What is a CGM? (Continuous Glucose Monitor) The Bionic Pancreas Is Coming

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1 The Bionic Pancreas Is Coming Montana Diabetes Professional Conference October 23, 2014 H. Peter Chase, MD Professor of Pediatrics University of Colorado Barbara Davis Center Stanford: Bruce Buckingham, Darrell Wilson UCSB: Frank Doyle, Eyal Dassau Rensselaer Polytechnic Institute: Wayne Bequette, Hyunjin Lee, Fraser Cameron JAEB: Roy Beck, John Lum, Craig Kollman, Judy Sibayan Disclosure- Research Grant from DexCom 1 Q: What is an Artificial ( Bionic ) Pancreas? (also known as closed-loop pancreas ) Answer: An insulin pump, continuous glucose monitor (CGM) and a receiver with algorithms to regulate insulin output based on the CGM glucose values. 2 What is a CGM? (Continuous Glucose Monitor) A device that provides real-time glucose readings from a sensor embedded in skin. Reads the glucose levels every 1-5 minutes ( 10 minute delay behind blood glucose) Provides alarms for high and low glucose levels and trend information The 3rd era in diabetes management 3 1

2 Who Should Use a CGM? 1) Children AND parents must both want a CGM 2) Willing to wear the sensor (and carry the receiver) 3) Practices good diabetes care (4 BGs/day) 4) Good support system 5) Adequate body real estate 6) Can afford ongoing cost 4 Three Parts to All CGMs: A. Sensor B. Transmitter C. Receiver/Monitor 5 A)Sensor 6 2

3 B)Transmitter 7 C)Receiver or Monitor 8 What type of data will we get? 1) Real-time (Immediate) feedback Trend graphs Glucose alerts Trend arrows Barbara Davis Center 9 3

4 Trend Graphs Trend graphs Knowing a glucose level is 240 mg/dl may not be as important as knowing the trend. Rate of Change Arrows and Alerts Glucose rising quickly >2 (mg/dl)/min Glucose rising 1 to 2 (mg/dl)/min Stable glucose -1 to 1 (mg/dl)/min Glucose falling -1 to -2 (mg/dl)/min Low glucose alert Glucose falling quickly >-2 (mg/dl)/min Second type of data: (Retrospective, must download) 2) Retrospective Data A.Sensor overlays B.Charts and graphs C.Data Tables 12 4

5 A) Sensor Overlay Tracings of Individual Days 13 B) Charts and graphs BG, Carbs, Bolus Amount and LGS 14 C) Low Glucose Suspend and Bolus History 15 5

6 USE OF CGM RESULTS: Fine-tuning of Diabetes Management Important not to overwhelm families *** 1-2 insulin changes at a time *** Look for patterns 3 out of 4 days Can identify behavior issues: missed boluses, snacking, exercise, etc Do not make changes too often 16 WHY use CGM? 1. Prevention of high blood sugars 2. Prevention of low blood sugars 3. Minimize wide glucose fluctuations 4. Behavior Modification 5. Prevention of Complications (?) 17 Snapshot of BG levels 18 6

7 Continuous Glucose Monitoring 19 50% 40% Hyperglycemia is common, especially after meals 30% 20% Breakfast Lunch Dinner 10% 0% < > 300 Barbara Davis Center Boland et al, Diabetes Care 24:1858, WHY USE CGM? 1. Prevention of high blood sugars 2. Prevention of low blood sugars ***most helpful with artificial pancreas*** 3. Minimize wide glucose fluctuations 4. Behavior Modification 5. Prevention of Complications (?) 21 7

8 INSULIN PUMP and CGM COMBINED (Sensor Augmented Pump [SAP]) Major Clinical Studies in the Past Five Years 1) JDRF: MDI or CSII Half randomized to use CGM (NEJM 359, 1464, 2008) 2) Star 3: MDI Half randomized to insulin pump (CSII) plus CGM (sensor augmented pump or SAP) (NEJM 363:311, 2010) 3) Bionic- closed loop pancreas I) Low-Glucose Suspend (LGS) II) ASPIRE: In Clinic and In-Home Studies: US III) Predicted Low Glucose Suspend 22 Use of Continuous Glucose Monitoring (CGM) With Pump or MDI JDRF-RCT (NEJM 359:1464,2008) 322 (of 451) subjects 8-69 yo on CSII or MDI 10 Centers/JAEB coordination Randomized to CGM or Control x 6 mo 23 JDRF Cohort with HbA1c 7.0% (NEJM 359:1464,2008) Primary outcome = in 6 mo Found only in subjects > 25 yo (p < 0.001) CGM: , vs Control: Secondary endpoints (CGM vs. Control group > 25 yo) i) in A1c > 10% (p = ) ii) A1c < 6 mo (p = 0.005) iii) More time in mg/dl range (p < 0.001) 24 8

