Assessment of the impact of measurable behaviors on glycemic control using continuous subcutaneous insulin infusion

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1 Research Article Assessmet of the impact of measurable behaviors o glycemic cotrol usig cotiuous subcutaeous isuli ifusio Mary White 1, Michele A O Coell 1 & Fergus J Camero* 1,2 Practice Poits The success of glycemic cotrol whe usig cotiuous subcutaeous isuli ifusio (CSII) is kow to be directly related to the umber of daily boluses ad blood glucose levels etered ito the device. A glycemic target of 7.5% (58.5 mmol/mol) is sought for all youth with Type 1 diabetes mellitus at our ceter. This study aimed to explore the reasos why, despite apparetly high levels of daily self-maagemet, some youth with Type 1 diabetes mellitus do ot attai or maitai this target usig CSII. This retrospective study reviews the HbA1c ad correspodig CSII behaviors as recorded from the dowloaded iformatio at both 3 6 ad moths post CSII commecemet betwee April 2008 ad Data were aalyzed for 60 youth with a mea age of 11 ± 3.7 years. At moths post CSII commecemet, oly 51.5% of youth had attaied a HbA1c of 7.5% (58.5 mmol/mol). Measurable CSII behaviors aloe do ot predict glycemic trajectories, whereas glycemic cotrol at baselie is a idicator of HbA1c at moths post CSII commecemet. Despite cosistet adherece with cliical guidelies i terms of the umbers of daily boluses ad blood glucose levels etered, a subgroup of patiets fail to demostrate the expected improvemet i glycemic cotrol i the medium term. I the future, we pla to explore the potetial barriers to glycemic improvemet, which iclude a possible cliical maifestatio of the fear of hypoglycemia or a passive attitude towards diabetes maagemet. Summary Aim: To explore cotiuous subcutaeous isuli ifusio (CSII) behaviors i a pediatric populatio with Type 1 diabetes mellitus, ad their associatio with glycemic cotrol. Research desig & methods: Youth were defied as withi target (HbA1c 1 The Murdoch Childre s Research Istitute, The Royal Childre s Hospital, Melboure, Australia 2 Departmet of Edocriology, The Royal Childre s Hospital, 50 Flemigto Road, Parkville, VIC 3052, Australia *Author for correspodece: Tel.: ; Fax: ; fergus.camero@rch.org.au part of /DMT Future Medicie Ltd Diabetes Maage. (2013) 3(2), ISSN

2 Research Article White, O Coell & Camero 7.5%/58.5 mmol/mol) ad above target (HbA1c >7.5%/58.5 mmol/mol), moths post CSII. The above-target group was subdivided ito: adheret yet above target (at least four blood glucose levels ad at least six bolus wizard evets etered per day) ad oadheret (fewer tha four blood glucose levels or fewer tha six bolus wizard evets etered per day). Results: Out of 60 patiets, 51.5% (31 out of 60) were withi target. Adheret yet above target youth demostrated similar CSII behaviors to the withi-target group, yet their glycemic trajectory mimicked that of their oadheret peers. Coclusio: CSII requires users to be target drive ad proactive i adjustig settigs to achieve glycemic cotrol. A passive attitude towards CSII is potetially as detrimetal to glycemic cotrol as frak oadherece to recommeded behaviors. Glycemic cotrol with cotiuous subcutaeous isuli ifusio (CSII) use is related to the umber of blood glucose level (BGL) ad daily bolus evets (combiig food ad correctio boluses) etered ito the device [1 4]. Our ceter, therefore, recommeds that a miimum of four BGL ad six bolus wizard evets (BWEs; comprisig both food ad correctio boluses) are etered ito the pump daily, usig the bolus wizard fuctio. Failure to icorporate these recommedatios is kow to result i suboptimal glycemic cotrol [3]. These importat associatios are routiely reiforced at our stadardized CSII iitiatio ad routie follow-up cliic sessios, which are scheduled every 3 4 moths as stadard for all patiets regardless of isuli delivery modality. Educatio is provided regardig basal rates ad CSII