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Original article
The relationship between glycosylated hemoglobin, time-in-range and glycemic variability in type 1 diabetes patients under flash glucose monitoring
Relación entre hemoglobina glucosilada, tiempo en rango y variabilidad glucémica en una cohorte de pacientes pediátricos y adultos con diabetes tipo 1 con monitorización flash de glucosa
Gonzalo Díaz-Sotoa,1,
Corresponding author
diazsotogonzalo@gmail.com

Corresponding author.
, M. Pilar Bahíllo-Curiesesb,1, Rebeca Jimeneza, Maria de la O. Nietoa, Emilia Gomeza, Beatriz Torresa, Juan Jose López Gomeza, Daniel de Luisa
a Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid, Centro de Investigación de Endocrinología y Nutrición Clínica (IENVa), Universidad de Valladolid, Valladolid, Spain
b Servicio de Pediatría, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The progressive implementation of continuous glucose monitoring &#40;CGM&#41;&#44; along with its further technological development and funding&#44; have led to a revolution in the approach to metabolic control in type 1 diabetes mellitus &#40;DM1&#41;&#46; Although the relationship between HbA<span class="elsevierStyleInf">1c</span> and the development of chronic complications is widely accepted&#44; the huge amount of data provided by CGM has led to a change in the perception of blood glucose control &#8220;beyond HbA<span class="elsevierStyleInf">1c</span>&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">1</span></a> In fact&#44; many authors advocate replacing the classic DM1 control parameters &#40;HbA<span class="elsevierStyleInf">1c</span> and hypoglycaemia&#41; with new glucose parameters derived from the CGM evaluation&#44; both measures of centrality &#40;time in range &#91;TIR&#93;&#41; and of blood glucose variability &#40;BGV&#41; &#40;coefficient of variation &#91;CV&#93;&#44; standard deviation &#91;SD&#93;&#44; etc&#46;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The limitations cited for the replacement of HbA<span class="elsevierStyleInf">1c</span> include&#58; the lack of precision measuring it in the laboratory in common clinical situations &#40;haemoglobinopathies&#44; anaemia&#44; uraemia and pregnancy&#44; among others&#41;&#59; its variable and unpredictable relationship with the mean glucose on an individual level&#59; and a half-life of around three months which does not allow for detecting rapid changes in the evaluation of blood glucose control&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">As an alternative to the classic control parameters&#44; TIR and CV have been postulated as the preferred metrics&#44; partly due to their close relationship with the levels of HbA<span class="elsevierStyleInf">1c</span> and hypoglycaemia&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">4&#44;5</span></a> Moreover&#44; preliminary studies have associated these levels with the development of chronic complications&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">6</span></a> Despite this&#44; the reference intervals assumed to be normal &#40;TIR<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>70&#37; and CV<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37;&#41; have not been derived directly from prospective studies&#44; but based on their linear relationship with the classic parameters&#58; HbA<span class="elsevierStyleInf">1c</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>7&#46;0&#37; and increased incidence of severe hypoglycaemia episodes&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5&#44;7</span></a> Several authors recently questioned this correlation due to the lack of precision in the linear relationship between HbA<span class="elsevierStyleInf">1c</span> and TIR&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">7</span></a> similar to that between HbA<span class="elsevierStyleInf">1c</span> and mean glucose&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">8</span></a> In fact&#44; recent studies in patients with type 2 diabetes and retrospective continuous glucose monitoring explain the lack of correlation between TIR and HbA<span class="elsevierStyleInf">1c</span> as due to the influence of BGV&#44; and insist on the need to establish individualised TIR targets taking this into account&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to assess the correlation between TIR and HbA<span class="elsevierStyleInf">1c</span> and their relationship with BGV&#44; in a cohort of paediatric and adult patients with DM1 on treatment with multiple dose injection &#40;MDI&#41; insulin therapy or continuous subcutaneous insulin infusion &#40;CSII&#41; and flash glucose monitoring&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">Cross-sectional study in a cohort of patients with DM1 on intensive insulin treatment &#40;CSII or MDI&#41; with flash glucose monitoring &#40;Free Style Libre&#44; Abbot Diabetes Care&#44; Witney&#44; United Kingdom&#41; under follow-up at the Paediatric Endocrinology Unit and the Adult Endocrinology and Nutrition Department of a tertiary hospital&#46; Flash glucose monitoring was prescribed following the public funding and prioritisation criteria approved by the Spanish National Health Service &#40;visual impairment or severe functional limitations&#44; recurrent hypoglycaemia&#44; and pregnant women or women planning a pregnancy&#41;&#46; We collected clinical and analytical data &#40;HbA<span class="elsevierStyleInf">1c</span>&#58; turbidimetric inhibition immunoassay&#59; NGSP&#44; Roche Diagnostics&#44; Geneva&#44; Switzerland&#41;&#46; We also analysed metabolic control data downloaded from the device for the last 15 days of flash glucose monitoring prior to the face-to-face consultation&#44; when the device had been used for at least three months&#46; Data collected from flash glucose monitoring were defined as&#58; mean blood glucose&#59; TIR &#40;&#37;&#41; &#40;defined as time with glucose 70&#8211;180<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#59; CV &#40;&#37;&#41;&#59; SD &#40;mg&#47;dl&#41;&#44; Glucose