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THE
GLUCOWATCH ® BIOGRAPHER TM
G2
(automatic noninvasive blood glucose monitor)
Is it really worth a
diabetic’s time
(and money)?
Alex Yeung
ChE 4T3/6T3
1
March 31, 2004
Outline
What is diabetes?
History of BG testing
Technical aspects
Clinical results
Problems
Conclusions Figure 1. GlucoWatch® G2
BiographerTM (GW2B)1
2
Diabetes 101
Diabetes Mellitus in Canada
– Prevalence: >2.25 million
– Cause: absent/insufficient
insulin production;
cells can’t utilize
ingested glucose
– Cost: 9 BILLION dollars/year2
Diabetic Complications
– macrovascular
– microvascular
– neurological
Figure 2. Systemic effects of
diabetes mellitus3
3
Diabetes 101
What can be done?!
Landmark studies by the
Diabetes Control and Complications Trial Group and
United Kingdom Prospective Diabetes Study Group concluded that:
reducing high reduction in risk, and
BG levels
(hyperglycemia) = severity, of diabetes
complications4
in diabetics
Hypoglycemia (low BG levels) can be dangerous
too as they can cause comatose and death
4
Traditional BG Testing
a) b)
apply
blood
here
Figure 3. a) Prick finger5 b) Use biosensor to measure BG6
The ‘fingerstick’ method
– painful, cumbersome, inconvenient
– 4+ BG tests recommended per day
Potential alternatives
– boronic acid-containing fluorophores embedded in contact
lenses7, skin tissue measurements utilizing optical
coherence tomography8 or ultrasound9
But, these methods are expensive, inaccurate, too large, so…
5
Solution? The GW2B
GlucoWatch® G2
BiographerTM (GW2B)1
– 2nd generation device by
Cygnus Inc.
– FDA approved in 2002 for
diabetics 7+ years old
– performs noninvasive,
transdermal, near-continuous,
BG analysis
– tracks BG vales at 10-min Figure 4. GlucoWatch® G2
BiographerTM; available in the US
intervals for 13 hr, stores and UK10
BG data, identifies BG trends,
alerts user of hypo- and
hyperglycemia
6
Technical Aspects of GW2B
AutoSensor Component
– two cross-linked polymeric
hydrogel disks; must be
replaced every 15 hr
– disks contain electrolyte and
glucose oxidase enzyme
(GOx)
Biographer Component
– bulk of device
– stores, analyzes, and displays Figure 5. Components of GW2B
data from AutoSensor using (upside-down view)11
mixture of experts algorithm
7 (mech eng)
Technical Aspects of GW2B
Employs Reverse
Iontophoresis
1. apply 0.3 mA/cm2 current
across skin; electromigratory
and electroosmotic effects
result
2. interstitial neutral molecules
(glucose) migrate with
cations to cathodic Figure 6. Molecular flow from
hydrogel disk interstitial fluid of skin to GW2B
(cross-sectional view)12
8 (elec eng)
Technical Aspects of GW2B
Glucose selectivity Biographer Microprocessor, Data
memory, Display
– Size exclusion: skin’s IONTO(phoresis)
MW cutoff is ~500 Da electronics
MWGlucose = 180 Da Biosensor
MWHb = 64.5 kDa electronics
AutoSensor
GOx Gel GOx
– Charge exclusion: (anode)
pads (cathode)
current is preferentially Skin
carried by in vivo Na+
Na+, glucose
Uric and ascorbic
acid migrate to anode
Figure 7. Electronics and
structure of GW2B
(cross-sectional view)13
9 (mech/elec eng)
Technical Aspects of GW2B
1. Oxidation reaction in cathodic hydrogel disk:
GOx
Glucose O2 Gluconic Acid H2O2
2. Electrocatalytic oxidation in Pt/C composite
electrode adjacent to hydrogel disk:
2H O 2 2e
H 2O2
3. Electrons (current) are detected by Ag and Ag/Cl
electrodes; integration performed to yield net
charge, QA
10 (chem eng)
Technical Aspects of GW2B
4. Process is repeated using the other hydrogel disk,
and BG value is calculated from the data:
BG(calibra tion value)
Blood Glucose Value
Q A Q B 2000
-BG(calibration value) is obtained from fingerstick
initially used to calibrate GW2B
-QA: net charge from first hydrogel disk
-QB: net charge from second hydrogel disk
-2000 nCoulombs: empirically determined offset
constant used to optimize biographer readings
