CAROLINAS CHAPTER/AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS 2016 Annual Meeting HILTON HEAD ISLAND FRIDAY PRESENTATION September 9-11, 2016 ~ Sonesta Resort ~ Hilton Head Island, SC This continuing medical education activity is jointly provided by the Carolinas Chapter, AACE and Southern Regional Area Health Education Center 8.25 CME Credits!
Artificial Pancreas Systems Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Associate Professor of Medicine, Emory University Atlanta, Georgia
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 Not at Goal Excess Hypoglycemia The average type-1 patient has: Two symptomatic hypoglycemic events per week 1 One or more episodes of severe, temporally disabling hypoglycemia per year Nocturnal hypoglycemia occurs ~ 8.5% of nights 2 The Type 1 Exchange, n=25,000 subjects, 67 sites 2
INSULIN PUMP USE - CURRENT 100% 80% 60% 61% 62% 66% 60% 56% 65% 62% 58% 40% 20% 0% Overall <6 6-12 13-17 18-25 26-49 50-64 65 Age (years)
INSULIN PUMP USE IS INCREASING 100% 80% 60% 40% Enrolled 9/1/2010-8/1/2012 Current 4/1/2014-4/1/2015 58% 61% 62% 66% 65% 60% 61% 62% 58% 57% 56% 56% 60% 56% 50% 58% 20% 0% Overall <6 6-12 13-17 18-25 26-49 50-64 65 Age (years)
PUMP MANUFACTURER Animas 23% Other 1% Roche 1% Tandem 3% Medtronic 61% Insulet 11%
CONTINUOUS GLUCOSE MONITOR USE 50% 40% 30% 25% 21% 20% 10% 12% 17% 10% 6% 8% 14% 0% Overall <6 6-12 13-17 18-25 26-49 50-64 65 Age (years)
CGM USE IS INCREASING BUT STILL LOW 50% 40% 30% 20% 10% 0% 4% 17% Enrolled 2010-2012 (8% use CGM overall) Current 2014-2015 (12% use CGM overall) 10% 6% 8% 4% 3% 5% 25% 21% 17% 18% 14% 10% <6 6-12 13-17 18-25 26-49 50-64 65 Age (years)
CGM USE BY INSULIN DELIVERY METHOD 50% 40% Pump Injection 30% 23% 32% 28% 20% 10% 0% 18% 14% 12% 11% 9% 6% 10% 9% 2% 1% 3% <6 6-12 13-17 18-25 26-49 50-64 65 Age (years)
LOWER A1C IN INSULIN PUMP USERS 9.5% Injection 9.2% Insulin Pump Mean HbA1c % 9.0% 8.5% 8.0% 7.5% 8.7% 8.2% 8.6% 7.8% 7.5% 7.0% <13 13-25 26 Age (years)
LOWER A1C IN CGM USERS 9.0% Non CGM Users 8.9% CGM Users Mean HbA1c % 8.5% 8.0% 7.5% 8.4% 7.8% 8.1% 7.7% 7.3% 7.0% <13 13-25 26 Age (years)
LOWER A1C IN CGM USERS REGARDLESS OF INSULIN DELIVERY METHOD 9.5% Injection only Injection + CGM 9.3 Pump only Pump + CGM Mean HbA1c % 9.0% 8.5% 8.0% 7.5% 8.7 8.3 7.9 7.8 8.6 8.0 8.1 7.8 7.6 7.2 7.2 7.0% <13 N=3050 13-<26 N=6855 Age (years) 26 N=4077
LOWER A1C WITH INCREASED SMBG (EXCLUDES CURRENT CGM USERS) 10.0% 9.5% Age <18 Pump Injection Age 18 9.0% 8.5% 8.0% 7.5% 7.0% 6.5% 0-3 4-6 6-9 10 SMBG # Per Day 0-3 4-6 6-9 10 SMBG # Per Day
CURRENT PUMPS ON THE USA MARKET
CONTINUOUS MONITORING SYSTEMS IN USA CGMS ipro Recorder Paradigm or Guardian REAL-Time DexCom G5 Platinum
MINIMED CONNECT A better connection to diabetes care For healthcare providers: automatic CareLink uploads For people with diabetes: discreet display of pump and CGM information pump + sensor uploader mobile device any Internet-enabled device For care partners: online access to diabetes information
Dexcom Share/Follow Dexcom G5 Mobile G5 App
Percentage of subjects Change in glycated hemoglobin 80% 60% 40% 20% 0% 0.2 0.0-0.2-0.4-0.6-0.8 CGM Use <4.0 days/week 4.0-<6.0 days/week 6.0 days/week Age 25 Age 15-24 Age 8-14 Change in glycated hemoglobin JDRF CGM Study Group. N Engl J Med 2008; 359:1464-76.
MDT STAR 3 SENSOR-AUGMENTED PUMP TRIAL 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 A1C 8.5% 8.0% 7.5% 7.0% 8.0% 8.0% 8.1% 8.1% 8.3% 7.5% 7.5% 7.5% 7.3% 0 3 6 9 12 Months = SAP = MDI n = 244 n = 241-0.2-0.6-0.6 P<0.001 P<0.001-0.8 Values are means ± SE. Comparisons between SAP group and MDI group are significant for each time period (P<0.001).
A1C Reduction Correlates to Increased Sensor Use 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 Change in A1C at 1 Year vs Baseline 0-0.5-1 -1.5 Frequency of Sensor Use (% of Time) 21-40% 41-60% 61-80% 81-100% -0.19-0.64-0.79-1.21 n =27 n =46 n =108 n =56 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.
