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Las hipoglucemias son uno de los factores limitantes del tratamiento intensivo de la DM2&#59; en los pacientes con DM2 los episodios de hipoglucemias son menos frecuentes que en los pacientes con DM tipo<span class="elsevierStyleHsp" style=""></span>1 &#40;DM1&#41;&#59; sin embargo&#44; estos est&#225;n relacionados con un aumento del riesgo de aparici&#243;n de complicaciones micro y macrovasculares&#44; con el consiguiente incremento de coste asociado<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a>&#46; Por otro lado&#44; la adherencia al tratamiento tambi&#233;n puede contribuir a la reducci&#243;n de los costes asociados a la DM2 gracias a una mejora del control gluc&#233;mico y la consecuente reducci&#243;n en el uso de recursos<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46; Factores que pueden favorecer el desarrollo de la DM2&#44; como la obesidad&#44; tambi&#233;n pueden contribuir a generar costes adicionales al manejo de estos pacientes&#44; ya que la coexistencia de ambas patolog&#237;as incrementa el riesgo de aparici&#243;n de complicaciones macrovasculares<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">El objetivo principal de este trabajo es identificar los principales factores que explican cambios en el coste del paciente con DM2 de acuerdo con lo publicado en la literatura&#44; analizando particularmente los datos espa&#241;oles&#46; Adicionalmente&#44; se propone valorar la consistencia de los datos aportados y de los resultados hallados en la literatura&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material y m&#233;todos</span><p id="par0020" class="elsevierStylePara elsevierViewall">Se consultaron bases de datos bibliogr&#225;ficas electr&#243;nicas internacionales &#40;MedLine-PubMed&#44; ISI Wok&#44; Scopus&#44; Cochrane Library&#44; DARE&#41;&#44; nacionales &#40;Centro Superior de Investigaciones Cient&#237;ficas-&#205;ndice M&#233;dico Espa&#241;ol &#91;CSIC-IME&#93;&#44; &#205;ndice Bibliogr&#225;fico Espa&#241;ol en Ciencias de la Salud &#91;IBECS&#93;&#44; Medicina en Espa&#241;ol &#91;MEDES&#93;&#44; Medibooks&#41; y fuentes de literatura gris &#40;Google Scholar&#44; p&#225;ginas electr&#243;nicas de las principales Agencias de evaluaci&#243;n de tecnolog&#237;as sanitarias &#91;AETS&#93; europeas&#41;&#46; La b&#250;squeda se complement&#243; con la revisi&#243;n manual de las listas de referencias bibliogr&#225;ficas de las publicaciones clave identificadas&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Los criterios de b&#250;squeda fueron flexibles para recuperar el mayor n&#250;mero de publicaciones&#46; La b&#250;squeda en MedLine-PubMed se elabor&#243; conjugando con los operadores booleanos &#171;or&#187; y &#171;and&#187; los descriptores <span class="elsevierStyleItalic">Medical Subject Heading</span> &#40;MeSH&#41;&#58; <span class="elsevierStyleItalic">&#171;type 2 diabetes mellitus&#187;&#44; &#171;costs&#187;&#44; &#171;direct costs&#187;&#44; &#171;indirect costs&#187;&#44; &#171;costs burden&#187;&#44; &#171;oral antidiabetic agents&#187;&#44; &#171;insulin therapy&#187;&#44; &#171;hypoglycemia&#187;&#44; &#171;complications&#187;&#44; &#171;retinopathy&#187;&#44; &#171;foot care&#187;&#44; &#171;neuropathy&#187;&#44; &#171;obesity&#187;&#44; &#171;weight&#187;&#44; &#171;macrovascular complications&#187;&#44; &#171;adherence&#187;</span> y <span class="elsevierStyleItalic">&#171;compliance&#187;&#46;</span> Los t&#233;rminos que resultaron m&#225;s eficaces en la b&#250;squeda en MedLine-PubMed fueron posteriormente utilizados para revisar las restantes bases de datos y sitios web&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">La depuraci&#243;n de las publicaciones recuperadas se efectu&#243; mediante el an&#225;lisis de t&#237;tulos y res&#250;menes para descartar duplicaciones e informaci&#243;n no relevante&#46; Una vez identificadas las publicaciones que potencialmente ser&#237;an revisadas&#44; se valoraron los textos completos correspondientes y se procedi&#243; a la aplicaci&#243;n de los criterios de inclusi&#243;n&#47;exclusi&#243;n para la selecci&#243;n final de los art&#237;culos a revisar&#46; La selecci&#243;n de los art&#237;culos se realiz&#243; priorizando las publicaciones realizadas en Espa&#241;a y en el resto de Europa&#46; En el caso de no disponer de informaci&#243;n suficiente referente a Europa&#44; se ampli&#243; la selecci&#243;n a los estudios realizados en Estados Unidos y Canad&#225;&#46; La selecci&#243;n fue llevada a cabo por 2 investigadores independientes&#46; Las discrepancias de selecci&#243;n fueron consultadas con un tercer investigador y resueltas por consenso&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Se incluyeron art&#237;culos publicados entre enero de 2001 y diciembre de 2012 que fuesen&#58; a&#41;<span class="elsevierStyleHsp" style=""></span>estudios de costes en los que se describiese el uso de recursos y&#47;o el tipo de costes asociados al manejo de la DM2&#59; 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Los niveles de evidencia de las publicaciones seleccionadas se evaluaron seg&#250;n criterios del <span class="elsevierStyleItalic">Center for Evidence Based Medicine</span> &#40;CEBM&#41;&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Resultados</span><p id="par0050" class="elsevierStylePara elsevierViewall">Inicialmente se identificaron un total de 1&#46;530 documentos&#44; de los que se eliminaron 1&#46;388 publicaciones &#40;duplicados y no relevantes&#41;&#46; Con la aplicaci&#243;n de los criterios de inclusi&#243;n&#47;exclusi&#243;n se excluyeron 116 documentos&#44; y finalmente se revisaron 26 art&#237;culos &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Caracter&#237;sticas descriptivas&#44; metodol&#243;gicas y nivel de evidencia de los estudios analizados</span><p id="par0055" class="elsevierStylePara elsevierViewall">Los 26 art&#237;culos revisados describen el coste de la DM2 y los factores que determinan dicho coste &#40;complicaciones micro y macrovasculares&#44; hipoglucemias&#44; obesidad y adherencia&#41;&#46; Las publicaciones recuperadas corresponden mayoritariamente a estudios observacionales&#44; siendo el 57&#44;8&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#41; longitudinales retrospectivos&#44; el 15&#44;4&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; estudios de cohortes retrospectivos&#44; el 11&#44;5&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41; estudios prospectivos y el 7&#44;7&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41; estudios caso-control retrospectivos&#46; Las 2 publicaciones restantes son un estudio transversal retrospectivo y una estimaci&#243;n de costes utilizando la aproximaci&#243;n &#171;arriba abajo&#187; <span class="elsevierStyleItalic">&#40;topdown approach&#41;</span>&#44; respectivamente&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Un total de 9 publicaciones estiman el coste de la DM2 en Europa&#59; de ellos 3 estudios son espa&#241;oles&#44; 2 est&#225;n realizados en distintos pa&#237;ses europeos&#44; incluido Espa&#241;a&#44; y 4 en otros pa&#237;ses europeos &#40;Suiza&#44; Alemania&#44; Reino Unido y Grecia&#41;&#46; El resto de estudios &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#41; eval&#250;an los factores que determinan cambios en los costes de la DM2&#46; As&#237;&#44; 6 determinan el coste de las complicaciones micro y macrovasculares asociadas a la DM2&#44; siendo 4 de ellos realizados en Estados Unidos o Canad&#225; y 2 en pa&#237;ses europeos&#44; incluyendo Espa&#241;a&#46; Seis publicaciones determinan el impacto de las hipoglucemias en el uso de recursos y&#47;o coste de la DM2&#44; 4 son estudios norteamericanos&#44; uno