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The Future of Pumping. Henry Anhalt, DO, CDE Director, Pediatric Endocrinology and Diabetes Saint Barnabas Medical Center Livingston, NJ.

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slide1

The Future of Pumping

Henry Anhalt, DO, CDE

Director, Pediatric Endocrinology and Diabetes

Saint Barnabas Medical Center

Livingston, NJ

slide2
`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

slide3

DCCTRelationship of HbA1c to Risk of Microvascular Complications

15

Retinopathy

Nephropathy

13

Neuropathy

11

Microalbuminuria

9

Relative Risk

7

5

3

1

6

7

8

9

10

11

12

HbA1c(%)

Skyler. Endocrinol Metab Clin. 1996;25:243-254, with permission.

limitations challenges to better glycemic control
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
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
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
major research challenges
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

slide9

APPROACHES TO CURING TYPE 1 DIABETES

in vivo Differentiation of Pancreatic Progenitors

Immune Interventions/

Tolerance Induction

Manipulation

Of non-islet tissue

(Transdifferentiation

Transplantation

Stem Cells

Growth Factors

Islets

Adult

Whole pancreas

Gene Therapy

Modulate Autoimmunity

Islet neogenesis

Fetal

Embryonic

slide11

Glucose Contributions to HbA1c

HbA1c =

Postprandial Glucose

Influenced by:

  • Preprandial glucose
  • Insulin dose
  • Glucose load from meal
  • Insulin sensitivity in peripheral tissues

Fasting Glucose influenced by:

  • Liver glucose production
  • Liver sensitivity to insulin

+

Humalog, Novalog

Lantus, Basal rates,

slide12

HbA1c = 8%

HbA1c = 8%

Are All HbA1c Values Created Equal?

Blood Glucose

Time

slide13

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

slide14

Actual writing on Hospital charts:Top Ten

  • She has no rigors or shaking chills, but her husband states she was very hot in bed last night.
  • Patient has chest pain if she lies on her left side for over a year.
  • On the second day the knee was better, and on the third day it disappeared.
  • The patient is tearful and crying constantly. She also appears to be depressed.
  • The patient has been depressed since she began seeing me in 1993.
model of multihormonal regulation of glucose homeostasis

Model derived from animal studies

*Inferred satiety effect

GLP-1 central effect on glucose homeostasis isinferred from animal studies

Model of Multihormonal Regulationof Glucose Homeostasis

Brain

Food

Intake*

Gastric

Emptying

Liver

Stomach

PostprandialGlucagon

Rate ofglucoseappearance

Plasma Glucose

Gut

Rate ofglucosedisappearance

Glucose

Disposal

Insulin

Amylin

Pancreas

Tissues

GLP-1

excessive 24 hour glucose fluctuations in type 1 patients with mean a1c of 6 7

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

Excessive 24-Hour Glucose Fluctuations in Type 1 Patients with Mean A1C of 6.7%

400

300

Glucose Concentration (mg/dL)

200

100

12:00 AM

4:00 AM

8:00 AM

12:00 PM

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
Intensively-treated T1DM: Diurnal Glucose Fluctuation and Nocturnal Hypoglycemia

Mean A1C = 7.7%

Postprandial Hyperglycemia

Nocturnal Hypoglycemia

100

90

> 300 mg/dL

241–300 mg/dL

181–240 mg/dL

41–60 mg/dL

 40 mg/dL

80

80

70

70

60

60

% Peak Postmeal Glucose Levels Over Target

50

50

% Patients

40

40

30

30

20

20

10

10

0

0

1 Night

2 Nights

3 Nights

Breakfast

Lunch

Supper

90% of Postprandial Readings Exceeded ADA Guidelines

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 hba 1c values

WTR = within target range (70-150 mg/dl)

BTR = below target range (<70 mg/dl)

ATR = above target range (>150 mg/dl)

Blood Glucose Values (SMBG) Needed to Attain DifferentHbA1CValues

ATR

33%

ATR

41%

ATR

46%

WTR

45%

WTR

49%

WTR

42%

BTR

18%

BTR

12%

BTR

14%

HbA1c = 7.0%

HbA1c = 8.5%

HbA1c = 8.0%

Brewer KW, Chase PH, Owen S, Garg SK. Diabetes Care 1998;21(2):209-212.

need for continuous glucose monitoring
Need for Continuous glucose monitoring
  • Direction
  • Magnitude
  • Duration
  • Frequency
  • Cause of fluctuation
  • Alerts/Alarms
  • Improve therapeutics decisions
glucose sensors
Glucose Sensors
  • Continuous Glucose Monitoring System (CGMS)
  • GlucoWatch Automatic Biographer
  • Navigator
  • Near-InfraRed (NIR)
  • Implantable glucose sensors-Dexcom
  • Optical sensors
  • Ultrasonic sensors
slide22

Glucose Sensors

DexCom Implantable Sensors

Pendra®

GlucoWatch

FreeStyle Navigator

Sensys Medical NIR

MiniMed

schematics of the autosensor 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

slide26

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
slide27

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 development
Sensors in Development

