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Progress Towards an Artificial Pancreas for T1D

WILLIAM TAMBORLANE, MDChief of Pediatric Endocrinology, Yale University, Deputy Director, Yale Center for

Clinical Investigation

Progress Towards Development of an Artificial Pancreas for Type 1 Diabetes

William V. Tamborlane, MD

Professor of Pediatrics

Yale University School of Medicine

Georgetown University Class of ’68

“There are Careers Other Than Medicine”

Objectives

Review • how far we have come in treating T1D• How far we still need to go in treating T1D• how much progress has been made in a

mechanical solution to more effective treatment of T1D

“Bad Old Days” of Diabetes (Before 1980)

• Aggressive therapy unsafe and of unknown benefits

• HbA1c 11-12%• Eye & kidney complications

Era of Intensive Treatment (1980’s)

First Successful Study of Pumps in T1DM

Reduction to normal of plasma glucose in juvenile diabetes by subcutaneous administration of insulin with a portable infusion pump

WV Tamborlane, RS Sherwin, M Genel, and P Felig

NEJM 1979; 300:573-8

Diabetes Control and Complications Trial

Lowering HbA1c levels to 7.0% with intensive vs 9.0% with conventional treatment decreased the risk of development and progression of early:

• Retinopathy by 50-75%• Nephropathy by 35-55%• Neuropathy by 60%

DCCT Recommendation

Most children and adults with T1D should be treated with intensive therapy to prevent or markedly delay the development of diabetic complications

Treatment Advances Past 20 years

• Insulin Analogs• Smart Insulin Pumps• Improved Blood Glucose

Meters• Continuous Glucose

Monitoring Systems• New T2D Drugs for T1D

Why do we need an artificial pancreas?

• Too many T1D patients fail to achieve target A1c goals

• Rates of severe hypoglycemia and DKA remain too high

• Too few pediatric patients take full advantage of advances in diabetes technologies

T1D Exchange Clinic Network & Clinic Registry

>70 Adult and Pediatric Clinics – >150,000 patients with T1D

> 26,000 T1D Patients (age 2-95 yrs) Enrolled

Most Recent HbA1c Levels by Age in T1DX Registry

Percent of Patients Meeting HbA1c Targets

<6 6-<13 13-<18 18-<26 26-<50 ≥500%

20%

40%

60%

80%

100%

21% 21% 17% 13%

32% 29%

Current

Age (years)

Mean

Hb

A1c (

%) A1c Goal = <7.0%

A1c Goal = <7.5%

Frequency of Severe Hypoglycemia by Age

* Seizure or LOC: 1 or more events in 12m

Frequency of Diabetic Ketoacidosis byAge

<6 6-<13 13-<18

18-<26

26-<31

31-<50

50-<65

≥650%

10%

20%

8%6%

10% 10%

5% 5%4% 4%

Age (years)

1 or more events in 12 months

Insulin Delivery Method

Continuous Glucose Monitoring Use

<6 6-<13 13-<18

18-<26

26-<31

31-<50

50-<65

≥650%

10%

20%

30%

40%

50%

5% 5% 5%7%

20%22% 22%

13%

Age (years)

Why not pancreas transplants?

• Limited to small segments of population due to limitations in supply

• Problems with rejection have not been overcome

• They are not well suited for children with T1DM due to excessive morbidities related to immuno-suppression.

Essential elements of CL Systems Already Available

Continuous glucose sensor

Control Algorithm

Insulin pump

Proof of Concept: 2006 UCLA Medtronic Study

0

100

200

300 MEALS SG

GL

UC

OS

E (

mg

/dl)

0

2

4

6

8

10

12concentration

0

20

40

60

80

100delivery

model fit

INS

UL

IN (

U/h

) INS

UL

IN (

U/m

l)

1

5

10 SuplementalCarbohydrate

SU

BJ

EC

T

a)

b)

c)

d)Steil GM, et al. Diabetes. 2006;55:3344-3350.