es del Reino Unido y el otro corresponde a un estudio europeo que incluye Espa&#241;a entre los pa&#237;ses evaluados&#46; Tres estudios investigan la influencia de la obesidad en los costes&#44; 2 realizados en Estados Unidos y uno en Alemania&#46; Finalmente&#44; 2 publicaciones eval&#250;an la asociaci&#243;n entre la adherencia al tratamiento y el uso de recursos y el coste asociado&#44; ambos realizados en Estados Unidos&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">En relaci&#243;n con los niveles de evidencia de las publicaciones identificadas&#44; el 84&#44;6&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>22&#41; presentan un nivel de evidencia 4&#44; que corresponde a estudios observacionales de costes que no presentan an&#225;lisis de sensibilidad&#44; mientras que el 15&#44;4&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#41; restante son an&#225;lisis basados en alternativas o costes limitados que incluyen an&#225;lisis de sensibilidad y presentan un nivel de evidencia 3<span class="elsevierStyleHsp" style=""></span>c&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Estimaci&#243;n del coste sanitario total destinado al manejo del paciente con diabetes mellitus tipo 2 en Europa</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Coste sanitario total destinado a la diabetes mellitus tipo 2 en Europa</span><p id="par0070" class="elsevierStylePara elsevierViewall">El estudio m&#225;s relevante identificado en la literatura sobre el impacto econ&#243;mico de la DM2 en Europa es el <span class="elsevierStyleItalic">Cost of Diabetes in Europe-Type 2</span> &#40;CODE-2&#41;&#44; realizado entre 1998 y 1999&#44; el cual sit&#250;a el coste directo total del manejo integral de los pacientes con DM2 cerca de los 43 billones de euros&#47;a&#241;o&#44; representando aproximadamente el 5&#37; del total del coste sanitario europeo de 1999<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46; A ra&#237;z del estudio CODE-2 se realizaron estudios similares en otros pa&#237;ses europeos&#44; como Suiza o Grecia&#46; En Suiza&#44; el coste directo total de los pacientes con DM2 representa el 2&#44;2&#37; del coste sanitario total suizo de 1999<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#44; mientras que el manejo integral del paciente con DM2 en Grecia se sit&#250;a alrededor del 12&#37; en 2007 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">En la l&#237;nea del estudio CODE-2 se desarrollaron a nivel europeo otros 2 estudios sobre la DM2&#44; el <span class="elsevierStyleItalic">Self-Monitoring of Blood Glucose</span> &#40;SMBG&#41; <span class="elsevierStyleItalic">and Outcome in Patients with Type 2 Diabetes</span> &#40;ROSSO&#41;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> y el estudio INSTIGATE<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46; El primero pone de manifiesto la asociaci&#243;n entre los SMBG y el descenso de la morbimortalidad por cualquier causa&#44; asociada a la DM2<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46; De este modo&#44; aunque la implantaci&#243;n de los SMBG produce un incremento de coste anual entre 45 y 65<span class="elsevierStyleHsp" style=""></span>&#8364; paciente&#47;a&#241;o&#44; la disminuci&#243;n de las complicaciones micro y macrovasculares detectadas en estos pacientes reduce los costes directos totales entre un 10 y un 43&#37;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46; Por su parte&#44; el estudio INSTIGATE muestra una elevada heterogeneidad en los costes estimados entre los pa&#237;ses europeos evaluados&#46; Sin embargo&#44; en todos ellos&#44; una vez instaurada la insulinoterapia&#44; se observa un aumento de la utilizaci&#243;n de recursos sanitarios que conlleva un incremento del coste directo asociado a la enfermedad &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Finalmente&#44; en la literatura tambi&#233;n se ha identificado un trabajo que determina el coste directo actual de la DM2 en el Reino Unido en 10&#44;7 billones de euros y unos costes indirectos de 16 billones de euros&#44; estimando un incremento de dichos valores en el a&#241;o 2035&#47;2036 entre el 150&#37; y el 170&#37;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Coste sanitario total destinado a la diabetes mellitus tipo 2 en Espa&#241;a</span><p id="par0085" class="elsevierStylePara elsevierViewall">El estudio CODE-2 estima que en Espa&#241;a &#250;nicamente el 28&#44;6&#37; del coste directo anual de la DM2 est&#225; relacionado directamente con el control de la DM2&#44; estando la mayor parte asociado a las complicaciones<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; Por su parte&#44; el estudio ROSSO determina que el coste total anual del paciente con DM2 que realiza SMBG representa entre 50&#44;69 y 789<span class="elsevierStyleHsp" style=""></span>&#8364; anuales menos por paciente en comparaci&#243;n con el coste del paciente que no realiza SMBG<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#44; en funci&#243;n del tratamiento empleado &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46; La reducci&#243;n del coste es atribuible a la disminuci&#243;n de los costes derivados de las complicaciones<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; Finalmente&#44; el estudio INSTIGATE&#44; realizado en Espa&#241;a&#44; determina que el coste directo del paciente DM2 se incrementa en 1&#44;8 veces al iniciar el tratamiento con insulina&#44; principalmente a consecuencia del aumento del uso de recursos asociado a las hospitalizaciones &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Componentes explicativos del coste directo</span><p id="par0090" class="elsevierStylePara elsevierViewall">Los distintos estudios revisados se&#241;alan las hospitalizaciones como principal componente explicativo del coste directo de la DM2<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11-13&#44;17</span></a>&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">El estudio INSTIGATE pone de manifiesto que la instauraci&#243;n del tratamiento con insulina conlleva un cambio en los componentes explicativos de los costes asociados a la DM2<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46; As&#237;&#44; en Europa&#44; en los 6<span class="elsevierStyleHsp" style=""></span>meses posteriores al inicio de la terapia insul&#237;nica la proporci&#243;n de coste total relacionado con los antidiab&#233;ticos orales &#40;ADO&#41; y las hospitalizaciones disminuye&#44; incrementando la proporci&#243;n de coste asociada al control gluc&#233;mico&#44; posiblemente a consecuencia del aumento de las consultas sanitarias observada en este periodo<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46; Sin embargo&#44; en Espa&#241;a&#44; una vez instaurada la insulinoterapia se incrementan los costes asociados a las hospitalizaciones&#44; principalmente como resultado del incremento de las hipo e hiperglucemias relacionadas con la falta de adherencia al tratamiento y a las comorbilidades<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">An&#225;lisis de los factores que explican los cambios en el coste del paciente con diabetes mellitus tipo 2</span><p id="par0100" class="elsevierStylePara elsevierViewall">Al identificarse un escaso n&#250;mero de publicaciones &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41; que evaluasen los factores que impactan en el coste del paciente con DM2 en Espa&#241;a o en Europa&#44; se ampli&#243; la selecci&#243;n a aquellos art&#237;culos clave publicados en Estados Unidos y&#47;o Canad&#225;&#46;</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Influencia de las complicaciones vasculares en el coste asociado a la diabetes mellitus tipo 2</span><p id="par0105" class="elsevierStylePara