The Future of Pumping
Henry Anhalt, DO, CDE
Director, Pediatric Endocrinology and Diabetes
Saint Barnabas Medical Center
Livingston, NJ
`In the past we had a light that
flickered, in the present, a light
that flames, and in the future we
will have a light that shines over
all the land and the sea’
Winston Churchill
DCCT
Relationship of HbA1c to Risk of
Microvascular Complications
15
Retinopathy
13
Nephropathy
Neuropathy
Relative Risk
11
Microalbuminuria
9
7
5
3
1
6
7
8
9
10
11
HbA1c (%)
Skyler. Endocrinol Metab Clin. 1996;25:243-254, with permission.
12
Limitations/Challenges to
Better Glycemic Control
• A1c’centric
• Hypoglycemic Risk
• Glucose excursions above and below what
the HbA1c average represents may be
more important than HbA1c
• Inadequate Postprandial Glucose Control
• Weight Gain
Obstacles in Glycemic Control
• Invasive glucose monitoring devicesowie!!!!!
• Limited availability of reliable
continuous glucose monitoring
• Lack of alternate routes of insulin
delivery.
Alternate Site Glucose Testing
(Forearm, Thighs, Abdomen vs. Fingers)
• Rubbing/exercising/suction does not
uniformly increase the blood flow but
glucose values may be better correlated to
fingers.
• At extremes of glucose values fingerstick
testing is mandatory for confirmation.
• Rapid changes in glucose values, fingers
are the best
Alternate Site Glucose Measurements
350
300
250
Over-reads
200
150
Under-reads
100
50
Time (minutes) 0-360
34
5
31
5
28
5
25
5
22
5
19
5
16
5
13
5
10
5
75
45
0
15
Blood Glucose mg/dL
400
MAJOR RESEARCH
CHALLENGES?
• CLINICALLY
Development of new methods for achieving tight
control without hypoglycemia
• RESEARCH
Development of methods for replacing beta cell
function (islet cell transplantation, artificial pancreas)
Enhanced understanding of immunopathogenesis
(interaction of genes, environment and immune
system) allowing for more effective preventative
therapies
APPROACHES TO CURING TYPE 1
DIABETES
in vivo Differentiation of
Pancreatic Progenitors
Immune Interventions/
Tolerance Induction
Manipulation
Of non-islet tissue
(Transdifferentiation
Transplantation
Islets
Stem Cells
Growth Factors
Adult
Whole pancreas
Fetal
Embryonic
Gene Therapy
Modulate Autoimmunity
Islet neogenesis
TOWARDS CLOSED LOOP DELIVERY
External Closed-Loop
Implanted Closed-Loop
Glucose Contributions to HbA1c
HbA1c =
Fasting Glucose
influenced by:
• Liver glucose
production
• Liver sensitivity to
insulin
Lantus, Basal rates,
Postprandial Glucose
Influenced by:
+
• Preprandial glucose
• Insulin dose
• Glucose load from
meal
• Insulin sensitivity in
peripheral tissues
Humalog, Novalog
Blood Glucose
Are All HbA1c Values Created Equal?
Time
HbA1c = 8%
HbA1c = 8%
Lesser Known Outcomes from the DCCT
The DCCT Research Group stated HbA1c is not the
entire answer to glycemic control.
“The Average HbA1c is not the most
complete expression of the degree of
glycemia and the risk of complications may
be more highly dependent on the excursions
or influenced by counterregulatory hormonal
responses to hypoglycemia.”
Diabetes 44:968-983, 1995
Actual writing on Hospital
charts:Top Ten
1. She has no rigors or shaking chills, but
her husband states she was very hot in
bed last night.
2. Patient has chest pain if she lies on her
left side for over a year.
3. On the second day the knee was better,
and on the third day it disappeared.
4. The patient is tearful and crying
constantly. She also appears to be
depressed.
5. The patient has been depressed since
she began seeing me in 1993.
Why do we need
Glucose
Sensors?
