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Are We There Yet? Eda Cengiz, MD, MHS Assistant Professor of Pediatrics Yale University School of Medicine Update on Artificial Pancreas Project.

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Presentation on theme: "Are We There Yet? Eda Cengiz, MD, MHS Assistant Professor of Pediatrics Yale University School of Medicine Update on Artificial Pancreas Project."— Presentation transcript:

1 Are We There Yet? Eda Cengiz, MD, MHS Assistant Professor of Pediatrics Yale University School of Medicine Update on Artificial Pancreas Project

2 Artificial Pancreas / Bionic Pancreas ? utilizing electronic devices and mechanical parts to assist humans in performing difficult, dangerous, or intricate tasks, as by supplementing or duplicating parts of the body Artificial intelligence runs the algorithm

3 Sensor signals transmitted to a laptop computer that displays the sensor glucose and calculates rate of insulin delivery Rate of insulin delivery is transmitted to the insulin pump Determine insulin requirement real time, deliver proper insulin to achieve euglycemia. The Promise of Artificial Pancreas Glucose Sensor Algorithm Insulin Pump & Insulin

4 Medtronic Closed-loop System c Insulin Pump CGM Laptop Controller

5 What is taking so long ? During a Typical Clinic Visit at Yale Diabetes Center… How is it going with the Artificial Pancreas Dr. C? When is it going to be ready?

6 Challenges & Solutions: Artificial Pancreas (Closed-Loop System ) Glucose Sensors Insulin Delivery Algorithm Insulin Pumps Insulin (ultrafast action) Progress to date Pitfalls Solutions Future closed-loop studies (hot off the press!)

7 JDRF Road Map to Artificial Pancreas What is the plan?

8 Artificial Pancreas Do we need to wait until we have the Fully Automated Artificial Pancreas?

9 Artificial Pancreas Progress to date SENSOR-AUGMENTED PUMP THERAPY

10 CGM improved A1c, but not in everyone p=0.29p=0.52p<0.001 JDRF CGM Study Group. N Engl J Med 2008; 359:

11 Average Days of CGM Use by Age Group JDRF CGM Study Group. N Engl J Med 2008; 359:

12 Bergenstal RM, Tamborlane WV, Ahmann A, et al. N Engl J Med. Doi: /NEJMoa Medtronic 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= SAP n = 244n = P< P<0.001

13 Bergenstal RM, Tamborlane WV, Ahmann A, et al. N Engl J Med. Doi: /NEJMoa 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 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 n =27n =46n =108n =56

14 DirecNet / TrialNet Metabolic Control Study Does the rapid normalization of BG levels at the time of diagnosis of diabetes, followed by super- intensive control of BG levels, help to preserve residual beta-cell function? Use of an artificial pancreas in subjects AT DIAGNOSIS for 3-4 days to rapidly normalize BG levels, followed by sensor-augmented pump therapy x 2 years

15 Sensor and BG Levels During CL Therapy

16 Mean Sensor Glucose Levels Prior to, During, and Following CL Therapy

17 3 mth f/u: A1c = 5.9 % 6 wk f/u

18 6 mth f/u: A1c = 6.0 % typical tracing 12 mth f/u: A1c = 6.3 %

19 Artificial Pancreas Progress to Date SENSOR-AUGMENTED PUMP THERAPY PUMP SUSPENSION FOR ACTUAL HYPOGLYCEMIA

20 Prevention of Hypoglycemia with AP Insulin suspension prevented low BG (<60mg/dl) in 78% of the suspensions. Non resulted in hyperglycemia Reduction in CGM hypoglycemia alarms

