Glucose Monitors and Glucose Sensing

Applications for the 21st Century and Beyond The Quest for the Closed Loop

Why Glucose Sensing??

More real time assessment Ability to detect hypoglycemia and hyperglycemia at odd times Better administration and correlation of insulin dosagesless guessing May uncover eating disorders and other issues related to stress, diet and exercise Patient compliance with monitoring an issue many do not like to poke fingers or other sites so often. Pain and discomfort, lack of blood obtained, lost strips, etc.

Why Glucose Sensing??

Goal Closing the Loop An artificial pancreas Provide accurate and specific data to control glucose levels many individuals keep blood glucoses higher than optimal to avoid hypoglycemia Fear of hypoglycemia in the middle of the night not waking up Take the worry out of diabetes treatment Type 1 patients in particular; parents, children and physicians

Optimal Conditions for Glucose Measurement

Immediate availability of results and measurements High frequency of measurements
Measurements every 2-5 minutes would be ideal Ability to detect rapid rise or decline is necessity

Need quick signal stability after initiation or placement Stability over prolonged period of time (>3 days necessary)

Case for Glucose Sensing Recent Studies

23 patients participated hospitalized and ambulatory Both Type 1 and Type 2 individuals Study lasted 72 hours (key time limit) 75 capillary samples were obtained Microdialysis subcutaneous monitoring system used
microdialysis catheter; extracorporeal electrochemical sensor signal needed to be corrected for fluid transportation 31 minutes (lag time)
Diabetes Care 24: 1696, 2001 Jungheim et al

Results of Study and Conclusions

Studies showed no limitations to patients activity and only mild skin irritation Difference between SCGM and capillary glucose was ~ 7-9 % over the full range (meter differences can be as much as 10 15 %) Hypoglycemia was detected with SCGM but was missed 58-71% of the time by spot capillary measurements. This despite 5-7 or more measurements per day No decay in sensitivity over the 72 hour period SCGM could be useful in glucose control & therapy

Glucose Monitor Development

Race for the Closed Loop System, Painless, Continuous and the Gold

Types of Monitors in Development

Minimally invasive interstitial devices Transcutaneous optical devices Electrochemical sensing devices
subcutaneous Implantable

Implantable optical sensors

Physiology of Interstitial Fluid

Extracellular fluid and flows through the capillary walls Glucose levels in interstitial fluid blood glucose Lag time could be ~ 10 to 20 minutes Perspiration, oils and other environmental factors (lotions, etc.) can dilute the measurements and adversely affect the results as sample size is small

Interstitial Glucose Sensor

Glucowatch Biographer 2

Cygnus Corp: www.glucowatch.com

Glucowatch Schematic

Advantages and Limitations of Glucowatch System

Advantages Non-invasive Detects trends and patterns in glucose levels
readings every 10 minutes with up to 6/hour = 72 readings/monitoring session

Limitations 2 hour warm-up period Calibration is needed with each sensor use Skin irritation with sensor and adhesive Skipped readings possible with rapid changes in temperature, perspiration and if system is bumped or dislodged
If several readings in a row are skipped, the system must be recalibrated

Alerts patients to rapids changes in glucose levels Less painful?? Computer download capable ? Ability to determine insulin or medication adjustmens

Use of Glucowatch Biographer 2

Intended for use in adults and children to detect trends and patterns in glucose levels To detect and assess hyperglycemic and hypoglycemic patterns to help facilitate adjustments in therapy To be used as an adjunctive device, to supplement, not replace, information obtained from traditional and standard home glucose monitoring devices!

Glucowatch Biographer 2

Draws out interstitial fluid by reverse electroionophesis Glucose interacts with Glucose Oxidase Membrane to form hydrogen peroxide which interacts with biosensor producing low electric current which is measured and analyzed Glucowatch 2
Cost $599 to $799 Rebates can save $200 to $300

Auto sensor
Disposable transdermal pad Changed every 14-15 hours ~$4 each (2 needed) for each recording session Concerns with calibration time, risk of infection and irritation

Glucose Collection with the GlucoWatch G2 Biographer Uses Reverse Iontophoresis

Only small compounds pass through the skin.
CATHODE ANODE

No proteins (e.g., hemoglobin) in the extract

Glucose is collected at the cathode.

Interfering species (ascorbate and urate) collected at anode

Cl-, (ascorbate, urate) Na+, neutral species (i.e., glucose)

The charge and size exclusion properties of reverse iontophoretic extraction will lead to a very clean sample.

Data on file, Cygnus Inc. 2002.

