Potential of insulin deprescription adding a GLP-1 receptor agonist as a therapeutic strategy to improve the metabolic profiles of patients with type 2 diabetes mellitus

Perez de Arenaza Pozo, Victor; Cárdenas Salas, Jersy; Vázquez Martínez, Clotilde
doi:10.1016/j.endinu.2024.05.013
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        "titulo" => "La deprescripci&#243;n de insulina mediante agonistas del receptor de GLP-1 como estrategia terap&#233;utica para mejorar el perfil metab&#243;lico en pacientes con diabetes mellitus tipo 2"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Type 2 diabetes mellitus &#40;T2DM&#41; is the 9th leading cause of death worldwide&#44; affecting 462 million individuals&#46; To change the natural progression of diabetes&#44; glucagon-like peptide 1 receptor agonists &#40;GLP-1 RAs&#41; have emerged as renal and cardioprotective agents capable of achieving stable glycemic control&#46; Currently available literature demonstrates their efficacy profile in preventing MACE-3&#44; mitigating microvascular complications&#44; and improving metabolic profiles&#44; among other benefits&#46; Within this context&#44; an intriguing question arises&#58; can GLP-1 RAs be used to reduce insulin doses&#63;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The aim of our study is to assess whether the addition of subcutaneous semaglutide &#40;OW-semaglutide&#41; once a week to adult patients with T2DM and eGFR &#62;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min results in fewer insulin doses at the 12-month follow-up&#46; We present a prospective study initiated in 2019 on the T2DM population from four Spanish hospitals located in Madrid&#44; Spain&#46; The study protocol was approved by the Fundaci&#243;n Jim&#233;nez Diaz Instituto de Investigaci&#243;n Sanitaria Local Ethics Committee&#46; For this purpose&#44; a total of 316 patients&#44; utilizing various insulin regimens received additional OW-semaglutide and were monitored with visits at 6 and 12 months&#44; during which multiple variables including insulin doses were collected&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Forty-four out of 316 initially registered patients discontinued subcutaneous semaglutide &#40;13&#46;9&#37;&#41;&#44; and 20 patients were lost to follow-up&#44; mainly due to the pandemic&#46; Ultimately&#44; a total of 252 patients were eligible and included in the study&#46; The baseline characteristics of our study population were&#58; 61&#37; were men&#44; with a mean age of 62&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;1 years and a mean course of T2DM of 14&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;5 years&#46; Among the comorbidities reported&#44; 88&#46;8&#37; had dyslipidemia&#59; 84&#46;1&#37;&#44; arterial hypertension&#59; and 16&#46;9&#37; were smokers&#46; Microvascular disease was present in 40&#46;8&#37; of patients &#40;29&#46;9&#37; with diabetic nephropathy and 24&#46;5&#37; with diabetic retinopathy&#41;&#46; Macrovascular complications included a past medical history of ischemic heart disease in 17&#46;8&#37; of the patients&#44; acute myocardial infarction in 12&#46;2&#37;&#44; stroke in 9&#46;2&#37;&#44; and peripheral artery disease in 8&#46;7&#37;&#46; Although 56&#46;7&#37; of the patients were categorized under primary prevention they had a very high cardiovascular risk&#44; while 32&#46;4&#37; were categorized under secondary prevention&#46; Baseline weight and BMI averaged 96&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;4<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> and 34&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;2<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#44; respectively&#46; The mean HbA<span class="elsevierStyleInf">1c</span> level was 7&#46;97<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;40&#37;&#59; mean eGFR &#40;CKD-EPI&#41;&#44; 79&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22&#46;1<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#59; and mean C-peptide&#44; 2&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;6<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; Regarding basal antidiabetic treatment&#44; 84&#46;9&#37; were on metformin&#44; 47&#46;6&#37; on an SGLT2-inhibitor&#44; 53&#46;2&#37; on a GLP-1 RA&#44; 23&#46;0&#37; on a DPP4-inhibitor&#44; 13&#46;9&#37; on repaglinide&#44; 4&#46;8&#37; on a sulfonylurea&#44; and 1&#46;6&#37; on pioglitazone&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">As depicted in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; the results revealed a significant reduction in the total number of insulin doses by 6<span class="elsevierStyleHsp" style=""></span>IU&#47;day at 6 months and nearly 8<span class="elsevierStyleHsp" style=""></span>IU&#47;day at 12 months&#46; Both basal and rapid insulin doses exhibited decreases at both time periods &#40;&#8722;3 and &#8722;5 for basal insulin at 6 and 12 months&#44; respectively&#44; and &#8722;3 and &#8722;2 for rapid insulin at the same intervals&#44; respectively&#41;&#46; Furthermore&#44; 