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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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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
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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