CAROLINAS CHAPTER/AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS
2016 Annual MeetingHILTON HEAD ISLAND
FRIDAY HANDOUTSeptember 9-11, 2016 ~ Sonesta Resort ~ Hilton Head Island, SC
This continuing medical education activity is jointly provided by theCarolinas Chapter, AACE and Southern Regional Area Health Education Center
8.25 CME Credits!
1
Bruce W. Bode, MD, FACE
Atlanta Diabetes Associates
Associate Professor of Medicine, Emory University
Atlanta, Georgia
Artificial Pancreas Systems
DISCLOSURE STATEMENT
Research and Grant Support to Employer: Abbott, Animas, Biodel, DexCom, GSK, Janssen, JDRF, Lexicon, Lilly/BI, MannKind, Medtronic, NIH, Novo Nordisk, Pfizer, Sanofi, Sensonics
Consultant: Abbott, Janssen, Medtronic, Novo Nordisk, Sanofi, Thermalin, Valeritas
Speaker’s Bureau: Astra Zeneca, Janssen, Insulet, Mannkind, Medtronic, Merck, Novo Nordisk, Sanofi
STATUS OF TYPE 1 DIABETES CARE IN USA: 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
2
INSULIN PUMP USE - CURRENT
61% 62% 66%60% 56%
65% 62% 58%
0%
20%
40%
60%
80%
100%
Overall <6 6-12 13-17 18-25 26-49 50-64 ≥65
Age (years)
58%50%
58% 57% 56%61% 60%
56%61% 62% 66% 60%
56%
65%62% 58%
0%
20%
40%
60%
80%
100%
Overall <6 6-12 13-17 18-25 26-49 50-64 ≥65Age (years)
Enrolled 9/1/2010 - 8/1/2012
Current 4/1/2014 - 4/1/2015
INSULIN PUMP USE IS INCREASING
PUMP MANUFACTURER
Animas 23%
Medtronic 61%
Insulet 11%
Tandem 3%Roche 1%Other 1%
3
CONTINUOUS GLUCOSE MONITOR USE
12%17%
10%6% 8%
25%21%
14%
0%
10%
20%
30%
40%
50%
Overall <6 6-12 13-17 18-25 26-49 50-64 ≥65
Age (years)
CGM USE IS INCREASING BUT STILL LOW
4% 4% 3% 5%
17% 18%
10%
17%
10%6% 8%
25%21%
14%
0%
10%
20%
30%
40%
50%
<6 6-12 13-17 18-25 26-49 50-64 ≥ 65Age (years)
Enrolled 2010-2012 (8% use CGM overall)
Current 2014-2015 (12% use CGM overall)
CGM USE BY INSULIN DELIVERY METHOD
23%
14%
9%12%
32%28%
18%
6%2% 1% 3%
11%10% 9%
0%
10%
20%
30%
40%
50%
<6 6-12 13-17 18-25 26-49 50-64 ≥65
Age (years)
Pump Injection
4
LOWER A1C IN INSULIN PUMP USERS
8.7%
9.2%
7.8%
8.2%
8.6%
7.5%
7.0%
7.5%
8.0%
8.5%
9.0%
9.5%
<13 13-25 ≥26
Mea
n H
bA1c
%
Age (years)
Injection Insulin Pump
LOWER A1C IN CGM USERS
8.4%
8.9%
7.7%7.8%
8.1%
7.3%
7.0%
7.5%
8.0%
8.5%
9.0%
<13 13-25 ≥26
Mea
n H
bA1c
%
Age (years)
Non CGM Users CGM Users
LOWER A1C IN CGM USERS REGARDLESS OF INSULIN DELIVERY METHOD
8.7
9.3
7.8
8.38.6
7.67.9 8.0
7.2
7.88.1
7.2
7.0%
7.5%
8.0%
8.5%
9.0%
9.5%
<13N=3050
13-<26N=6855
≥26 N=4077
Mea
n H
bA1c
%
Age (years)
Injection only Pump only
Injection + CGM Pump + CGM
5
LOWER A1C WITH INCREASED SMBG (EXCLUDES CURRENT CGM USERS)
6.5%
7.0%
7.5%
8.0%
8.5%
9.0%
9.5%
10.0%
0-3 4-6 6-9 ≥10
SMBG # Per Day
Pump Injection
Age <18
0-3 4-6 6-9 ≥10SMBG # Per Day
Age ≥18
CURRENT PUMPS ON THE USA MARKET
CONTINUOUS MONITORING SYSTEMS IN USA
Paradigm or Guardian REAL-Time DexCom G5 Platinum
CGMS® iPro™ Recorder
6
pump + sensor uploader mobile device any Internet-enabled device
MINIMED CONNECT
For care partners:online access to diabetes information
For healthcare providers: automatic CareLink uploads
For people with diabetes: discreet display of pump and CGM information
A better connection to diabetes care
Dexcom G5 Mobile
Dexcom Share/Follow
G5 App
CGM Use
0%
20%
40%
60%
80%
Age ≥25 Age 15-24 Age 8-14
Pe
rce
nta
ge
of
su
bje
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
Ch
an
ge
in g
lyc
ate
d h
em
og
lob
in
JDRF CGM Study Group. N Engl J Med 2008; 359:1464-76.
