Are We There Yet?

Eda Cengiz, MD, MHSAssistant Professor of Pediatrics

Yale University School of Medicine

Update on Artificial Pancreas Project

Artificial Pancreas / Bionic Pancreas ?

utilizing electronic devices and mechanical parts to assist humans in performing difficult,

dangerous, or intricate tasks, as by supplementing or duplicating parts of the body

Artificial intelligence runs the algorithm

•Sensor signals transmitted to a laptop computer that displays the sensor glucose and calculates rate of insulin delivery

•Rate of insulin delivery is transmitted to the insulin pump

Determine insulin requirement real time, deliver proper insulin to achieve euglycemia.

The Promise of Artificial Pancreas

•Glucose Sensor•Algorithm•Insulin Pump & Insulin

Medtronic Closed-loop System c. 2011

Insulin Pump

CGM

Laptop Controller

What is taking so long ?

During a Typical Clinic Visit at Yale Diabetes Center…

How is it going with the Artificial Pancreas Dr. C?

When is it going to be ready?

Challenges & Solutions: Artificial Pancreas (Closed-Loop System)

•Progress to date

•Pitfalls

•Solutions

•Future closed-loop studies(hot off the press!)

JDRF Road Map to Artificial Pancreas

What is the plan?

Artificial Pancreas

Do we need to wait until we have the Fully Automated Artificial Pancreas?

Artificial Pancreas

Progress to date

SENSOR-AUGMENTED PUMP THERAPY

CGM improved A1c, but not in everyone

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

8 - 14 yrs 15 - 24 yrs > 25 yrs

RT-CGM Control

p=0.29 p=0.52 p<0.001

JDRF CGM Study Group. N Engl J Med 2008; 359:1464-76.

Average Days of CGM Use by Age Group

CGM Use

0%

20%

40%

60%

80%

Age ≥25 Age 15-24 Age 8-14

Per

cent

age

of s

ubje

cts

<4.0 days/week

4.0-<6.0 days/week

≥6.0 days/week

Change in glycated hemoglobin-0.8

-0.6

-0.4

-0.2

0.0

0.2

Cha

nge

in g

lyca

ted

hem

oglo

bin

JDRF CGM Study Group. N Engl J Med 2008; 359:1464-76.

Bergenstal RM, Tamborlane WV, Ahmann A, et al. N Engl J Med. Doi:10.1056/NEJMoa1002853.

8.3%

7.3%

7.5% 7.5% 7.5%

8.0% 8.0%8.1% 8.1%

7.0%

7.5%

8.0%

8.5%

0 3 6 9 12

Months

A1C

Medtronic STAR 3 Sensor-Augmented Pump Trial

Values are means ± SE. Comparisons between SAP group and MDI group are significant for each time period (P<0.001).

• The SAP group achieved a greater A1C reduction vs. MDI at 3 months and sustained it over 12 months

A1C Reduction for SAP and MDI Groups

= MDI= SAPn = 244 n = 241

- 0.6P<0.001

∆ -0.2

∆ -0.8

- 0.6P<0.001

Bergenstal RM, Tamborlane WV, Ahmann A, et al. N Engl J Med. Doi:10.1056/NEJMoa1002853.

A1C Reduction Correlates to Increased Sensor Use

Values are the difference between the means ± SE. p=0.003 for association between sensor wear and A1C reduction at 1 year. Only 7 participants had sensor use of 20% or less, with a change in A1C of -0.43 at 1 year vs. baseline.

• The majority of patients used sensors ≥61% of the time • Patients who used sensors ≥81% of the time reduced their mean A1C by

1.2% at 1 year vs. baseline

-0.19

-0.64-0.79

-1.21-1.5

-1

-0.5

021-40% 41-60% 61-80% 81-100%

Frequency of Sensor Use (% of Time)

Cha

nge

in A

1C a

t 1 Y

ear v

s B

asel

ine

n =27 n =46 n =108 n =56

DirecNet / TrialNet Metabolic Control Study

• Does the rapid normalization of BG levels at the time of diagnosis of diabetes, followed by super-intensive control of BG levels, help to preserve residual beta-cell function?

• Use of an artificial pancreas in subjects AT DIAGNOSIS for 3-4 days to rapidly normalize BG levels, followed by sensor-augmented pump therapy x 2 years

Sensor and BG Levels During CL TherapySensor and BG Levels During CL Therapy

Mean Sensor Glucose Levels Prior to, Mean Sensor Glucose Levels Prior to, During, and Following CL TherapyDuring, and Following CL Therapy

3 mth f/u: A1c = 5.9 %

6 wk f/u

6 wk f/u6 mth f/u: A1c = 6.0 %

“typical” tracing12 mth f/u: A1c = 6.3 %

Artificial Pancreas

Progress to Date

SENSOR-AUGMENTED PUMP THERAPY

PUMP SUSPENSION FORACTUAL

HYPOGLYCEMIA

Prevention of Hypoglycemia with AP

• Insulin suspension prevented low BG (<60mg/dl) in 78% of the suspensions.