Model of Multihormonal Regulation
of Glucose Homeostasis
Brain
Food
Intake*
—
Gastric
Emptying
—
Liver
Stomach
Postprandial
Glucagon
Rate of
glucose
appearance
Plasma Glucose
Amylin
Insulin
Rate of
glucose
disappearance
Glucose
Disposal
Gut
Pancreas
Tissues
GLP-1
Model derived from animal studies
*Inferred satiety effect
GLP-1 central effect on glucose homeostasis is
inferred from animal studies
Excessive 24-Hour Glucose Fluctuations in
Type 1 Patients with Mean A1C of 6.7%
Glucose Concentration (mg/dL)
400
300
200
100
12:00 AM
4:00 AM
8:00 AM
12:00 PM
N = 9, CSII treated (insulin lispro); A1C average 6.7%
(range 5.8%-7.1%) ; 24-hour CGMS glucose sensor data
Desired glycemic range in non-diabetic subjects: 80-140 mg/dL
4:00 PM
8:00 PM
12:00 AM
Levetan C, et al. Diabetes Care 2003; 26:1-8
Intensively-treated T1DM: Diurnal Glucose
Fluctuation and Nocturnal Hypoglycemia
Mean A1C = 7.7%
Postprandial Hyperglycemia
Nocturnal Hypoglycemia
90
> 300 mg/dL
241–300 mg/dL
181–240 mg/dL
80
80
70
70
60
60
% Patients
% Peak Postmeal Glucose
Levels Over Target
100
50
40
30
50
40
30
20
20
10
10
0
0
Breakfast Lunch Supper
90% of Postprandial Readings
Exceeded ADA Guidelines
41–60 mg/dL
 40 mg/dL
1 Night 2 Nights 3 Nights
Nearly 70% of Patients Had
1 Night With PG < 60 mg/dL
Continuous Glucose Monitoring System (CGMS) data, 56 adolescents, T1DM on CSII or MDI
CSII = Continuous subcutaneous insulin infusion; PG = Plasma glucose
Boland E, et al. Diabetes Care. 2001;24:1858-1864.
Blood Glucose Values (SMBG)
Needed to Attain Different HbA1C
Values
WTR
49%
ATR
33%
BTR
18%
HbA1c = 7.0%
WTR
45%
ATR
41%
WTR
42%
BTR
12%
BTR
14%
HbA1c = 8.0%
ATR
46%
HbA1c = 8.5%
WTR = within target range (70-150 mg/dl)
BTR = below target range (<70 mg/dl)
ATR = above target range (>150 mg/dl)
Brewer KW, Chase PH, Owen S, Garg SK. Diabetes Care 1998;21(2):209-212.
Need for Continuous glucose monitoring
•
•
•
•
•
•
•
Direction
Magnitude
Duration
Frequency
Cause of fluctuation
Alerts/Alarms
Improve therapeutics decisions
Glucose Sensors
• Continuous Glucose Monitoring
System (CGMS)
• GlucoWatch Automatic Biographer
• Navigator
• Near-InfraRed (NIR)
• Implantable glucose sensors-Dexcom
• Optical sensors
• Ultrasonic sensors
Glucose Sensors
GlucoWatch
Pendra®
DexCom Implantable
Sensors
FreeStyle
Navigator
Sensys Medical NIR
MiniMed
MiniMed® Continuous Glucose
Monitoring System (CGMS)
GlucoWatch® Biographer
Schematics of the Autosensor &
Biographer
Mask
Hydrogel Pads
Ionto
Sensor
Electrode
Assembly
AAA Battery
Electronic
Components
Garg et al. Diabetes Care 1999;22:1708-1714
Device Evaluation
Advantages
– Real-time measurement
– Non-invasive (no-biological
fluids)
– Calibration stability
– 71% of patients calibrate
– Trending capability
Disadvantages
–
–
–
–
–
Not portable
Skin temperature control
Sampling site critical
Failure modes not all identified
Requires daily finger stick
Near Infrared Ray (NIR)
•
•
•
•
Large desk-like apparatus
Skin temperature and hydration
Calibration is too cumbersome
Patient intervention required
Real Need!