7
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
MDT 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
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
0
21-40% 41-60% 61-80% 81-100%Frequency of Sensor Use (% of Time)
Ch
ang
e in
A1C
at
1 Y
ear
vs B
asel
ine
n =27 n =46 n =108 n =56
DCCT (Adolescents & Adults)Severe Hypo Rate: 62.0 per 100 pt-yrs,
A1C: 9.0% → 7.2%
STAR 3 SAP (Pediatrics & Adults)Severe Hypo Rate: 13.3 per 100 pt-yrs,
A1C: 8.3% → 7.5%
JDRF CGM (Adults, 1 Subject excluded)Severe Hypo Rate: 20.0 per 100 pt-yrs,
A1C: 7.6% → 7.1%
Nathan et al. The New Engl J Med. 1993; 329(14); Tamborlane et al. The New Engl J Med. 2008;359:1464-1476.:Bergenstal et al. N Engl J Med. doi:10.1056/NEJMoa1002853: Battelino et al. Diabetologia DOI 10.1007/s00125‐012‐2708‐9
SENSOR-AUGMENTED PUMPS IMPROVE A1C WITHOUT INCREASING HYPOGLYCEMIA
8
FUNDAMENTALS OF CLOSED-LOOP SYSTEMS
HCL FCLTS PLGM
Subject Burden Automation
Regulatory Ease System Complexity
FIRST COMMERCIAL STEP IN THE ARTIFICIAL PANCREAS
Threshold Suspend
EXAMPLE OF THRESHOLD SUSPEND CYCLE
24
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
9
Threshold Suspend Manual Suspend(Not represented in above report)
Daily Detail Report
Threshold Suspend in CareLink® Professional
THRESHOLD SUSPEND: ASPIRE IN-HOME STUDY
nducted 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.al 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)
THRESHOLD SUSPEND: ASPIRE IN-HOME STUDY
Hypoglycemic events were less frequent in the Threshold Suspend Group.
nducted 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.al 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)
10
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%.
nducted 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.al 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.
2
*Measured as sensor glucose values
SmartGuard™ Technology
Protection from lows*
Takes action when patients need it most
√√
630G640G670G
Systems
530G System
MDT PATHWAY TO HYBRID CLOSE LOOP
PIVOTAL TRIALOF A HYBRIDCLOSED-LOOP SYSTEM (MDT 670G) IN TYPE 1 DIABETES
11
INVESTIGATORSName Affiliation and Location
Richard M. Bergenstal, MD International Diabetes CenterMinneapolis, MN
Bruce A. Buckinham, MD Stanford UniversityStanford, CA
Satish Garg, MD Barbara Davis Center for Childhood DiabetesAurora, CO
Stuart A. Weinzimer, MD Yale UniversityNew Haven, CT
Ronald Brazg, MD Rainier Clinical ResearchRenton, WA
Jacob Ilany, MD Sheba Medical CenterTel-Hashomer, Israel
Bruce Bode, MD, FACE Atlanta Diabetes AssociatesAtlanta, GA
Timothy Bailey, MD, FACE AMCR InstituteEscondido, CA
Stacey M. Anderson, MD University of VirginiaCharlottesville, VA
Robert Slover, MD Barbara Davis Center for Childhood DiabetesAurora, CO
John Shin, PhD, MBAScott W. Lee, MDFrancine R. Kaufman, MD
Medtronic plcNorthridge, CA
BACKGROUND
Pump systems that automatically suspend insulin delivery can reduce hypoglycemia, but no commercially-available systems can increase the insulin delivery rate to prevent or mitigate hyperglycemia.
Hybrid closed-loop (HCL) systems can automatically increase or decrease basal insulin, but boluses require user input and confirmation.
The 670G system was evaluated in a pivotal clinical trial of adults and adolescents with type 1 diabetes that included supervised hotel and 3-month unsupervised home use of the system 24 hours per day.
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
SYSTEM COMPONENTS
The MDT 670G system included the new pump platform, closed-loop algorithm, and CGM display for the investigational 4th-generation subcutaneous glucose sensor and transmitter.
Sensors were calibrated with readings from the CONTOUR®NEXTLINK blood glucose meter (not shown).