DexCom and Vascular Sensors

NIR, Nostix, Therasense

The Pendra, Pendragon MedicaSensys Glucose Tracking System, SensysGlucon Solution, GluconSugartrac, Lifetrac SystemsGlucoNIR, CME TelemetrixReSense, MedOptixPindi, Pindi ProductsHead-Mounted Goggles, NASA

more frequent testing improves hba 1c in type 1 patients
More Frequent Testing Improves HbA1c in Type 1 Patients

11

< 2

< 2

10

HbA1c (%)

9

8

> 4

> 4

> 4

7

6

Initial

No Contact

Cross-Over

Intensify

Schiffrin A, Belmonte M. Diabetes Care 1982;(5):479-84.

current medical practice

400

360

320

280

240

Glucose (mg/dL)

200

160

121

120

80

Pre Dinner

80

Pre Lunch

40

0

11:00

1:00

3:00

5:00

7:00

9:00

11:00

1:00

AM

PM

PM

PM

PM

PM

PM

AM

Current Medical Practice
  • Repeated finger-sticks are required to obtain glucose readings periodically
  • Testing is generally performed before meals
  • Occasional measurements provide limited information about glucose levels

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

with the glucowatch biographer
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

400

360

Biographer

Blood Glucose

320

Calibration Point

280

240

Glucose (mg/dL)

200

160

120

Pre Dinner

80

Pre Lunch

40

0

11:00

1:00

3:00

5:00

7:00

9:00

11:00

1:00

AM

PM

PM

PM

PM

PM

PM

AM

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

measurement of blood glucose conventional blood glucose meters

Biographer

Blood Glucose

Calibration Point

Measurement of Blood GlucoseConventional Blood Glucose Meters

400

360

  • 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.

320

280

240

Glucose (mg/dL)

200

121

160

80

120

Pre Dinner

80

Pre Lunch

40

0

11:00

1:00

3:00

5:00

7:00

9:00

11:00

1:00

AM

PM

PM

PM

PM

PM

PM

AM

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

continuous subcutaneous glucose monitoring in a subject with type 1 diabetes
Continuous Subcutaneous Glucose Monitoring in a Subject with Type 1 Diabetes

Meter Value

Sensor Value

Insulin

Meal

450

400

350

300

250

Glucose Concentration (mg/dL)

200

150

100

50

0

12 MN

12 MN

1:30 PM

3:00 PM

4:30 PM

6:00 PM

1:30 AM

3:00 AM

4:30 AM

6:00 AM

7:30 AM

9:00 AM

7:30 PM

9:00 PM

10:30 AM

12 NOON

10:30 PM

Time

Chase and Garg , Pediatrics:107; 222-226, 2001

technical aspects of continuous glucose monitoring
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
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
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
Device Description: DEXCOM ReceiverLong Or Short Term Use

Receives and processes data from sensorUpdates and displays glucose values every 5 minutesDisplays 1, 3 and 9 hour trendsHigh and low glucose alerts

Garg et al., Diabetes Care, 27:734-38, 2004

profile with continuous glucose sensor in patients with insulin requiring diabetes
Profile With Continuous Glucose Sensor in Patients With Insulin-requiring Diabetes

Blinded period

Unblinded period

10

37%*increase

Mean A1C = 7.2%

4%*decrease

31%*decrease

8

6

41%*increase

Time Spent (hours/day)

38%*decrease

4

2

8.74

6.46

6.16

4.57

2.46

1.53

2.13

3.00

6.37

6.58

0

40–55

56–79

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

WTR = within target range (60-150 mg/dl)

BTR = below target range(<60 mg/dl)

ATR = above target range (>150 mg/dl)

Slicing the Pie from DCGM Sensor Downloads Blinded vs. Unblinded phases (n=14)

Unblinded phase

Blinded phase

WTR

51%

ATR

41%

WTR

37%

ATR

51%

BTR

12%

BTR

8%

results g2
Results (G2)

* Expressed as Mean  SEM

** Two-sided paired t-Test, p  0.05

Scott and Garg. ADA (LB5), o4 and EASD 2004

results g242
Results (G2)

* 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
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
slide44

B

Medtronic MiniMed’s

Family of Insulin Pumps

Remote Control

Paradigm 511

MiniMed 508

Paradigm 512

Paradigm Link Meter

102 mg/dL

Pardigm Link & Bolus Wizard Paradigm 512 ONLY

slide45

Actual writing on Hospital charts:Top Ten (cont.)

  • Discharge status: Alive but without my permission.
  • Healthy appearing decrepit 69 year old male, mentally alert but forgetful.
  • Patient has left white blood cells at another hospital.
  • The patient has no previous history of suicides.
  • The patient refused autopsy.
until the cure the realities
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
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
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
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
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.

slide51

Predictions are difficult - particularly when you’re talking about thefuture!

Casey Stengel

Adapted from Niels Bohr - Nobel Prize (Physics) 1922