ratios (carbohydrate ad isuli sesitivity factor) ad the impact that these factors have o blood sugar levels; however, may youth still struggle to attai the target HbA1c of 7.5% (58.5 mmol/mol) despite apparetly high levels of self-maagemet. This study aimed to explore the prevalece of, ad further characterize, the subset of patiets who demostrate high levels of user pump iteractio ad yet fail to achieve HbA1c targets. Research desig & methods This was a retrospective all-of-cliic study of patiets with Type 1 diabetes mellitus (T1DM) commeced o Medtroic (MC, USA) isuli pump devices. All patiets with dowload data (Medtroic Carelik ) at both 3 6 ad moths after CSII iitiatio were icluded, whe a iitial improvemet i glycemic cotrol is expected with a subsequet deterioratio towards baselie; patiets were excluded if the available CSII data were obtaied outside of these timepoits. HbA1c (HPLC io exchage, Bio-Rad D10 ; Bio-Rad, CA, USA) levels were documeted at CSII iitiatio ad at the time of data dowloads. Baselie characteristics, icludig age ad duratio of T1DM at CSII iitiatio, as well as BMI z scores ad pre CSII isuli regimes, were documeted. Total daily doses of isuli were documeted prior to CSII ad at the time of the 3 6 ad moth dowloads. I the absece of the measuremet of C peptide levels, a assessmet of the possibility of a partial remissio ( hoey moo phase ) was made usig the isuli dose-adjusted HbA1c (IDAAC; calculated by HbA1c [%] + [4 isuli dose per kilogram per day]) prior to CSII commecemet, whereby a calculated value of 9 idicated a partial remissio [5]. CSII-related behaviors recorded icluded mea frequecy of BGLs ad umber ad types of BWE etered daily, frequecy of lie chages, CSII suspesio times ad mea BGL values obtaied from the Carelik dowload iformatio. The idicatio for CSII referral was idetified from cliical records where available. Subjects were classified accordig to glycemic cotrol at moths post CSII commecemet, ad were defied as withi target (HbA1c 7.5%/58.8 mmol/mol) or above target (HbA1c >7.5%/58.5 mmol/mol). The above target group was the further subdivided accordig to their level of user pump iteractio to ecompass: adheret yet above target (HbA1c >7.5%/58.5 mmol/mol, with at least four BGLs ad at least six BWEs etered per day) ad oadheret (HbA1c >7.5%/58.5 mmol/mol, with fewer tha four BGLs or fewer tha six BWEs etered per day) subgroups. Comparisos were made usig the studet t-test, where p 0.05 was cosidered sigificat. Results At the time of publicatio, over 1600 childre ad youg adults were attedig The Royal Childre s Hospital (Melboure, Australia) for maagemet of T1DM, 580 of whom are curretly usig CSII. Data were aalyzed for 60 youth (31 male), aged 11.0 ± 3.7 years (rage: years), who commeced CSII betwee April Diabetes Maage. (2013) 3(2) future sciece group

3 Impact of measurable behaviors o glycemic cotrol usig cotiuous isuli ifusio Research Article ad Durig this time period, a total of 117 youth were iitiated o CSII, of whom 92 were usig a Medtroic device. Youth were oly excluded if the required data were ot available. Overall, HbA1c was 8.0% (63.9 mmol/mol) pre CSII, 7.4% (57.4 mmol/mol) at 3 6 moths ad 7.5% (58.5 mmol/mol) at moths (p < 0.01). While 50 out of 60 (83.3%) of the cohort met our BGL ad BWE recommedatios at moths, oly 31 out of 60 (51.7%) were withi target. A total of 19 (65.5%) youth were adheret yet above target, while the remaiig te out of 29 (34.5%) were oadheret to recommeded CSII behaviors. The oadheret group were older at CSII iitiatio with a loger duratio of diabetes whe compared with the withi-target group aloe (p < 0.01), as show i Table 1 alog with patiet characteristics ad isuli regimes prior to CSII commecemet. Oly oe patiet, a female i the withi-target group, had a IDAAC value of 9 at baselie, ad cotiued to do so for the duratio of the study period. BMI prior to CSII commecemet was withi the ormal rage for all three