Transcript Insulin Pumping and Glucose Monitoring: Putting It All Together Robert Slover, M.D. Barbara Davis Center for Childhood Diabetes Aurora, Colorado.

Insulin Pumping and Glucose
Monitoring:
Putting It All Together
Robert Slover, M.D.
Barbara Davis Center for Childhood Diabetes
Aurora, Colorado
Presentation Overview
Diabetes Management
Insulin Pump Therapy
Continuous Glucose Monitoring
Closing the Loop
2
New Proposed ADA A1C Goals for
Children
6 – 11 yo = <7.5%
12 – 20 yo = <7.0%
How to accomplish?
• New insulin analogues?
• New “smart” pumps?
• New devices?
• CGM?
3
Recent HbA1c Values in Children
Number
 300
Value (mean)
8.7%
Source
Joslin Clinic
(J Pediatr 139:197,2001)
 2,873
8.6%
20 Countries
(Diab Care 20:714,1997)
 2,579
9.0%
France
(Diab Care 21:1146,1998)
30 – 32% of children currently have values <8.0%
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12
120
severe hypoglycemia
10
8
6
risk of
retinopathy
4
2
0
60
0
5.5
6
6.5
7
7.5
8
8.5
9
9.5
10
10.5
0
Rate of severe hypoglycemia (per 100 patient years)
Rate pf progression of retinopathy (per 100 patient years)
DCCT: the price of improved
diabetic control – hypoglycemia
HbA1c (%)
Adapted from: N Engl J Med 1993;329:977–86
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Insulin Pump Therapy
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Insulin Pump Therapy (IPT)
Programmable Insulin Delivery with Medtronic MiniMed Pump Therapy
6.0
Bolus insulin delivery
Units of Insulin
5.0
Dual Wave™
Bolus for brunch
4.0
3.0
Basal reduced
to help prevent
nocturnal
hypoglycemia
Basal insulin delivery
Basal programmed
to help prevent
dawn phenomenon
Temporary basal
during walking
to help prevent
hypoglycemia
2.0
Dinner
Bolus
1.0
0
12 am
Note: This is a schematic representation.
4 am
8 am
12 pm
4 pm
8 pm
12 am
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Insulin Pump Therapy Reduces Number
of Severe Hypoglycemic Episodes
MDI vs CSII in type 1 patients
140
MDI
Events per Hundred
Patient-Years
120
Pump
100
80
60
40
20
0
Bode1
(n=55)
1. Bode BW, et al. Diabetes Care. 1996;19(4):324-327.
2. Boland EA, et al. Diabetes Care. 1999;22(11):1779-1784.
3. Rudolph DS, et al. Endocr Pract. 2002;8(6):401-405.
Boland2
(n=25)
Rudolph3
(n=107)
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Outcomes of Pump Therapy
Kauffman et al.Diabetes Metabolism and Reviews, 2000
6 months data 130 subjects
PRE
POST
P Value
HbA1C %
8.4 +/-1.8
7.8 +/-1.2
0.01
Hypoglycemia
0.06
0.03
0.05
DKA
0.15
0.09
0.05
Events/pt/year
Events/pt/year
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Benefits of Insulin Pump Therapy
 Improved glycemic control
 Less frequent / severe
hypoglycemia
 Enhanced quality of life
 Improved patient satisfaction
 Ease of management
 Reduced glucose toxicity, which
may also result in improved -cell
function
1. Wainstein J, et al. Diabet Med. 2005;22(8):1037-1046.
2. Labrousse-Lhermine F, et al. Diabetes Metab. 2007;33(4):253-260.
Hb
A1C
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Basal Insulin Flexibility
 Multiple basal rates to match diurnal variations
• Up to 48 different basal rates in a 24 hr period
− “Most type 1 patients use 3-5 basal rates.” Customized basal
rate profiles for different occasions
 Up to 3 basal rate patterns:
• Weekend vs. Weekday, Menses
 Temporary Basal rate feature:
• Exercise, Illness, etc.
Medtronic Minimed, Inc. 508 insulin pump. http://www.minimed.com/products/otherpumps/508/.
Accessed February 8, 2008.
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The Bolus Wizard® Calculator
Individually customized with:
•
•
•
•
Blood glucose targets
Carbohydrate ratios
Insulin-sensitivity factors
Active Insulin Time
Simplifies diabetes management
• Calculates estimated bolus for the patient
• Tracks active insulin
• Reduces hypoglycemic events resulting from
stacking of insulin
Bolus Wizard® is a registered trademark of Medtronic Diabetes.