elsevierViewall">Seg&#250;n el estudio CODE-2&#44; realizado en Europa&#44; la presencia de complicaciones microvasculares incrementa los costes directos en un 70&#37;&#44; mientras que las complicaciones macrovasculares o la presencia de ambas multiplican por 2&#44;1 y por 3&#44;5 dicho coste&#44; explicado por el aumento del coste asociado a las hospitalizaciones<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46; As&#237;&#44; las complicaciones micro y macrovasculares ampl&#237;an el coste de las hospitalizaciones en un 100 y un 200&#37;&#44; respectivamente&#44; pudiendo ascender hasta en un 450&#37; cuando el paciente presenta ambas complicaciones<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46; En Espa&#241;a&#44; los resultados obtenidos van en l&#237;nea con los obtenidos en Europa&#59; as&#237;&#44; las complicaciones incrementan entre 1&#44;6 y 2&#44;4 veces los costes&#44; siendo el principal factor explicativo del aumento de coste las hospitalizaciones<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; En Suiza tambi&#233;n se observa que el coste del paciente con complicaciones microvasculares y macrovasculares es 2 y 3 veces superior que el coste del paciente sin complicaciones&#44; elevando hasta 4 veces dicho coste al coexistir ambas complicaciones &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Fu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> determinan que los pacientes europeos con DM2 y complicaciones macrovasculares presentan una mayor probabilidad de visitas a urgencias &#40;2&#44;69 veces&#41;&#44; de necesitar procedimientos m&#233;dicos o quir&#250;rgicos &#40;2&#44;57 veces&#41; y de hospitalizaci&#243;n &#40;2&#44;58 veces&#41; que los pacientes sin complicaciones&#46; Adem&#225;s&#44; estas complicaciones est&#225;n asociadas a unas 1&#44;49 consultas m&#233;dicas adiciones anuales &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;036&#41; y a 0&#44;32 d&#237;as m&#225;s de hospitalizaci&#243;n por a&#241;o &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;023&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Por otro lado&#44; Pelletier et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#44; en Estados Unidos&#44; observan diferencias estad&#237;sticamente significativas en todos los recursos sanitarios evaluados &#40;consumo farmacol&#243;gico&#44; visitas a urgencias&#44; consultas sanitarias&#44; test diagn&#243;sticos y hospitalizaciones&#41; entre los pacientes con DM2 con o sin complicaci&#243;n microvascular&#46; El coste sanitario total de los pacientes con complicaciones microvasculares es casi el doble que el asociado a los pacientes sin complicaciones&#44; principalmente a consecuencia de un mayor uso de recursos sanitarios &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">De acuerdo con los trabajos revisados&#44; publicados en Europa y en Estados Unidos o Canad&#225;&#44; las complicaciones macrovasculares&#44; como el accidente cerebrovascular o el infarto agudo de miocardio&#44; son las que presentan un mayor coste asociado&#44; aunque complicaciones microvasculares leves&#44; como la microalbuminuria o la neuropat&#237;a sintom&#225;tica&#44; que a priori generan un menor coste&#44; si no son controladas&#44; pueden desarrollar eventos mayores como fallo renal o amputaciones de las extremidades&#44; las cuales pueden incrementar considerablemente el coste de la DM2<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;23-25</span></a>&#46; Las complicaciones que generan un mayor coste son las que presentan un mayor riesgo de hospitalizaci&#243;n y un n&#250;mero m&#225;s elevado de d&#237;as de hospitalizaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Costes asociados al control de las hipoglucemias en los pacientes con diabetes mellitus tipo 2</span><p id="par0125" class="elsevierStylePara elsevierViewall">En la literatura se identificaron 6 publicaciones que eval&#250;an el impacto de las hipoglucemias en los costes de la DM2&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">El estudio realizado por Hammer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> en 3 pa&#237;ses europeos estima que en Espa&#241;a los costes del tratamiento de la hipoglucemia var&#237;an en funci&#243;n del marco donde esta es tratada&#59; as&#237;&#44; los costes directos de un episodio de hipoglucemia son de 58&#44;75&#44; de 419&#44;14 o de 1&#46;547&#44;75<span class="elsevierStyleHsp" style=""></span>&#8364; al ser tratada por un familiar o amigo&#44; por un profesional sanitario de atenci&#243;n primaria&#44; o si precisa atenci&#243;n hospitalaria&#46; Los pacientes que requieren tratamiento hospitalario tambi&#233;n suponen un mayor coste indirecto&#44; alcanzando valores de 38&#44;41<span class="elsevierStyleHsp" style=""></span>&#8364; por episodio&#44; siendo estos costes 7 y 8 veces mayores que los asociados a los otros grupos de pacientes &#40;5&#44;65-4&#44;52<span class="elsevierStyleHsp" style=""></span>&#8364;&#41;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#46; El otro estudio europeo seleccionado&#44; realizado en el Reino Unido&#44; indica que al incrementarse la frecuencia y la severidad de los episodios de hipoglucemias aumenta la p&#233;rdida de productividad laboral y el uso de recursos sanitarios<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46; As&#237;&#44; despu&#233;s de un episodio de hipoglucemia la media de d&#237;as laborables perdidos por paciente con DM2 se incrementa de 2&#44;5 a 8&#44;6<span class="elsevierStyleHsp" style=""></span>d&#237;as y el n&#250;mero de contactos con el profesional sanitario aumenta de 11&#44;5 a 13&#44;2 al pasar de una hipoglucemia moderada&#47;leve a una hipoglucemia severa<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">El resto de estudios seleccionados est&#225;n realizados en Norteam&#233;rica y son incluidos en la revisi&#243;n porque aportan informaci&#243;n acerca del impacto de las hipoglucemias en el uso de recursos sanitarios y el coste asociado&#46; De este modo&#44; en el primer estudio se observa un impacto negativo de las hipoglucemias en el estado de salud general y la calidad de vida de los pacientes&#44; y se estima que los individuos con hipoglucemias realizan un 19&#37; m&#225;s de visitas ambulatorias anuales y presentan cerca de un 65&#37; m&#225;s de coste farmacol&#243;gico&#44; lo que se traduce en aproximadamente un 71&#37; m&#225;s de costes sanitarios relacionados con la DM2 que los pacientes sin hipoglucemias<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#46; El segundo trabajo se&#241;ala la insulina y las sulfonilureas como los f&#225;rmacos relacionados con mayor frecuencia con el desarrollo de las hipoglucemias y muestra una asociaci&#243;n entre las hipoglucemias y la no adherencia al tratamiento<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&#46; Asimismo indica que las hipoglucemias conllevan un incremento de costes totales anuales &#40;&#43;3&#46;980&#44;75<span class="elsevierStyleHsp" style=""></span>&#8364;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41; y costes relacionados con la DM2 &#40;&#43;2&#46;968&#44;78<span class="elsevierStyleHsp" style=""></span>&#8364;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&#46; Por su parte&#44; Curkendall et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> tambi&#233;n observan una mayor frecuencia de aparici&#243;n de hipoglucemias en los pacientes con insulinoterapia o que emplean sulfonilureas&#46; Estos autores estiman un coste anual de las hipoglucemias entre 95&#44;37 y 8&#44;49<span class="elsevierStyleHsp" style=""></span>&#8364; para el paciente con insulina y ADO distintos a las sulfonilureas&#44; respectivamente<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&#46; Por otro