Smart Pumps And Tomorrow’s Intelligent Devices

July 21, 2005

John Walsh, P.A., C.D.E.

Diabetes Clinical Specialist North County Endocrine President Diabetes Services, Inc.

San Diego, California (619) 497-0900 www.diabetesnet.com

Highlights

• A1c levels remain high despite DCCT • What lowers the A1c • Classic meters • Glucose exposure and variability • Classic pumps • Smart pumps • Future intelligent devices Healthcare Across Borders - September 2003

Where We Are

The Graduate: “Plastics” The Post-Graduate: “Medical Devices” Healthcare Across Borders - September 2003

Where It Started

Patent issued September 14, 1971 to Anton Herbert “Tom” Clemens for the Ames Reflectance Meter Healthcare Across Borders - September 2003

Why We Do It

Better Control Reduces Complications

60 50 40 30 20 10 0

76% Risk Reduction

•

55.0

13.0

Retinopathy Progression 59% Risk Reduction 39% Risk Reduction 29.8

•

23.9

16.4

7.9

Laser Rx 1 Micro albuminuria

2

54% Risk Reduction

•

5.1

2.5

64% Risk Reduction Conventional Intensive

•

13.4

5.0

Clinical Neuropathy

3 1.

2.

3.

DCCT Research Group,

Ophthalmology.

1995;102:647-661 DCCT Research Group,

Kidney Int.

1995;47:1703-1720 DCCT Research Group.

Ann Intern Med.

1995;122:561-568.

Any Rise In A1c Causes More Damage Any Fall Helps

Better

Healthcare Across Borders - September 2003

Short-term Costs In Diabetes Versus A1c

Total average yearly cost of care over 3 years (1994 to 1998) for 2,394 diabetes patients relative to their A1c level. Patients were followed at the Fallon Clinic in Worchester, MA. There were a total of 447 hospital admissions plus various clinic visits, infections, etc.

New DCCT/EDIC Data

Starting in 1993, the EDIC study has followed DCCT participants for 12 years.

For 11 years, A1c levels between the intensive and conventional control groups have been identical at 8.4% despite different treatments and education during the DCCT study.

After 12 years, only 46 heart attacks and strokes occurred in the original intensive control group compared to 98 in the conventional control group. This 53% reduction occurred even though the A1c levels were identical

for the last 11 years

.

CVD is 10 times higher in Type 1 diabetes, so start good control now.

Healthcare Across Borders - September 2003

A1c Levels Remain High Despite DCCT

Healthcare Across Borders - September 2003

A1cs Since The DCCT

8.6% in 396 Canadian Type 1s in 1992 1 9.7% in 1,120 German children in 1996 2 9.7% in in U.S. in NHANES III, 1988 to 1994 8.6% in 2,873 European kids and adolescents in 1997 3 9.2% in 62 Canadian Type 1s in 2004 8.4% in EDIC trial (followup to DCCT study)

A1c GOAL < 6.5% to 7%

1.

2.

3.

Diabetes Care. 1997 May;20(5):714-20 Horm Res 1998;50:107 –140 HB Mortensen et al: Diabetes Care. 1997 May;20(5):714-20 Healthcare Across Borders - September 2003

Current Diabetes Therapy Falls Short

Noncompliance is not a patient problem. It is a system failure.

When a system fails, trying harder will not work.

Only changing the diabetes care system will work.

Healthcare Across Borders - September 2003

Therapy Fails Between Office Visits

In most chronic diseases, treatment intervals with a doctor visit every 3 to 4 months works well.

Diabetes is unlike any other chronic disease. A complex disease with unclear accountability, it has a required treatment interval of 2 to 5 hours. Only intelligent pumps or devices can make the frequent treatment decisions necessary to ease the care burden on patients and health providers.