11
Clinical Results of GW2B
Figure 7a-f. Sample BG measurements obtained from home
environment study comparing biographer and fingerstick
readings14
Biographer and fingerstick BG profiles
correlate well with one another
12
Clinical Results of GW2B
Biographer and
fingerstick BG results
are correlated because:
obtained correlation
coefficient of 0.80
Deming slope (linear
regression) is near unity
94.2% distribution of
paired biographer and
fingerstick results in
clinically acceptable
Figure 8. Overall results obtained
from home environment study regions of Clarke Error
comparing biographer and fingerstick Grid Analysis
readings14
13
Clinical Results of GW2B
Biographer readings (mmol/L)
Comparative readings (mmol/L)
Figure 9. Clarke Error Grid Analysis comparing 2167 paired
biographer versus serum BG values in clinical study. Regions A
and B are the therapeutically relevant areas.15
96.8% of the biographer’s data falls into
14
clinically acceptable regions A and B
Problems with GW2B
Inaccurate hypoglycemic BG analyses:
– 192 GW2B glucose tests performed on 89 hypoglycemic
patients (BG ≤ 60 mg/dl)
– Results:
26 mg/dl difference between GW2B and serum BG results
alarming of prehypoglycemia when alarm was set to 60 mg/dl
happened only 23% of the time with false-alarm rate of 51%16
Skin irritation:
– 124 patients; 5 day biographer use
– Results:
87% of subjects: minimal/no skin irritation
0.06% of subjects: intense erythema
Figure 10. Example of
0.8% of subjects: strong edema13
forearm erythema
15
Problems with GW2B
Very few large-scale trials have been conducted
– Demographic effects? Drug effects?
1000 mg of acetaminophen consumed prior to device use does
not affect BG results17, but what about other topical drugs…?
Studies with biographer have not exceeded 6 wks
– long-term alterations to skin structure and function?
GW2B requires a two hour warm-up period and
fingerstick-involving calibration
– research into using Na+ in skin as an internal standard is
underway
Problems with novel device are expected.
As well, GW2B can be easily removed
should problems arise.
16
Interesting GW2B Analysis
Cost of GW2B:
– $698US, $85US for 16 AutoSensors (~10 d)
– GW2B’s lifespan is ~4 years
– not covered by insurance
But, Monte-Carlo simulation study by Eastman
et al.18 predicted that life-long biographer use
would:
– delay serious diabetes complications by 4.1 yr
– prevent one case of blindness and 1.4 cases of renal
failure in every 18 users
– cause significant gains in terms of long-term cost
savings
17
Conclusions
GW2B’s chemical/electronic mechanisms have been
comprehensively researched and optimized
clinical trials have validated the GW2B’s accuracy and
sensitivity with clinically acceptable results
although slight problems exist (e.g. inaccurate
hypoglycemic readings), GW2B provides real-time BG
monitoring that will enable more aggressive insulin, diet,
and exercise regimes to control diabetes
more widespread use and studies will provide data for
future biographer versions
GW2B’s attributes (1/2 pancreas) could be used in the
development of a true artificial pancreas!
Better treatment offered right now, and possibly cure for
diabetes in the future?...
18
References
1. www.glucowatch.com
2. Health Canada. Diabetes in Canada. 1999.
3. www.abc.net.au
4. Lancet 352:837-853 (1998).
5. userweb.port.ac.uk
6. www.lifescan.com
7. Anal Chem 76(3):610-618 (2004).
8. Phys Med Biol. 48(10):1371-90 (2003).
9. Diabetes Technol Ther 4(4):489-97 (2002)
10. www.diabetes.org.uk
11. Clin Chem 45(9):1681-1683 (1999).
12. www.glucowatch.com
13. Annals of Medicine 32(9):632–641 (2000).
14. Biosens Bioelectron 16(9-12):621-9 (2001).
15. JAMA 282(19):1839-44 (1999).
16. Diabetes Technol Ther 5(5):791-800 (2003).
17. Diabetes Technol Ther 2(2):199-207 (2000).
18. Pediatr Diabetes 4(2):82-6 (2003).
19
Questions?
20 CONGRATS!
