The Future of PumpingThe Future of Pumping
Henry Anhalt, DO, CDEDirector, Pediatric Endocrinology and Diabetes
Saint Barnabas Medical CenterLivingston, 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
DCCTRelationship of HbA1c to Risk of
Microvascular Complications
Skyler. Skyler. Endocrinol Metab Clin.Endocrinol Metab Clin. 1996;25:243-254, with permission. 1996;25:243-254, with permission.
Rel
ativ
eR
elat
ive
Ris
k R
isk
RetinopathyRetinopathy
NephropathyNephropathy
NeuropathyNeuropathy
MicroalbuminuriaMicroalbuminuria
HbA1cHbA1c (%)(%)
1515
1313
1111
99
77
55
33
11
66 77 88 99 1010 1111 1212
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 devices-
owie!!!!!
• 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
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MAJOR RESEARCH CHALLENGES?
• CLINICALLY Development of new methods for achieving tight control without hypoglycemia
• RESEARCHDevelopment 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
APPROACHES TO CURING TYPE 1 DIABETES
Immune Interventions/ Tolerance InductionImmune Interventions/ Tolerance Induction
IsletsIsletsStem Cells Stem Cells
AdultAdult
Fetal Fetal
EmbryonicEmbryonic
in vivo Differentiation of Pancreatic Progenitors in vivo Differentiation of Pancreatic Progenitors
Growth FactorsGrowth Factors
ManipulationOf non-islet tissue (Transdifferentiation
ManipulationOf non-islet tissue (Transdifferentiation
Gene Therapy Modulate Autoimmunity Islet neogenesis
Gene Therapy Modulate Autoimmunity Islet neogenesis
Whole pancreasWhole pancreas
Transplantation
Implanted Closed-LoopExternal Closed-Loop
TOWARDS CLOSED LOOP DELIVERY
Glucose Contributions to HbA1c
Fasting Glucose influenced by:
• Liver glucose production
• Liver sensitivity to insulin
Postprandial GlucoseInfluenced by:
• Preprandial glucose• Insulin dose• Glucose load from
meal• Insulin sensitivity in
peripheral tissues
HbA1c =
+
Lantus, Basal rates, Lantus, Basal rates, Humalog, NovalogHumalog, Novalog
Are All HbA1c Values Created Equal?
Time
Blo
od
Glu
cose
HbA1c = 8%
HbA1c = 8%
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.”
Lesser Known Outcomes from the DCCT
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 Regulationof Glucose Homeostasis
Model derived from animal studies*Inferred satiety effectGLP-1 central effect on glucose homeostasis isinferred from animal studies
GlucoseDisposal
GLP-1
GutGut
Plasma Glucose
PostprandialGlucagon
Tissues
LiverLiver
Insulin
PancreasPancreas
Rate ofglucose
appearance
Rate ofglucose
disappearanceAmylin
GastricEmptying
—
FoodIntake*
—
StomachStomach
BrainBrain
Excessive 24-Hour Glucose Fluctuations in Type 1 Patients with Mean A1C of 6.7%
Levetan C, et al. Diabetes Care 2003; 26:1-8
N = 9, CSII treated (insulin lispro); A1C average 6.7% (range 5.8%-7.1%) ; 24-hour CGMS glucose sensor dataDesired glycemic range in non-diabetic subjects: 80-140 mg/dL
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Glu
co
se
Co
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mg
/dL
)
Intensively-treated T1DM: Diurnal Glucose Fluctuation and Nocturnal Hypoglycemia
Continuous Glucose Monitoring System (CGMS) data, 56 adolescents, T1DM on CSII or MDICSII = Continuous subcutaneous insulin infusion; PG = Plasma glucose
Boland E, et al. Diabetes Care. 2001;24:1858-1864.
% P
eak
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Postprandial Hyperglycemia Nocturnal Hypoglycemia
> 300 mg/dL241–300 mg/dL181–240 mg/dL
41–60 mg/dL 40 mg/dL
90% of Postprandial Readings Exceeded ADA Guidelines
Nearly 70% of Patients Had 1 Night With PG < 60 mg/dL
Mean A1C = 7.7%
WTR49%
WTR42%
WTR45%
ATR33%
BTR18%
ATR46%
BTR12%
ATR41%
BTR14%
Brewer KW, Chase PH, Owen S, Garg SK. Diabetes Care 1998;21(2):209-212.Brewer KW, Chase PH, Owen S, Garg SK. Diabetes Care 1998;21(2):209-212.
WTR = within target range (70-150 mg/dl)
BTR = below target range (<70 mg/dl)
ATR = above target range (>150 mg/dl)
HbAHbA1c1c = 7.0% = 7.0% HbAHbA1c1c = 8.0% = 8.0% HbAHbA1c1c = 8.5% = 8.5%
Blood Glucose Values (SMBG) Needed to Attain Different HbA1C
Values
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
MiniMed
GlucoWatch
Sensys Medical NIR
FreeStyle Navigator
DexCom Implantable Sensors
Pendra®
MiniMed® Continuous Glucose Monitoring System (CGMS)
MiniMed® Continuous Glucose Monitoring System (CGMS)
GlucoWatch® BiographerGlucoWatch® Biographer
Schematics of the Autosensor & Biographer
Mask
Hydrogel Pads
IontoSensor
ElectrodeAssembly
ElectronicComponents
Garg et al. Diabetes Care 1999;22:1708-1714Garg et al. Diabetes Care 1999;22:1708-1714
AAA Battery
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, patient-
friendly continuous glucose monitor with alarms and remote displays and feed the information to insulin pumps (closed-loop system)
Sensors in DevelopmentDexCom and Vascular SensorsNIR, Nostix, Therasense The Pendra, Pendragon MedicaSensys Glucose Tracking System, SensysGlucon Solution, GluconSugartrac, Lifetrac SystemsGlucoNIR, CME TelemetrixReSense, MedOptixPindi, Pindi ProductsHead-Mounted Goggles, NASA
Role of Frequent Glucose Monitoring
6
7
8
9
10
11
Initial No Contact Cross-Over Intensify
Schiffrin A, Belmonte M. Diabetes Care 1982;(5):479-84. Schiffrin A, Belmonte M. Diabetes Care 1982;(5):479-84.