Healthcare Across Borders - September 2003

What Lowers The A1c

Frequent testing * Frequent boluses * Rapid insulin * Accurate carb counting * Easy bolus calculations * Easy history * Basal can be adjusted to precise need * Bolus based on carbs and BG * Properly set doses --> Walsh Pump Formulas

* Where a pump helps

Healthcare Across Borders - September 2003

Benefit Of Frequent Testing

400 (22) 300 (17) 200 (11) 100 (5.6)

1 test versus 7 tests a day

Breakfast Lunch Healthcare Across Borders - September 2003 Dinner Bed

12

Actual A1c Versus Testing Frequency

Data From 378 People On Pumps

11 10 Atlanta Diabetes Associates study: 378 patients sorted from a database of 591 Pumps=MM 511 or earlier BG Target=100 C peptide <0.1

9 HbA1c=5.99+5.32 / (BGpd+1.39) 8

ADA: < 7%% AACE: < 6.5%

7 6 5 4 0 2 4 6 8 10

SMBG Frequency (BG per day)

12 14

Glucose Exposure and Glucose Variability

Healthcare Across Borders - September 2003

Glucose Exposure and Glucose Variability

Glucose exposure is measured by • A1c • 14/30 day average on a meter Glucose variability is measured by • Standard deviation, currently via meter download Healthcare Across Borders - September 2003

Exposure And Variability

A Day’s Blood Sugars

Monitoring every 30-60 min with usual meals and insulin doses 400 380 360 340 320 300 280 260 240 220 200 180 160 140 120 100 80 60 40 2:00 PM 3:00 PM 4:00 PM 5:00 PM 6:00 PM 7:00 PM 8:00 PM 9:00 PM

Variability or Swing Exposure or Average

10:00 PM 11:00 PM 12:00 AM 1:00 AM 2:00 AM 3:00 AM 4:00 AM 5:00 AM 6:00 AM 7:00 AM 8:00 AM 9:00 AM 10:00 AM 11:00 AM 12:00 PM 1:00 PM 2:00 PM Healthcare Across Borders - September 2003

Exposure And Variability Are Different

Glucose variability (SD) and A1cs in two individuals: Top: A1c = 6.6% SD = 20 mg/dl (1.1 mmol) Bottom: A1c = 6.7% SD = 61 mg/dl (3.4 mmol)

Exposure And Variability Are Unrelated

This study of 256 consecutive meter downloads demonstrated no relation between glucose exposure (A1c) and glucose variability (SD) SD varied from very stable at 8.1 mg/dl (0.4 mmol) to very unstable at 152.5 mg/dl (8.4 mmol)

Comparison of A1c and meter downloads from 256 subjects at Johns Hopkins

Average SD was 63.3 mg/dl (3.5 mmol)

Take home: Keep SD below 63

Glucose Variability

Like weight cycling, variable blood sugars may be more damaging than consistently high blood sugars Healthcare Across Borders - September 2003

Pumps Or MDI Are Better Despite A1c

The DCCT conventional group (top) was 22 times more likely to get retinopathy at an A1c of 9%.

The intensive group

at the same A1c

was only 8 times as likely to get retinopathy.

The reduced risk may result from less glucose variability seen with pumps and MDI.

Impact Of Glucose Variability

from Irl Hirsch, MD

Cell death is about 2.5 times as likely in human umbilical vein endothelial cell cultures after 14 days when glucose varies between 90 and 360 mg/dl compared to cells kept at 360 mg/dl. 1 Activation of PKC-beta after 14 days is about 80% higher when glucose varies between 90 and 360 mg/dl compared to cells kept at 360 mg/dl. 2 1. Amer J Physiol Endocrinol Metab 281: E924-E930, 2001 2. Diabetes 52: 2795, 2003 Healthcare Across Borders - September 2003

Pumps Reduce Glucose Variability

In the Kumamoto trial of Type 2 diabetes, those on pumps had significantly lower glucose variability (SD): MDI: A1c = 6.7%

SD = 61 mg/dl (3.4 mmol)

Pump: A1c = 6.6%

SD = 20 mg/dl (1.1 mmol)

Healthcare Across Borders - September 2003

Pumps Versus MDI (Aspart/Glargine)

200 180 160 140 CSII (n=93) MDI (n=91) 120 100 BB Mean ± 2 SEM AB BL AL BD AD Midnight 3 AM

Bode, et al.

