianza &#91;IC&#93; del 95&#37;&#58; &#8722;0&#44;47&#44; &#8722;0&#44;32&#41; y la metformina &#40;DMP&#58; &#8722;0&#44;32&#58; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;0&#44;47 a &#8722;0&#44;14&#41;&#46; Tanto los inhibidores del SGLT2 como la metformina favorecieron mayores disminuciones de peso corporal que el placebo &#40;DMP&#58; &#8722;1&#44;54&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;2&#44;93 a &#8722;0&#44;09&#41;&#46; Los inhibidores del SGLT2 produjeron mayores disminuciones de peso corporal que la metformina &#40;DMP&#58; &#8722;1&#44;54&#59; IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; &#8722;2&#44;93 a &#8722;0&#44;09&#41;&#46; Los inhibidores del SGLT2 y la metformina dieron lugar a mayores reducciones de la dosis total de insulina que el placebo&#44; no encontr&#225;ndose diferencias entre la metformina y los inhibidores del SGLT2&#46; En cuanto a la hipoglucemia grave&#44; no se encontraron diferencias entre los inhibidores del SGLT2 y la metformina&#46; Los inhibidores del SGLT2 provocaron un mayor riesgo de cetoacidosis diab&#233;tica &#40;CAD&#41; que la metformina&#47;placebo&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusi&#243;n</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Los inhibidores del SGLT2 proporcionan mayores reducciones en la HbA1c y de peso corporal que la metformina&#47;placebo&#46; Tanto los inhibidores del SGLT2 como la metformina provocaron mayores disminuciones en la dosificaci&#243;n total de insulina que el placebo&#44; no observ&#225;ndose diferencias significativas entre los inhibidores del SGLT2 y la metformina&#46; Los inhibidores del SGLT2 indujeron un mayor riesgo de CAD que la metformina&#47;placebo&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Aim</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">To compare the efficacy and safety of sodium-glucose co-transporter-2 &#40;SGLT2&#41; inhibitors and metformin in adults with type<span class="elsevierStyleHsp" style=""></span>1 diabetes mellitus &#40;T1DM&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Randomized clinical trials until February 2019&#44; designed to assess the efficacy and safety of SGLT2 inhibitors&#47;metformin in adults with T1DM&#44; were searched on PubMed&#44; EMBASE&#44; the Cochrane Library&#44; and Web of Science&#46; Safety and efficacy data were synthesized using Bayesian network meta-analyses&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Twenty eligible studies with 5868 participants were included in network meta-analysis&#46; SGLT2 inhibitors provided greater reductions in HbA1c than placebo &#40;weighted mean difference &#91;WMD&#93; &#8722;0&#46;40&#59; 95&#37; confidence interval &#91;CI&#93; &#8722;0&#46;47&#44; &#8722;0&#46;32&#41; and metformin &#40;WMD&#58; &#8722;0&#46;32&#59; 95&#37;<span class="elsevierStyleHsp" style=""></span>CI&#58; &#8722;0&#46;47&#44; &#8722;0&#46;14&#41;&#46; Both SGLT2 inhibitors and metformin promoted greater reductions in body weight than placebo&#46; SGLT2 inhibitors caused greater reductions in body weight than metformin &#40;WMD&#58; &#8722;1&#46;54&#59; 95&#37;<span class="elsevierStyleHsp" style=""></span>CI&#58; &#8722;2&#46;93&#44; &#8722;0&#46;09&#41;&#46; Both SGLT2 inhibitors and metformin provided greater reductions in total insulin dose than placebo&#44; while no difference between metformin and SGLT2 inhibitors was found&#46; No difference in severe hypoglycemia was found between SGLT2 inhibitors and metformin&#46; SGLT2 inhibitors induced a higher risk for diabetic ketoacidosis &#40;DKA&#41; than metformin&#47;placebo&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusion</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">SGLT2 inhibitors provided greater reductions in HbA1c and body weight than metformin&#47;placebo&#46; Both SGLT2 inhibitors and metformin induced greater reductions in total insulin dosage than placebo&#44; with no significant differences observed between SGLT2 inhibitors and metformin&#46; SGLT2 inhibitors induced a higher risk for DKA than metformin&#47;placebo&#46;</p></span>"
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          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Diagrama de flujo de los 20 art&#237;culos incluidos&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Estudio&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Edad&#44; a&#241;os&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Duraci&#243;n de la diabetes tipo 1&#44; a&#241;os&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Peso corporal&#44; kg&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IMC basal&#44; kg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Insulina basal&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Canagliflozina</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Henry RR et al&#46; &#40;2015&#41;</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="4" align="left" valign="\n
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                  \t\t\t\t">18</td><td class="td" title="\n
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                  \t\t\t\t">300<span class="elsevierStyleHsp" style=""></span>mg CANA</td><td class="td" title="\n
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                  \t\t\t\t">117</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">42&#44;8 &#177; 11&#44;0</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">21&#44;9 &#177; 10&#44;6</td><td class="td" title="\n
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                  \t\t\t\t">8&#44;0 &#177; 0&#44;5</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">MDI&#58; 44 &#177; 37&#44;6 UI&#47;d&#237;a&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">ISCI&#58; 73 &#177; 62&#44;4 UI&#47;d&#237;a&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">117</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">MDI&#58; 45 &#177; 38&#44;5 UI&#47;d&#237;a&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">ISCI&#58; 72 &#177; 61&#44;5 UI&#47;d&#237;a&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="10" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Dapagliflozina</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Henry RR et al&#46; &#40;2015&#41;</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">2</td><td class="td" title="\n