Management Indicator &#40;GMI&#41;&#59; time above range &#40;TAR &#91;&#37;&#93;&#44; defined as time with glucose &#62;180<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#59; time below range &#40;TBR &#91;&#37;&#93;&#44; defined as time with glucose &#60;70<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#59; number of scans&#59; and sensor use&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> Those patients with less than 80&#37; use of the device were excluded&#46; The study was approved by the hospital&#39;s Independent Ethics Committee&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The results are expressed as mean and SD&#46; Normal distribution of the variables was analysed with the Kolmogorov&#8211;Smirnov test&#46; Quantitative variables with normal distribution were analysed with a two-sided Student&#39;s <span class="elsevierStyleItalic">t</span> test&#46; Non-parametric variables were evaluated using the Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#46; Qualitative variables were evaluated using the Chi-square test and&#44; where necessary&#44; Fisher&#39;s exact test&#46; The association of quantitative variables was calculated using Pearson&#39;s linear correlation coefficient&#46; Finally&#44; a multiple regression model was used that incorporated as independent variables the effect of TIR&#44; CV&#44; age and type of treatment&#44; as well as the interaction between TIR and CV &#40;TIR-CV&#41; on HbA<span class="elsevierStyleInf">1c</span> as dependent variable&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">P</span> values &#60;0&#46;05 were considered statistically significant&#46; We used the SPSS&#174; statistical package&#44; version 17&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41; for the analysis&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0040" class="elsevierStylePara elsevierViewall">We studied 195 patients with DM1&#58; 70 were paediatric patients &#40;children and adolescents under 20 years of age&#41; and 125 adults &#40;&#8805;20 years of age&#41;&#59; 42&#46;6&#37; were female&#59; 26&#46;2&#37; were on treatment with CSII and 28&#46;7&#37; had a CV<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37;&#46; In the paediatric group&#44; the mean age was 12&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;4 years&#44; the mean time since onset of diabetes was 5&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;5 years and the mean HbA<span class="elsevierStyleInf">1c</span> was 6&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&#37;&#44; with 28&#46;6&#37; on treatment with CSII&#46; The mean number of flash glucose monitoring scans per day was 12&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;8&#44; with mean blood glucose of 150<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27 mg&#47;dl&#44; SD of 63&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;7 mg&#47;dl&#44; CV of 42&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;6&#37; and TIR of 64&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;9&#37;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In the adult group &#40;aged &#8805;20&#41;&#44; the mean age was 37&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;3 years&#44; the mean time since onset of diabetes was 18&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;8 years and the mean HbA<span class="elsevierStyleInf">1c</span> was 7&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;1&#37;&#46; The mean number of flash glucose monitoring scans per day was 10&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;6&#44; with mean blood glucose of 173<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>37 mg&#47;dl&#44; SD of 68&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>21&#46;8 mg&#47;dl&#44; CV of 40&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;1&#37; and TIR of 52&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;2&#37; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Analysis of the association between TIR and HbA<span class="elsevierStyleInf">1c</span> revealed a strong negative linear correlation &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;746&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;557&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; In other words&#44; each absolute increase in TIR of 10&#37; would mean a 0&#46;75&#37; change in HbA<span class="elsevierStyleInf">1c</span>&#46; However&#44; when analysed in patients with low BGV&#44; this correlation was altered &#40;CV<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37;&#41; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;852&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;836&#41;&#44; showing a higher correlation compared to patients with a high BGV index &#40;CV<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>36&#37;&#41; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;703&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;551&#41;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Analysis of the association between TIR and GMI revealed a strong negative linear correlation &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;846&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;715&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; This correlation was also altered when analysing patients with low BGV &#40;CV<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37;&#41; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;980&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;960&#41; versus those with high BGV &#40;CV<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>36&#37;&#41; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;837&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;701&#41;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The TIR-HbA<span class="elsevierStyleInf">1c</span> correlation remained stable when analysed separately in the paediatric group &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;724&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;525&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and