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
12
METHODS
The study was conducted at 10 sites in the US and Israel
Patients had type 1 diabetes for ≥2 years
A1C <10%, were age 14-21 years old (adolescents) or 22-75 years old (adults)
Using pump therapy for ≥6 months, with or without CGM
The pump was used in open-loop mode during a 2-week run-in phase
Then the pump was used in closed-loop mode in a 3-month study phase that included a 6-day, 5-night hotel stay for supervised activity and frequent venous BG measurements (during one 24 hour period) with a reference instrument (i-STAT)
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
PARTICIPANTS
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
STUDY FLOW
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
13
COMPARING OPEN LOOP TO HYBRID CLOSED LOOP BETTER GLUCOSE CONTROL AS AUTOMATION ADVANCES
Patient with Diabetes – Open Loop Insulin Delivery System
Patient with Diabetes-Closed Loop Insulin Delivery System
Investigative device not approved for sale or use
HIGHLIGHTS OF THE 670G SYSTEM
Auto Mode- target set at 120 mg/dl; option to
raise to 150 mg/dl for exercise, etc
- Patients must put carbs in pump to deliver meal insulin
- If sensor glucose is above 300 mg/dl or not working, system is placed into manual mode
- Must troubleshoot the system to get back into Auto Mode
HCP- Can only adjust Insulin to Carb
ratio and Active Insulin Time- During trial, patients upload daily
for 2 weeks then weekly thereafter
RESULTSMODAL DAY SENSOR (SG) GLUCOSE TRACINGS
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
14
RESULTSA1C VALUES ANDPROPORTIONS OF NOCTURNAL VALUES ≤ 50 MG/DL
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
RESULTSDISTRIBUTION OF A1C VALUES
0%
20%
40%
60%
80%
100%
5 6 7 8 9 10
Cu
mu
lati
ve P
erce
nta
ge
A1C (%)
Run-In
End of Study
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
RESULTSKEY ENDPOINTS
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
15
RESULTS
NUMBER OF SUBJECTS, ∆ A1C AND ∆ SD AS FUNCTIONS OF STARTING A1C
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
RESULTS
SENSOR ACCURACY AND DISTRIBUTION OF i-STAT AND SG VALUES DURING HOTEL PHASE
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
DEVICE RELATED ADVERSE EVENTS
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
16
STRENGTHS
Multicenter design to evaluate safety
Large number of subjects, both adults and adolescents, using the system for 24 hours/day
Three months of unsupervised home use of system
Time in target confirmed by reference BG measurements during hotel stay
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
LIMITATIONS
Single-arm, nonrandomized design with no pre-specified efficacy endpoints
Data quantity imbalance between run-in (2 weeks) and study phase (3 months)
Exclusion of subjects with A1C >10%, recent episodes of severe hypoglycemia or recent DKA
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
SUMMARY
Three months of unsupervised at-home use of the HCL system (670G) was safe, with no severe hypoglycemia or DKA.
The 4th-generation sensors were accurate.
Compared to the run-in phase, HCL control was associated with less glycemic variability, more time in the target range, less exposure to hypo- and hyperglycemia, and reductions in A1C.
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
17
CONCLUSIONS
Hybrid closed-loop insulin delivery can help patients reduce hypo- and hyperglycemia and safely achieve ADA-recommended A1C goals.
This study suggests that the 67G HCL system should be considered for non-investigational use in adults and adolescents with type 1 diabetes in the home setting.
FDA has approved subjects to remain on the Hybrid Closed Loop system till approved
FDA approval is under review
If approved, hopeful launch in 1st to 2nd quarter 2017
Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
MDT ALGORITHMS FOR CLOSED LOOPTHE PATH TO REDUCING PATIENT BURDEN
Pat
h t
o C
lose
d L
oo
p
Threshold/ Low GlucoseSuspendMiniMed® 530G System and MiniMed 630G System
Predictive Suspend*
Hybrid Closed Loop**
Towards PersonalizedClosed Loop***
Automatically doses insulin with minimal mealtime and exercise inputs from the patient
Suspends delivery when the system predicts a low is approaching
Suspends delivery when a low occurs
Improving interface & meal announcement: small, medium, large meal bolus settings and set meal insulin delivery buttons
Pattern recognition
Additional sensor inputs: Activity, food, heart rate, sleep, free fatty acids
Detecting sensor or infusion set failure
Advanced HybridClosed Loop***
Addition of meal detection algorithm, allows for more front-loading of meal insulin and earlier delivery of correction post meal
PID for insulin delivery & MPC for safety
Suspension protocol based on actual values
Suspension protocol w/ predictive algorithm
PID for delivery MPC for safety, FL for meals
PID, MPC & Fuzzy logic + cognitive computing
Partners / Collaborators:
Current USA
Standard
Next Advancemen
t
*Investigative device not approved for sale in the U.S.** Investigational device, not approved for sale or use ***Conceptual device
THE RACE TO THE CLOSED LOOPHOW THE COMPANIES LINE UP
5
Group ControllerType
Hormone Time InteractionRequired
Medtronic Next Generation with DreaMed
PID Fuzzy Logic Insulin 24 hour Meals, Exercise
Bigfoot Biomedical Proprietary Algorithm
Insulin 24 hour Meals, Exercise
University of Cambridge
MPC Insulin 24 hour Meals, Exercise
University of Virginia Type ZERO
MPC Insulin 24 hour Meals, Exercise
Boston University MPC Insulin + Glucagon 24 hour Meals, Exercise
Animas MPC:Treat-to-RangeHypo-Hyper Minimizer
Insulin 24 hour Meals, Exercise
18
CONCLUSIONS
Closed Loop Technology is evolving quickly
HCL technology is a game changer for both both patients and HCPs
Studies on cost effectiveness are under development and will start later this year
Progression from Hybrid Closed Loop to fully Closed Loop is undergoing investigation currently but approval will be in the future
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