• Need a small wearable, patientfriendly continuous glucose monitor
with alarms and remote displays
and feed the information to insulin
pumps (closed-loop system)
Sensors in Development
DexCom and Vascular Sensors
NIR, Nostix, Therasense
The Pendra, Pendragon Medica
Sensys Glucose Tracking System, Sensys
Glucon Solution, Glucon
Sugartrac, Lifetrac Systems
GlucoNIR, CME Telemetrix
ReSense, MedOptix
Pindi, Pindi Products
Head-Mounted Goggles, NASA
Role of Frequent
Glucose Monitoring
More Frequent Testing Improves
HbA1c in Type 1 Patients
HbA1c (%)
11
<2
<2
10
9
8
>4
>4
>4
Cross-Over
Intensify
7
6
Initial
No Contact
Schiffrin A, Belmonte M. Diabetes Care 1982;(5):479-84.
Current Medical Practice
400
•
Repeated fingersticks are
required to
obtain glucose
readings
periodically
•
Testing is
generally
performed before
meals
360
Glucose (mg/dL)
320
280
240
200
160
120
121
80
80
40
0
11:00
AM
Pre Dinner
Pre Lunch
•
1:00
PM
3:00
PM
5:00
PM
Occasional
measurements
7:00
9:00 11:00 1:00
provide limited
PM
PM
PM
AM
information
about glucose
Garg et al Diabetes Care ; 22; levels
1708-1714, 1999
With the GlucoWatch®
Biographer • After one fingerstick
for calibration,
glucose readings are
available
automatically
400
360
Biographer
Blood Glucose
Calibration Point
Glucose (mg/dL)
320
280
240
•
Frequent readings
provide more
information about
glucose levels
•
Trend information
helps to identify
opportunities for
improved glucose
control
200
160
120
80
40
0
11:00
AM
Pre Dinner
Pre Lunch
1:00
PM
3:00
PM
5:00
PM
7:00
PM
9:00
PM
11:00
PM
1:00
AM
Garg SK et al Diabetes Care ; 22; 1708-1714, 1999
Measurement of Blood Glucose
Conventional Blood Glucose Meters
400
Biographer
Blood Glucose
Calibration Point
360
Glucose (mg/dL)
320
280
240
200
160
121
80
120
80
40
0
11:00
AM
Pre Lunch
3:00
PM
5:00
PM
7:00
PM
9:00
PM
Based on significant
postprandial
hyperglycemia, the
dose of pre-meal
boluses on insulin
lispro were adjusted
and HbA1c values
have remained
consistently below
6.5% during the
subsequent year.
Pre Dinner
1:00
PM
•
11:00
PM
1:00
AM
Garg et al Diabetes Care ; 22; 1708-1714, 1999
Glucose Concentration (mg/dL)
Continuous Subcutaneous Glucose Monitoring in a
Subject with Type 1 Diabetes
450
400
350
300
Meter Value
Sensor Value
Insulin
Meal
250
200
150
100
50
0
Time
Chase and Garg , Pediatrics:107; 222-226, 2001
Technical Aspects of Continuous
Glucose Monitoring
• Interstitial vs. Blood glucose –reported
Lag of few seconds to 15 minutes
• High frequency of measurements
• Signal Stability –Quick and over time
• Calibration Issues
• Duration of Sensor application
Limitations with Current
Technologies
• SMBG
– Solitary Data points with no trend information
• CGMS
– No real time feedback, 4T/day calibration
– Unreliable data, size of the needle
• GlucoWatch
- Prospective data but too many skips,12 hr.sensor
- Skin irritation, Sweating,Temperature changes
* HbA1c and Fructosamine Assay
– Purely retrospective
– No immediate Feedback
Device Description: Sensor
DexCom G1 Sensor
– Subcutaneous implant in the
abdominal wall
– Multi-layer membrane system
– Measures glucose every 30
seconds
– Wireless transmission to
receiver
Garg et al., Diabetes Care, 27:734-38, 2004
Device Description: DEXCOM Receiver
Long Or Short Term Use
Receives and processes data
from sensor
Updates and displays
glucose values every 5
minutes
Displays 1, 3 and 9 hour
trends
High and low glucose alerts
Garg et al., Diabetes Care, 27:734-38, 2004
Profile With Continuous Glucose Sensor
in Patients With Insulin-requiring Diabetes
Time Spent (hours/day)
Blinded period
Unblinded period
10
Mean A1C = 7.2%
37%*
increase
8
6
4
38%*
decrease
4%*
decrease
31%*
decrease
41%*
increase
2
0
2.46 1.53
2.13 3.00
40–55
56–79
6.37 8.74
6.46 6.16
6.58 4.57
80–140
141–239
240–400
Glucose Range (mg/dL)
*P < 0.05, Student’s t test
Garg SK, et al. Diabetes Care. 2004;27:734-738.
