La tecnologia nella gestione del DMT1

La tecnologia nella gestione del DMT1 Giorgio Grassi SCDU Endocrinologia, Diabetologia e malattie del metabolismo Az. Ospedaliero-Universitaria San Giovanni Battista di Torino Le Molinette

Subcutaneous Insulin Infusion: First Insulin Pump and Modern Pumps

EVOLUZIONE TECNOLOGICA CSII: INTERFACCIA Pz INDOSSABILITA DEL DEVICE Ipump Nano Patch Pump Medtronic User Friendly Insulin Pump Medtronic Omnipod Cellnovo

Agenda Monitoraggio glicemico in continuo (CGM) Integrazione CSII-CGM CSII: calcolatore di Bolo Telemedicina Trapianto di isole Nuove tecnologia per l insulina

Studio STAR1: efficacia della PRT sulla riduzione delle ipoglicemie Iperglicemie Ipoglicemie Da Irsch I et al, Diabet Technol Ther. Volume 10, Number 5, 2008

N Engl J Med Volume 359(14):1464-1476 October 2, 2008

The J uv e nile Dia be te s Re s e a rc h Fo unda tio n Co ntinuo us Gluc o s e Mo nito ring Study Gro up. N Eng l J Me d 2 0 0 8 ;3 5 9 :1 4 6 4-1 4 7 6 Studio randomizzato in pazienti DMT1 trattati intensivamente, con HbA1c fra 7.0 e 10.0% [MEDIA 7.6%] stratificati in 3 gruppi a differente fascia di età. Assegnati a CGM RT o SMBG convenzionale. Outcome primario la modificazione della Hba1c dopo 26 settimane Il monitoraggio continuo é risultato associato ad un miglioramento del controllo negli adulti, ma non nei bambini e negli adolescenti

Cum ula tiv e Dis tributio n o f Gly c a te d He m o g lo bin Le v e ls, Ac c o rding to Ag e The J uv e nile Dia be te s Re s e a rc h Fo unda tio n Co ntinuo us Gluc o s e Mo nito ring Study Gro up. N Eng l J Me d 2 0 0 8 ;3 5 9 :1 4 6 4-1 4 7 6

CONCLUSIONI Riduzione HbA1c solo negli adulti Riduzione relativa di HbA1c media > 10% in adulti e anche in bambini 8 14 aa HbA1c < 7% + no severe hypos in adulti e anche in bambini 8 14 anni

Us e o f Co ntinuo us Gluc o s e Mo nito rs in the Co ntinuo us -Mo nito ring Gro up, Ac c o rding to Ag e The J uv e nile Dia be te s Re s e a rc h Fo unda tio n Co ntinuo us Gluc o s e Mo nito ring Study Gro up. N Eng l J Me d 2 0 0 8 ;3 5 9 :1 4 6 4-1 4 7 6

Obje ctive : The pote ntial be nefts of continuous glucos e monitoring (CGM) in the manage me nt of adults and children with well controlled type 1 diabetes have not been examined. Re s e arch De s ign and Me thods : 129 adults and childre n with inte ns ive ly-tre ate d type 1 diabe te s (age range 8 to 69 years) and HbA1 c <7.0 % were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level <70 mg/dl, HbA1c level, and severe hypoglycemic events

Median time per day with a glucose level <70 mg/dl (as measured with CGM) decreased from 91 minutes at baseline to 54 minutes at 26 weeks in the CGM group (P=0.002) Stronger statistical evidence of a treatment group difference favoring the CGM group for hypoglycemia time <60 mg/dl, <50 mg/dl and area under the curve for 70 mg/dl

Dato integrato andamento A1c e ipoglicemie

Lower HbA1c values in the CGM group than in the control group were not associated with an increased frequency of severe hypoglycemic events.

Re s ults : The only bas e line factors found to be as s ociate d with gre ate r CGM us e in month 6 we re age >25 years (P<0.001) and more frequent self-reported pre-study blood glucose meter measurements per day (P<0.001). CGM use and the percentage of CGM glucose values between 71-180 mg/dl during the first month were predictive of CGM use in month 6 (P<0.001 and P=0.002, respectively).