Lessons Learned

Exaggerated post-meal excursions and a tendency to late post-prandial hypoglycemia due to lags in:

• Carbohydrate absorption• Increases in interstitial glucose

concentrations• Insulin absorption from subcutaneous site

Excellent overnight control but lingering concerns re sensor accuracy

Possible Solutions

Exaggerated post-meal excursions:• Hybrid, semi-automatic control with

“priming” conventional pre-meal bolus to cover some of carbohydrate in meal

Sensor error:• Set slightly higher than normal target

glucose value (e.g. 120 rather than 90 mg/dL) to avoid nocturnal hypoglycemia

First Pediatric Study: 2008 Yale Hybrid vs Full CL Study

6A Noon 6P MidN 6A Noon 6P0

100

200

300Closed Loop (N=8)

meals

setpoint

Hybrid CL (N=9)

Glu

cose

(m

g/d

l)

Mean Daytime Peak PP

Full CL 147 58 154 60 219 54

Hybrid 138 49 143 50 196 52

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

Conclusions

• Short-term closed-loop control is feasible in children with T1D

• Night-time control is outstanding

• Meal-related excursions are as good or better than traditional open-loop therapy and improved with manual priming bolus

Learnings from Inpatient CRC Studies Last 6 Years

• Testing of improved controller algorithms• Testing under simulated outpatient conditions

– Exercise– Varied meal plans

• Testing of dual hormone systems– Insulin + Glucagon to prevent hypoglycemia– Insulin + Pramlintide or GLP1 Agonists to reduce post-meal hyperglycemia

Learnings from Inpatient CRC Studies Last 6 Years

• Testing of improved controller algorithms• Testing under simulated outpatient conditions

– Exercise

• Testing of dual hormone systems– Insulin + Glucagon to prevent hypoglycemia– Insulin + Pramlintide to reduce post-meal hyperglycemia

• Testing ways to accelerate insulin absorption and action– Ultra-fast acting insulin preparations– Infusion site warming– Hyaluronidase

Hardware and Software Improvements: Still A Work in Progress

• More reliable and accurate sensors• Dual sensors• Integrity of RF transmissions• Preventing computer malfunctions• Limiting maximal delivery rates• Minimizing the risk of user error• Better and easier systems for patients to

operate

Major Obstacle to Outpatient Use: Patient Safety

Outpatient systems must have as many safety features as possible in place to ensure that excessive insulin administration due to a system malfunction is extremely unlikely.

Essential CL Functions

• Turn off insulin if glucose Safe• Turn on insulin if glucose

Dangerous

First Step to Outpatient CL Control: Veo (AKA 530G) Threshold Suspend System

System automatically suspends basal insulin for 2 hrs if:• the hypoglycemia

alarm level has been reached

• the patient has not responded to the alarm

Perth Low Glucose Suspend Study (2012)

• 126 episodes of LGS before 3am with no patient response

insu

lin s

uspe

nded

insu

lin re

sum

ed

No adverse outcomesafter suspension

Rationale: Prolonged Nocturnal Hypoglycemia Prior to Seizures

Buckingham B, et al., Diabetes Care, 2008, 31:2110

Next Step: Automatic Shut Off for Projected Hypoglycemia

• Shuts off the pump for a predicted low based on the rate of fall of glucose• System alarms only for actual low glucose event

Hypoglycemia averted

in 13 of 16 cases

Outpatient Full CL Studies

• Overnight only• Diabetes Summer Camp Studies• “Bionic Pancreas” (Insulin + Glucagon) Studies• Hybrid CL Studies with Hourly Limits on Rate

of Insulin Delivery

Overnight CL – Camp

Phillip, N Engl J Med 2013

Dual Hormone Delivery in 20 Adults and 32 Adolescents

Russell SJ et al. N Engl J Med 2014;371:313-325

Medtronic Hybrid CL with Restricted Insulin Infusion Rates

Hotel Android CL Study: Getting Yale Subject 201 Started

Hotel Android CL Study: Yale Subject #201 (Day – 02)

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:000

4080

120160200240280320360400

Glu

cose

(m

g/d

L)

Date: 29-Sep-2014

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:000123456789

10

Infu

sion

Rat

e (

U/h

)

Clock (HH:MM)

Hotel Android CL Study: Yale Subject #203 (Day 04)

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:000

40

80

120

160

200

240

280

320

360

400

Glu

cose

(m

g/d

L)

Date: 1-Oct-2014

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:000123456789

101112131415

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sion

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U/h

)

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