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.