groups, with some statistical differeces betwee the groups i the absece of cliical sigificace (withi target vs adheret yet above target: p = 0.7; withi target vs oadheret: p = 0.03; ad adheret yet above target vs oadheret: p = 0.004). Baselie total daily doses of isuli o pre CSII regimes were similar i the withi-target ad adheret yet above target groups (p = 0.6), but icreased i the older oadheret group (p = 0.02 ad 0.07, respectively). Whe pre CSII isuli requiremets were compared with those at follow-up, all groups showed a decrease i total daily doses per kilogram at both 3 6 ad moths (p 0.02 i each case). Compariso of CSII behaviors showed equivalet levels of daily BGL ad BWE i the withitarget ad adheret yet above target groups, cosistet over time (Figure 1A & 1B). By cotrast, the oadheret group iitially demostrated recommeded levels of CSII behaviors at 3 6 moths, which were ot sustaied at moths. Mea HbA1c at CSII-iitiatio for the withitarget group was 7.6% (59.6 mmol/mol), 7.0% (53.0 mmol/mol) at 3 6 moths (p < 0.001) ad 6.9% (51.9 mmol/mol) at moths (p < ) (Figure 1C). By cotrast, despite disparate user pump iteractio levels, glycemic trajectories of adheret yet above target ad oadheret groups were similar. Although some iitial improvemet i glycemic cotrol was see i these subgroups, by moths mea HbA1c had retured to pre CSII suboptimal levels. Mea BGL values were cosistetly lower i the withi-target versus adheret yet above target groups at 3 6 ad moths (Table 1). These groups had similar percetages of time spet below CSII target BGL (3 6 moths: p = 0.5; moths: p = 0.18), but differed sigificatly i the percetage of time spet above this value (3 6 moths: p = 0.019; moths: p = 0.019). Neither bolus type or total daily doses of isuli differed betwee the groups. No differeces were see i the frequecy of CSII lie site chages or CSII suspesio times (data ot show). Table 1. Patiet characteristics ad cotiuous subcutaeous isuli ifusio related iformatio. Characteristics Withi target Adheret yet Noadheret above target Patiet characteristics at CSII start Male () 31 (16) 19 (8) 10 (7) Age (years) 10.7 ± ± ± 1.8* Duratio of T1DM (years) 2.7 ± ± ± 4.2* BMI z score 0.5 ± ± ± 0.7 Total daily isuli dose (U/kg per day) 1.0 ± ± ± 0.4 IDACC 11.5 ± ± ± 2.1 Isuli regimes BD MDI BGL (mmol/l) 23 (74.2) 8 (25.8) 14 (73.7) 5 (26.3) 6 (60) 4 (40) 3 6 moths 8.8 ± ± ± moths 8.9 ± ± ± 2.2 Time above target (%) 3 6 moths 47.4 ± ± ± moths 48.4 ± ± ± 23.7 Time below target (%) 3 6 moths 10.5 ± ± ± moths 11.6 ± ± ± 3.4 Total daily isuli dose (U/kg per day) 3 6 moths 0.74 ± ± ± moths 0.8 ± ± ± 0.19 Basal isuli (% of total daily dose) 3 6 moths 41.4 ± ± ± moths 40.6 ± ± ± 6.6 Results are preseted as mea ± stadard deviatio, with the exceptio of isuli regimes, which are show as umber of patiets (%). Time above ad below target refers to the umber of BGL readigs (%) etered ito the pump, which are <4 mmol/l or >7.8 mmol/l as directed by CSII settigs. Sigificat comparisos betwee the withi target ad adheret yet above target or oadheret groups are show. IDACC calculated as HbA1c (%) + (4 isuli dose/kg per day), whereby a value 9 idicates partial remissio ( hoeymoo phase ). *p 0.01; p BD: Twice daily; BGL: Blood glucose level; CSII: Cotiuous subcutaeous isuli ifusio; IDACC: Isuli dose-adjusted HbA1c; MDI: Multiple daily isuli; T1DM: Type 1 diabetes mellitus. future sciece group 111