• Non resulted in hyperglycemia

• Reduction in CGM hypoglycemia alarms

A Semi-Closed-Loop System: The Paradigm® Veo™*

• Integrated sensor• Improved Calibration Routines• Glucose trend• Alarms

– Outside target zone– Predictive– Missing insulin bolus

• Minimum basal rate of 0.025 U/h• Hypoglycemia suspend

– Suspend for 2 hours– Re-suspend after 4 hours if

needed

* Investigational device. Limited by U.S. law to investigational use.

Keenan et al., J. Diabetes Sci. Tech., 2010; 4(1):111-118Buckingham et al., Diabetes Technol. Ther., 2009; 11:93-97Attia et al., Diabetes Care, 1998; 21:817-821.Guerci et al., J Clin Endocrinol Metab, 1999; 84:2673-2678.Zisser, Diabetes Care, 2008; 31:238-239.

S L I D E 22

Automatic Low-Glucose Suspend

LGS off LGS onMean Glucose (mg/dL) 145 ± 23 148 ± 19

Time < 70 per day (min) 101 ± 68 58 ± 33 *

Time > 140 per day (min) 651 ± 240 639 ± 182

Number of excursions < 70 and < 40 mg/dL reduced with LGS

* p=0.002

Danne T, Diabetes Technol Ther 2011; 13: 1129-1134

Artificial Pancreas

SENSOR-AUGMENTED PUMP THERAPY

PUMP SUSPENSION FORACTUAL HYPOGLYCEMIA

PUMP SUSPENSION FORPREDICTED

HYPOGLYCEMIA

Progress to Date

CL2-MW 9/3/08

Time in Minutes Beginning at 9:30 PM

0 100 200 300 400 500 600

Ser

um G

luco

se (m

g/dl

)

20

40

60

80

100

120

140

160

Y A

xis

2

0.0

0.5

1.0

1.5

2.0

Controller GlucoseYSI Basal Insulin

ROC = -.36 mg/dl-min3 Alarm, Threshold 80 mg/dl, Horizon 35 minAutomatic pump suspension for predicted hypoglycemia

Exercise AP Study objective

• To evaluate whether use of a AP system reduces the risk of delayed (nocturnal) hypoglycemia following antecedent daytime exercise

Subject recruitment, consent, enrollment

(n = 12)

Closed-Loop

Open-LoopOpen-Loop

Closed-Loop

Exercise Study Protocol Schematic

48-hour evaluation period2 overnights

48-hour evaluation period2 overnights

Plasma BG q30 min, insulin q30 min x 3h @ meals

Nocturnal Hypoglycemia

Closed LoopOpen Loop

0

5

10

15

20

25

3

22

All Nocturnal Hypo

Num

ber

of T

reat

men

ts G

iven

p=0.05

1

14

Night Following Exercise

p=0.06

Glucose Frequency DistributionNight after sedentary condition

1 % 99 % 0% 3 % 90 % 7 %

P<0.0001

3 % 93 % 4 %8 % 76 % 16 %

P<0.0001

Glucose Frequency DistributionNight following afternoon exercise

Artificial Pancreas

SENSOR-AUGMENTED PUMP THERAPY

PUMP SUSPENSION FORACTUAL HYPOGLYCEMIA

PUMP SUSPENSION FORPREDICTED HYPOGLYCEMIA

BASAL/BOLUS ACTIVATION

FOR HYPERGLYCEMIA

Progress to Date

Conceptual Scheme for “Treat-to-Range”

Artificial Pancreas

Progress to Date

SENSOR-AUGMENTED PUMP THERAPY

PUMP SUSPENSION FORACTUAL HYPOGLYCEMIA

PUMP SUSPENSION FORPREDICTED HYPOGLYCEMIA

BASAL/BOLUS ACTIVATIONFOR HYPERGLYCEMIA

CLOSED-LOOP BASAL

MANUAL MEALS

Studies of Overnight CL

• Increased time in target BG

• Reduction of hypoglycemia

• Incorporation of daytime challenges– Exercise– Alcohol– Pregnancy

Hybrid control improves performance

6A Noon 6P MidN 6A Noon 6P0

100

200

300Closed Loop (N=8)

meals

setpoint

Hybrid CL (N=9)

Glu

cose

(mg/

dl)

Mean Daytime Peak PPFull CL 147 58 154 60 219 54Hybrid 138 49 143 50 196 52

Weinzimer SA. Diabetes Care 2008; 31:934-939.