Medtronic Minimed, Inc. Bolus Wizard® Calculator. http://www.minimed.com/products/insulinpumps/features/boluswizard.html.
Accessed February 7, 2008.
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Insulin Pump Therapy (IPT)
Programmable Insulin Delivery with Medtronic MiniMed Pump Therapy
6.0
Bolus insulin delivery
Units of Insulin
5.0
Dual Wave™
Bolus for brunch
4.0
3.0
Basal reduced
to help prevent
nocturnal
hypoglycemia
Basal insulin delivery
Basal programmed
to help prevent
dawn phenomenon
Temporary basal
during walking
to help prevent
hypoglycemia
2.0
Dinner
Bolus
1.0
0
12 am
Note: This is a schematic representation.
4 am
8 am
12 pm
4 pm
8 pm
12 am
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CONTINUOUS GLUCOSE
MONITORING (CGM)
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Increased SMBG Testing Frequency
is Associated With Lower HbA1c
Subcutaneous Insulin
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Insulin Pump
Oral Medications
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No Insulin
HbA1c
9
8
 n=1255 patients
 n=552 no
insulin
 Results indicate
frequent BG
testing reduces
HbA1C
7
6
5
0
1
2
3
4
5
6
7
8
SMBG Frequency (BGpd)
Adapted with permission from Davidson PC, et al. J Diabet Sci Technol. 2007;1(6):850-856.
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Logbook Diary Limitations:
The Traditional Approach
 Problems faced with
logbook approach1,2:
• Noncompliance: inconsistent
record-keeping
• Incorrect transcription of
glucose
• Missing data: “I forgot at
home” or “I left it in the car”
• Adding data: falsification of
information
• Illegibility of diary
1. Gonder-Frederick LA, et al. Diabetes Care. 1988;11(7):579-585.
2. Ziegler O, et al. Diabetes Care. 1990;13(2):182-184.
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CGM Devices
Dexcom
Medtronic
Real Time
Abbott Navigator
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Continuous Subcutaneous Insulin Infusion
(CSII) Improves Control
Compared with MDI, insulin pumps are more effective at reducing HbA1C
9.5
Type 1 Patients
MDI
9.0
CSII
HbA1C, %
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
Duration
Bruttomesso1
Bell2
(n=138)
(n=58)
89 months
36 months
Rudolph3 Chantelau4
(n=116)
(n=107)
36 months
54 months
Boland5
(n=25)
12 months
Maniatis6
(n=56)
12 months
Litton7
(n= 9)
13 months
1. Bruttomesso D, et al. Diabet Med. 2002;19(8):628-634. 2. Bell DSH, et al. Endocr Pract. 2000;6(5):357-360. 3. Rudolph DS, et al. Endocr Pract. 2002;8(6):401-405. 4. Chantelau E, et al.
Diabetologia. 1989;32(7):421-426. 5. Boland EA, et al. Diabetes Care. 1999;22(11):1779-1784. 6. Maniatis AK, et al. Pediatrics. 2001;107(2):351-356. 7. Litton J, et al. J Pediatr. 2002;141(4):490-495.
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Sensor Carelink Tracings
Pediatric Patients
on the 722 system
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20
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7yo Female
Week 1 – A1C 8.2%...6 months – A1C 7.2%
(night time changes)
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14 yo Female
Start – A1C 9.0%
9 months of wear – A1C 7.6%
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11 yo Male
Start – A1C 8.7%
3 months – A1C 7.5%
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STAR 3
Medtronic Pump/Sensor Study
Robert Slover, MD
H. Peter Chase, MD
Stephanie Kassels, RN BSN
Yolanda Hall, PRA
STAR 3
Purpose
• To compare the efficacy of the MiniMed Paradigm
REAL-Time System versus insulin administration via
MDI.
− A1C
− Severe hypoglycemia
− Hypoglycemia intensity, frequency and duration as measured
with pump and guardian device.
− DKA
− Questionnaires-IDSRQ, QOL, Hypoglycemia Fear Scale,
sensor and Carelink acceptance questionnaires.
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STAR 3
 Study Design
• Randomized 722 versus MDI
 Number of Subjects
• 552 across all sites, 28 sites.