6&#46;6&#37; of patients discontinued their total insulin regimen&#44; while notably&#44; 26&#46;1&#37; of patients previously on rapid insulin discontinued this regimen by the end of the 12-month period&#46; Only four patients initiated a rapid insulin regimen at the follow-up&#46; The number of patients with &#8805;3 daily insulin injections decreased&#46; Additionally&#44; weight and HbA1c levels showed significant reductions at the follow-up &#40;&#8722;4&#46;4<span class="elsevierStyleHsp" style=""></span>kg and &#8722;0&#46;77&#37; at 12 months&#44; respectively&#41;&#46; Moreover&#44; the number of patients achieving HbA1c levels &#60;7&#37; increased from 26&#46;1&#37; up to 54&#46;6&#37; at 12 months&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">We conducted a multiple regression analysis to identify predictors of insulin dose reduction at 12 months following the initiation of OW-semaglutide&#46; The independent variables included age&#44; sex&#44; course of T2DM&#44; total insulin dose&#44; baseline HbA1c levels &#40;&#60;7&#37; vs &#8805;7&#37;&#41;&#44; BMI&#44; C-peptide&#44; and eGFR &#40;&#60;60 vs &#8805;60&#41;&#46; Additionally&#44; we considered the semaglutide dose achieved at 12 months &#40;1&#46;0<span class="elsevierStyleHsp" style=""></span>mg vs &#8804;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#41;&#44; reductions in HbA1c levels and weight at the follow-up&#44; the number of oral antidiabetic drugs used&#44; basal antidiabetic treatment&#44; and changes in antidiabetic treatment at the follow-up&#46; Our analysis revealed that higher baseline insulin doses &#40;beta &#8722;0&#46;44&#41;&#44; baseline HbA1c levels &#60;7&#37; &#40;beta &#8722;0&#46;17&#41;&#44; greater reductions in weight at the follow-up &#40;beta &#8722;0&#46;04&#41;&#44; eGFR &#8805;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min &#40;beta &#8722;0&#46;26&#41;&#44; GLP-1 RA-na&#239;ve patients &#40;beta &#8722;0&#46;21&#41;&#44; and initiation of metformin &#40;beta &#8722;0&#46;20&#41; were independent predictors associated with greater reductions in insulin doses at 12 months&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">As evidenced by randomized controlled trials &#40;RCTs&#41; and real-world data &#40;RWD&#41; studies in the literature&#44; our investigation confirms that the addition of a GLP-1 RA leads to a significant reduction in the daily insulin requirements of our patients&#46; Regarding basal insulin&#44; we saw that the addition of a GLP-1 RA can reduce insulin over-basalization in up to 46&#46;6&#37; of patients&#46; In cases of patients on intensive therapy &#40;&#62;100<span class="elsevierStyleHsp" style=""></span>IU&#47;day&#41;&#44; numerous studies have explored the effect of adding liraglutide or exenatide&#44; revealing notable reductions in HbA1c&#44; weight&#44; insulin dose&#44; and glycemic variability &#40;GV&#41; as measured by continuous glucose monitor &#40;CGM&#41;&#46; We also observed a reduction in daily insulin injections&#44; which could be associated with a decrease in lipodystrophies and improved glycemic control&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">3&#8211;6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The significance of these studies lies in improving the quality of life&#44; managing symptoms&#44; mitigating organ damage&#44; reducing the risk of hypoglycemia&#44; and enhancing the overall prognosis of patients with T2DM by reducing insulin doses and improving disease control&#46; Several investigations&#44; such as the one conducted by Gamble et al&#46; with 6072 patients have indicated that although high insulin doses may be associated with higher mortality rates&#44; the risk also varies depending on the duration of insulin exposure&#44; glycemic control&#44; weight gain&#44; and occurrences of cardiovascular events and hypoglycemia&#46; It is obvious that the addition of GLP-1 RA to these patients led to better glycemic control while reducing insulin doses&#44; thereby ameliorating disease comorbidities and mitigating adverse effects associated with insulin therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">4&#8211;9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion&#44; our findings suggest that the addition of OW-semaglutide to a Spanish population of T2DM patients led to fewer daily insulin dosage requirements&#44; thereby contributing to improved metabolic profiles when combined with insulin deprescription&#46; These results highlight the potential of insulin deprescription as a therapeutic strategy&#44; underscoring the necessity for further trials to elucidate its efficacy profile and clinical applicability&#46;</p></span>"
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                  \t\t\t\t"><span class="elsevierStyleItalic">Maximum semaglutide dose &#40;1&#46;0</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg&#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="" 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="char" valign="\n