lado&#44; Quilliam et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> estiman que las hipoglucemias representan un 1&#37; del coste de las hospitalizaciones&#44; el 2&#44;7&#37; del coste de urgencias y el 0&#44;3&#37; del coste ambulatorio&#44; constituyendo el 9&#44;7&#37; del total del coste de la DM2&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Adherencia al tratamiento y relaci&#243;n con el coste en diabetes mellitus tipo 2</span><p id="par0140" class="elsevierStylePara elsevierViewall">No se han recuperado estudios europeos que eval&#250;en la variaci&#243;n del coste y el uso de recursos de los pacientes con DM2 asociados a la adherencia del tratamiento&#44; por lo que se seleccionaron 2 art&#237;culos publicados en Estados Unidos&#46; El primer estudio seleccionado muestra que el incremento en la adherencia terap&#233;utica en pacientes con DM2 mayores de 65<span class="elsevierStyleHsp" style=""></span>a&#241;os&#44; que a priori presentan una menor tasa de adherencia al tratamiento antidiab&#233;tico&#44; es el principal factor predictor de disminuci&#243;n de costes sanitarios totales &#40;&#8211;1&#44;96&#59; desviaci&#243;n est&#225;ndar &#91;DE&#93;&#58; 0&#44;14&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; As&#237;&#44; el 10&#37; de aumento en <span class="elsevierStyleItalic">Medication Possession Ratio</span> &#40;MPR&#41; se asocia a una reducci&#243;n del coste sanitario total del 8&#44;6&#37; &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46; Por otro lado&#44; en el segundo trabajo se observa una relaci&#243;n estad&#237;sticamente significativa entre la adherencia al tratamiento antidiab&#233;tico y la hospitalizaci&#243;n&#59; de este modo&#44; los pacientes que no son adherentes &#40;MPR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>80&#37;&#41; en 2000 tienen 2&#44;53 veces &#40;IC<span class="elsevierStyleHsp" style=""></span>95&#37;&#58; 1&#44;38-4&#44;64&#41; m&#225;s probabilidad de ser hospitalizados en 2001 que los que son adherentes &#40;MPR<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>80&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Influencia de la obesidad en el coste del manejo del paciente con diabetes mellitus tipo 2</span><p id="par0145" class="elsevierStylePara elsevierViewall">Se ha identificado un estudio espa&#241;ol que estima el impacto econ&#243;mico del cambio en el &#237;ndice de masa corporal &#40;IMC&#41; del paciente con DM2 &#40;estudio ECOBIM&#41;&#46; En &#233;l se determina que la reducci&#243;n de una unidad del IMC se traduce en una disminuci&#243;n del 9&#44;4&#37; de los costes sanitarios del paciente obeso y del 2&#44;7&#37; de los costes sanitarios del paciente no obeso<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a>&#46; Asimismo se ha incluido un estudio alem&#225;n que determina el coste incremental asociado a la obesidad en el paciente con DM2<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#46; As&#237;&#44; la obesidad se asocia a un incremento del 18&#37; del coste sanitario total del paciente con DM2&#44; siendo el mayor incremento de coste observado relacionado con la rehabilitaci&#243;n &#40;69&#37;&#41; y las hospitalizaciones &#40;22&#37;&#41;&#46; En los pacientes obesos se observa una interacci&#243;n entre la obesidad y las complicaciones macrovasculares&#44; detect&#225;ndose un incremento de coste de 342&#44;82<span class="elsevierStyleHsp" style=""></span>&#8364;&#44; lo que podr&#237;a explicar el incremento de coste observado en estos pacientes<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Por otro lado&#44; se ha incluido una publicaci&#243;n norteamericana al proporcionar informaci&#243;n relacionada con la asociaci&#243;n entre la p&#233;rdida de peso y el coste de la DM2&#46; En ella el 1&#37; de p&#233;rdida de peso se asocia con una disminuci&#243;n del 3&#44;6&#37; del coste sanitario total&#59; mientras que el 1&#37; de aumento de peso se correlaciona con un incremento del 2&#44;3&#37; del coste sanitario total<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46; En relaci&#243;n con los costes directos asociados a la DM2&#44; los resultados obtenidos son similares&#44; aunque las diferencias son m&#225;s pronunciadas&#59; as&#237;&#44; el 1&#37; de p&#233;rdida de peso conlleva una reducci&#243;n del coste directo relacionado con la DM2 del 5&#44;8&#37;&#44; mientras que el 1&#37; de aumento de peso se traduce &#250;nicamente a el 0&#44;40&#37; de incremento de los costes directos relacionados con la patolog&#237;a<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46; De este modo&#44; la reducci&#243;n de los costes asociados a la DM2 derivados de la p&#233;rdida de peso contribuyen a una disminuci&#243;n del 51&#37; de los costes sanitarios totales de estos pacientes y del 37&#37; de los costes sanitarios totales de los pacientes obesos<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46;</p></span></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discusi&#243;n</span><p id="par0155" class="elsevierStylePara elsevierViewall">Esta revisi&#243;n pone de manifiesto el escaso n&#250;mero de publicaciones espa&#241;olas existentes que estiman &#250;nicamente los costes de la DM2&#44; sin incluir la poblaci&#243;n con DM1&#44; y eval&#250;a los factores que contribuyen a la variaci&#243;n de los mismos&#44; mostrando la necesidad de la inclusi&#243;n de art&#237;culos de otros pa&#237;ses para lograr una visi&#243;n inclusiva de los factores que pueden modificar el coste del paciente con DM2&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Aunque algunos autores estiman conjuntamente el coste de la DM sin diferenciar entre subtipos&#44; es importante estimar el coste de la DM2 por separado<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a>&#46; Ambos tipos de DM difieren en el uso de recursos sanitarios&#44; empleo de terapias farmacol&#243;gicas&#44; distinta regularidad en los controles gluc&#233;micos requeridos&#44; aparici&#243;n de complicaciones y coexistencia de comorbilidades<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a>&#44; por lo que es anticipable que los costes y los factores explicativos entre ambas poblaciones de pacientes difieran sustancialmente&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">La mayor&#237;a de estudios identificados en la revisi&#243;n estiman el coste del manejo del paciente con DM2 explicado por uso de recursos y los costes directos asociados&#44; mientras que determinan el coste indirecto con menor frecuencia&#46; En la misma l&#237;nea&#44; los estudios que examinan los costes generados por las complicaciones micro y macrovasculares asociadas a la DM2 se centran o en la determinaci&#243;n del incremento de los costes directos o en el aumento del uso de recursos asociado&#44; sin evaluar los costes indirectos&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">En l&#237;neas generales&#44; los estudios de costes de la DM2 indican que las complicaciones son el principal responsable de los costes directos de la patolog&#237;a&#46; De esta forma&#44; en Espa&#241;a&#44; los principales factores explicativos tanto del consumo farmacol&#243;gico como de las hospitalizaciones son las complicaciones de la DM2&#44; sugiriendo que estrategias que permitan disminuir la frecuencia de aparici&#243;n de complicaciones contribuir&#237;an a la reducci&#243;n de los costes de la patolog&#237;a&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">En este sentido&#44; el estudio ROSSO&#44; realizado en Europa&#44; pone de manifiesto que la realizaci&#243;n de SMBG permite un mayor control gluc&#233;mico y una reducci&#243;n de las complicaciones asociadas&#44; contribuyendo as&#237; a una disminuci&#243;n de los costes&#46; Sin embargo&#44; los SMBG han