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                  \t\t\t\t">10<span class="elsevierStyleHsp" style=""></span>mg DAPA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">37&#44;5 &#177; 15&#44;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">18&#44;1 &#177; 14&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">78&#44;4 &#177; 19&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">25&#44;8 &#177; 4&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8&#44;39 &#177; 0&#44;82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">NI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">34&#44;5 &#177; 12&#44;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">16&#44;2 &#177; 9&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">78 &#177; 11&#44;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">25&#44;3 &#177; 3&#44;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8&#44;75 &#177; 0&#44;92&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dandona P et al&#46; &#40;2017&#41; &#47;Dandona P et al&#46; &#40;2018&#41;</td><td class="td" title="\n
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                  \t\t\t\t">24&#47;52</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10<span class="elsevierStyleHsp" style=""></span>mg DAPA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">296&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Shimada A et al&#46; &#40;2018&#41;</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Rosenstock J et al&#46; &#40;2018&#41;</td><td class="td" title="\n
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                  \t\t\t\t">25<span class="elsevierStyleHsp" style=""></span>mg EMPA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sands AT et al&#46; &#40;2015&#41;</td><td class="td" title="\n
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                  \t\t\t\t">18&#44;5 &#40;4&#44;7&#44; 40&#44;8&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Garg SK et al&#46; &#40;2017&#41;</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Buse JB et al&#46; &#40;2018&#41;</td><td class="td" title="\n
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                  \t\t\t\t">400<span class="elsevierStyleHsp" style=""></span>mg SOTA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;72&#177; 0&#44;335 UI&#47;kg&#47;d&#237;a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;74 &#177; 0&#44;357 UI&#47;kg&#47;d&#237;a&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Danne T et al&#46; &#40;2018&#41;</td><td class="td" title="\n
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                  \t\t\t\t">52</td><td class="td" title="\n
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                  \t\t\t\t">263&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7&#44;71 &#177; 0&#44;819&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;74 &#177; 0&#44;267 UI&#47;kg&#47;d&#237;a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">258&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="10" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Metformina</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Jacobsen IB et al&#46; &#40;2009&#41;</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">24</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;000<span class="elsevierStyleHsp" style=""></span>mg Metformina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8&#44;37 &#177; 0&#44;20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">B&#46; Peso corporal&#58; DMP &#40;IC</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">95&#37;&#41;&#44; kg</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Metformina</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1&#44;54 &#40;0&#44;09 a 2&#44;93&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">iSGLT2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#8722;2&#44;02 &#40;&#8722;3&#44;29 a &#8722;0&#44;77&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>3&#44;09 &#40;&#8722;1&#44;53 a 7&#44;09&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">iSGLT2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#8722;3&#44;88 &#40;&#8722;7&#44;46 a &#8722;0&#44;59&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8722;6&#44;94 &#40;&#8722;9&#44;55 a &#8722;4&#44;32&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1&#44;40 &#40;0&#44;63 a 2&#44;90&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>0&#44;00 &#40;0&#44;00 a 0&#44;11&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">9&#44;21 &#40;2&#44;69 a 79&#44;82&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8722;0&#44;32 &#40;&#8722;0&#44;52 a &#8722;0&#44;09&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">B&#46; Peso corporal&#58; DMP &#40;IC</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">95&#37;&#41;&#44; kg</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">C&#46; Dosis total de insulina&#58; DMP &#40;IC</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">95&#37;&#41;&#44; unidades</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>0&#44;48 &#40;&#8722;9&#44;19 a 9&#44;37&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#8722;1&#44;61 &#40;&#8722;10&#44;36 a 7&#44;25&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#8722;3&#44;71 &#40;&#8722;12&#44;12 a 5&#44;12&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#8722;7&#44;59 &#40;&#8722;15&#44;56 a 0&#44;34&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">D&#46; Hipoglucemia grave&#58; OR &#40;IC</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">95&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">E&#46; Cetoacidosis diab&#233;tica&#58; OR &#40;IC</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">95&#37;&#41;</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>0&#44;00 &#40;0&#44;00 a 0&#44;03&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#44;59 &#40;0&#44;03 a 168&#44;02&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Dapagliflozina</span>&nbsp;\t\t\t\t\t\t\n
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Vol. 220. Núm. 1.
Páginas 8-21 (enero - febrero 2020)
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Vol. 220. Núm. 1.
Páginas 8-21 (enero - febrero 2020)
Original
Eficacia y seguridad de la metformina y de los inhibidores del cotransportador-2 de sodio-glucosa en adultos con diabetes tipo 1: una revisión sistemática y metaanálisis en red
Efficacy and safety of metformin and sodium-glucose co-transporter-2 inhibitors in adults with type1 diabetes: A systematic review and network meta-analysis
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930
Q. Zhanga,
Autor para correspondencia
18061986120@189.cn