Obje ctive : To de te rmine whe the r continuous glucos e monitoring (CGM) is e ffe ctive in the management of type 1 diabetes (T1D) when implemented in a manner that more closely approximates clinical practice.

Re s e arch De s ign and Me thods : After completion of a 6-month randomized clinical trial (RCT) evaluating CGM in children, adolescents, and adults with T1D, CGM was initiated in the trial s control group with less intensive training and follow up than was included in the RCT. Subjects had an outpatient training session, two follow-up phone calls, and outpatient visits at 1, 4, 13, and 26 weeks.

Re s e arch De s ign and Me thods : After completion of a 6-month randomized clinical trial (RCT) evaluating CGM in children, adolescents, and adults with T1D, CGM was initiated in the trial s control group with less intensive training and follow up than was included in the RCT. Subjects had an outpatient training session, two follow-up phone calls, and outpatient visits at 1, 4, 13, and 26 weeks.

Adult subjects with baseline A1c levels >7.0% had a significant reduction in A1c (-0.4%); no reduction in A1c was seen in the two younger age groups. As in the RCT, after adjusting for frequency of CGM use, there was no significant relationship between age and change in A1c. Subjects in the 6-month extension study who used the devices consistently also saw a significant increase in the amount of time spent in the target glucose range.

Monitoraggio Continuo Care Link Pro

As CGM technology continues to evolve, focus should be placed on improvements likely to increase independent use of the devices, such as: reduction in sensor size less frequent need for calibration greater accuracy resulting in fewer false alarms computer or web-based training modules to aid in the interpretation and application of sensor data

Verso la chiusura dell ansa Blood (interstitial) glucose Insulin delivering system Glucose sensor Il paziente ed il team diabetologico

Obiettivo aggiustamenti sull analisi retrospettiva dei dati scaricati 33 pazienti arruolati Sistema usato: Navigator Età media: 11.2 ± 4.1 anni M:F=6:4 Durata media di diabete: 5.8 ± 3 anni 93% razza caucasica Obiettivo aggiustamenti terapeutici in real-time sulla base del trend

Calculated premeal insulin bolus: ± 10 20%, in base alle frecce di trend glicemico (aumento/decremento glicemico > 1 o 2 mg/dl/min) Hypoglycemia alarm (dopo conferma SMBG): 15 g CHO Alarm for impending hypoglycemia: 10 g CHO

The Diabetes Educator 2009; 35; 124

Verso la chiusura dell ansa Blood (interstitial) glucose Insulin delivering system Glucose sensor Algoritmi semiautomatici Il paziente ed il team diabetologico

REAL TIME Continuous Glucose monitoring

Nocturnal Hypoglycemia Hypoglycemic events are common during sleep Percentage of Patients Experiencing Nocturnal Hypoglycemic Episode by Blood Glucose Level 1. 2006 Standards of medical care for patients with diabetes mellitus. Diabetes Care 29(Suppl 1):S16 S17 Even well-controlled patients can suffer from nocturnal hypoglycemia

La CSII riduc e g li e v e nti ipo g lic e m ic i ( ins ulina um a na ) Pre-CSII Eventi per 100 pz per anno Post-CSII n = 55 Età media (anni) 39 n = 107 36 n = 25 14 n = 56 17 Bode BW, Diabe te s Care. 1996;19:324 7; Boland EA, Diabe te s Care. 1999;22:1779 84; Chase HP, Pe diatrics. 2001;107:351 6; Rudolph JW. Endoc r Pract. 2002;8:401-5.

Ipoglicemia in gravidanza Allarme non sentito dalla paziente

Ipoglicemie inavvertite M.T 48 an ni di DMT1.