Late post-prandial hypoglycemia in CL

6 12 18 24 30 36 420

3

6

9

12

15

18

0

50

100

150

Plasma InsulinEVP

Insu

lin (U

/h)

Insulin ( U/ml)

6 12 18 24 30 36 420

100

200

300

0

25

50

SG CHO

Glu

cose

(mg/

dl)

Artificial Pancreas

Progress to date

SENSOR-AUGMENTED PUMP THERAPY

PUMP SUSPENSION FORACTUAL HYPOGLYCEMIA

PUMP SUSPENSION FORPREDICTED HYPOGLYCEMIA

BASAL/BOLUS ACTIVATIONFOR HYPERGLYCEMIA

CLOSED-LOOP MULTIHORMONAL

FULL CLOSED-LOOP CONTROL

CLOSED-LOOP BASALMANUAL MEALS

AP Multi-hormonal Approach

• Can the addition of pramlintide improve the performance of a CL system by reducing the peak post-prandial glucose excursions?

Pramlintide

• Analog of human amylin

• Co-secreted with insulin from -cell

• Used as adjunct to insulin in T1D to reduce post-prandial glycemic excursions

– Delay gastric emptying– Suppress endogenous glucagon

Subject recruitment, consent, enrollment

(n = 8)

Closed-Loop

Closed-Loop + Pramlintide

(30 mcg per meal)

Closed-Loop + Pramlintide

(30 mcg per meal)

Closed-Loop

Pramlintide Study Protocol Schematic

24-hour evaluation period3 meals (BF, L, Din)

24-hour evaluation period3 meals (BF, L, Din)

Plasma BG q30 min, insulin q30 min x 3h @ meals

Glucose excursions with/without pramlintide

6 9 12 15 18 21 24 27 30 330

100

200

300

Control DaySymlin Day

Time (hrs)

Blo

od G

luco

se (m

g/dL

)

Summary and conclusions

• Pramlintide had modest effect on prandial glucose

• Would require manual injection or at best, manual bolus

• Faster insulin absorption / action clearly needed

Artificial Pancreas

Progress to date

SENSOR-AUGMENTED PUMP THERAPY

PUMP SUSPENSION FORACTUAL HYPOGLYCEMIA

PUMP SUSPENSION FORPREDICTED HYPOGLYCEMIA

BASAL/BOLUS ACTIVATIONFOR HYPERGLYCEMIA

CLOSED-LOOP MULTIHORMONAL

FULL CLOSED-LOOP CONTROL

CLOSED-LOOP BASALMANUAL MEALS

?

What do we need to achieve AP?

• Better accuracy, user interface, reliability.

• Better algorithm• One site for CGM &

Insulin

Single Port, Multiple Sensor

• One site, two catheters for insulin infusion and glucose sensing

• Single port for CGM and insulin

• CGM with an optic sensor back up

What do we need to achieve AP?

• Better accuracy, user interface, reliability.

• Better algorithm• One site for CGM &

Insulin

• Faster acting insulin

Dangerous Delays in Insulin Action after SC Injection

1. Delays due to the chemical properties of insulin.

1. Tissue delays

Insulin Time-Action Curves

0 30 60 90 120 150 180 210 240 270 3000

10

20

30

40

50

60

70

80

90

100

0

1

2

3

4

5

6

7

InsulinGIR

Time (min)

Plas

ma

Insu

lin (u

U/m

L) GIR

(mg/kg/m

in)

•The InsuPatchTM device applies controlled heat around the insulin infusion site.

InsuPatch

Temp. Sensor

with InsuPatch activation:

Aspart insulin bolus maximum effect was 35 min earlier compared

to the same dose bolus without InsuPatch activation .

Peak aspart insulin action curve shifted to the left .

The Effect of InsuPatch on The Effect of InsuPatch on Insulin Action Insulin Action

51

Hyaluronidase Mechanism of Action

The Accu-Chek DiaPort is a port system for continuous intraperitoneal insulin infusion.

DiaPort

The catheter tip is placed in the peritoneal cavity where the insulin is directly infused.

Pathway to Closed-Loop (CL)

Pump

Platform and Connectivity for Ambulatory Studies

Artificial Pancreas

Progress to date

SENSOR-AUGMENTED PUMP THERAPY

PUMP SUSPENSION FORACTUAL HYPOGLYCEMIA

PUMP SUSPENSION FORPREDICTED HYPOGLYCEMIA

BASAL/BOLUS ACTIVATIONFOR HYPERGLYCEMIA

CLOSED-LOOP MULTIHORMONAL

FULL CLOSED-LOOP CONTROL

CLOSED-LOOP BASALMANUAL MEALS

?Outpatient studies

The “Dream” Study

• http://www.youtube.com/watch?v=9HMx8yy2nVw

Thank you!

• Yale Closed Loop Team– Stu Weinzimer– Jennifer Sherr– William Tamborlane– Grace Kim– Miladys Palau– Camille Michaud– Lori Carria– Amy Steffen– Kate Weyman– Melinda Zgorski– Eileen Tichy