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                  \t\t\t\t">97 &#40;38&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">175 &#40;77&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Total insulin &#40;IU&#47;day&#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">55&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>43&#46;2&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">&#8722;6&#46;1 &#40;&#8722;8&#46;2 to &#8722;4&#46;1&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;7&#46;7 &#40;&#8722;10&#46;4 to &#8722;4&#46;9&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Basal insulin &#40;IU&#47;day&#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">44&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#46;9&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">&#8722;3&#46;2 &#40;&#8722;4&#46;6 to &#8722;1&#46;9&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;5&#46;3 &#40;&#8722;7&#46;2 to &#8722;3&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Rapid insulin &#40;IU&#47;day&#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">11&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;3&#46;0 &#40;&#8722;4&#46;1 to &#8722;1&#46;8&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;2&#46;4 &#40;&#8722;4&#46;0 to &#8722;0&#46;8&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Total insulin &#40;IU&#47;kg&#47;day&#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">0&#46;58<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;40&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">&#8722;0&#46;05 &#40;&#8722;0&#46;08 to &#8722;0&#46;03&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;07 &#40;&#8722;0&#46;09 to &#8722;0&#46;04&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Weight &#40;kg&#41;</span>&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">96&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \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">&#8722;3&#46;1 &#40;&#8722;3&#46;8 to &#8722;2&#46;3&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</span></a>&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">&#8722;4&#46;4 &#40;&#8722;5&#46;4 to &#8722;3&#46;5&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HbA1c &#40;&#37;&#41;</span>&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">7&#46;97<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;40&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">&#8722;0&#46;82 &#40;&#8722;1&#46;01 to &#8722;0&#46;63&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;78 &#40;&#8722;0&#46;98 to &#8722;0&#46;58&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-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"><span class="elsevierStyleItalic">No&#46; of daily insulin injections</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&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\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>0&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">0&nbsp;\t\t\t\t\t\t\n
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                  \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">9 &#40;3&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 &#40;6&#46;6&#41;&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"><span class="elsevierStyleHsp" style=""></span>1&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">164 &#40;65&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">176 &#40;69&#46;8&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">154 &#40;68&#46;1&#41;&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"><span class="elsevierStyleHsp" style=""></span>2&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">15 &#40;6&#46;0&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;4&#46;4&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;4&#46;0&#41;&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"><span class="elsevierStyleHsp" style=""></span>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">18 &#40;7&#46;1&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;4&#46;8&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;5&#46;3&#41;&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"><span class="elsevierStyleHsp" style=""></span>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">50 &#40;19&#46;8&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38 &#40;15&#46;1&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;13&#46;7&#41;&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"><span class="elsevierStyleHsp" style=""></span>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">5 &#40;2&#46;0&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;2&#46;4&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;2&#46;2&#41;&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="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-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"><span class="elsevierStyleItalic">Stop total insulin</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="" 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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