Sensor augmented pump therapy: sospensione automatica in caso di allarme predittivo di ipoglicemia 17 adolescenti, T1DM, Medtronic 715 insulin pump, Guardian Real Time, Medtronic PID controller

Controllore PID (adattativo) Glicemia Insulina Derivativo Integrativo Proporzionale Proporzionale al livello glicemico Derivativo velocità di cambiamento del glucosio Integrativo aggiusta lentamente il profilo basale

Sensor augmented pump therapy: sospensione automatica in caso di allarme predittivo di ipoglicemia In caso di allarme predittivo di ipoglicemia rilevato dal sensore del glucosio L algoritmo sospende automaticamente l infusione di insulina

Efficacia e sicurezza sospensione automatica in caso di allarme predittivo di ipoglicemia La sospensione automatica previene efficacemente le ipoglicemie Nessuno episodio di iperglicemia marcata o chetoacisodi in seguito alla sospensione

o ur fnding s s uppo rt the po te ntia l utility o f a dding s uc h a g luc o s e -re s po ns iv e pro g ra m to a n o pe n-lo o p pla tfo rm, w hic h c o uld s e rv e a s a n im po rta nt frs t s te p to w a rds the g o a l o f a fully c lo s e d-lo o p s y s te m fo r tre a tm e nt o f T1 D.

Furthe r de v e lo pm e nt o f a lg o rithm s is ne e de d to pre v e nt a ll e pis o de s o f hy po g ly c e m ia fro m o c c urring.

Hypoglycemic sensitivity analysis Six Day Algorithm 6.92% 2.53% Guardian RT Algoithm 5.39% 5.6% 9.59% 11.1% 12.1% 49.5% 21.9% 75.4% Threshold alarm only true positive Threshold & Projected alarm true positive Projected alarm only true positive No alarm, accurate glucose No alarm, false negative Unpublished STAR 1 data.

Hyperglycemic sensitivity analysis Six Day Algorithm. % Guardian RT Algoithm 3.01% 9.14% 1.67% 10.9% 3.12% 4.44% 72.7% Threshold alarm only true positive Threshold & Projected alarm true positive Projected alarm only true positive No alarm, accurate glucose No alarm, false negative Unpublished STAR 1 data. 8.95% 77.1%

Low Glucose Suspend (LGS) Scopo Per rilevare automaticamente l ipoglicemia e sospendere l erogazione di insulina prima dell insorgenza di ipoglicemia grave Goal Ridurre la severità dell ipoglicemia Non prevenire l ipoglicemia An airbag, not an early warning system Low Glucose Suspend aims to reduce the severity of hypoglycemic events

LGS Settings funzione: On/Off Range: 40 110 mg/dl (allarme di soglia non predittivo) Sospende erogazione dell insulina per due ore Se la glicemia rimane bassa 4 ore dopo la ripresa dell erogazione dell insulina il microinfusore risospende l erogazione dell insulian Le altre funzioni del sensore e altri allarmi rimangono operativi durante la sospensione Once engaged, LGS will cycle insulin delivery on/off until cancelled

Feature Overview: Schematic Low Glucose Suspend Triggered Patient does not respond to alarm Patient responds to alarm Pump suspends and alarms I have diabetes, call for emergency assistance. Patient can choose to suspend or resume basal Pump suspends insulin delivery for 2 hours If suspend, pump suspends Insulin delivery for 2 hours After 2 hours pump resumes basal After 2 hours pump resumes basal If BG still low 4 hours after resuming basal, insulin re-suspends If BG still low 4 hours after resuming basal, insulin re-suspends Patient can interrupt Low Glucose Suspend at any time