21 A Semi-Closed-Loop System: The Paradigm® Veo * Integrated sensor Improved Calibration Routines Glucose trend Alarms –Outside target zone –Predictive –Missing insulin bolus Minimum basal rate of U/h Hypoglycemia suspend –Suspend for 2 hours –Re-suspend after 4 hours if needed * Investigational device. Limited by U.S. law to investigational use. Keenan et al., J. Diabetes Sci. Tech., 2010; 4(1): Buckingham et al., Diabetes Technol. Ther., 2009; 11:93-97 Attia et al., Diabetes Care, 1998; 21: Guerci et al., J Clin Endocrinol Metab, 1999; 84: Zisser, Diabetes Care, 2008; 31:

22 S L I D E 22 Automatic Low-Glucose Suspend LGS offLGS on Mean Glucose (mg/dL)145 ± ± 19 Time < 70 per day (min)101 ± ± 33 * Time > 140 per day (min)651 ± ± 182 Number of excursions < 70 and < 40 mg/dL reduced with LGS * p=0.002 Danne T, Diabetes Technol Ther 2011; 13:

23 Artificial Pancreas SENSOR-AUGMENTED PUMP THERAPY PUMP SUSPENSION FOR ACTUAL HYPOGLYCEMIA PUMP SUSPENSION FOR PREDICTED HYPOGLYCEMIA Progress to Date

24 Automatic pump suspension for predicted hypoglycemia

25 Exercise AP Study objective To evaluate whether use of a AP system reduces the risk of delayed (nocturnal) hypoglycemia following antecedent daytime exercise

26 Subject recruitment, consent, enrollment (n = 12) Closed-Loop Open-Loop Closed-Loop Exercise Study Protocol Schematic 48-hour evaluation period 2 overnights 48-hour evaluation period 2 overnights Plasma BG q30 min, insulin q30 min x meals

27 Nocturnal Hypoglycemia Closed Loop Open Loop All Nocturnal Hypo Number of Treatments Given p= Night Following Exercise p=0.06

28 Glucose Frequency Distribution Night after sedentary condition 1 %99 % 0% 3 %90 % 7 % P<0.0001

29 3 %93 %4 % 8 %76 %16 % P< Glucose Frequency Distribution Night following afternoon exercise

30 Artificial Pancreas SENSOR-AUGMENTED PUMP THERAPY PUMP SUSPENSION FOR ACTUAL HYPOGLYCEMIA PUMP SUSPENSION FOR PREDICTED HYPOGLYCEMIA BASAL/BOLUS ACTIVATION FOR HYPERGLYCEMIA Progress to Date

31 Conceptual Scheme for Treat-to-Range

32

33 Artificial Pancreas Progress to Date SENSOR-AUGMENTED PUMP THERAPY PUMP SUSPENSION FOR ACTUAL HYPOGLYCEMIA PUMP SUSPENSION FOR PREDICTED HYPOGLYCEMIA BASAL/BOLUS ACTIVATION FOR HYPERGLYCEMIA CLOSED-LOOP BASAL MANUAL MEALS

34 Studies of Overnight CL Increased time in target BG Reduction of hypoglycemia Incorporation of daytime challenges –Exercise –Alcohol –Pregnancy

35 Hybrid control improves performance 6ANoon6PMidN6ANoon6P Closed Loop (N=8) meals setpoint Hybrid CL (N=9) Glucose (mg/dl) MeanDaytimePeak PP Full CL Hybrid Weinzimer SA. Diabetes Care 2008; 31:

36 Late post-prandial hypoglycemia in CL

37 Artificial Pancreas Progress to date SENSOR-AUGMENTED PUMP THERAPY PUMP SUSPENSION FOR ACTUAL HYPOGLYCEMIA PUMP SUSPENSION FOR PREDICTED HYPOGLYCEMIA BASAL/BOLUS ACTIVATION FOR HYPERGLYCEMIA CLOSED-LOOP MULTIHORMONAL FULL CLOSED-LOOP CONTROL CLOSED-LOOP BASAL MANUAL MEALS

38 AP Multi-hormonal Approach Can the addition of pramlintide improve the performance of a CL system by reducing the peak post-prandial glucose excursions?