4 Research Article White, O Coell & Camero Mea BGL per day moths moths * Mea BWE per day moths moths * Adheret Adheret yet above target Noadheret 0 Adheret Adheret yet above target Noadheret HbA1c (%) Adheret Adheret yet above target Noadheret Pre-CSII 3 6 moths moths Figure 1. Summary of daily cotiuous subcutaeous isuli ifusio tasks ad HbA1c trajectories. Comparisio of (A) daily BGLs, (B) BWEs ad (C) HbA1c trajectory. Results are preseted as mea ± stadard deviatio. P-values are show for compariso betwee the withi-target, adheret yet above target ad oadheret groups. Other comparisos were osigificat (p > 0.05). HbA1c is show i the Natioal Glycohemoglobi Stadardizatio Program (NGSP) uits (%), whereby the Iteratioal Federatio of Cliical Chemistry (IFCC) uit (mmol/mol) is derived from the followig formula: HbA1c% *p < 0.05; p < BGL: Blood glucose level; BWE: Bolus wizard evet; CSII: Cotiuous subcutaeous isuli ifusio. A formal record of idicatio for CSII referral was available i oly 37 out of 61 patiets (51.7%); of these, recurret hypoglycemia prompted referral i oly two patiets, both with mild recurret hypoglycemia ad both i the withi-target group. For the remaider, lifestyle, improved cotrol or a combiatio of the two were cited. Coclusio The overall glycemic trajectory of this cohort reflects both our istitutioal CSII experiece ad that of other ceters [6,7]; however, the fact that 48.3% fail to achieve our uiversal target HbA1c 7.5% (58.5 mmol/mol) moths post CSII iitiatio idicates deficits i daily maagemet. This is a particular cocer for the 19 out of 60 patiets (31.6%) for whom this is true despite their adherece to measurable daily maagemet tasks that are prescribed based o published associatios with glycemic outcomes. While older age at CSII start ad frak oadherece with recommeded levels of user pump iteractio were, agai, associated with HbA1c >7.5% (58.5 mmol/mol), these curret data demo strate that measurable CSII behaviors aloe do ot predict glycemic outcomes i all patiets. Glycemic cotrol at baselie predicts follow-up HbA1c at moths post CSII iitiatio ad may serve as a guide for CSII suitability [1,8,9]. Exploratio ito the potetial reasos for this is beyod the scope of this paper, but it 112 Diabetes Maage. (2013) 3(2) future sciece group

5 Impact of measurable behaviors o glycemic cotrol usig cotiuous isuli ifusio Research Article is likely to be multifactorial, icludig pre CSII adherece to cliical recommedatios, belief systems ad behavioral patters. Notably, o chage i CSII behaviors occurred i the adheret yet above target group to explai the deterioratio i HbA1c at moths. This group exhibited cosistetly high levels of daily CSII behaviors, almost idetical to those of the withi-target group. By cotrast, they ot oly failed to obtai glycemic beefits, but their HbA1c trajectory mimicked the poor outcomes see i oadheret youth, suggestig that perhaps the quality of these behaviors is somehow differet betwee the groups. There are a umber of possible explaatios for this discrepacy betwee pump iteractio ad glycemic outcomes. All patiets demostrated a reductio i daily isuli doses, which appears to be iappropriate i the cotext of the icreasig HbA1c of the adheret yet above target ad oadheret groups [10]. Based o the calculated IDAAC values, a partial remissio phase does ot appear to be cotributory [5]. The oset of adolescece, with its associated isuli resistace, may have a effect i additio to oadherece with cliical recommedatios ad dimiishig paretal ivolvemet i diabetes maagemet, which may explai the suboptimal ad deterioratig cotrol of the older oadheret group. However, it does ot accout for the divergig glycemic trajectory of the withi-target ad adheret yet above target groups. Both of these groups share similar baselie characteristics, icludig age, BMI ad isuli doses, ad they also demostrate equivalet levels of CSIIrelated iteractio; yet the latter have higher mea BGL levels ad sped a greater percetage of time above the CSII programmed target BGL. Despite stadardized educatio emphasizig the importace of esurig that correctio boluses attai BGLs close to target (5.0 ± 0.5 mmol/l), this group appeared to accept hyperglycemia. It is possible that the adheret yet above target group have made a active decisio to avoid hypoglycemia, ad as a cosequece allow higher mea BGLs as a protective measure. However, from the limited iformatio o idicatios for CSII i this cohort, it appears that sigificat hypo glycemia