Slicing the Pie from DCGM Sensor Downloads
Blinded vs. Unblinded phases (n=14)
Blinded phase
WTR
37%
ATR
51%
Unblinded phase
WTR
51%
BTR
12%
ATR
41%
BTR
8%
WTR = within target range (60-150 mg/dl)
BTR = below target range (<60 mg/dl)
ATR = above target range (>150 mg/dl)
Results (G2)
Excursion Duration (min)*
Blinded
Excursion Amplitude (mg/dl)*
Unblinded
Blinded
Unblinded
Change
Change
Hyperglycemic
(200 mg/dl)
307 
62
215  29
-30%**
352 
12
332  14
-13%**
Hypoglycemic
(80 mg/dl)
181 
15
138  10
-24%**
50  3
51  4
+3%
* Expressed as Mean  SEM
** Two-sided paired t-Test, p  0.05
Scott and Garg. ADA (LB5), o4 and EASD 2004
Results (G2)
Hyperglycemia Exposure
(mg/dl*hrs)*
Blinded
Unblinded
573  123
340  64
Change
-40%**
* Expressed as Mean  SEM
** Two-sided paired t-Test, p  0.05
Scott and Garg. ADA (LB5)and EASD 2004
Closing the Loop:
The Artificial Pancreas
• Accurate, reliable continuous glucose
monitoring systems, in progress
• Algorithms to incorporate glucose trend
data into proper dose adjustments
• External or internal insulin pump
systems
Medtronic MiniMed’s
Family of Insulin Pumps
Remote Control
Paradigm 511
MiniMed 508
Paradigm 512
Paradigm Link Meter
Pardigm Link & Bolus Wizard
Paradigm 512 ONLY
Actual writing on Hospital
charts:Top Ten (cont.)
6. Discharge status: Alive but without
my permission.
7. Healthy appearing decrepit 69 year
old male, mentally alert but
forgetful.
8. Patient has left white blood cells
at another hospital.
9. The patient has no previous history
of suicides.
10.The patient refused autopsy.
Until the Cure-The Realities:
• Learn to manage glucose TRENDS
rather than isolated numbers
• Minimize the moodiness associated with
wide glucose excursions
• Understand glucose profiles over
extended time
• Improve implementation of new
regimens
• Knowledge and acceptance of
inaccuracies and data interpretation
Conclusions
• Continuous glucose monitoring promises the goal of
normalization of blood sugars while minimizing risk of
hypoglycemia
• The result of full implementation will be normal HbA1c
with further reduction in complications of diabetes
• A closed loop, artificial pancreas either externally or
internally based is now on the horizon
Implantable pump
• Implanted under the skin of the
abdomen through a minor surgical
procedure.
• Controlled today by hand-held
radio frequency telemetry.
• Delivers short, frequent pulses of
insulin into the peritoneal cavity.
• Designed to be refilled in a
physician’s office every 3 months.
• Projected 10 year battery life.
• Hypoglycemic events reduced
400%.
Out-takes from a Web Blog Of RT
User
“Now, I never look at a single reading. I check
my NOW number and then quickly scroll back in
time using the down arrow button. Five minutes
per click. I usually glance at half an hour…I think
about what I’m looking at. Direction? Is the BG
going up or down? Or is it fairly stable? Speed?
Speed I’m not always so good at, because that
takes mental mathematics, which is my weak
spot. That said I can get a rough idea of how fast
things are moving.”
THE RUB
Even if the continuous sensors are refined,
reimbursement for the devices as well as
for providers’ time to help analyze data
remains a problem. As things now stand,
relatively few doctors and nurses have the
time or expertise to assess the log records
of individual glucose readings.
Predictions are difficult - particularly
when you’re talking about the future!
Casey Stengel
Adapted from Niels Bohr - Nobel Prize (Physics) 1922