The Automatic Monitoring Process with the GlucoWatch G2 Biographer *

A RUNNING AVERAGE PROVIDES READINGS EVERY 10 MINUTES
3

min

min

min

min

min

min

min

min

Internal measure

127 mg/dL

109 mg/dL

101 mg/dL

112 mg/dL

Displayed reading TIME

3

118 mg/dL
3:10 pm 3:20 pm

105 mg/dL
3:30 pm

107 mg/dL
3:40 pm

* Following a 2 hour warm-up and calibration min glucose collection 7 min glucose measurement

Data on file, Cygnus Inc. 2002.

GlucoWatch Biographer
Home Study Clarke Error Grid Analysis
Slope = 0.95, Intercept = 12.6 mg/dL, r = 0.80
400

ZONE A

Biographer Readings 60% 34% 1% 4% 0.1%

2996 paired points

A

B C

350

Biographer Readings (mg/dL)

300

D E

250

200

(A) Accurate. Biographer within 20% of finger-stick test result (or both below 70 mg/dL) (B) Acceptable. Difference greater than 20% but Biographer would not lead to bad decision

150

D B D

100

50

(C) Might cause an over-correction of normal glucose levels. Finger-stick blood glucose test result in the normal range, but Biographer reading is high or low. (D) Failure to detect a high or low glucose level. Biographer reading in the normal range, but fingerstick blood glucose test result is high or low

C
0 0 100 Profile Touch 200

E
300 400

One

One Touch Profile

* Glucose Readings (mg/dL)

(E) Treatment error could occur. Biographer reading low when finger-stick blood glucose is high or Biographer reading high when finger-stick is low.

* One Touch Profile Johnson and Johnson, New Brunswick New Jersey

Data on file, Cygnus Inc. 2002.

Studies of Glucowatch vs. Meters

Differences between interstitial fluid and blood glucose Time lag: 17.2 minutes 7 minutes with Glucowatch Time lag: 13 minutes with most blood glucose meters With glucose increasing, changes were less as measured by Glucowatch as compared with blood With glucose decreasing, changes were greater as measured by Glucowatch as compared with blood or meters Conclusion: possible false hyperglycemia and false hypoglycemia if taken unilaterally
Kulcu et al: ADA Meeting 2002

SpectRx Glucose Sensing System

Transdermal Biophotonic System Fluid is collected through micropores Laser system used on the outer layer of skin Measured in a patch which contains a glucose sensor Clinical trials are ongoing Is not FDA approved at this time Still similar to Glucowatch in that it provides information on trends and not necessarily real-time for treatment adjustments
SpectRx website: www.spectrx.com

SpectRx Glucose Sensing System

Laser device on the skin surface

Patch with sensor system embedded

www.spectrx.com

Preliminary data with SpectRx ISF System

www.spectrx.com

Preliminary data with SpectRx ISF System

Pendragon Glucose Sensing System

Uses electromagnetic waves Attached to lower forearm similar to the Glucowatch Performs measurements every minute but averaging occurs

Pendragon Glucose Sensing System

Recent Study with PENDRA

15 individuals without diabetes Changes in microcirculation of the arms resulted in varying glucose values Temperature changes, other environmental issues had to address via a complex calibration procedure Conclusions:
Need to fix device appropriately to arm to avoid possible variations Needs extensive physician and patient training to operate Needs further studies prior to any extensive use in the clinical setting
Diabetes Technology and Therapeutics 6:435, 2004

Electrochemical Glucose Sensors

CGMS TGMS DexCOM

Continuous Glucose Monitoring System--CGMS

Basic Premise: Glucose + Oxygen = Gluconic Acid + H 2O 2 Reaction is submitted to an electrical current which is proportional to the glucose concentration which is measured Enzymatic or Electrochemical Sensors are implanted in the subcutaneous tissue (under the skin) Similar to the catheters used in insulin pump therapy Short term use at present; reliability just 48 to 72 hours

Medtronic (MiniMed) CGMS System

Two Views of CGMS

Mechanism of Action of CGMS

Enzymatic Reaction is measured by sensor in IF through skin

CGMS System

Sensor is percutaneous an ~1mm in diameter Measures an average glucose value every 5 minutes and is stored in the monitor Hard wired system; worn externally Requires calibration at 4-5 times per day, otherwise data is not able to be downloaded Able to enter events on the monitor to assist with interpretation of results 3 day use only at this time Not real timerequires return to physician office for download and interpretation

CGMS System

Problems with encapsulation tissue which can cause errors in data collection Anything implanted in the body over time becomes covered with a protein layer initially and then a collagen like layer Encapsulation tissue is to protect the body from foreign objects which may be perceived as harmful and to isolate the object chemically (ie.broken port in pulmonary artery) This chemical isolation could decrease the sensitivity and response time of electrochemical subcutaneous systems such as CGMS