adult group &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;706&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;498&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; and by type of treatment used&#58; MDI &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;747&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;558&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and CSII &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;711&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;506&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">When analysing HbA<span class="elsevierStyleInf">1c</span> as a dependent variable in a multiple regression model that included TIR&#44; CV&#44; TIR&#8211;CV interaction&#44; age and type of treatment as independent variables&#44; the only variables that maintained statistical significance were TIR &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;031&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; CV &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;843&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and TIR-CV interaction &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;017&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Lastly&#44; we analysed the correlation between the different glucose metres used&#44; finding a statistically significant higher correlation between the variables with a higher centrality component &#40;mean glucose&#44; HbA<span class="elsevierStyleInf">1c</span>&#44; GMI&#44; TIR and TAR&#41; and those with a higher dispersion component &#40;SD&#44; CV and TBR&#41;&#46; Finally&#44; a higher percentage of device use &#40;number of scans and sensor use&#41; was correlated with better values in the metabolic control parameters &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">CGM has revolutionised the approach to metabolic control in DM1&#46; In fact&#44; some authors advocate replacing HbA<span class="elsevierStyleInf">1c</span> as the only control parameter&#44; as it almost exclusively examines the central distribution of glucose levels&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">6</span></a> Nevertheless&#44; although it is true that HbA<span class="elsevierStyleInf">1c</span> has certain well-known limitations that can make it difficult to interpret&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">3</span></a> it is also the parameter with the most scientific evidence relating to the development of long-term complications&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">11</span></a> Therefore&#44; having new alternative blood glucose parameters which allow a more complete assessment of the blood glucose profile without the limitations of HbA<span class="elsevierStyleInf">1c</span> &#40;centrality &#91;TIR&#93;&#44; hypoglycaemia &#91;TBR&#93;&#44; hyperglycaemia &#91;TAR&#93; and BGV &#91;CV&#93;&#41; is a promising prospect&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The association between TIR and HbA<span class="elsevierStyleInf">1c</span>&#44; both parameters of centrality&#44; is of particular interest when considering replacing HbA<span class="elsevierStyleInf">1c</span> or the complementary use of the two variables&#46; Recent studies have described a strong linear association between HbA<span class="elsevierStyleInf">1c</span> and TIR&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5&#44;7</span></a> In fact&#44; the authors who support this substitution base their arguments on the close correlation&#46; However&#44; it seems reasonable to think that patients with higher BGV should have lower TIR indices even with the same HbA<span class="elsevierStyleInf">1c</span>&#44; so the TIR control objective should be personalised&#44; taking the BGV of each individual into account&#44; or even their type of diabetes&#46; To date&#44; only one study in patients with type 2 diabetes and retrospective continuous glucose monitoring for 72 h has assessed the influence of BGV on the correlation between GMI and TIR&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">9</span></a> To our knowledge&#44; this study is one of the first to assess the association between these glucose measurement systems in a population with DM1 treated with MDI or CSII and with different age ranges&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">When we analysed the association between plasma HbA<span class="elsevierStyleInf">1c</span> and TIR&#44; we found a strong linear correlation&#44; similar to those described in previous studies &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;746&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;557&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; In other words&#44; each absolute increase in TIR of 10&#37; would mean a 0&#46;75&#37; reduction in HbA<span class="elsevierStyleInf">1c</span>&#46; However&#44; this linear correlation clearly changes according to the BGV and the TIR value&#46; In fact&#44; both regression lines stratified according to the CV intersect at an HbA<span class="elsevierStyleInf">1c</span> of around 7&#46;7&#37;&#44; similar to the study published by Lu et al&#46; in type 2 diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">9</span></a> Therefore&#44; the behaviour of the association between TIR and plasma HbA<span class="elsevierStyleInf">1c</span> depends directly on the CV&#46; In other words&#44; with HbA<span class="elsevierStyleInf">1c</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>7&#46;8&#37;&#44; the higher the CV&#44; the greater the TIR&#59; and inversely&#44; with HbA<span class="elsevierStyleInf">1c</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>7&#46;8&#37;&#44; the higher the CV&#44; the lesser the TIR &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; This interdependence of the three variables &#40;TIR&#44; HbA<span class="elsevierStyleInf">1c</span> and CV&#41; is similar to that found when analysing TIR compared to GMI &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;846&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;715&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; being modified by the CV in a similar way to the association between plasma HbA<span class="elsevierStyleInf">1c</span> and TIR for a GMI cut-off point of 8&#46;1&#37;&#46; Moreover&#44; it is particularly significant that the correlation between TIR and GMI in patients with low BGV is close to 1&#44; i&#46;e&#46; practically perfect &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;980&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;960&#41;&#46; That should not be so surprising&#44; since the GMI comes from mathematical calculation using the mean blood glucose for the last 15 days of downloaded data&#44; so it is logical that patients with practically no amplitude in their excursions&#44; determined by BGV&#44; should have a virtually &#8220;flat and non-fluctuating&#8221; blood glucose profile&#44; with TIR and GMI matching in a perfect linear fashion &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">12</span></a> In fact&#44; divergences between GMI and HbA<span class="elsevierStyleInf">1c</span> have recently been related by the glycosylation index more than other biological factors&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">13</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Our study found this relationship between the variables analysed regardless of the age of the patients studied &#40;adult or paediatric&#41; and the type of treatment used &#40;MDI or CSII&#41;&#46; In other words&#44; as supported by the multiple regression analysis&#44; the relationship between HbA<span class="elsevierStyleInf">1</span>c&#47;GMI and TIR is modified by the CV in the different groups studied&#44; and not by age or the type of treatment&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Lastly&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the correlations between the different glucose measurement parameters most used in daily clinical practice according to international consensus&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> The statistically significant relationship between practically all the variables analysed clarifies things greatly&#46; This relationship reflects the close dependence between the different parameters and&#44; as has been recently described&#44; highlights the difficulty of modifying some of them independently from the others&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">14</span></a> Obviously&#44; this relationship is particularly close between variables that measure the same distribution pattern&#44; such as centrality &#40;HbA<span class="elsevierStyleInf">1c</span>&#44; GMI&#44; mean glucose&#44; TIR&#41; and BGV-amplitude of blood glucose excursions &#40;SD&#44; CV&#44; TAR and TBR&#41;&#44; in addition to the relationship between intensive use of the device &#40;percentage of use and number of scans&#41; and better metabolic control&#46; This interrelation supports the use of the new glucose metres as descriptive variables of metabolic control to be used together&#44; and not as a replacement for the classic control parameters&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">This study is one of the first to analyse the relationship between TIR and HbA<span class="elsevierStyleInf">1c</span> and their association with BGV in a cohort of adult and paediatric patients with DM1 on treatment with MDI or CSII and using flash glucose monitoring in real clinical practice&#46; Although the relatively small sample size may be considered one of its main limitations &#40;especially compared to big data studies&#41;&#44; the fact that it was conducted in a DM1 cohort under follow-up at a tertiary hospital ensures a thorough overall analysis of the patients&#8217; clinical characteristics and metabolic control analytical variables&#44; traditionally absent in this type of study&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In conclusion&#44; the CV changes the association between the TIR and HbA<span class="elsevierStyleInf">1c</span>&#47;GMI and must be taken into account when personalising TIR targets&#44; regardless of age or the type of treatment used&#46; This close interrelation between the different glucose metres as variables of metabolic control supports them being used together&#44; and not as replacements for the classic control parameters&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflicts of interest</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Flash glucose monitoring in patients with type 1 diabetes provides new glucometric data that allow for the assessment of glycemic control beyond HbA<span class="elsevierStyleInf">1c</span>&#46; The objective of the study was to evaluate the relationship between HbA<span class="elsevierStyleInf">1c</span>&#44; time-in-range &#40;TIR&#41; and glycemic variability in a cohort of paediatric and adult patients with type 1 diabetes and treatment with flash glucose monitoring&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This was a cross-sectional study in 195 patients with type 1 diabetes &#40;42&#46;6&#37; females&#44; 70 paediatric&#44; 26&#46;2&#37; continuous subcutaneous insulin infusion&#44; 28&#46;7&#37; coefficient of variation &#91;CV&#93;<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37;&#41; in intensive treatment and flash glucose monitoring&#46; Clinical&#44; analytical and glucometric data were evaluated&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The relationship between the TIR and HbA<span class="elsevierStyleInf">1c</span> showed a strong negative linear correlation &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;746&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;557&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; modified in those patients with CV<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;852&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;836&#41; compared to CV<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>36&#37; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;703&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;551&#41;&#46; A