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

0

50

100

150

200

250

300

350

400

Time (minutes) 0-360

Bloo

d G

luco

se m

g/dL

Under-readsUnder-reads

Over-readsOver-reads

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

100

200

300

400

12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM

Glu

co

se

Co

nc

en

tra

tio

n (

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

Po

stm

eal

Glu

cose

L

evel

s O

ver

Tar

get

100

90

80

70

60

50

40

30

20

10

0

Breakfast Lunch Supper

% P

atie

nts

80

70

60

50

40

30

20

10

01 Night 2 Nights 3 Nights

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

121121

00

4040

8080

120120

160160

200200

240240

280280

320320

360360

400400

11:0011:00AMAM

1:001:00PMPM

3:003:00PMPM

5:005:00PMPM

7:007:00PMPM

9:009:00PMPM

11:0011:00PMPM

1:001:00AMAM

Glu

cose

(m

g/d

L)

Glu

cose

(m

g/d

L)

Pre LunchPre Lunch

Pre DinnerPre Dinner

Garg et al Diabetes Care ; 22; 1708-1714, 1999

00

4040

8080

120120

160160

200200

240240

280280

320320

360360

400400

11:0011:00AMAM

1:001:00PMPM

3:003:00PMPM

5:005:00PMPM

7:007:00PMPM

9:009:00PMPM

11:0011:00PMPM

1:001:00AMAM

Glu

cose

(m

g/d

L)

Glu

cose

(m

g/d

L)

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

00

4040

8080

120120

160160

200200

240240

280280

320320

360360

400400

11:0011:00AMAM

1:001:00PMPM

3:003:00PMPM

5:005:00PMPM

7:007:00PMPM

9:009:00PMPM

11:0011:00PMPM

1:001:00AMAM

Glu

cose

(m

g/d

L)

Glu

cose

(m

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

0

50

100

150

200

250

300

350

400

450

12 M

N

1:30

AM

3:00

AM

4:30

AM

6:00

AM

7:30

AM

9:00

AM

10:3

0 AM

12 N

OON

1:30

PM

3:00

PM

4:30

PM

6:00

PM

7:30

PM

9:00

PM

10:3

0 PM

12 M

N

Time

Glu

cose

Con

cen

trat

ion

(m

g/d

L)

Meter Value

Sensor Value

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