generado una gran controversia en los &#250;ltimos a&#241;os&#46; Algunos estudios han indicado que en pacientes con DM2 de m&#225;s de un a&#241;o de evoluci&#243;n y sin tratamiento con insulina no existen evidencias de que los SMBG permitan obtener mejores beneficios cl&#237;nicos o mejoras en la satisfacci&#243;n y en la calidad de vida relacionada con la salud<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#46; Por lo tanto&#44; conocer el impacto de los SMBG en esta poblaci&#243;n aportar&#237;a informaci&#243;n valiosa desde la perspectiva de los pacientes&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Por otro lado&#44; el momento adecuado de la iniciaci&#243;n de la terapia con insulina y las caracter&#237;sticas del paciente que lo hacen candidato a la insulinoterapia tambi&#233;n es un tema que genera gran debate<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#46; Como se observa en el estudio europeo INSTIGATE&#44; el inicio de la terapia insul&#237;nica mejora el control gluc&#233;mico&#44; aunque lleve consigo mayores costes asociados&#46; Las principales barreras relacionadas con el tratamiento con insulina en el paciente con DM2 son las hipoglucemias y la ganancia de peso asociadas<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&#46; El estudio realizado por Kostev y Rathmann<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> muestra que el empleo de ADO tipo<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">i</span>-DPP4 permite retrasar el empleo de insulina y permite un control gluc&#233;mico &#243;ptimo&#44; con una menor frecuencia de hipoglucemias y con un nulo aumento de peso asociado&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Llama la atenci&#243;n que los costes indirectos asociados a la DM2 solo se calculan en los estudios que eval&#250;an el efecto de las hipoglucemias en los costes de la patolog&#237;a&#44; denotando la posible importancia que los autores atribuyen a la repercusi&#243;n sobre la vida diaria de los pacientes y sobre la p&#233;rdida de productividad de esta complicaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a>&#46; Adicionalmente&#44; pocas publicaciones europeas estudian los costes de la DM2 explicados por la adherencia al tratamiento o la influencia de la obesidad en dichos costes&#44; sin describir el uso de recursos asociado&#46; Al mismo tiempo&#44; se observa la ausencia de publicaciones que eval&#250;en la asociaci&#243;n entre cambios en la calidad de vida relacionada con la salud &#40;CVRS&#41; y los costes de estos pacientes&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Los resultados del estudio <span class="elsevierStyleItalic">Real-life Effectiveness and Care Patterns of Diabetes Management</span> &#40;RECAP-DM&#41;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> en la poblaci&#243;n espa&#241;ola muestran una asociaci&#243;n entre la aparici&#243;n de hipoglucemias y una menor satisfacci&#243;n y adherencia con el tratamiento&#44; la cual se relaciona&#44; a la vez&#44; con un peor control gluc&#233;mico y peores resultados cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>&#46; En este sentido&#44; los atributos de los ADO mejor valorados por los pacientes con DM2 son la menor frecuencia de eventos hipogluc&#233;micos&#44; ausencia de aumento de peso y de efectos gastrointestinales &#40;n&#225;useas&#41; y la eficacia<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>&#46; Por lo tanto&#44; es presumible que tratamientos que presenten estas caracter&#237;sticas generar&#225;n mayor satisfacci&#243;n en el paciente&#44; la cual se puede traducir en una mayor tasa de adherencia al tratamiento y en resultados cl&#237;nicos m&#225;s &#243;ptimos<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a>&#46; Estudios que eval&#250;en la asociaci&#243;n entre la adherencia al tratamiento de la DM2 y los costes asociados a la misma proporcionar&#237;an una valiosa informaci&#243;n acerca de las consecuencias cl&#237;nicas y econ&#243;micas de la no adherencia al tratamiento&#44; siendo a la vez esenciales para la implementaci&#243;n de estrategias encaminadas a mejorar los resultados cl&#237;nicos a alcanzar&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Finalmente&#44; otro factor que influye en los costes de la DM2 es la obesidad&#44; y existe una relaci&#243;n exponencial entre el IMC y el riesgo de DM2<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&#46; La coexistencia de DM2 y obesidad aumenta el riesgo de complicaciones a largo plazo&#46; Desafortunadamente&#44; el aumento de peso en los pacientes con DM2 muchas veces es consecuencia del empleo de algunos principios activos&#44; principalmente sulfonilureas&#44; tiazolidindionas o glinidas<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a>&#46; La mayor&#237;a de gu&#237;as recomiendan opciones terap&#233;uticas asociadas a un leve o nulo aumento de peso&#44; o a p&#233;rdida de peso&#46; Adem&#225;s&#44; seg&#250;n los distintos estudios evaluados&#44; la reducci&#243;n del IMC se traduce en beneficios econ&#243;micos a corto plazo&#44; principalmente en pacientes obesos<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">El conjunto de estos datos sugiere que la incorporaci&#243;n de alternativas de tratamiento hipoglucemiantes que&#44; adem&#225;s del cumplimiento del objetivo terap&#233;utico del control m&#225;s &#243;ptimo de las glucemias con una menor frecuencia de hipoglucemias&#44; favorezcan una regulaci&#243;n m&#225;s adecuada del peso&#44; puede contribuir a reducir los costes asociados al manejo integral del paciente con DM2&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Limitaciones de la revisi&#243;n sistem&#225;tica</span><p id="par0205" class="elsevierStylePara elsevierViewall">Una de las principales limitaciones de la presente revisi&#243;n es la escasez de publicaciones espa&#241;olas con datos de costes actualizados&#44; con la consecuente dificultad de extrapolar los resultados obtenidos en los distintos estudios identificados a la poblaci&#243;n diab&#233;tica actual&#44; dado el tiempo transcurrido desde la publicaci&#243;n de los estudios que eval&#250;an el coste de la DM2 en Europa y Espa&#241;a y los grandes cambios en relaci&#243;n al manejo del paciente con DM2&#44; tanto asociados con la introducci&#243;n en el mercado de nuevos principios activos&#44; como con los cambios en las pol&#237;ticas sanitarias que se han producido durante la &#250;ltima d&#233;cada<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclusiones</span><p id="par0210" class="elsevierStylePara elsevierViewall">Esta revisi&#243;n de la literatura revela el coste elevado que representa la DM2 para los sistemas de salud&#44; aun cuando la contribuci&#243;n de los costes indirectos a la carga econ&#243;mica de la enfermedad ha sido poco explorada&#46; Anualmente&#44; el n&#250;mero de hospitalizaciones y de hipoglucemias&#44; el aumento de peso&#44; la aparici&#243;n de complicaciones vasculares relacionadas con la DM2 y la escasa adherencia al tratamiento determinan un coste m&#225;s alto del manejo del paciente diab&#233;tico en los diversos sistemas sanitarios analizados&#44; incluyendo el sistema p&#250;blico de salud espa&#241;ol&#46; La relaci&#243;n entre los cambios en CVRS y en adherencia con los costes&#44; directos e indirectos&#44; de la patolog&#237;a necesita ser investigada&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Financiaci&#243;n</span><p id="par0215" class="elsevierStylePara elsevierViewall">El proyecto descrito en este manuscrito&#44; as&#237; como la elaboraci&#243;n del mismo&#44; han sido financiados por Almirall S&#46;A&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflicto de intereses</span><p id="par0220" class="elsevierStylePara elsevierViewall">Este estudio fue patrocinado por Almirall&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Diego Gonz&#225;lez Segura y Anna Raya Torres trabajan actualmente en Almirall&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Silvia Paz y Luis Lizan trabajan para una entidad independiente de investigaci&#243;n a trav&#233;s de la cual llevaron a cabo la revisi&#243;n de la literatura y la redacci&#243;n del manuscrito&#46;</p></span></span>"