More Frequent Testing Improves HbA1c in Type 1 Patients
> 4> 4 > 4> 4 > 4> 4
< 2< 2 < 2< 2
Hb
A1
c (
%)
Hb
A1
c (
%)
Current Medical Practice
• Repeated finger-Repeated finger-sticks are sticks are required to obtain required to obtain glucose readings glucose readings periodicallyperiodically
• Testing is Testing is generally generally performed before performed before mealsmeals
• Occasional Occasional measurements measurements provide limited provide limited information about information about glucose levelsglucose levels
• Repeated finger-Repeated finger-sticks are sticks are required to obtain required to obtain glucose readings glucose readings periodicallyperiodically
• Testing is Testing is generally generally performed before performed before mealsmeals
• Occasional Occasional measurements measurements provide limited provide limited information about information about glucose levelsglucose levels
8080
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cose
(m
g/d
L)
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cose
(m
g/d
L)
Pre LunchPre Lunch
Pre DinnerPre Dinner
Garg et al Diabetes Care ; 22; 1708-1714, 1999
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cose
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BiographerBiographerBlood GlucoseBlood GlucoseCalibration PointCalibration Point
With the GlucoWatch® Biographer
• After one fingerstick for calibration, glucose readings are available automatically
• Frequent readings provide more information about glucose levels
• Trend information helps to identify opportunities for improved glucose control
• After one fingerstick for calibration, glucose readings are available automatically
• Frequent readings provide more information about glucose levels
• Trend information helps to identify opportunities for improved glucose control
Pre LunchPre Lunch
Pre DinnerPre Dinner
Garg SK et al Diabetes Care ; 22; 1708-1714, 1999
Measurement of Blood GlucoseConventional Blood Glucose Meters
8080121121
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cose
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g/d
L)
Pre LunchPre Lunch
Pre DinnerPre Dinner
BiographerBiographerBlood GlucoseBlood GlucoseCalibration PointCalibration Point
• 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.
• 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.
Garg et al Diabetes Care ; 22; 1708-1714, 1999
Continuous Subcutaneous Glucose Monitoring in a Subject with Type 1 Diabetes
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Insulin
Meal
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
DexCom G1 Sensor
– Subcutaneous implant in the abdominal wall
– Multi-layer membrane system
– Measures glucose every 30 seconds
– Wireless transmission to receiver
Device Description: Sensor
Garg et al., Diabetes Care, 27:734-38, 2004
Receives and processes data from sensorUpdates and displays glucose values every 5 minutesDisplays 1, 3 and 9 hour trendsHigh and low glucose alerts
Device Description: DEXCOM ReceiverLong Or Short Term Use
Garg et al., Diabetes Care, 27:734-38, 2004
Profile With Continuous Glucose Sensor in Patients With Insulin-requiring Diabetes
Tim
e S
pe
nt
(ho
urs
/da
y)
*P < 0.05, Student’s t test
Garg SK, et al. Diabetes Care. 2004;27:734-738.
2.46 2.13 6.37 6.46 6.581.53 3.00 8.74 6.16 4.570
2
4
6
8
10
40–55 56–79 80–140 141–239 240–400
Glucose Range (mg/dL)
Blinded periodUnblinded period
38%*decrease
Mean A1C = 7.2%37%*
increase 4%*decrease
31%*decrease
41%*increase
Slicing the Pie from DCGM Sensor Downloads Blinded vs. Unblinded phases (n=14)
WTR = within target range (60-150 mg/dl)WTR = within target range (60-150 mg/dl)BTR = below target range (<60 mg/dl)BTR = below target range (<60 mg/dl)ATR = above target range (>150 mg/dl) ATR = above target range (>150 mg/dl)
WTR51%
ATR41%
BTR8%
WTR37%
BTR12%
ATR51%
Blinded phaseBlinded phase Unblinded phaseUnblinded phase
Results (G2)Excursion Duration (min)* Excursion Amplitude (mg/dl)*
Blinded UnblindedChange
Blinded UnblindedChange
Hyperglycemic (200 mg/dl)
307 62
215 29 -30%** 352 12
332 14 -13%**
Hypoglycemic
(80 mg/dl)181
15138 10 -24%** 50 3 51 4 +3%
* Expressed as Mean SEM
** Two-sided paired t-Test, p 0.05Scott and Garg. ADA (LB5), o4 and EASD 2004
Results (G2)Hyperglycemia Exposure
(mg/dl*hrs)*
Blinded UnblindedChange
573 123 340 64 -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
Pardigm Link & Bolus Wizard Paradigm 512 ONLY
Medtronic MiniMed’sFamily of Insulin Pumps
MiniMed 508 Paradigm 511
Paradigm Link MeterParadigm 512
Remote Control
B
102 mg/dL
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
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