39 Pramlintide Analog of human amylin Co-secreted with insulin from -cell Used as adjunct to insulin in T1D to reduce post- prandial glycemic excursions –Delay gastric emptying –Suppress endogenous glucagon

40 Subject recruitment, consent, enrollment (n = 8) Closed-Loop Closed-Loop + Pramlintide (30 mcg per meal) Closed-Loop + Pramlintide (30 mcg per meal) Closed-Loop Pramlintide Study Protocol Schematic 24-hour evaluation period 3 meals (BF, L, Din) 24-hour evaluation period 3 meals (BF, L, Din) Plasma BG q30 min, insulin q30 min x meals

41 Glucose excursions with/without pramlintide

42 Summary and conclusions Pramlintide had modest effect on prandial glucose Would require manual injection or at best, manual bolus Faster insulin absorption / action clearly needed

43 Artificial Pancreas Progress to date SENSOR-AUGMENTED PUMP THERAPY PUMP SUSPENSION FOR ACTUAL HYPOGLYCEMIA PUMP SUSPENSION FOR PREDICTED HYPOGLYCEMIA BASAL/BOLUS ACTIVATION FOR HYPERGLYCEMIA CLOSED-LOOP MULTIHORMONAL FULL CLOSED-LOOP CONTROL CLOSED-LOOP BASAL MANUAL MEALS ?

44 What do we need to achieve AP? Better accuracy, user interface, reliability. Better algorithm One site for CGM & Insulin Glucose Sensors Insulin Delivery Algorithm Insulin Pumps Insulin (ultrafast action)

45 Single Port, Multiple Sensor One site, two catheters for insulin infusion and glucose sensing Single port for CGM and insulin CGM with an optic sensor back up

46 What do we need to achieve AP? Better accuracy, user interface, reliability. Better algorithm One site for CGM & Insulin Faster acting insulin Glucose Sensors Insulin Delivery Algorithm Insulin Pumps Insulin (ultrafast action)

47 Dangerous Delays in Insulin Action after SC Injection 1. Delays due to the chemical properties of insulin. 1. Tissue delays

48 Insulin Time-Action Curves

49 The InsuPatch TM device applies controlled heat around the insulin infusion site. InsuPatch Temp. Sensor

50 with InsuPatch activation: Aspart insulin bolus maximum effect was 35 min earlier compared to the same dose bolus without InsuPatch activation. Peak aspart insulin action curve shifted to the left. The Effect of InsuPatch on Insulin Action

51 51 Hyaluronidase Mechanism of Action

52 The Accu-Chek DiaPort is a port system for continuous intraperitoneal insulin infusion. DiaPort The catheter tip is placed in the peritoneal cavity where the insulin is directly infused. Fixation disc Port body Polyester Felt Membrane Catheter Infusion set with ball cannula

53 Pathway to Closed-Loop (CL) Closed Loop studies at Yale InsuPatch CL studies in France, ? in US DiaPort CL studies are planned. Hyaluronidase (rhUPH20)

54 Pump Platform and Connectivity for Ambulatory Studies

55 Artificial Pancreas Progress to date SENSOR-AUGMENTED PUMP THERAPY PUMP SUSPENSION FOR ACTUAL HYPOGLYCEMIA PUMP SUSPENSION FOR PREDICTED HYPOGLYCEMIA BASAL/BOLUS ACTIVATION FOR HYPERGLYCEMIA CLOSED-LOOP MULTIHORMONAL FULL CLOSED-LOOP CONTROL CLOSED-LOOP BASAL MANUAL MEALS ? Outpatient studies

56

57 The Dream Study

58 Thank you! Yale Closed Loop Team –Stu Weinzimer –Jennifer Sherr –William Tamborlane –Grace Kim –Miladys Palau –Camille Michaud –Lori Carria –Amy Steffen –Kate Weyman –Melinda Zgorski –Eileen Tichy


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