precedig CSII is ot cotributory. It is also possible that a passive attitude, characterized by a lack of reflective practice or target-drive care may be causative. The value of the fidigs of this study is limited by its retrospective ature ad small sample size; a meaigful assessmet i terms of geder, pubertal status, frequecy of allied health cotact, the umber of chages to pump settigs over the study period, frequecy of blood glucose testig ot etered ito the CSII device, history of severe hypoglycemia/diabetic ketoacidosis ad reasos for CSII referral could ot be accurately assessed. A prospective study would be useful to address ot oly these issues, but also to examie patters i the timig of boluses, glucose variability ad postpradial hyperglycemia idicative of isuli resistace [11]. The cohort was limited to those who were commeced o a Medtroic CSII device due to the availability ad cliical use of the compaio Carelik software. A questioaire tool or psychological assessmet would be required to formally address patiet/paret attitudes to CSII ad glycemic cotrol i order to defie whether or ot a passive attitude is truly accoutable for the glycemic trajectory of the adheret yet above target group, or if it represets a sigificat fear of hypoglycemia. CSII is a itesive isuli regime that offers patiets with T1DM flexibility i terms of lifestyle. For success i terms of attaimet of the glycemic targets that are essetial for log-term health beefits, adherece to cliical guidelies is essetial ad is more likely to be achieved by those with a HbA1c that is approximately 7.5% (58.5 mmol/mol) at baselie. This should be emphasized to patiets/parets durig pre CSII couselig, as target settig is kow to correlate with glycemic cotrol [12]. Regardless of the possible physiological or psychological atecedets, it is cocerig that oly 51.6% of this cohort achieved their target HbA1c. Give that pediatric patiets with T1DM are routiely reviewed i the cliic settig o a 3 4-mothly basis, it is vital that active self-maagemet occurs i the iterveig periods. We propose that our data may idicate that a passive attitude to CSII i the adheret yet above target group, whereby patiets ad families (or their healthcare professioals) do ot proactively itervee to alter CSII settigs to reduce hyperglycemia, may be as detrimetal to the achievemet of HbA1c targets as frak oadherece. The fact that 31.6% of our cohort was adheret yet above target idicates that the egative impact of passive pumpig may be a commo cliical etity, ad successful progressio ito a more active model of self-maagemet has the potetial to sigificatly improve the glycemic beefits attaied. Itervetios to empower CSII users to cofidetly attai target future sciece group 113

6 Research Article White, O Coell & Camero BGLs are curretly beig itroduced ad will be prospectively moitored. Future perspective The use of CSII has become a accessible ad feasible treatmet optio i the maagemet of childre with T1DM. With icreasig demads o limited resources, there is a correspodig icrease i pressure o cliicias to deliver cost-effective ad efficacious healthcare. The results of this study have show that CSII use is ot successful i terms of glycemic cotrol for all patiets at our ceter, which cofirms our aecdotal experiece. Previously, formal educatio was give at CSII commecemet ad was cliicia-, patiet- ad paret-depedet thereafter. We pla to itroduce a itervetio program that will be offered to all CSII users at our ceter, aimig to explore the potetial barriers to optimal glycemic cotrol ad provide the practical skills ad motivatio to achieve ad maitai HbA1c withi the target of 7.5% (58.5 mmol/mol). Fiacial & competig iterests disclosure The authors have o relevat affiliatios or fiacial ivolvemet with ay orgaizatio or etity with a fiacial iterest i or fiacial coflict with the subject matter or materials discussed i the mauscript. This icludes employmet, cosultacies, hooraria, stock