Diabetes

52,(Suppl 1), 2003 Abstract 438.

CVD And Mortality In Relation To BG

In this study, heart attacks and death were more closely linked to postmeal blood sugars, suggesting that glucose variability may play a role.

Myocardial Infarction Mortality Rate Postmeal Premeal

1139 diet-controlled subjects, 30-55 yo at diagnosis. During 11 yr followup, 112 (15.2%) suffered from myocardial infarction, 197 (19.82%) of 994 had died. Odds ratio for all-cause mortality for males at the age of 36-45 years was 5.1 and for females 7.0

Reality: Postmeal Peaks In Children

>300 46% <180 10% 180-240 18% 241-300 26%

Continuous Monitors Reduce Glucose Variability

15 users with implanted Dexcom continuous monitors were blinded to glucose during the first 50 days, followed by open readout for the next 44 days.

Blinded Open 8.91

hrs/day 9 8 7 6 5 4 3 2 1 0 - 65 min 2.62

1.53

+ 250 min + 32 min 1.52

2.06

4.75

-13 min 6.38

6.16

-160 min 7.23

4.57

40-55 56-80 81-140 blood sugar 141-240

Healthcare Across Borders - September 2003

241-400

Glucose Exposure: Pumps vs MDI (Aspart/Glargine) During CGMS Less area under the glucose curve (AUC) shows that pumps reduced glucose exposure and variability better than MDI P = 0.0027 3000 2500 2000 1500 1000 N = 63 in each treatment 500 0 Pumps MDI Measurement of AUC (glu) ≥ 80 mg/dL during 48-hour continuous glucose monitoring period

Bode, et al.

Diabetes

52,(Suppl 1), 2003 Abstract 438.

Glucose Exposure and Glucose Variability

Both damage health Both need to be lowered Frequent testing and devices help

Healthcare Across Borders - September 2003

Classic Meters

Healthcare Across Borders - September 2003

Testing Frequency

In a Kaiser study of actual prescription fulfillment among 44,181 patients with diabetes: • 60% of Type 1s were not testing 3-4 times a day as recommended by the ADA • 67% of Type 2s were not testing once a day as recommended by the ADA

Why Aren’t People Testing?

Lack of understanding No direct benefit No mechanism for long-term benefit No link to cause of BG problems Finger-pricking required No guidance for lowering highs No reward for good readings No easy way to record other things Healthcare Across Borders - September 2003

Current Meters

• In use 35 years • Still dumb to very dumb • Do not measure true hypoglycemia – missed lows and lows treated without testing • No direct benefit for outcomes • $2,000 a year for 7 x a day testing • Not fun Healthcare Across Borders - September 2003

Logbook And Meter Inaccuracies

In a study 1 that compared logbook entries to meter downloads: • One of every seven entries was not recorded because it was high • One of every seven entries was made up • No difference was found between adolescents and adults in the entry of fictitious and missing data Time and date settings in meters are often incorrectly set. This causes patterns of high or low readings to be associated with the wrong time of day. Insulin adjustments made on faulty timing can worsen control raher than improve it.

Current Tools Have Had Little Effect DCCT Pre

1992

Post

2003 On 4 inj. (or pump) 27.8% (0.4%) 72.6% (6.4%) Median A1c 8.3% 8.3% 18,403 German children followed over 10 years of “improving diabetes care”.

