1 progress towards an artificial pancreas for t1d william tamborlane, md chief of pediatric...
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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
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8
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12concentration
0
20
40
60
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100delivery
model fit
INS
UL
IN (
U/h
) INS
UL
IN (
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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
Infu
sion
Rat
e (
U/h
)
Clock (HH:MM)