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002


 

Self monitoring of glucoses several times per day will leave gaps gaps large excursions can occur without patient knowledge Hypothesis: to test the reproducibility of the CGMS in realreal-life setting CGMS may be a tool that could alleviate this difficulty System measures glucose concentration every 5 minutes for a 72 hour period

    

Preliminary Study performed in Type 2 patients ~ 150 separate glucose tracings Included healthy volunteers and patients on only metformin Correlated with frequent blood glucose measurements Noted exceeding high incidence of hypoglycemic events with no symptoms and not confirmed by simultaneous blood glucose measurements Correlation coefficient r=0.74

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002
      

Real Life Study was undertaken to determine accuracy and reproducibility of tracings utilizing the CGMS device 11 patients involved in the study 6 had Type 1 diabetes 3 had Type 2 diabetes 2 healthy volunteers with no history of DM 10 male, 1 female Placed on two glucose sensor devices simultaneously for a 3 day period with usual normal activity

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002
     

Protocol Sensors were attached according to the manufacturers instructions Sensors were placed in the abdominal SQ tissue 4-5 cm to 4the right or left of the umbilicus Calibration and Initialization were performed and 1 hour was elapsed before first capillary glucose Meal times were recorded Capillary glucoses were done immediately post meals, during the night and early AM Capillary glucoses were entered into the monitor within 5 minutes of determination

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002EA

Download was done upon completion and analysis was performed immediately  Anonymity was preserved  Each day was divided into 8 time intervals according to the meal times of the patient  Classifications:


A: Satisfactory B: if all glucose values are between 80 150 C: glucose > 150 during >1 hr., too low D: glucose < 70 during >30 minutes or impossible to evaluate due to technical reasons

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002

D Classification was further subclassified:

D1: Low concordance between sensor and glucometer r < 0.8 or

the difference is too high (28%) D2: Insufficient number of meter glucose values entered for calibration D3: Strong midnight shift: usual sensor glucose values post midnight. Usually secondary to insufficient number of calibration values.

Evaluations were analyzed by two different observers independently and concordance rates were determined

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002


Mean sensor not recording glucose values

46 classified in the D group and not use of sensor: 60.4

16.9

hours each patient

432 single time intervals were initially evaluated  78 (18%) were discarded for technical reasons

32 due to interpretable

139 paired sets of data were available for sensor-sensor sensorcomparison.

92 from Type 1 patients 30 from Type 2 patients 17 from non-diabetes volunteers non-

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002

    

Concordance was seen in only 65% of the time periods 25% noted glucose levels too high in one sensor and satisfactory in the other 9% noted glucose levels too low with satisfactory levels in the other 1 case noted: sensor 1 showed hyperglycemia, sensor 2 showed hypoglycemia No difference between patients with DM and non DM

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002

Conclusions:
Accuracy and reproducibility is lower than

previously thought Differences were greatest between the 125 and 225 mg/dl range most important area in treatment of patients with diabetes mellitus Correlation between two simultaneous sensors was lower than that of capillary vs. sensor (r = 0.84 vs. 0.90)

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002

Conclusions:
35% clinically important discrepancies between

two simultaneous sensor tracings Could result in incorrect clinical advice in 17% of patient cases @ RESULTS OBTAINED IN REAL LIFE SITUATIONS MUST BE INTERPRETED IN INDIVIDUAL CLINICAL TERMS

CGMS CGMS Reproducibility Study

Metzger, M. et al: Diabetes Care 25:1185, July 2002

Development of a reliable device for continuous glucose monitoring is of outmost importance in the treatment of diabetes Future endeavors in this area must be rigorously evaluated in real life situations before release to the general public Rebuttal from Medtronic concerns in the above study: software used was earlier version, device was used for more than planned or approved

Additional Studies--2003 Studies--2003

        

Armstrong and King: ADA Meeting 2003 11 subjects: 2 No Diabetes, 6 Type 1, 3 Type 2 Measured Glucoses with 1 Touch Ultra 7 times per day Wore 2 sensors (CGMS) concurrently for 3 days Mean Sensor life: 67 hours Used updated software Found accuracy with newer software ~94% Most of differences between modalities within 10% Sensor-sensor differences less than previous study

Rebuttal to Metzger Findings

   

 