1

State-of-Art Meter Technology- 2005

Healthcare Across Borders - September 2003

Today’s Most Common Analysis Tool

Healthcare Across Borders - September 2003

Better Analysis Tools

Standard Deviation

Graphs courtesy of BD InterActiv™ Diabetes Software

Glucose Goals

• A1c less than 7.5% in children and less than 6.5% in adults • Lows • Never below 50 mg/dl (3 mmol) • Never frequent Meters can suggest interventions based on • Not at night goals and patterns • Highs • Never above 250 mg/dl (14 mmol) • Never frequent • Mealtime Age Pre Post Variation <5 yo 5-11 yo 70-160 70-140 < 250 mg/dl < 225 mg/dl with < 120 rise with < 100 rise 12+ yo 70-140 < 200 mg/dl with < 80 rise • Write down a reason for all readings below 50 or above 250 Poor control? Change your lifestyle, basals or boluses.

Healthcare Across Borders - September 2003

Classic Pumps

Healthcare Across Borders - September 2003

Basal And Bolus In Pumps

Breakfast Lunch Dinner Bolus Bolus Bolus Basal 2:00 7:00 12:00 16:00 Time 20:00

Healthcare Across Borders - September 2003

24:00 7:00

Classic Pump Features

• More physiologic insulin delivery to mimic the pancreas • Basal: steady background insulin delivery to keep BG from rising while fasting • Bolus: spurts of insulin to cover carbs or lower high BGs Healthcare Across Borders - September 2003

Pumps Offer More Normal Lifestyle

Liberalization of diet — timing & amount (by user) Increased control with exercise (by user) Able to work shifts & through lunch (by user) Less hassle with travel and time zones (by user) Aid to weight control (by user) Less anxiety in trying to keep on schedule (by user)

Pumps vs MDI in Type 2 DM

People with Type 2 diabetes who have tried both a pump and MDI strongly prefer the pump.

CSII MDI Less Pain Less Social Limitations Preference Advocacy Less Hassle Less Life Interference General Satisfaction Flexibility Convenience Less Burden -5 * ** * * *** *** *** *** *** 0 5 10 15 20 25 30 Change in Scores (Raw Units) From Baseline to Endpoint 35

Classic Pumps vs MDI

Meta-analysis of 12 controlled trials (600 people) found classic pumps lower A1c by 0.56%, lessen BG variability and require 7.58 fewer u/day 1 Another meta analysis of 20 studies found a “modest but worthwhile improvement” of 0.61% in A1c with pumps using 11.9 fewer units a day 2 In glargine vs pump (#24 each), no difference in A1c, but glycemic variability (MAGE) and doses were lower 3 1.

2.

3.

BMJ. 2002 Mar 23;324(7339):7052 Health Technol Assess. 2004 Oct;8(43):1-186 Diabetes Nutr Metab. 2004 Apr;17(2):84-9 Healthcare Across Borders - September 2003

Classic Pump Issues

• Carb and correction boluses calculated by user • Underestimating carbs in meals with inaccurate boluses 1 • 34% low before training • 17% low after training • No carb entry or database • Boluses easy to forget • No accounting of BOB leads to insulin stacking • No direct BG entry • No exercise component

Today’s Smart Pumps

Healthcare Across Borders - September 2003

Walsh Pump Formulas To Improve Dose Accuracy

Total Daily Dose = weight in lbs / 4 (kg / 1.8) Basal Dose = 50% (35% to 65%) of TDD Carb Factor = 500 / TDD Correction Factor = 2000 / TDD (110 / TDD in mmol) BG target = 90-120 mg/dl (5-6.7 mmol) before meals Carb rise = Less than 80 mg/dl rise after meals Basal target = +/- 30 mg/dl (1.7 mmol) BOB = 20-25% used per hour (auto in smart pump) Correction boluses = < 8% of TDD J Walsh and R Roberts:

Pumping Insulin

, 2005

Smart Pump – Boluses

Carb boluses Accuracy improved with personal carb factor adjusted for different times of day Personal carb database Correction boluses Personalized correction factors for different times of day Safer correction of high BGs Reports amount of correction bolus used (ie, over 8% of TDD)

An accurate TDD --> accurate basals & boluses

Healthcare Across Borders - September 2003

Carb Bolus Assistance

Each manufacturer provides bolus dose recommendations differently.

Healthcare Across Borders - September 2003

Smart Pump – Correction Boluses

Average Summary screen from Cozmo history

6 day average: Meal Corr Basal Total Carb 19.41 u 11.34 u 23.34 u 54.09u

175 g

Here,

correction boluses

make up 21% of TDD When correction boluses make up more than 8 to 10% of the TDD, 1/3 of this amount is moved to basal rates or carb boluses (as long as hypoglycemia is not the primary problem).

Healthcare Across Borders - September 2003

Overlapping Boluses

When several boluses are given in the evening, how much total bolus insulin remains at bedtime?

Dinner Dessert Correction

Bedtime BG 163

6 pm 8 pm 10 pm Healthcare Across Borders - September 2003 12 am

Smart Pump – Bolus On Board

Bolus On Board (BOB) Discounts bolus for residual BOB Improves accuracy Avoids stacking of bolus insulin Acts as guide to whether carbs or insulin are needed, ie, BG is 130 mg/dl but BOB = 5 u Requires a blood sugar test, an accurate duration of insulin action, and BG targets

Prevents hypoglycemia!

Healthcare Across Borders - September 2003

Dose Size Affects Duration

As bolus size increases, so too does duration of action.

For 154 lb (70 kg) person: 0.05 = 3.5 u 0.1 = 7 u 0.2 = 14 u 0.3 = 21 u

Smart Pump – Reminders

Reminders (alarms) to • test glucose following a bolus • test glucose after a low reading • test glucose after a high reading • give a bolus at certain time of day • warn when bolus delivery was not completed, etc.

• change infusion site Healthcare Across Borders - September 2003

Pump Is Carb Counter

Pump or external controller contains user-selected food list for accurate carb counting Healthcare Across Borders - September 2003

Meter Talks to Pump

108 Healthcare Across Borders - September 2003

Pump is Meter

Healthcare Across Borders - September 2003

Blood Sugar History

11 day average: BG Tests 167 mg/dl 2.1/day

From Cozmo: Average blood sugar history This person tests infrequently and only before meals, so correction boluses are underestimated Correction bolus totals cannot be accurate until more testing is done Healthcare Across Borders - September 2003

Ways To Reduce Glucose Exposure

A lower glucose at the start of a meal reduces glucose exposure.

Rules:

Test early Bolus early Don’t forget to eat on time Don’t forget you’ve already bolused Healthcare Across Borders - September 2003

Intelligent Timer For High Premeal BG

An intelligent pump would alert the user when the BG is likely to cross a selected threshold value, such as 120 mg/dl (6.7 mmol). This safe meal delay reduces glucose exposure, especially when combined with a Super Bolus Max. drop ~4-5 mg/dl per min Healthcare Across Borders - September 2003

Super Bolus For High GI Meal

In future pumps, a Super Bolus could be given when the user wants to eat more than a pre selected quantity of carbs, such as 40 or 50 grams A Super Bolus shifts future basal insulin into an immediate bolus. Part of the next 2 to 4 hours of basal insulin is shifted into a bolus for faster effect without causing a low. Helps cover high GI and large carb meals. Healthcare Across Borders - September 2003

Pump And Meter Combos

Direct glucose entry into database eliminates data errors and offers optimum use of glucose/insulin data • AccuChek Spirit + meter • CozMore System + Therasense CoZmonitor • Soill Diabecare III pump + meter • Medtronic 515/715 + BD Paradigm Link • Soon: Animas + ? Lifescan or Glucowatch Healthcare Across Borders - September 2003

Smart Pump – Data Collection

Current pumps track basals, boluses, blood sugars, carb intake, and timing (exercise/activity soon) Better analysis and many intelligent features, such as automatic testing of basals and boluses, can be done now with current pumps and meters Graphs courtesy of BD InterActiv™ Diabetes Software

Future Intelligent Pumps And Devices

Healthcare Across Borders - September 2003

M o n i t r i o n g l i n I n s u D e r i l v e y Convergence Toward Automation 1922 Insulin & syringes We are here 1979 Pumps 1983 Pens Open Loop Connectivity Data Management 1971 Home Monitors Advice/Feedback Continuous Monitors Closed Loop There is 1926 Clinic Monitoring

HCP Self Management Automation Healthcare Across Borders - September 2003

Adapted courtesy Roche/Disetronic

Intelligence (Improved Control) Can Be Added To:

Pumps Pens Meters PDAs Smart phones Any combination of above

Goal: Better management of complex situations

Requires a central reporting station to identify problems and notify user, guardian, or MD/RN Healthcare Across Borders - September 2003

Device IQ History Classic Smart Intelligent Automatic Meters 1971 ?

?

?

Pumps 1979 2003 ? 2006 ?

24 years

Judge devices not by their features, but by whether they reduce glucose exposure and variability.

Healthcare Across Borders - September 2003

An Intelligent Insulin Pen

300 personal carb selections with accurate carb counts Carb factor (1:1 TO 1: 100) Correction factor (1:4 to 1: 400)  5 sec microdraw BG meter  0.1 unit precision motor  Non-volatile memory  3,000 events  Bluetooth data transfer

Wearable Pumps

Relatively large Lower upfront cost Best suited for Type 2?

Omnipod Animas 200 u 200 u 2.4 x 1.6 x 0.7

2.9 x 2.0 x 0.75

Healthcare Across Borders - September 2003 1.1 oz 3.1 oz

Animas-Debiotech Micropump

Debiotech has been developing small pumps from Micro-Electro Mechanical Systems or MEMS technology. These devices are made from silicon (not silicone!) and easily mass-produced to keep cost low.

Silicon is harmless, but it is not clear how insulin may interact with silicon surfaces.

Healthcare Across Borders - September 2003

Smart Phones And PDAs

Convenient bolusing from a remote device Easy messaging Better graphics Larger carb database and memory Improved data analysis Direct fax to physician Bidirectional communication Able to combine data from all devices (pen, pump, meter, carb database, exercise component, communication) Healthcare Across Borders - September 2003

Today Meter size Sample size Alternate site testing Test speed Accuracy Calibration Memory Battery Ketone testing Built-in lancet

Meters

Tomorrow Measure glucose variability Pattern recognition/correction Intelligent timers Recommends test timing/frequency Tied to insulin delivery Gameboy attitude Improved accuracy to calibrate continuous monitors Smart phone enabled Healthcare Across Borders - September 2003

NIR-Based Noninvasive Glucose Monitor

Healthcare Across Borders - September 2003

Sensys Medical Systems

Measures glucose non-invasively with NIR spectroscopy Device weighs less than 1.5 pounds Fiber-optic head secured to the forearm 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 Rechargeable battery Studies underway

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

Hemoglobin

1.3 1.4 1.5 1.6 1.7 1.8 Wavelength (microns) Absorbance 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 1.3 1.4

Glucose

1.5 1.6 1.7 1.8 Wavelength (microns) 1.9 2.0 2.1 2.2 2.3 1.9 2.0 2.1 2.2 2.3 2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

1.2 1.3

Water

1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.6

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

1.2 1.3 1.4

Blood

1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 Healthcare Across Borders - September 2003

Medtronic Guardian RT

Real time readings Add-on to routine BG monitoring Radio communication from sensor to monitor High and low glucose alarms FDA pending

Guardian RT System

Healthcare Across Borders - September 2003

Sample CGMS Reports

Daily Report of Blood Glucoses Healthcare Across Borders - September 2003

Sample CGMS Reports

Modal time reports for breakfast, lunch, dinner, etc.

Healthcare Across Borders - September 2003

Sample CGMS Reports

Composite 3 day report Healthcare Across Borders - September 2003

GlucoWatch

®

Biographer

First To Receive FDA Approval

Healthcare Across Borders - September 2003

Animas-Debiotech Microneedles

Silicon microneedles can be used to infuse insulin or allow glucose measurements in interstitial fluid. This needle array could replace the AutoSensor in a GlucoWatch for effective continuous monitoring.

Healthcare Across Borders - September 2003

FreeStyle Navigator

TheraSense Continuous Glucose Monitor

Meter replacement

DexCom Monitors

Implanted And Transdermal

DexCom Subcutaneous Sensor

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

Healthcare Across Borders - September 2003

Endocrinology Clinics NA 33:175, 2004

Therasense Navigator System

Interstitial transdermal system Wireless Calibrated 1-2 times per day Readings every 1-2 minutes High and low glucose alarms Most accurate meter below 100 mg/dl

SpectRx Glucose Sensing System

Laser device on the skin surface Patch with sensor system embedded Healthcare Across Borders - September 2003 www.spectrx.com

Preliminary data with SpectRx ISF System

Healthcare Across Borders - September 2003

ADICOL Project –Disetronic / Roche

Advanced Insulin Infusion with a Control Loop

Open-flow Microperfusion System Inserted into the subcutaneous adipose tissue Double lumen catheter Acquires glucose readings every 30 minutes Goal – subcutaneous glucose sensing/insulin delivery system Healthcare Across Borders - September 2003

Future Intelligent Device Features

• Intelligent timers • Super bolus for better carb coverage and faster corrections • Accounting for exercise • Meaningful advice • Pattern spotting and analysis • Direct communication capabilities Healthcare Across Borders - September 2003

Intelligent Device Pattern Alert

Smart devices should reduce glucose exposure and glucose variability Healthcare Across Borders - September 2003

Intelligent Pump Features

Automatic TDD adjustment • • • Average blood sugar and standard deviation % TDD used for corrections Basal/bolus balance Automatic basal testing • • Overnight Daytime, when meal is skipped Automatic carb factor testing • Premeal, 2 hr postmeal peak, normal in 4-5 hrs?

Automatic correction factor testing • High-to-normal in 4-5 hours?

Healthcare Across Borders - September 2003

Smart Versus Intelligent Devices Feature

Carb list Basal/bolus testing Exercise adjustment Timer % of corr. bolus Super Bolus # of hypos Communication

Smart

Alphabetic By user By user By user Ignored By user By user Verbal/fax

Intelligent

By recent use Automatic Automatic Automatic Automatic Automatic Automatic Bidirectional Healthcare Across Borders - September 2003

Non-Invasive Status

No system is close to being used for a closed loop No current system can replace the “finger stick” monitor for “real time” glucose values and treatment decisions Current “finger stick’ systems continue to be poorly leveraged Well over 40 companies are attempting to develop continuous glucose monitoring systems Healthcare Across Borders - September 2003

User Interface – The Critical Component

Despite 30 years of pump and meter development, device communication to users is still in it’s infancy.

Healthcare Across Borders - September 2003

Future Intelligent Devices

Carb database for accurate carb counts.

Healthcare Across Borders - September 2003

Future Intelligent Devices

Suggestions for carb intake Healthcare Across Borders - September 2003

Future Intelligent Devices

A high glucose can be analyzed to determine the magnitude of the error Healthcare Across Borders - September 2003

Future Intelligent Devices

Recommended carb intake or insulin reduction to balance activity.

Healthcare Across Borders - September 2003

Future Intelligent Devices

New dose recommendations based on A1c, % of TDD given as correction boluses, and frequency of hypoglycemia Healthcare Across Borders - September 2003

A Few Needs

A faster “rapid” insulin with consistent action Define duration of insulin action so it can be associated with an intelligent device delivering different bolus amounts in the same individual Effective control algorithms for automated basal and bolus testing and for internet advice centers Healthcare Across Borders - September 2003

Take Home

Frequent testing reduces glucose exposure and variability Pumpers test more often, but few people with diabetes test enough Diabetes devices have barely begun to tap their capabilities More can be done now with pumps and classic meters Many opportunities to combine and enhance devices Healthcare Across Borders - September 2003

Pumps Have Come A Long Way

Healthcare Across Borders - September 2003

Questions

Healthcare Across Borders - September 2003