Transcript Progress Towards an Artificial Pancreas for T1D WILLIAM TAMBORLANE, MD Chief of Pediatric Endocrinology, Yale University, Deputy Director, Yale Center for Clinical Investigation.

Progress Towards an Artificial
Pancreas for T1D
WILLIAM TAMBORLANE, MD
Chief of Pediatric Endocrinology, Yale University, Deputy
Director, Yale Center for Clinical Investigation
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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
•
•
•
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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
Current
Current
Mean HbA1c (%)
100%
A1c Goal = <7.0%
80%
A1c Goal = <7.5%
60%
40%
20%
32%
21%
21%
<6
6-<13
17%
29%
13%
0%
13-<18 18-<26
Age (years)
26-<50
≥50
Frequency of Severe Hypoglycemia by Age
* Seizure or LOC: 1 or more events in 12m
Frequency of Diabetic Ketoacidosis byAge
20%
1 or more events in 12 months
10%
10%
10%
8%
6%
5%
5%
4%
4%
0%
<6
6-<13 13-<18 18-<26 26-<31 31-<50 50-<65 ≥65
Age (years)
Insulin Delivery Method
Continuous Glucose Monitoring Use
50%
40%
30%
20%
20%
22%
22%
13%
10%
5%
5%
5%
7%
0%
<6
6-<13 13-<18 18-<26 26-<31 31-<50 50-<65 ≥65
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
Control Algorithm
Continuous
glucose sensor
Insulin
pump
a)
GLUCOSE (mg/dl)
Proof of Concept: 2006 UCLA Medtronic Study
300
MEALS
SG
200
100
b)
SUBJECT
0
10
Suplemental
Carbohydrate
5
1
10
100
delivery
8
concentration
model fit
80
60
6
4
40
2
20
0
0
d)
Steil GM, et al. Diabetes. 2006;55:3344-3350.
INSULIN (U/ml)
c)
INSULIN (U/h)
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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
Glucose (mg/dl)
300
setpoint
Closed Loop (N=8)
meals
Hybrid CL (N=9)
200
100
0
6A
Noon
6P
MidN
6A
Noon
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.
6P
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
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•
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•
•
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
No adverse
outcomes
after 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)
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Clock (HH:MM)
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Infusion Rate (U/h)
Glucose (mg/dL)
Date: 29-Sep-2014
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Hotel Android CL Study: Yale Subject #203 (Day 04)
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Glucose (mg/dL)
Date: 1-Oct-2014
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