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          "titulo" => "Material y m&#233;todos"
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          "titulo" => "Resultados"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Caracter&#237;sticas descriptivas&#44; metodol&#243;gicas y nivel de evidencia de los estudios analizados"
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              "identificador" => "sec0025"
              "titulo" => "Estimaci&#243;n del coste sanitario total destinado al manejo del paciente con diabetes mellitus tipo 2 en Europa"
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                0 => array:2 [
                  "identificador" => "sec0030"
                  "titulo" => "Coste sanitario total destinado a la diabetes mellitus tipo 2 en Europa"
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                1 => array:2 [
                  "identificador" => "sec0035"
                  "titulo" => "Coste sanitario total destinado a la diabetes mellitus tipo 2 en Espa&#241;a"
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                2 => array:2 [
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                  "titulo" => "Componentes explicativos del coste directo"
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              "titulo" => "An&#225;lisis de los factores que explican los cambios en el coste del paciente con diabetes mellitus tipo 2"
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                0 => array:2 [
                  "identificador" => "sec0050"
                  "titulo" => "Influencia de las complicaciones vasculares en el coste asociado a la diabetes mellitus tipo 2"
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                1 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "Costes asociados al control de las hipoglucemias en los pacientes con diabetes mellitus tipo 2"
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                2 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "Adherencia al tratamiento y relaci&#243;n con el coste en diabetes mellitus tipo 2"
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                3 => array:2 [
                  "identificador" => "sec0065"
                  "titulo" => "Influencia de la obesidad en el coste del manejo del paciente con diabetes mellitus tipo 2"
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          "titulo" => "Discusi&#243;n"
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          "titulo" => "Limitaciones de la revisi&#243;n sistem&#225;tica"
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          "titulo" => "Conclusiones"
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          "titulo" => "Financiaci&#243;n"
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          "identificador" => "sec0090"
          "titulo" => "Conflicto de intereses"
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        12 => array:1 [
          "titulo" => "Bibliograf&#237;a"
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    "fechaRecibido" => "2013-11-18"
    "fechaAceptado" => "2014-02-26"
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec314656"
          "palabras" => array:5 [
            0 => "Diabetes mellitus tipo 2"
            1 => "Costes"
            2 => "Adherencia"
            3 => "Hipoglucemia"
            4 => "Obesidad"
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        ]
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        0 => array:4 [
          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "Type 2 diabetes mellitus"
            1 => "Cost"
            2 => "Adherence"
            3 => "Hypoglycemia"
            4 => "Obesity"
          ]
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    "resumen" => array:2 [
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Identificar los factores que explican cambios en el coste del paciente con diabetes mellitus tipo<span class="elsevierStyleHsp" style=""></span>2 &#40;DM2&#41; seg&#250;n la literatura&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">M&#233;todo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se consultaron bases de datos electr&#243;nicas nacionales e internacionales para identificar art&#237;culos publicados entre enero de 2001 y diciembre de 2012 que estimasen el coste de la DM2 en Espa&#241;a y Europa&#59; y evaluasen los factores determinantes del coste&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Se revisaron 26 publicaciones de las 1&#46;530 identificadas&#59; 9 estimaban el coste de la DM2 en Europa y 17 evaluaban los factores que determinaban cambios en los costes&#46; Las complicaciones y las hipoglucemias incrementan hasta 4 veces el coste&#44; mientras que la optimizaci&#243;n de la adherencia y del control del peso lo reduce&#46; Las complicaciones explican el 71&#44;4&#37; del coste directo en Espa&#241;a&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Estrategias terap&#233;uticas asociadas a una menor frecuencia de hipoglucemias y a una mejor adherencia y un &#243;ptimo control del peso permitir&#237;an reducir el coste de la DM2&#46;</p>"
      ]
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objective</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">To analyze the main factors that influence the health care costs of treating type 2 diabetes mellitus &#40;T2DM&#41; patients&#44; using a literature review&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">National and international electronic data bases were searched to identify articles published between January 2001 and December 2012 that estimated T2DM costs and evaluated cost determining factors&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A total of 26 articles were reviewed out of the 1530 relevant titles identified&#46; In Spain&#44; 71&#46;4&#37; of the direct costs of T2DM is related to T2DM complications&#46; Hypoglycemia and other complications could increase T2DM costs by up to 4-fold&#46; Improving adherence and weight control reduce T2DM costs&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusion</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Therapeutic strategies associated to less hypoglycemia events&#44; better adherence&#44; and weight control may lead to lower T2DM costs&#46;</p>"
      ]
    ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figura 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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            "Alto" => 1405
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        "descripcion" => array:1 [
          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flujo de la revisi&#243;n sistem&#225;tica&#46;</p>"