similar correlation was found when evaluating the TIR and the Glucose Management Indicator &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;846&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;715&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#59; in patients with CV<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;980&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;960&#41; versus CV<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>36&#37; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;837&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;701&#41;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#46; Both correlations remained stable in the paediatric population &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;724&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;525&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and adults &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;706&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;498&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and by type of treatment&#58; multiple doses of insulin &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;747&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;558&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and continuous subcutaneous insulin infusion &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;711&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;506&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; In a multiple regression analysis evaluating HbA<span class="elsevierStyleInf">1c</span> as dependent variable&#44; the only parameters that maintained statistical significance were the TIR &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;031&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; CV &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;843&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; and TIR-CV interaction &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;017&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The glycemic variability defined by the CV modifies the relationship between the TIR and HbA<span class="elsevierStyleInf">1c</span>&#47;Glucose Management Indicator and should be taken into account when individualising TIR targets&#44; regardless of age or the type of treatment used&#46;</p></span>"
        "secciones" => array:4 [
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La monitorizaci&#243;n flash de glucosa en pacientes con diabetes tipo 1 proporciona nuevos datos glucom&#233;tricos que permiten evaluar el control gluc&#233;mico m&#225;s all&#225; de la HbA<span class="elsevierStyleInf">1c</span>&#46; El objetivo del presente estudio fue evaluar la relaci&#243;n de la HbA<span class="elsevierStyleInf">1c</span>&#44; el tiempo en rango &#40;TIR&#41; y la variabilidad gluc&#233;mica en una cohorte de pacientes pedi&#225;tricos y adultos con diabetes tipo 1 y monitorizaci&#243;n flash de glucosa&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio transversal en 195 pacientes con diabetes tipo 1 &#40;42&#44;6&#37; mujeres&#44; 70 pedi&#225;tricos&#44; 26&#44;2&#37; infusor subcut&#225;neo de insulina&#44; 28&#44;7&#37; coeficiente de variaci&#243;n &#91;CV&#93;<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37;&#41; en tratamiento intensivo y monitorizaci&#243;n flash de glucosa&#46; Se evaluaron datos cl&#237;nicos&#44; anal&#237;ticos y glucom&#233;tricos&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La relaci&#243;n entre el TIR y la HbA<span class="elsevierStyleInf">1c</span> mostr&#243; una correlaci&#243;n lineal fuerte negativa &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;746&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;557&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; modificada en pacientes con CV<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;852&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;836&#41; frente a aquellos con un CV<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>36&#37; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;703&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;551&#41;&#46; Esta misma correlaci&#243;n se observ&#243; al evaluar el TIR y el Glucose Management Indicator &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;846&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;715&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; tanto en pacientes con CV<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>36&#37; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;980&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;960&#41; como en aquellos con CV<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>36&#37; &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;837&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;701&#41;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#46; Ambas correlaciones se mantuvieron estables al ser evaluadas de manera independiente en poblaci&#243;n pedi&#225;trica &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;724&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;525&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; adultos &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;706&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;498&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; y por tipo de tratamiento&#58; m&#250;ltiples dosis de insulina &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;747&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;558&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; e infusor subcut&#225;neo de insulina &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;711&#59; <span class="elsevierStyleItalic">R</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;506&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; En un modelo de regresi&#243;n multivariante adoptando la HbA<span class="elsevierStyleInf">1c</span> como variable dependiente&#44; exclusivamente el TIR &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;031&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; el CV &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;843&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; y la interacci&#243;n TIR-CV &#40;<span class="elsevierStyleItalic">&#946;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;017&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41; mantuvieron la significaci&#243;n estad&#237;stica&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La variabilidad gluc&#233;mica definida por el CV modifica la relaci&#243;n entre el TIR y la HbA<span class="elsevierStyleInf">1c</span>&#47;Glucose Management Indicator y debe tenerse en cuenta a la hora de individualizar objetivos de TIR&#44; independientemente de la edad o el tipo de tratamiento utilizado&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