Clinical Justification - Guerci, et al (1999) Obje c tiv e Evaluate metabolic changes during a after resuming insulin infusion Me tho ds Re s ults 5 hr period of CSII interruption and the 5 hr period Randomized, cross-over, open-label design comparing CSII with insulin lispro against CSII using human insulin in 10 type-1 diabetic participants. Each participant served as his own control. Participants underwent a 1 month run-in period using CSII with human insulin. Participants were then randomized to a 1 month run-in of either Velosulin or lispro. After testing, participants began a 1 month run-in leading to the second test using the alternate insulin type. Testing took place at one site (INSERM-Centre Hospitalier Universitaire de Nancy). Participants were given a calibrated meal at 8pm the night prior to testing and fasted until 7am (no breakfast), when CSII interruption began. CSII was resumed 5 hrs later, at 12pm (calibrated lunch and usual prelunch boluses). Blood samples were taken hourly from 7am to 5pm (600 minutes) At 12pm, basal insulin infusion was resumed. In addition, participants received corrective boluses hourly of 4U if blood glucose was above 11.1 mmol/l (and/or major ketonuria present), 2U if blood glucose below 11.1 (and/or moderate ketonuria present), or 1U if blood glucose below 11.1 (without ketonuria) until reaching a blood glucose below 8.3 mmol/l. Blood glucose levels rose ~2.5 mmol/l (~45 mg/dl) over the first two hours of lispro interruption Blood glucose levels rose 9.2mmol/L (~165 mg/dl) over five hours of lispro interruption Plasma glucose remained stable in the 2 hours after resuming lispro infusion and decreased over time as corrective boluses were administered hourly since pump reactivation Guerci et. Al. J. of Clin Endo & Metab. May, 1999

Attia, et al. (1998) Obje c tiv e Compare the rapidity of metabolic decompensation after CSII interruption between human and lispro insulin and examine each type s ability to correct hyperglycemia and ketosis of a mildly decompensated IDDM Me thods 18 well-controlled IDDM patients on CSII participated in a two-phase study Phase 1 involved an 8 ho ur inte rruptio n of CSII beginning at 3 am and continuing until 11 am. Plasma glucose levels were tested every 15 minutes; insulin every 10-30 minutes; and Beta-O-hydroxybutyrate, bicarbonate, and ph every hour over the 8hr period. Urinary ketones were checked with every void. Phase 1 was halted prematurely if the participant registered plasma glucose above 19.4 mmol/l [350 mg/dl] or developed ketosis. Participants were eligible if plasma glucose was between 3.3 and 8.3 mmol/l [60-150 mg/dl] in the hour preceding basal insulin interruption. Phase 2 followed completion of Phase 1. Participants were randomized to receive a single subcutaneous injection of either human or lispro insulin (0.2 U/kg of body weight). Blood sampling was continued over the subsequent two hour period. To be eligible, participants must have developed either moderate hyperglycemia (plasma glucose > 13.9 mmol/l [250 mg/dl]) or moderate ketonuria during the insulin interruption phase. Re s ults Eighteen participants completed Phase 1 of the study ( s ho rte ne d fo r m o s t o f the pa tie nts ). Seventeen completed Phase 2. One was ineligible due to insufficient elevations in plasma glucose and urinary ketone levels. Pla s m a g luc o s e le v e ls did no t ris e s ubs ta ntia lly o v e r the 1 s t ho ur o f CSII inte rruptio n, but ro s e ~2 m m o l/l [ ~3 6 m g /dl] o v e r the frs t tw o ho urs, increasing ~12.2mmol/L [220mg/dL] over the entirety of Phase 1. Plasma glucose decreased 7.8 mmol/l [~140mg/dL] over the two hours following a corrective bolus of lispro to ~9.7mmol/L [~175 mg/dl]. Attia et. Al. Diabetes Care. May 1998