SENSOR-AUGMENTED PUMPS IMPROVE A1C WITHOUT INCREASING HYPOGLYCEMIA DCCT (Adolescents & Adults) Severe Hypo Rate: 62.0 per 100 pt-yrs, A1C: 9.0% 7.2% JDRF CGM (Adults, 1 Subject excluded) Severe Hypo Rate: 20.0 per 100 pt-yrs, A1C: 7.6% 7.1% STAR 3 SAP (Pediatrics & Adults) Severe Hypo Rate: 13.3 per 100 pt-yrs, A1C: 8.3% 7.5% 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
FUNDAMENTALS OF CLOSED-LOOP SYSTEMS TS PLGM HCL FCL Subject Burden Regulatory Ease Automation System Complexity
FIRST COMMERCIAL STEP IN THE ARTIFICIAL PANCREAS Threshold Suspend
EXAMPLE OF THRESHOLD SUSPEND CYCLE Automatically suspends insulin delivery if sensor glucose reaches the user-set limit Insulin Suspends for 2 hours / Resumes for 4 hours Insulin infusion stops Suspend time maximum = 2 hrs Basal insulin infusion will resume even if glucose is below Thresh Suspend limit Basal Insulin 2 Hour Suspend Basal Insulin
Threshold Suspend in CareLink Professional Daily Detail Report Threshold Suspend Manual Suspend (Not represented in above report)
THRESHOLD SUSPEND: ASPIRE IN-HOME STUDY 37.5% reduction (p<0.001) 1547 980 1406 1568 The severity and/or duration of nocturnal hypoglycemic events was lower 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.
THRESHOLD SUSPEND: ASPIRE IN-HOME STUDY 30% reduction (p<0.001) 32% reduction (p<0.001) 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.
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.
MDT PATHWAY TO HYBRID CLOSE LOOP 530G System SmartGuard Technology 630G 640G 670G Systems Protection from lows* Takes action when patients need it most *Measured as sensor glucose values
PIVOTAL TRIAL OF A HYBRID CLOSED-LOOP SYSTEM (MDT 670G) IN TYPE 1 DIABETES
INVESTIGATORS Name Richard M. Bergenstal, MD Bruce A. Buckinham, MD Satish Garg, MD Stuart A. Weinzimer, MD Ronald Brazg, MD Jacob Ilany, MD Bruce Bode, MD, FACE Timothy Bailey, MD, FACE Stacey M. Anderson, MD Robert Slover, MD John Shin, PhD, MBA Scott W. Lee, MD Francine R. Kaufman, MD Affiliation and Location International Diabetes Center Minneapolis, MN Stanford University Stanford, CA Barbara Davis Center for Childhood Diabetes Aurora, CO Yale University New Haven, CT Rainier Clinical Research Renton, WA Sheba Medical Center Tel-Hashomer, Israel Atlanta Diabetes Associates Atlanta, GA AMCR Institute Escondido, CA University of Virginia Charlottesville, VA Barbara Davis Center for Childhood Diabetes Aurora, CO Medtronic plc Northridge, 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 76 th 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, closedloop algorithm, and CGM display for the investigational 4 th - 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 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
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 76 th 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 76 th 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 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
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
RESULTS MODAL DAY SENSOR (SG) GLUCOSE TRACINGS Investigational device, not approved for sale or use. Bergenstal R, et al. Poster presented at the 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
RESULTS A1C VALUES AND PROPORTIONS OF NOCTURNAL VALUES 50 MG/DL Investigational device, not approved for sale or use. Bergenstal R, et al. Poster presented at the 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
RESULTS DISTRIBUTION OF A1C VALUES 100% Cumulative Percentage 80% 60% 40% 20% Run- In End of Study 0% 5 6 7 8 9 10 A1C (%) Investigational device, not approved for sale or use. Bergenstal R, et al. Poster presented at the 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
RESULTS KEY ENDPOINTS Investigational device, not approved for sale or use. Bergenstal R, et al. Poster presented at the 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
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 76 th 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 76 th 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 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
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 76 th 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 76 th 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 4 th -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 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
CONCLUSIONS Hybrid closed-loop insulin delivery can help patients reduce hypo- and hyperglycemia and safely achieve ADArecommended 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 1 st to 2 nd quarter 2017 Investigational device, not approved for sale or use. Bergenstal R, et al. Poster presented at the 76 th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.
Path to Closed Loop MDT ALGORITHMS FOR CLOSED LOOP THE PATH TO REDUCING PATIENT BURDEN Current USA Standard Threshold/ Low Glucose Suspend MiniMed 530G System and MiniMed 630G System Suspends delivery when a low occurs Predictive Suspend* Suspends delivery when the system predicts a low is approaching Next Advancemen t Hybrid Closed Loop** Automatically doses insulin with minimal mealtime and exercise inputs from the patient Advanced Hybrid Closed Loop*** Addition of meal detection algorithm, allows for more frontloading of meal insulin and earlier delivery of correction post meal Towards Personalized Closed Loop*** 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 Suspension protocol based on actual values Suspension protocol w/ predictive algorithm PID for insulin delivery & MPC for safety PID for delivery MPC for safety, FL for meals PID, MPC & Fuzzy logic + cognitive computing Partners / Collaborators: *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 LOOP HOW THE COMPANIES LINE UP Group Controller Type Hormone Time Interaction Required 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-Range Hypo-Hyper Minimizer Insulin 24 hour Meals, Exercise
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