Autor para correspondencia.
, Y. Wub, Y. Lua, X. Feia
a Departamento de Endocrinología, Hospital Popular de Taizhou, Taizhou, Jiangsu, China
b Departamento de Cardiología, Hospital Popular de Taizhou, Taizhou, Jiangsu, China
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Tablas (3)
Tabla 1. Características de los estudios incluidos
Tabla 2. Comparación de los resultados de eficacia y seguridad de la metformina, los inhibidores del cotransportador-2 de sodio-glucosa (iSGLT2) y el placebo
Tabla 3. Comparación de eficacia y seguridad de canagliflozina, dapagliflozina, empagliflozina, sotagliflozina, metformina y placebo
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Material adicional (2)
Resumen
Objetivo

Comparar la eficacia y la seguridad de los inhibidores del cotransportador-2 de sodio-glucosa (SGLT2) y de la metformina en adultos con diabetes mellitus tipo 1 (DM1).

Métodos

Se buscaron en PubMed, EMBASE, Cochrane Library y Web of Science los ensayos clínicos aleatorizados llevados a cabo hasta febrero de 2019 diseñados para evaluar la eficacia y la seguridad de los inhibidores del SGLT2/metformina en adultos con DM1. Los datos de seguridad y eficacia fueron recopilados empleando el metaanálisis en red bayesiana.

Resultados

Veinte estudios, con 5.868 participantes, fueron aptos para ser incluidos en el metaanálisis en red. Los inhibidores del SGLT2 proporcionaron mayores reducciones en la HbA1c que el placebo (diferencia de media ponderada [DMP] −0,40; intervalo de confianza [IC] del 95%: −0,47, −0,32) y la metformina (DMP: −0,32: IC95%: −0,47 a −0,14). Tanto los inhibidores del SGLT2 como la metformina favorecieron mayores disminuciones de peso corporal que el placebo (DMP: −1,54; IC95%: −2,93 a −0,09). Los inhibidores del SGLT2 produjeron mayores disminuciones de peso corporal que la metformina (DMP: −1,54; IC95%: −2,93 a −0,09). Los inhibidores del SGLT2 y la metformina dieron lugar a mayores reducciones de la dosis total de insulina que el placebo, no encontrándose diferencias entre la metformina y los inhibidores del SGLT2. En cuanto a la hipoglucemia grave, no se encontraron diferencias entre los inhibidores del SGLT2 y la metformina. Los inhibidores del SGLT2 provocaron un mayor riesgo de cetoacidosis diabética (CAD) que la metformina/placebo.

Conclusión

Los inhibidores del SGLT2 proporcionan mayores reducciones en la HbA1c y de peso corporal que la metformina/placebo. Tanto los inhibidores del SGLT2 como la metformina provocaron mayores disminuciones en la dosificación total de insulina que el placebo, no observándose diferencias significativas entre los inhibidores del SGLT2 y la metformina. Los inhibidores del SGLT2 indujeron un mayor riesgo de CAD que la metformina/placebo.

Palabras clave:
Inhibidores del SGLT2
Metformina
Diabetes tipo 1
Metaanálisis
Abstract
Aim

To compare the efficacy and safety of sodium-glucose co-transporter-2 (SGLT2) inhibitors and metformin in adults with type1 diabetes mellitus (T1DM).

Methods

Randomized clinical trials until February 2019, designed to assess the efficacy and safety of SGLT2 inhibitors/metformin in adults with T1DM, were searched on PubMed, EMBASE, the Cochrane Library, and Web of Science. Safety and efficacy data were synthesized using Bayesian network meta-analyses.

Results

Twenty eligible studies with 5868 participants were included in network meta-analysis. SGLT2 inhibitors provided greater reductions in HbA1c than placebo (weighted mean difference [WMD] −0.40; 95% confidence interval [CI] −0.47, −0.32) and metformin (WMD: −0.32; 95%CI: −0.47, −0.14). Both SGLT2 inhibitors and metformin promoted greater reductions in body weight than placebo. SGLT2 inhibitors caused greater reductions in body weight than metformin (WMD: −1.54; 95%CI: −2.93, −0.09). Both SGLT2 inhibitors and metformin provided greater reductions in total insulin dose than placebo, while no difference between metformin and SGLT2 inhibitors was found. No difference in severe hypoglycemia was found between SGLT2 inhibitors and metformin. SGLT2 inhibitors induced a higher risk for diabetic ketoacidosis (DKA) than metformin/placebo.

Conclusion

SGLT2 inhibitors provided greater reductions in HbA1c and body weight than metformin/placebo. Both SGLT2 inhibitors and metformin induced greater reductions in total insulin dosage than placebo, with no significant differences observed between SGLT2 inhibitors and metformin. SGLT2 inhibitors induced a higher risk for DKA than metformin/placebo.

Keywords:
SGLT2 inhibitors
Metformin
Type 1 diabetes
Meta-analysis

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