Obje c tiv e Zisser (2008) Measure the impact of s ho rt-te rm infus io n-s e t dis c o nne c ts on glucose levels Me tho ds 19 subjects with type-1 diabetes participated in the study. Subjects treatment varied by insulin pump (twelve used a Medtronic Minimed, four used a Deltec Cozmo, and three used an Animas insulin pump); insulin type (five used insulin aspart, ten used insulin lispro, and four used insulin glulisine); and infusion set used. All wore the Medtronic CGMS Gold continuous glucose monitoring system throughout the study to record glucose levels. Participants arrived at the study center at 7am in a fasting state, having taken no corrective boluses, treatment for hypolycemia or food since midnight the night prior. Participants disconnected their infusion sets one hour after arrival and reconnected 30 minutes later. On a separate day, subjects only changed their infusion sets. Glucose results were downloaded from the CGMS system at the end of each day. Re s ults All participants completed the study. Blood glucose levels were stable at 149.1± 9.0 mg/dl [8.3mmol/L ± 0.5] in the hour leading to disconnection. Blood glucose levels increased to 154.5 ± 4.8 mg/dl [8.6 ± 0.3 mmol/l] during the 30min after disconnecting and continued to rise for 70min after reconnecting. Glucose peaked at 181.5 ± 9.2mg/dL [10.1 ± 0.5 mmol/l]. Blood glucose rose ~33 mg/dl [~1.8mmol/L] during 30min of CSII interruption and the 70min following reconnection Blood glucose levels did not change significantly during infusion-set change Zisser, Diabetes Care. Feb 2008

Possibili condizioni che rendono utile il protocollo LGS: Ipoglicemia inavvertita Ipoglicemie notturne frequenti Ricerca controllo glicemico stretto Diabete tipo 1 in pediatria paura dell ipoglicemia attività fisica a rischio ipoglicermico

Pathway from CGM to partial insulin automation. Kovalski AJ. Diabetes Technology & Therapeutics, 2009, suppl 1

Fully Automated Closed-Loop Insulin Delivery Versus Semiautomated Hybrid Control in Pediatric Patients With Type 1 Diabetes Using an Artificial Pancreas. Diabetes Care 31:934 939, 2008 STUART A. WEINZIMER -The Medtronic MiniMed epid system is designed to emulate the characteristics of the Beta cell. However,sensor delays in insulin Closed-loop glucose control using an external absorption associated with the sc and insulin pump provides a means to achieve route near-normal of delivery inevitably lead to glucose concentrations in youth with type large 1 postprandial diabetes glucose excursions during the overnight period. The addition of small manual priming -RCT comparing FCL system with bolus doses of insulin, given 15 min before meals, HCL (pre-meal insulin priming) on improves postprandial glycemic excursions 17 young pediatric patients

New effort has been made to develop closed-loop glucose control, using subcutaneous (SC) glucose sensing and continuous subcutaneous insulin infusion (CSII) from a pump, and a control algorithm. An approach based on a model predictive control (MPC) algorithm has been utilized during closed-loop control in type 1 diabetes patients. Here we describe the preliminary clinical experience with this approach.

New effort has been made to develop the algorithm showed a good efficiency in maintaining BG in a safe range at nighttime. In contrast, postbreakfast glucose excursions were poorly anticipated and mastered by the algorithm. The algorithm needs to be further improved to fully allow a condition of normoglycemia.

But a semiautomated, partial closed-loop system that is less aggressive A fully automated, completely in the target glucose control hands-off closed-loop an artificial couldembodiment be deployed withofexisting pancreas wouldglucose likelysensor require: continuous technology in the near future that and is more reliable glucose sensor technology result in significant improvements and accurate; in glycemic control contains redundant components that minimizes both the frequency the riskby ofreducing miscalibration; and severity of high and require insulin with improved (faster) low glycemic pharmacokinetics and excursions pharmacodynamics.

Conclusion At this time, although, we have very promising preliminary closed-loop studies, is more like that a semiautomated closed-loop system could be developed, in the near future, with existing continuous glucose sensor technology. This system, together with an improvement in the size and the shape of the different component, will finaly result in significant improvements in glycemic control by reducing both the frequency and severity of high and low glycemic excursions.