• 30 at Barbara Davis Center (up to 50
once 30 is reached)
 Duration of Participation
• 1.5 years (If in MDI group, will start pump
at one year and wear for 6 months)
 Population
• Peds and adult (Peds only at our site)
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STAR 3
Current Status at the Barbara Davis
Center
• Started in August 2007
• Enrolled 19 (9-722, 10-MDI)
• Goal is to enroll 1/week and finish enrollment
by end of August 2008 and study collection by
Feb 2010.
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Closing the Loop
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Fully Automated ClosedLoop Insulin Delivery Versus
Semiautomated Hybrid
Control in Pediatric Patients
With Type 1 Diabetes Using
an Artificial Pancreas
Weinzimer et al. Diabetes Care 31:934 May 2008
Rationale for a Closed-Loop System
 Present methods of diabetes treatment
improve, but don’t normalize, blood glucose
levels, even with CGM
 Burden of care extremely high
 Islet cell replacement therapies limited to small
segments of population and not well-suited for
children with Type 1 DM
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Components of a Closed-Loop System
1. Insulin pump
2. Continuous real-time glucose sensor
3. Computerized algorithm to specify insulin
delivery based on continuous glucose input
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Yale Pediatric CL Study Objective
 To study the feasibility of a fully-automated CL
system in youth with Type 1 DM in an inpatient
setting
 To evaluate the use of pre-meal “priming” doses
of insulin on postprandial glucose excursions
(CL w/ meal announcement or “hybrid” control)
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Study Protocol
 Subjects admitted to Yale Inpatient GCRC for
overnight blood glucose stabilization utilizing
traditional open-loop control
 Two continuous glucose sensors were placed
in the subcutaneous space of the abdomen
 Closed-loop control was commenced at 7 AM
on day #1 and continued until 5 PM of day #2,
for 34 hours
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Study Protocol (cont.)
 Daytime (6A-10P) target glucose level was set at
100 mg/dL; nighttime (10P-6A) target glucose
level was set at 120 mg/dL
 Sensors calibrated on day #1 at 7A and 10P, day
#2 at 6A
 Meals were provided at 8A, noon, and 5P
 “Priming” bolus given 5-15 min before meal,
equivalent to ½ usual meal bolus
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Glucose Control During Closed-Loop
Glucose (mg/dl)
300
Reference BG
Sensor Glucose
setpoint
200
100
0
6A
All Subjects
Noon
6P
MidN
6A
Noon
Mean
Daytime
Peak PP
142  53
148  54
207  54
6P
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Reference Glucose Levels in
CL vs. Hybrid Control
Glucose (mg/dl)
300
setpoint
Closed Loop (N=8)
meals
Hybrid CL (N=9)
200
100
0
6A
Full CL
Hybrid
Noon
6P
6A
MidN
Noon
Mean
Daytime
Peak PP
147  58
138  49
154  60
143  50
219  54
196  52
6P
37
Single Meal Example
Plasma Insulin (  U/mL)
100
80
60
40
Closed Loop
20
Hybrid CL
0
0
60
120
Time (min)
180
240
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Distribution of Sensor Glucose Levels During CL
Control vs. Usual Home Therapy
8
15
3
33
<70
70-180
>180
58
Home CSII
82
Closed-Loop
P<0.002
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Plasma Insulin Levels Demonstrate Late
Postprandial Hyperinsulinemia
Glucose(mg/dl)
300
250
Mean BG
meals
200
150
100
50
H
0
18
30
36
42
9
Plasma Insulin
Insulin Delivery Rate
80
6
40
3
0
Insulin Delivery (u/h)
Insulin (U/ml)
120
24
0
18
24
30
36
42
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Conclusions
 Closed-loop is feasible in people with Type 1 DM
 Glucose control during CL control is superior to
traditional OL therapy under controlled conditions
 Use of a manual priming bolus improves prandial
glycemic excursions but still results in postprandial hyperinsulinemia
 Further refinements are necessary to accelerate
insulin action and decay rates
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Consumer Friendly Design
M
Confidential. Not to be circulated outside of Medtronic
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Discrete and Flexible Delivery Systems
Confidential. Not to be circulated outside of Medtronic
43
Therapy Accessibility & Consumer Electronics Integration
Confidential. Not to be circulated outside of Medtronic
44
Therapy Accessibility & Consumer Electronics Integration
Confidential. Not to be circulated outside of Medtronic
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Thank You
Robert Slover, M.D.
Barbara Davis Center for Childhood Diabetes
Aurora, Colorado