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        "etiqueta" => "Tabla 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ADO&#58; antidiab&#233;ticos orales&#59; AP&#58; atenci&#243;n primaria&#59; CD&#58; coste directo&#59; <span class="elsevierStyleSmallCaps">I</span>&#58; insulina&#59; NA&#58; no aplicable&#59; SD&#58; sin datos disponibles&#59; SMBG&#58; <span class="elsevierStyleItalic">Self Monitoring of Blood Glucose</span>&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                  \t\t\t\t" style="border-bottom: 2px solid black">Autor &#40;estudio&#41; &#40;pa&#237;s&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Enfermer&#237;a&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Pruebas diagn&#243;stica&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Pruebas complementarias&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" style="border-bottom: 2px solid black">Hospitalizaci&#243;n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Material SMBG&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Otros f&#225;rmacos&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">CD total&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">J&#246;nsson et al&#46; &#40;CODE-2&#41;</span><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleBold">&#40;Europa</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleBold">&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">891&#44;84&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;974&#44;51&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">152&#44;34&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">122&#44;76&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">SD&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">704&#44;00&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="char" valign="\n
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                  \t\t\t\t">4&#46;191&#44;49&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  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Schmitt-Koopmann et al&#46;</span><a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleBold">&#40;Suiza&#41;</span>&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">280&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">24&#44;41<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">163&#44;70&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">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;764&#44;84&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">1&#46;006&#44;64&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&#46;335&#44;83&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"><span class="elsevierStyleBold">Athanasakis et al&#46;</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleBold">&#40;Grecia&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&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">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&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">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Controlado</span>&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">SD&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">257&#44;61<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">497&#44;75<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;844&#44;89&nbsp;\t\t\t\t\t\t\n
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                  \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  " colspan="14" align="char" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Weber et al&#46; &#40;ROSSO&#41;</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleBold">&#40;Alemania&#41;</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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADO</span>&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">735&#44;29&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;898&#44;75<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">217&#44;36&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&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">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&#46;851&#44;34&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADO &#43; SMBG</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;615&#44;83<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADO &#43; <span class="elsevierStyleSmallCaps">I</span></span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADO &#43; <span class="elsevierStyleSmallCaps">I</span> &#43; SMBG</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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">56&#44;54&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">339&#44;26&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">NA&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">147&#44;25&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">SD&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">581&#44;93&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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Insulina&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">16&#44;49&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">22&#44;38&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">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
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                  \t\t\t\t</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">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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">16&#44;49&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</td><td class="td" title="\n
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                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">679&#44;71&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\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Basal&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">121&#44;33&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</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">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">54&#44;19&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">NA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">811&#44;64&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>Insulina&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">227&#44;35&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">SD&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">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">77&#44;75&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">246&#44;67&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</td><td class="td" title="\n
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                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">910&#44;59&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Test laboratorio&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" style="border-bottom: 2px solid black">Pruebas complementarias&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Hospitalizaci&#243;n&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">ADO&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Insulina&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Material SMBG&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" style="border-bottom: 2px solid black">Otros F&#225;rmacos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">CD total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><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"><span class="elsevierStyleItalic">Mata et al&#46; &#40;CODE-2&#41;</span><a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleItalic">&#40;Espa&#241;a&#41;</span>&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">115&#44;44&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">139&#44;69&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116&#44;26<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a>&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#44;12&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#44;87&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">617&#44;16&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89&#44;76&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">90&#44;59&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#44;68&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;930&#44;32&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="14" align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Nesser