            "titulo" => "Objetivos"
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          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Material y m&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
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      0 => array:3 [
        "etiqueta" => "1"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">GDS and MPBH made equal contributions to this manuscript&#46;</p>"
        "identificador" => "fn1"
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      1 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; D&#237;az-Soto G&#44; Bah&#237;llo-Curieses MP&#44; Jimenez R&#44; Nieto MO&#44; Gomez E&#44; Torres B&#44; et al&#46; Relaci&#243;n entre hemoglobina glucosilada&#44; tiempo en rango y variabilidad gluc&#233;mica en una cohorte de pacientes pedi&#225;tricos y adultos con diabetes tipo 1 con monitorizaci&#243;n flash de glucosa&#46; Endocrinol Diabetes Nutr&#46; 2021&#59;68&#58;465&#8211;471&#46;</p>"
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        "etiqueta" => "Figure 1"
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Correlation between plasma HbA<span class="elsevierStyleInf">1c</span> and time in range&#46;</p>"
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      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Correlation of plasma HbA<span class="elsevierStyleInf">1c</span> &#40;A&#41; and GMI &#40;B&#41; with respect to time in range stratified by coefficient of variation&#46;</p>"
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        "identificador" => "tbl0005"
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        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">CSII&#58; continuous subcutaneous insulin infusion&#59; CV&#58; coefficient of variation&#59; GMI&#58; Glucose Management Indicator&#59; HbA<span class="elsevierStyleInf">1c</span>&#58; plasma glycated haemoglobin&#59; ns&#58; not significant&#59; SD&#58; standard deviation&#59; TAR&#58; time above range&#59; TBR&#58; time below range&#59; TIR&#58; time in range&#46;</p>"
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                  \t\t\t\t" scope="col" 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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>20 years&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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>20 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Number of patients&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">70&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">125&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">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mean age &#40;years&#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">12&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;4&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">37&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;3&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">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mean duration diabetes &#40;years&#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">5&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;5&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">18&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;8&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">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female &#40;&#37;&#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">48&#46;3&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">41&#46;6&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">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CSII &#40;&#37;&#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">28&#46;6&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">24&#46;8&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">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HbA1c &#40;&#37;&#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">6&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&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">7&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;1&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">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GMI &#40;&#37;&#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">6&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&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">7&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;6&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">&#60;0&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mean blood glucose &#40;mg&#47;dl&#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">150<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&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">173<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>37&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">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD &#40;mg&#47;dl&#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
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es en pt

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