9 Conclusions: CGM is good if it is used! 1) Use of Insulin pump + CGM (SAP) reduces HbA1c > MDI (STAR-3) 2) CGM lowers HbA1c for patients on pump or MDI if the CGM is used 6 days/week (JDRF study) 3) Next: Three studies to demonstrate reduction of hypoglycemia with bionic pancreas: i) Low Glucose Suspend (LGS) in clinic ii) LGS at home iii) Predictive Low Glucose Suspend (PLGS) (NEJM 363:311, 2010) STAR 3 was a large-scale, multicenter, randomized, controlled trial of 485 patients, ages 7 to 70 years, with T1D at 30 Centers 26 Results Over Time: 485 Patients 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 = SAP = MDI n = 244 n = 241 Values are means ± SE. Comparisons between SAP group and MDI group are significant for each time period (P<0.001). 27 9

10 A1C Reduction is Correlated with Increased Sensor Use The majority of patients used sensors >60% of the time Patients who used sensors 81% of the time reduced their mean A1C by 1.2% at 1 year vs. baseline 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 at 1 year vs. baseline. 28 I. Hypoglycemia Prevention with Use of Low Glucose Suspend (LGS) in Sensor-Augmented Pumps (SAP) Source Patients/ Methods Results 21 youth with T1D from 3 centers in Germany 2 wks=sap 4 wks=sap with LGS Danne, T. et al., Diab. Tech. Ther. 13, 1129, 2011 Choudhary, P. et al., Diabetes Care 34, 2023, 2011 Agrawal, P. et al., J. Diab. Sci Tech. 5, 1137, adults with T1D in. 2 wks=sap 3 wks= SAP with LGS 935 patients 28,401 pt days/278 pts. > 3mos LGS feature in Real World SAP with LGS= 1) No SH or DKA 2) Decrease time spent (and decrease number of episodes) <70mg/dL 3) Positive device satisfaction SAP with LGS= 1) No deterioration of glucose control 2) time of nocturnal hypoglycemia in those with highest quartile of hypoglycemia at baseline 3) All subjects found LGS useful and 93%= (more secure at night) 1) Sensor 2 hours=150±69 mg/dl 2) Significant reduction in BG values < 50 mg/dl when LGS in use (p < 0.001). Summary: in initial studies, time spent in hypoglycemia is reduced as a result of the use of the LGS feature. 29 ASPIRE: I. Randomized Trial of LGS after Exercise in Clinic 10

11 ASPIRE In-Clinic Study: Results Mean YSI Glucose Values by Time for LGS On and LGS Off Sessions Garg S, Brazg RL, Bailey TS, et al. Diabetes Technol Ther. 2012;14: ASPIRE In-Clinic Study: Results Duration and Severity of Hypoglycemia Duration of hypoglycemia (minutes) Nadir (mg/dl) End-Observation YSI (mg/dl) LGS On ± ± ± LGS Off ± ± ± P < % CI to Mean + SD Garg S, Brazg RL, Bailey TS, et al. Diabetes Technol Ther. 2012;14: c Threshold Suspend Control 247 patients were randomized to low glucose (threshold) suspend or control arms for a 3 month study. Age 41.6 ± ± 13.8 % Male Diabetes Duration 27.1 ± ± 12.7 BMI, kg/m ± ± 4.3 Bergenstal RM, Klonoff DC, Garg SK et al. N Engl J Med 2013; 369:

12 ASPIRE In-Home Study: Reduction in Nocturnal Hypoglycemia (Bergenstal RM, Klonoff DC, Garg SK et al. N Engl J Med 2013; 369: ) 38% reduction p< (2035) 980 (1200) 1406 (1950) 1568 (1995) Mean AUC of Nocturnal Hypoglycemia events was 38% lower in the Threshold Suspend Group. Similar A1c values at the End of the Study Similar Benefits in Children and Young Adults 34 ASPIRE In-Home Study: Percentage of time that SG values were in the <50, 50 to <60, and 60 to <70 mg/dl ranges. Bergenstal, Klonoff, Garg et al: NEJM II. