Bruce W. Bode, MD, FACE

Atlanta Diabetes Associates

Atlanta, Georgia

Technology Update in DiabetesPumps, Sensors, and Progress Toward Closed Loop Systems

Disclosures

� Research and Grant Support to Employer: Abbott, Biodel, DexCom, Halozyme, Lilly, MannKind, Medtronic, Novo Nordisk, Sanofi, Valeritas

� Consultant: Abbott, Halozyme, Medtronic, Novo Nordisk, Sanofi, Valeritas

� Speaker’s Bureau: DexCom, Lilly, Medtronic, Novo Nordisk, Sanofi, Valeritas

1

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15

6 7 8 9 10 11 12

Eye disease

Kidney disease

Nerve damage

HbA1c

Relative Riskof

Complications

Skyler, J: Endo Met Cl N Am, vol 25, 2, p.243- 254, June 1996 Adapted from DCCT Research Group: NEJM 1993;329:977-986Minshall M, et al. Clin Ther. 2005;27:940–950.

DCCT ResultsHbA1c and Relative Risk of Diabetic Complications

6.5*

Average US HbA1c Range

7.8-8.6%

AACE recommendation is

6.5%

DCCT Research Group, 1993

Trade-off between: Reducing Long-term Complications & Minimizing Hypoglycemia

Patients used:

• Regular insulin/ Intensive therapy via injections or insulin

pump

• Self monitoring blood glucose (SMBG)

DCCT ResultsP

rogression of Retinopathy

(per 100 patient years)

10

8

6

4

2

0Rat

e of

Sev

ere

Hyp

ogly

cem

ia(p

er 1

00 p

atie

nt-y

ears

)

0

20

40

60

80

100

120

Percentage of A1C Level

Published 1993

Risk of Death Over a Range of Average A1c

Riddle et al. Diabetes Care 2010

Average A1c %

Adjusted log (HR) by Treatment StrategyRelative to standard at A1c of 6%

Standard strategy

6 8 97

Steady increase of risk from 6 to 9% A1c with intensive strategy

Excess risk with intensive strategy vs standard occurred above A1c 7%

Intensive strategy1

0

–1

HR = hazard ratio

Hypoglycemia and Cardiovascular Events

� Tachycardia and high blood pressure

� Myocardial ischemia

– Silent ischemia, angina, infarction� Cardiac arrhythmias

– Transiently prolonged corrected QT interval,

– Increased QT dispersion� Sudden death

Wright RJ, Frier BM, Diabetes Metab Res Rev 2008; 24: 353–363.

Mean Glucose & In-Hospital Mortalityin 16,871 Patients with AMI

(Reference: Mean BG 100-110 mg/dl)

Kosiborod M et al. Circulation 2008:117:1018

2005 Blinded CGM Study

� 101 people with diabetes were placed on a blinded CGM and were told to do 10 finger stick blood tests a day; they averaged 9 tests per day

- < 30% of day was 90-130 mg/dL

- 30% of the day was >180 mg/dL

- two hours a day was <60 mg/dL

� New technology is needed to help patients get to goal

Bode BW et al. Diabetes Care 2005 Oct. 28(10):2361-6.

Status of Diabetes Care: Therapy Advances Needed

The Type 1 Exchange, n=25,000 subjects, 67 sites2

Not at Goal Excess Hypoglycemia

The average type-1 patient has:• Two symptomatic hypoglycemic events per week1

• One or more episodes of severe, temporally disabling hypoglycemia per year• Nocturnal hypoglycemia occurs ~ 8.5% of nights2

Indications for Basal Bolus Therapy (MDI or Insulin Pump)

� All Type 1 DM patients

� All Type 2 DM patients not at goal (>6.5 to 7%)

� All Hospital patients not at goal (>140 mg/dL)

� All Pregnancy patients not at goal (Fasting >90 mg/dL; 1 hr PC >120 mg/dL)

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargineor

Detemir

RAI RAI RAI

Plas

ma

insu

linBasal/Bolus Treatment Program withRapid-acting and Long-acting Analogs

RAI: Rapid Acting Insulin(Aspart, Glulisine, Lispro)

Initiating SC Basal Bolus

Starting total dose (TDD) = 0.5 x wgt. in kgWt. is 100 kg; 0.5 x 100 = 50 units

Basal dose (basal analog) = 50% of TDD at HS 0.5 x 50 = 25 units at HS

Bolus doses (rapid analog) = 50% of TDD 0.5 x 50 = 25 divided by 3 = ~8 units pc (tid)

Correction bolus = (BG - 100)/ CF, where CF = 1700/total daily dose; CF = 30

The pump delivers basal and bolus insulin precisely and can be easily customized as needed to meet individual requirements.

0

1.0

2.0

3.0

4.0

5.0

6.0

12am 4am 8am 12pm 4pm 8pm 12am

Bolus insulin delivery

Basal insulin delivery

Basal programmedto help preventdawn phenomenon

Dual Wave™Bolus for brunch

Temporary basalduring walkingto help preventhypoglycemia

Dinnerbolus

Basal reducedto help prevent

nocturnalhypoglycemia

Uni

ts o

f ins

ulin

Insulin Pump Therapy

Photograph reproduced with permission of manufacturer.

Current Durable Insulin Pumps

– Durable light aluminum case

– Shatter-resistant glass

– Rechargeable battery

Touch Screen Insulin Delivery System

Combo system• Offers an easy, quick* & discreet way to manage

insulin pump therapy

• “smart meter”

Intelligent communication in both directions using Bluetooth® technology

Snap Pump with Insulin Cartridge

Snap Pump with Prefilled Insulin Cartridges� Uses prefilled 300 unit insulin cartridges that take seconds to drop in.

� Automatically fills your tubing (autoprime) – saving you time.

� Is 25% lighter than the leading pump.†

� Never needs to have the battery changed or charged. Dispose post 300 units is used

� Never requires an insulin reservoir to be filled

Infusion Sets

• Subcutaneous indwelling catheters• Teflon cannula or steel needle• Must be changed every 2-3 days• pump and tubing may be disconnected without removing insertion

site

Crimped soft canulae

Pump infusion sets: perpendicular vs oblique

Perpendicular (Sof-set™, Quick-set™, Ultraflex™)

- Easier insertion

- Prone to kink

Oblique (Silouette™, Tender™, Comfort™)

- More difficultinsertion

- Less kinking

Patch Pump platform Just two simple parts

�Fully integrated two-part design

• Built-in FreeStyle® BG meter that automatically incorporates BG levels into suggested bolus calculations and history records

• Integrated infusion set, insulin reservoir, automated inserter, and batteries

�Automated processes• Cannula insertion

• Priming

� Intuitive user interface• Full text navigation

• Set-up wizard

• Easy to teach, easy to learn

� Waterproof Pod22

Simple Patch Pump for Type 2 DM

23

– Continuous preset basal insulin rate (20, 30 or 40 units/24 hrs)

– On-demand mealtime insulin via 2 unit clicks (Max 18 clicks/36 units)

– Uses only RAI – Easy to fill, apply, use, and

remove every 24 hours– No electronics, batteries, infusion sets,

or programming– Fully disposable

Metabolic Advantages with CSII

� Improved glycemic control

� Better pharmacokinetic delivery of insulin

– Less hypoglycemia than NPH based therapy

– Less insulin required

� Improved quality of life

Current Pump Therapy Indications� Need to normalize blood glucose (BG)

–A1C > 6.5% or 7%

–Glycemic excursions

� Hypoglycemia or Hypoglycemia unawareness

� Need for a flexible insulin regimen

Medicare requires: Fasting C-peptide to be ≤110% lower limit of normal or ≤200% lower limit of normal if CrCl ≤50 ml/min with concurrent FPG ≤225 mg/dL;or Beta Cell autoantibody positive (+ICA or +GAD antibodies)

US Pump Usage: Patients Using Insulin Pumps

Industry estimates

Insulin Therapy Segmentation (US) – 2008

T2 Conventional3,080,160(69%)

T1 Conventional368,160 (48%)

T1 MDI398,840 (52%)

T1 Pump Therapy361,000

T2 Pump Therapy37,000

T2 MDI1,383,840 (31%)

4.5 Million Type 2 (T2)>5.6 Million = 1.2 Million Type 1 (T1)

>31% Penetrationin Type 1

<1% Penetrationin Type 2

Source: Medtronic with 78% of the market

Insulin Therapy:

� Monitoring– A1C = 8.3 - (0.21 x BG per day)

CSIIFactors Affecting A1C

Bode et al. Diabetes 1999;48 Suppl 1:264

Bode et al. Diabetes Care 2002;25 439

Correlation between HbA1c levels and number of SMBG measurements

6.006.256.506.757.007.257.507.75

8.50

8.008.25

HbA

1c(%

)

≤1 2 3 4 5 6 7 8 9 10 10Number of BG measurements per day

Mean 0.95 CIn = 12,725

Hammond P, et al. Prim Care Diabetes 2007;1:143–6.

� Monitoring– A1C = 8.3 - (0.21 x BG per day)

� Recording 7.4% vs 7.8%

� Diet practiced– CHO: 7.2%– Fixed: 7.5%– WAG: 8.0%

CSIIFactors Affecting A1C

Bode et al. Diabetes 1999;48 Suppl 1:264

Bode et al. Diabetes Care 2002;25 439

� Monitor sends BG value to pump via radio waves : No transcribing error

� Enter carbohydrate intake into pump

� “Bolus Wizard” calculates suggested dose

Paradigm Link™

Paradigm 512™

Bolus Calculator: meter-entered

Estimate DetailsEst total:

Food intake:

BG:

Food:

Correction:

Active ins:

ACT to proceed

ESC to back up

Automatically calculates insulin bolus for the patient

7.0 U

20060 gr

2.0 U

ICR 1:10 gr

200 - 100 = 2.0 u 50 (SF)

6.0 U

1.0 U

Bolus Calculator: Example

Active insulin is subtracted from correction

Wizard: OnCarb Units: GramsCarb Ratios: 10BG Units: mg/dlSensitivity: 40BG Target: 90-100Active Insulin Time: 5 hours

Bolus Calculator Set Up Screen

If on Smart Pumps and not at Goal

� Post meal too high

Lower CIR (Carb to Insulin Ratio)

� All BGs too high

Lower target and / or change CF (ISF)

� Fasting or pre meal too high

Increase basal

Case 1: Type 1 DM on pump at goal

� 28-year-old male with type 1 DM since age 17

� On pump since age 22

� No complaints; No assisted hypoglycemia

� A1C 6.7%

� Current insulin: 62 +/- 8 units/day (0.6 units/kg) with 59% basal; 41% Bolus

� SMBG 3.9/day; mean BG 155 +/- 118 mg/dL

Do Smart Pumps Enable Others To Go To CSII?

� YES

� All patients with diabetes not at goal are candidates for Insulin Pump Therapy

- Type 1 any age

- Type 2

- Diabetes in Pregnancy

If A1C is Not to Goal

� SMBG frequency and recording

� Diet practiced– Do they know what they

are eating?– Do they bolus for all

food and snacks?

� Infusion site areas– Are they in areas of

lipohypertrophy?

� Other factors:– Bolus % <50% TDD– Fear of low BG– Overtreatment of low BG

Must look at:

Traditional glucose monitoring looks at only one point in time.

It doesn’t tell you where you’ve really been, or where you’re going.

Limitations of SMBG

mg/dL

What action should a patient take?

CGM Provides Patient with Live Bio-Feedback

mg/dL

What action should be taken now?

• In 30 minutes, what might patient’s glucose be?• What if patient is about to go to sleep or drive?

Seeing How Glucose is Trending

• 1 arrow indicates glucose has beenchanging1 to 2 mg/dL/min

• 2 arrows indicate glucose has been changing >2 mg/dL/min.

mg/dL

How might a patient react differently, to this?CGM ProvidesImportant Live Biofeedback

Sensor data provides information that allows patients to make more informed decisions

• 1 arrow indicates glucose has beenchanging1 to 2 mg/dL/min

• 2 arrows indicate glucose has been changing >2 mg/dL/min.

Continuous Monitoring Systems

Paradigm or Guardian REAL-Time

DexCom G4 Platinum

CGMS® iPro™ Recorder

Interstitial Glucose Readings

Issues with Lag Time

� Occurs with all subcutaneous sensors� Will delay alarm for hypoglycemia� Will affect calibration of sensor

– Calibration should not be done when glucose values are changing rapidly

CGM

Professional� Owned by Professional

(HCP, CDE, Clinic, Hospital)

� Can be Masked or Real-time

� Reimbursement for Technical fee (95250) and Interpretation (95251)

� Covered by most insurers including CMS

Personal� Owned by the Patient

� Real-time only

� Reimbursement for the Interpretation (95251)

� Covered by most insurers but not CMS

Indications for CGM

� Patient is not at goal

- A1C above target

- Labile BG values

- Hypoglycemia

- Lifestyle or Employment reasons

� Pharmaceutical Research (Masked)

Case 1: Type 2 DM not at goal

� 64 year-old female with type 2 DM since age 37, 1984

� On insulin since 1994; pump since 2000

� Gastric bypass 2006; BMI 48 to 29

� Current insulin: 26 units/day (0.35 units/kg) with 69% basal; 31% Bolus

� SMBG 1.5/day; mean BG 149 +/- 97 mg/dL

� A1C 7.9%

Patient PG: Case 1; Type 2 DM on pump

Patient PG: Case 1; Type 2 DM on pump

Ordered a Professional CGM on Case 1

Patient PG: Case 1; Type 2 DM on pumpDaily Sensor Overlay

Patient PG: Case 1; Type 2 DM on pumpMeal Sensor Overlay

Patient PG: Case 1; Type 2 DM on pumpNight Time Sensor Overlay

Case 2: Type 1 DM on pumpnot at goal

Recommendations:

1. Bolus for each meal

- Start with 4 to 6 units and increase as needed to keep next BG <120 mg/dL or post meal <180 mg/dL

2. Increase SMBG to 4/day

Short-term, Episodic, Real-Time Continuous Glucose Monitoring (RT-CGM) Improves Short-Term and Legacy Glycemic Control in Patients with Type 2 Diabetes

� Study population:– Type 2 diabetes with an

A1C of > 7.0%.

– N=50 real-time CGM group; N=50 SMBG/control group.

– No subjects were on meal-time/prandial insulin.

Vigersky RA, Ehrhardt NM, Chellappa M, Walker S, Fonda SJ. Diabetes Late-Breaking Abstract 0026-LB ADA, 2011.

7

51

9

33

0

10

20

30

40

50

60

%

Lifestyle Orals Orals+Byetta Orals+BasalInsulinTherapy

Selected Characteristics of Study Subjects

Characteristics SMBG Group RT-CGM Group

Age [mean (SD)] 60.0 (11.9) 55.5 (9.6)

Male [n (%)] 22 (44.0) 33 (66.0)

Baseline A1c [mean (SD)]

8.2 (1.1) 8.4 (1.3)

Vigersky RA, Ehrhardt NM, Chellappa M, Walker S, Fonda SJ. Diabetes Late-Breaking Abstract 0026-LB ADA, 2011.

N=100; 50 per group

Study Protocol

Vigersky RA, Ehrhardt NM, Chellappa M, Walker S, Fonda SJ. Diabetes Late-Breaking Abstract 0026-LB ADA, 2011.

Mean A1c Change From Baseline(RT-CGM vs. SMBG)

Vigersky RA, Ehrhardt NM, Chellappa M, Walker S, Fonda SJ. Diabetes Late-Breaking Abstract 0026-LB ADA, 2011.

Conclusion of CGM in Type 2 DM� Intermittent use of real-time CGM in the type 2, non-

intensive insulin treated diabetes patients showed a significantly greater reduction in A1C than SMBG alone and was sustained for 1 year (p=0.05).

� More regular use of real time CGM (>48 out of 56 days) led to greater reductions in A1C.

� Study suggests that real time CGM is a powerful behavior modification tool.– Real time CGM increases glycemic awareness and promotes

lifestyle changes and medication adherence.

Vigersky RA, et al Diabetes Late-Breaking Abstract 0026-LB ADA, 2011.

JDRF Study HbA1c Change in ≥ 7.0% Cohortwith CGM Use ≥ 6 days/week in Month 12

-0.5 -0.5

-1.0

-0.5

-0.7-0.8

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0-26wks0-52wks

Age > = 25 Age 15-24 Age 8-14n = 34 n = 6 n = 15

Changein

A1c (%)

JDRF A1c < 7% Cohort: Change in the frequency of sensor glucose levels < 70 mg /dL

Medianminutes/day

9154

p = 0.002

96 91

p = 0.43

Baseline Baseline26 Wks 26 Wks

Severe hypoglycemia

n = 49

1-year study 6-month continuation phase485 type 1 adults and children30 sitesPublished 2010

Two Arms:MDI + meter + CareLink (control)Pump + CGM + CareLink

• Pump + CGM improves A1c 1.21%• Pump + CGM improves A1c 1.0% compared to MDI + meter• No increase in hypoglycemia

n = 56

-1.21%

n = 27 n = 46 n = 10881 – 100%61 – 80%41 – 60%21 – 40%

-0.79%-0.64%

-0.19%

-1.5%

-1.0%

-0.5%

0.0%

% A

1cre

duct

ion

% CGM Usage

Bergenstal RM, et al. N Engl J Med. 2010;363:311-20.

STAR 3: Randomized, controlled SAPT vs MDI

6 month study115 subjects, A1c ≥ 8.0 69 adults 46 children

On MDI + meter ≥ 3 meter readings / day

8 French centersPublished 2009

Two Arms:Pump + meterPump + CGM (CGM group instructed to wear sensors 70% of the time (5 d/wk)

RealTrend: Randomized, controlled SAPT vs Pump

• Pump improves A1c > 0.5% compared to MDI

• Pump + CGM improves A1c 1.2% compared to MDI + meterRaccah D et al. The RealTrend Study. Diabetes Care 2009.

p = 0.004

0.55%

0.96%

MDI + meter

0.2

0.4

0.6

0.8

1.0

1.2

Pump + meter Pump + CGM ≥ 70%

A1C

Red

uctio

n (%

)

1.23%

6 Month Study83 adults type 1: Age 18-65 years Using MDI (multiple daily injections) HbA1c ≥ 8.2%

Multicenter: 8 European centers 8 European countries

Two Arms:

Stay on MDI + meter (control)Pump + CGM (Paradigm REAL-Time) No specified CGM usage frequency

1.2%

7.0

7.5

8.0

8.5

9.0

Baseline 13 weeks 26 weeks

HbA

1c (%

)Pump + CGM

MDI + meter

EURYTHMICS: Investigator-initiated, randomized, controlled

• Pump + CGM improves A1c 1.2% compared to MDI + meter• No increase in hypoglycemia

Abstract, EASD 2010 to be published 2011.

Adapted from Figure 5B of: DCCT. N Engl J Med. 1993;329:977-986.

Severe Hypoglycemia and A1C:DCCT15 (1993), JDRF2 (2008), and STAR 316 (2010) Studies

DCCT (intensive therapy):62 per 100 pt-yrs,

A1C(6.5 yr): 9.0% 7.2%

JDRF CGM (adults):43.4 per 100 pt-yrs;

A1C (6 mo): 7.5% 7.1%

JDRF data from: JDRF CGM Study Group. N Engl J Med. 2008;359:1465-1476.

Adapted from Figure 5B of: DCCT. N Engl J Med. 1993;329:977-986.

Severe Hypoglycemia and A1C:DCCT15 (1993), JDRF2 (2008), and STAR 316 (2010) Studies

JDRF CGM (adults, 1 subject excluded):20.0 per 100 pt-yrs;

A1C (6 mo): 7.5% 7.1%

DCCT (intensive therapy):62 per 100 pt-yrs,

A1C(6.5 yr): 9.0% 7.2%

STAR 3 SAP (all ages): 13.3 per 100 pt-yrs;

A1C (1 yr): 8.3% 7.5%

STAR 3 MDI (all ages): 13.5 per 100 pt-yrs;

A1C (1 yr): 8.3% 8.1%

JDRF data from: JDRF CGM Study Group. N Engl J Med. 2008;359:1465-1476.

Bergenstal RM, et al. N Engl J Med. 2010;363:311-320.

74

CGM Concepts and Guidelines

1. Empower patients to use trending

75

Preventing Hypoglycemia with CGM:

Fruit juice

Breakfast Lunch Dinner

Hypoglycemia avoided

76

CGM Concepts and Guidelines

1. Empower patients to use trending2. Look for patterns in foods commonly eaten

77

How CGM Provides Information Missed By SMBG

High Fat Meal

Delayed increase after rapid analog wears off

Insulin Bolus

Insulin Boluses

78

CGM Concepts and Guidelines

1. Empower patients to use trending2. Look for patterns in foods commonly eaten3. Be patient: avoid over treatment of both highs and

lows

79

Welcome to the GlucoseRoller Coaster…

Correction dose given, no breakfast

Hypoglycemia overtreated with 3 chocolate bars

Marked hyperglycemia after over treatment of hypoglycemia, followed by stacking insulin boluses, leading to more hypoglycemia

Insulin given

80

CGM Concepts and Guidelines

1. Empower patients to use trending2. Look for patterns in foods commonly eaten3. Be patient: avoid over treatment of both highs and

lows4. Calibration is key: get a high quality fingerstick

81

How important is a clean fingerstick…

SMBG reading 182 mg/dl

SMBG 2 minutes later 48 mg/dl

82

CGM Concepts and Guidelines

1. Empower patients to use trending2. Look for patterns in foods commonly eaten3. Be patient: avoid over treatment of both highs and

lows4. Calibration is key: get a high quality fingerstick5. Alarms should mean something

The Sensor Report

Normal Bolus w/ BW; followed by low in late meal period may indicate Basalsare too high

CGM Concepts and Guidelines1. Empower patients to use trending2. Look for patterns in foods commonly eaten3. Be patient: avoid over treatment of both highs and

lows4. Calibration is key: get a high quality fingerstick5. Alarms should mean something6. Timing is everything: bolus 20 minutes ahead to lower

post prandial hyperglycemia

Ultimate Goal

A closed-loop system

Pipeline Overview: Closed Loop

SENSINGCOMMUNICATING

PUMPINGTHINKING

FuturePresent 2013-2014Past

ACTING AUTOMATING

Phase IV:Closing the Loop

•Predictive LGS algorithm

•Treat-to-Range

•Overnight closed loop

•Fully-automated delivery

Phase II:The First Big Step

•Pump & Sensor combined

•REAL-Time data integration

•Improved algorithms

•Enhanced data management

Phase III:The Next Big Step

•Semi-automated insulin dosing

•Threshold suspend if low

•Enhanced data management

•Optimized sensor performance

Phase I:Building the Foundation

•Standard pump

•Data/pump integration

•Sensor technology

•Bolus Wizard

First Commercial Step in the Artificial Pancreas

� Threshold Suspend

Example of Threshold Suspend Cycle

88

Suspend time maximum = 2 hrs

Insulin infusion stops

Basal insulin infusion will resume even if glucose is below

Thresh Suspend limit

Basal Insulin Basal Insulin2 Hour Suspend

Insulin Suspends for 2 hours / Resumes for 4 hours

Automatically suspends insulin delivery if sensor glucose reaches the user-set limit

Threshold Suspend Manual Suspend(Not represented in

above report)

Daily Detail Report

Threshold Suspend in CareLink® Professional

Threshold Suspend: Two Hour Suspension

• Patient did not respond to TS alarm

• Basal suspended for two hours, then automatically resumed

©2014 Medtronic MiniMed, Inc. and Bayer Healthcare, LLC. All rights reserved.

Threshold Suspend: Insulin Restarted

Patient: • Cleared the alarm• Tested BG • Resumed insulin delivery

immediately

©2014 Medtronic MiniMed, Inc. and Bayer Healthcare, LLC. All rights reserved.

Threshold Suspend: Insulin Restarted after One Hour

Patient:• Cleared alarm and kept the

basal rate suspended. • Confirmed low with a

fingerstick• Resumed basal delivery after

approximately one hour

©2014 Medtronic MiniMed, Inc. and Bayer Healthcare, LLC. All rights reserved.

Therapy Management Dashboard

CareLink® Sample ReportAdherence Report

Start with Overnight

Evaluate Overnight & Meal Glucose

ASPIRE In-HomeOutpatient Study to Evaluate Safety and Effectiveness of the Threshold Suspend

Feature (NCT01497938)

Primary endpoints: – Efficacy: Nocturnal hypoglycemia event mean area under the curve (AUC)– Safety: Change in A1C from baseline

19 Centers in the United StatesRonald Brazg, MD

Renton, WA

Andrew Ahmann, MDPortland, OR

David Klonoff, MDSan Mateo, CA

Timothy Bailey, MDEscondido, CA

David Liljenquist, MDIdaho Falls, ID

Robert Slover, MDSatish Garg, MD

Aurora, CO

Luis Casaubon, MDAustin, TX

Richard Bergenstal, MDMinneapolis, MN

Melissa Meredith, MDMadison, WI

Anuj Bhargava, MDDes Moines, IA

James Thrasher, MDLittle Rock, AR John Reed III, MD

Bruce Bode, MDOla Odugbesan, MD

Atlanta, GA

Frank Schwartz, MDAthens, OH

Robin Goland, MDNew York, NY

Ruth Weinstock, MDSyracuse, NY

Barry Horowitz, MDWest Palm Beach, FL

ASPIRE In-Home Study: Participants

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

Screen failuresor withdrawals (94)

Withdrawals or did notmeet randomization

criteria (73)

BaselineEnrollment

(414)Run-in Phase

(2 weeks)(320)

Randomized(247)

Threshold Suspend (121)

Control (126)

Early withdrawals(5 Threshold

Suspend, 2 Control)

A1C and Nocturnal

Hypoglycemia AUC

Study Phase (3 months)

Threshold Suspend ControlAge 41.6 ± 12.8 44.8 ± 13.8

% Male 38 39.7Diabetes Duration 27.1 ± 12.5 26.7 ± 12.7

BMI, kg/m2 27.6 ± 4.7 27.1 ± 4.3

ASPIRE In-Home Study: Predictors of Nocturnal Hypoglycemia

Data taken from the run-in phase of the ASPIRE study

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

Continuous Variable P value P value(adjusted for GV)

Baseline A1c <0.001 <0.001

Coefficient of Variation <0.001 N/A

Basal : Bolus Ratio 0.76 0.20

Age <0.001 0.26

Diabetes Duration <0.001 0.92

BMI 0.026 0.39

ASPIRE In-Home Study: Results

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

The severity and/or duration of nocturnal hypoglycemic events was lower in the Threshold Suspend Group.

1547 980 1406 1568

37.5% reduction (p<0.001)

ASPIRE In-Home Study: Results

Hypoglycemic events were less frequent in the Threshold Suspend Group.

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

30% reduction (p<0.001)

32% reduction (p<0.001)

ASPIRE In-Home Study: ResultsReduction in hypoglycemia in the Group Threshold Suspend

There were fewer SG values in hypoglycemic ranges in the Threshold Suspend Group.

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med 2013 June 22;DOI: 10.1056/NEJMoa1303576.

40% reduction (p<0.001)

35% reduction (p<0.001)

ASPIRE In-Home Study: Results

∆A1C was similar in the two groups. The 95% CI of the difference in ∆A1C (-0.05, 0.15) did not include the non-inferiority limit of 0.4%.

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

Phase IV:Closing the Loop

•Predictive LGS algorithm

•Treat-to-Range

•Overnight closed loop

•Fully-automated delivery

104Veo and Enlite are not FDA approved, and other products and features mentioned are under development.

TechnologyTechnology

DataData

InvestigatorsInvestigators

AlgorithmsAlgorithms

Artificial Pancreas

Closed-loop vs. Hybrid Closed-loop control

6 12 18 24 30 36 420

100

200

300

400Closed Loop (N=5)

mealssetpoint

Hybrid Closed Loop (N=5)

Glu

cose

(mg/

dl)

Mean Nocturnal Peak PP

Full Closed Loop 156 (149-163) 109 (87-131) 232 (208-256)Hybrid Closed Loop 135 (129-141) 114 (98-131) 191 (168-215)

Connectivity – Remote Monitoring

Connectivity - Future

Connectivity - Future

Conclusions

� We have a lot to learn

� The future is bright

� Technology will revolutionize diabetes care

� Continuous glucose sensing will drive CSII

� Thank you

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