Benefits of an insulin dosage calculation device for adolescents with type 1 diabetes mellitus. Errors in calculation of insulin dosage by adolescents occur frequently. Consistent use of an insulin dosage calculation device may help to improve metabolic control in adolescents using MDI or CSII. J Pediatr Endocrinol Metab. 2004 Dec;17(12):1641-51

Bolus Calculator: A Review of Four Smart Insulin Pumps Assistente al calcolo dei carboidrati Differenze relative tra i diversi infusori dotati di bolus calculator Il calcolo dell insulina attiva Utilizzo dell insulina attiva per intervenire sulla quota di insulina calcolata per i carboidrati Possibilità di inserire correttivi legati ad altri parametri: attività fisica

Il Ca lc o la to re de l bo lo Roche s BC Tutta l insulina = insulina attiva Attiva Insulina Attiva Current BCs Solo l insulina del bolo correttivo= insulina attiva L insulina richiesta per il bolo pasto è impegnata per coprire i CHO assunti. Solo l insulina richiesta per un bolo correttivo è da considerarsi attiva, perché possiede un impatto proporzionale sul BG atteso. 65

board: Animas insulin Pump

Clinical usefulness of a bolus calculator in maintaining normoglycaemia in active professional patients with type 1 diabetes treated with continuous subcutaneousinsulin infusion Caratteristiche dei soggetti : 18 pazienti seguiti dal medesimo medico Almeno 4 anni di CSII Con esperienza nella conta dei CHO, proteine e lipidi e stima dell indice glicemico In dieta libera Indicatori: A1c, mean FPG, PPG, CGM 3 days J Int Med Res. 2008 Sep-Oct;36(5):1112-6.

Clinical usefulness of a bolus calculator in maintaining normoglycaemia in active professional patients with type 1 diabetes treated with continuous subcutaneousinsulin infusion Bo lus Ca lc ula to r Us e rs ( N=8 ) SMDB: mean ± SD num/day 8.1± 2.8 No n-us e rs ( n=1 0 ) 7.2± 2.4 Mean A1c 6.8% 7.0% Fasting blood glucose 106±32.4 108±34.2 2-h PPG 1 3 6.8 ±3 9.6 * 78% 149.4±43.2 Blood glucose within targets (70-140 mg/dl) CGM *= p < 0,05 J Int Med Res. 2008 Sep-Oct;36(5):1112-6 69%

Benefits of a bolus calculator in pre- and postprandial glycaemic control andmeal flexibility of paediatric patients using continuous subcutaneous insulin infusion (CSII) Randomised two periods cross-over study 36 pazienti in CSII (19M e 17F) Età: 13,3 ± 6,4 anni 2 settimane con calcolatore bolo poi 2 settimane senza supporto calcolatore Shashaj B, et al. Diabet Med. 2008 Sep;25(9):1036-42.

Utilizzo Bo lus Ca lc. più e ffc a c e ne l c o ntro lla re la g lic e m ia pre a nd po s tpra ndia le c o n m ino ri bo li di c o rre ttiv i. Fa bbis o g no ins ulinic o a i pa s ti inv a ria to Se nza re s trizio ne de l c o nte nuto di CHO. Utilizzo de l Bo lus Ca lc. g iudic a to fa c ile e s o ddis fa c e nte. Dis c o rda nza tra fo rm ule s e m plif c a te pe r il c a lc o lo de l ra ppo rto ins ulina / c a rbo idra ti e c a lc o lo pe rs o na lizza to Shashaj B, et al. Diabet Med. 2008 Sep;25(9):1036-42. Sulli N, Shashaj B Diab Med 2008

Considerazioni sui Bolus Calculator Pochi studi: manca una evidenza forte di effetto sul controllo glicemico Efficacia: glicemia post-prandiale, Numero correttivi Graditi dagli utilizzatori Sono un momento di efficace educazione terapeutica Necessitano di un percorso educativo strutturato Necessitano di buona capacità di autogestione della persona con diabete

. Abituati al percorso EBM con le innovazioni tecnologiche, rapidamente immesse sul mercato anche attraverso un percorso deduttivo relativo alla loro utilità, si tratta di mantenere l attenzione al nostro obbiettivo la cura del diabete non il progresso tecnologico per il progresso tecnologico.