Expectations did not coincide with CGMS intended use Study did not use Clarke error grid but was one of subjective assessment Study did use updated software (Solutions 3.0) Results are similar to those reported in the postmarketing studies (Diabetes Technology and Therapeutics, 2000) CGMS is intended to supplement, not replace, blood glucose information using standard monitoring devices CGMS, when used with home monitoring devices and HbA1C values can help optimize clinical management
Mastrototaro and Gross; Diabetes Care 26:256 2003

Rebuttal to Metzger Findings



Solutions 3.0 software resolves most of the 18% rate of technical problems encountered in the study Correction of the midnight shift Improvement in the accuracy and reproducibility of the downloads Improvement in the agreement between sensor and meter values

Mastrototaro and Gross; Diabetes Care 26:256 2003

Rebuttal to Metzger Findings




CONCLUSIONS:
Results should be weighed against the encouraging results and conclusions from previous and evolving reports and research Appears that this is a work in progress and should not be utilized as the sole clinical indicator! should not be used at present as the only source for change in treatment regimens -Speakers judgment after reviewing literature

Sample CGMS Reports

Daily Report of Blood Glucoses

Sample CGMS Reports

Modal Time Reports Can be varied individually

Sample CGMS Reports

Composite 3 day report for comparison

Additional Studies Involving Children

Accuracy of Glucowatch 2 system and CGMS in detecting hypoglycemia Multi-center study Involved the Children in Diabetes Research Network 91 children enrolled Ages 3-17 Patients were enrolled in a CRC-clinical research center for 24 hours

Diabetes Care 27:722-726 2004

Glucowatch 2 vs. CGMS

Patients used CGMS and Glucowatch 2 during each admission 1/3 patients started CGMS 48 hours prior to admission 1/3 patients started CGMS 24 hours prior to admission 1/3 patients started CGMS on the day of admission Each patient used 2 sensors for the G-watch 2 during the study 2 hour overlap 1 Touch Ultra meter used as calibration and control

Glucowatch 2 vs. CGMS

Samples: every hour during the day every 30 minutes during the night Hypoglycemia induction test: samples obtained every 5 minutes for 90 minutes Adjustment of values for lag time: time involved in sampling the interstitial fluid measuring glucose as compared with blood
Glucowatch 2 Biographer 17.5 minutes CGMS 2.5 minutes

Glucowatch 2 vs. CGMS

Results of Study Glucowatch 2 Biographer
~ 23 % of values were within reference range when glucoses were < 60 mg% 51% false alarms were detected with use

CGMS System
Both modified and original sensors noted < 50% detection within reference range (36 and 48 %) 58% to 60% false alarms were detected with use

Study Conclusions

Neither Glucowatch 2 nor CGMS is accurate in reporting glucose values in the hypoglycemic range Accuracy of both devices is better when reference glucose levels are >100 mg/dl Neither device is appropriate at this time for real time detection Both systems are more likely to be of value in adjusting bolus and basal insulin doses in patients with consistently elevated glucoses and A1C levels The accuracy of these early generation sensors is similar to the early generation meters (circa 1970s-early 1980s)

Modified Home Use of CGMS Guardian System

Guardian Home System

Sensor can be set to alarm at certain levels both high and low Monitor can be placed up to 6 feet away; does not have to be worn Monitor can store up to 21 days of data Can be downloaded to personal computer Still needs calibration similar to CGMS system Alerts or alarms need to be verified with finger stick glucose Cost is not set at present (~ $800- $1500 anticipated)

Anticipated Sample Guardian Report

Reports similar to CGMS System

www.minimed.com

Paradigm 522 System Patient Use

Consists of Glucose Sensor, Radio Transmitter and Pump receiver Abstract presented at ADA 2004 (Orlando) 9 Patients involved; Ages 10-21, Type 1 DM Used CSII Did 4 Blood Glucoses/day via HGM Wore 7 sensors during the 3 week trial A1C levels decreased 0.3% Glucoses decreased average 20 mg% Work in progress; Not available yet!!!

Implantable Subcutaneous Systems

Enzyme electrode system Electrochemical device

DexCom Subcutaneous Sensor System

Implantable Sensor device

Pager monitoring system

DexCom Subcutaneous Sensor System

Special bioprotective layer prevents foreign body reaction with sensor Can measure glucoses ranging from 40 mg/dl to 700 mg/dl (2.2-38.9 mmol/L) Recalibration every 20 days 160 180 day lifespan for sensor Still need to do HGM 2-3 times/day to initiate glucose algorithm Easily implanted in subcutaneous tissue Can be accomplished as outpatient procedure
Diabetes Care 27:734, 2004 Endocrinology Clinics NA 33:175, 2004

Therasense Navigator System

Interstitial System Wireless system Needs calibration 1-2 times per day Readings every 1-2 minutes conceptualized High and low glucose alarms to be incorporated Currently experimental Company not distributing info at this time