et al&#46; &#40;ROSSO&#41;</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleItalic">&#40;Espa&#241;a&#41;</span></td></tr><tr title="table-row"><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"><span class="elsevierStyleHsp" style=""></span>ADO&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">722&#44;91 &#43; 930&#44;09<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a>&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">409&#44;94&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">119&#44;02&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;181&#44;96&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ADO &#43; SMBG&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">747&#44;16 &#43; 862&#44;87<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a>&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">365&#44;86&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">130&#44;04&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="" valign="\n
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                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#44;35&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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="char" valign="\n
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                  \t\t\t\t">2&#46;131&#44;27&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ADO &#43; <span class="elsevierStyleSmallCaps">I</span>&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">865&#44;07 &#43; 2&#46;440&#44;93<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a>&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="" valign="\n
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                  \t\t\t\t">&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="" valign="\n
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                  \t\t\t\t">&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">998&#44;41&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">865&#44;07&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="" valign="\n
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                  \t\t\t\t">&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
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                  \t\t\t\t">0&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">SD&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="char" valign="\n
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                  \t\t\t\t">4&#46;592&#44;03&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ADO &#43; <span class="elsevierStyleSmallCaps">I</span> &#43; SMBG&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">927&#44;88 &#43; 1&#46;852&#44;46<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a>&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">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SD&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  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">SD&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">673&#44;32&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
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                  \t\t\t\t">274&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="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">47&#44;39&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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="char" 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
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                  \t\t\t\t"><span class="elsevierStyleItalic">Costi et al&#46;</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleItalic">&#40;Espa&#241;a&#41;</span></td></tr><tr title="table-row"><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"><span class="elsevierStyleHsp" style=""></span>Basal&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">157&#44;85&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">124&#44;87<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">c</span></a>&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">SD&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">SD&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">SD&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">SD&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">127&#44;22&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">190&#44;84&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">NA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">114&#44;27&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Insulina&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">187&#44;30&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">174&#44;34<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">c</span></a>&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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">SD&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">SD&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">399&#44;34&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">102&#44;49&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">212&#44;04&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">180&#44;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autor &#40;estudio&#41; &#40;pa&#237;s&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="9" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Uso de recursos</td><td class="td" title="\n
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                  \t\t\t\t  " colspan="8" align="center" valign="\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&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" style="border-bottom: 2px solid black">CM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">U&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">TL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">IQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">H&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">DH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">ADO<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">b</span></a>&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">I<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Otros<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">b</span></a>&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" style="border-bottom: 2px solid black">CM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">U&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">TL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">H&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">ADOs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleSmallCaps">I</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Otros&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" style="border-bottom: 2px solid black">CD<span class="elsevierStyleInf">T</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="18" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">William et al&#46;&#40;CODE-2&#41;</span><a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a><span class="elsevierStyleItalic">&#44; Europa</span><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><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"><span class="elsevierStyleHsp" style=""></span>S&#47;C&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
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD&nbsp;\t\t\t\t\t\t\n
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