owership or optios, expert t estimoy, grats or patets received or pedig, or royalties. No writig assistace was utilized i the productio of this mauscript. Ethical coduct of research The authors state that they have obtaied appropriate istitutioal review board approval or have followed the priciples outlied i the Declaratio of Helsiki for all huma or aimal experimetal ivestigatios. I additio, for ivesti gatios ivolvig huma subjects, iformed coset has bee obtaied from the participats ivolved. Refereces Papers of special ote have bee highlighted as: of iterest 1 Dae T, Battelio T, Jarosz-Chobot P et al. Establishig glycaemic cotrol with cotiuous subcutaeous isuli ifusio i childre ad adolescets with Type 1 diabetes: experiece of the PedPump Study i 17 coutries. Diabetologia 51(9), (2008). 2 Olider AL, Kerell A, Smide B. Missed bolus doses: devastatig for metabolic cotrol i CSII-treated adolescets with Type 1 diabetes. Pediatr. Diabetes 10(2), (2009). Cross-sectioal study showig the effect of a umber of daily boluses ad blood sugar levels o glycemic cotrol i youth with Type 1 diabetes mellitus (T1DM) o cotiuous subcutaeous isuli ifusio (CSII). 3 O Coell MA, Doath S, Camero FJ. Poor adherece to itegral daily tasks limits the efficacy of CSII i youth. Pediatr. Diabetes 12, (2011). Cross-sectioal study that demostrates the relatioship betwee dimiished adherece to itegral CSII tasks ad glycemic cotrol i youth with T1DM. 4 Burdick J, Chase HP, Slover RH et al. Missed isuli meal boluses ad elevated hemoglobi A1c levels i childre receivig isuli pump therapy. Pediatrics 113(3 Pt 1), e221 e224 (2004). Cross-sectioal study that reported that missed mealtime boluses appear to be the major cause of suboptimal glycemic cotrol i youth o CSII. 5 Mortese HB, Hougaard P, Swift P et al. New defiitio for the partial remissio period i childre ad adolescets with Type 1 diabetes. Diabetes Care 32(8), (2009). 6 Kordoouri O, Hartma R, Lauterbor R, Barekow C, Hoeffe J, Deiss D. Age-specific advatages of cotiuous subcutaeous isuli ifusio as compared with multiple daily ijectios i pediatric patiets: oe-year follow-up compariso by matched-pair aalysis. Diabetes Care 29(1), (2006). 7 Shaliti S, Gil M, Nimri R, de Vries L, Gava MY, Phillip M. Predictors of glycaemic cotrol i patiets with Type 1 diabetes commecig cotiuous subcutaeous isuli ifusio therapy. Diabet. Med. 27(3), (2010). Demostrates that youger age at CSII start ad frequet self-moitorig of blood glucose levels are associated with improved glycemic cotrol. 8 McVea JJ, Eickhoff JC, Macdoald MJ. Factors correlatig with improved A1C i childre usig cotiuous subcutaeous isuli ifusio. Diabetes Care 30(10), (2007). Shorter duratio of diabetes ad lower HbA1c at pump start are associated with improved glycemic cotrol i youth o CSII. 9 Pihas-Hamiel O, Tzadok M, Hirsh G et al. The impact of baselie hemoglobi A1c levels prior to iitiatio of pump therapy o log term metabolic cotrol. Diabetes Techol. Ther. 12(7), (2010). HbA1c at CSII commecemet predicts follow-up levels of glycemic cotrol. 10 Pakowska E, Blazik M, Dziechciarz P, Szypowska A, Szajewska H. Cotiuous subcutaeous isuli ifusio vs. multiple daily ijectios i childre with Type 1 diabetes: a systematic review ad meta-aa lysis of radomized cotrol trials. Pediatr. Diabetes 10(1), (2009). 11 Amiel SA, Sherwi RS, Simoso DC, Lauritao AA, Tamborlae WV. Impaired isuli actio i puberty. A cotributig factor to poor glycemic cotrol i adolescets with diabetes. N. Egl. J. Med. 315(4), (1986). Isuli resistace durig puberty is likely to be a cotributig factor to deterioratig glycemic cotrol that is ofte see i adolescets with T1DM. 12 Swift PG, Skier TC, De Beaufort CE et al. Target settig i itesive isuli maagemet is associated with metabolic cotrol: the Hvidoere childhood diabetes study group ceter differeces study Pediatr. Diabetes 11(4), (2010). 114 Diabetes Maage. (2013) 3(2) future sciece group