Near Infrared Spectroscopy

Non-invasive techniques

Sensys Medical Systems

Endocrinology Clinics of NA 33: 163-173 2004

Sensys Medical Systems

Measures glucose non-invasively via NIR spectroscopy Device weighs less than 1.5 pounds Fiber-optic head secured to the forearm Still needs HGM for calibration Various components such as sweat, fat, etc. can interfere with efficacy Can use either volar or dorsal aspects of the forearm Uses a rechargeable battery Studies ongoing with patient use

Open-flow Microperfusion Systems ADICOL ProjectDisetronic/Roche

Advanced Insulin Infusion with a Control Loop

ADICOL Project Disetronic / Roche

Inserted into the subcutaneous adipose tissue Double lumen catheter Acquires glucose readings every 30 minutes Goal subcutaneous glucose sensing/insulin delivery system

ADICOL Project Disetronic / Roche

Large bore catheter Readings only every 30 minutes Small study sample with patient use

Infrared Spectroscopy
Animas Corporation Continuous Glucose Monitoring System

Infrared Spectroscopy

Infrared light is absorbed by molecules Each molecule has its own spectra (absorption characteristic)similar to its own footprint Theoretically-by measuring the absorbed light vs. wavelength, one could delineate the species and concentration In reality this is difficult
Water absorbs most IR light Blood scatters light Different species overlap in their spectra or footprint

Spectra of Water, Hemoglobin, Blood & Glucose

Absorbance 0.042 0.040 0.038 0.036 0.034 0.032 0.030 0.028 0.026 0.024 0.022 0.020 0.018 0.016 0.014 0.012 0.010 0.008 0.006 0.004 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3
1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 0.0 0.4 0.2 0.6 1.6 2.0

2.2

Water
1.8

Hemoglobin
Absorbance

1.4 1.2 1.0 0.8

Wavelength (microns) Absorbance

2.6 2.4 2.2

mic Wavelength (microns)

0.062 0.060 0.058 0.056 0.054 0.052 0.050 0.048 0.046 0.044 0.042 0.040 0.038 1.2
Absorbance

Blood

Glucose

2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0

1.3

1.4

1.5

1.6

1.7

1.8

1.9

2.0

2.1

2.2

2.3

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

2.0

2.1

2.2

2.3

Wavelength (microns)

mic Wavelength (microns)

Sketch of Animas Sensor

Implanted Extravascular Sensor Head

Early Animas Sensor Head

Correlation (r2=.94) between optical and conventional means (500 people)

C o n c e n tr a tio n (m g /d l), u s in g O p tic a l M e a n s

450 400 350 300 250 200 150 100 50 0 0 50 100 150 200 250 300 350 400 450
Concentration (mg/dl) Determined by Glucometer

In vivo Measurements in Dog: Glucometer and Sensor Head vs. Time

350

Glucose Concentration (mg/dl)

300 250 200 150 100 50 0

Glucometer Sensor

Time

Animas Continuous System

Has designed and built short term prototype and demonstrated stability in animals Need to miniaturize system
Laser diodes under development Telemetry developed Electronics being modified and mostly developed

Clinical trials in humans projected to start 2005 or 2006. Projected as early Phase 2 studies with sites to be determined. No pediatric patients to be involved!

Advantages of Animas Monitor

y Provides continuous reading of blood glucose without patient intervention y Measures glucose in blood as opposed to some other body fluid, e.g. interstitial fluid, ocular fluid y The encapsulation/ fibrin tissue has no effect on monitor accuracy y Provides direct access to blood, obviating loss and interference associated with light transmission through intervening tissues. y Sensor stays implanted for at least 5 years, limited by battery life. No percutaneous wires or cables are utilized.

What is the Goal of These Technologies?

Development of a Closed Loop System The Artificial Pancreas

*Put the Endocrinologist into Early or Permanent Retirement

Have We Achieved Goal??? Not Yet!!

What Has Been Accomplished?

New Technology to determine patterns and facilitate changes in therapy Prototypes for long term glucose monitoring More awareness by patients and families regarding the importance of intensive therapy and tight control of blood glucoses Consumer driven research for an artificial pancreas More physicians are implementing intensive therapy with technology now available to compliment the treatment

Final Thoughts

No system at present is appropriate for a closed loop system No system developed at present can replace the finger stick monitor for real time glucose values and treatment decisions Presently, there are 50+ companies or individuals attempting to develop a continuous glucose monitoring system

EVENTUALLY, THAT DAY WILL ARRIVE!! WHEN, ONE ONLY KNOWS!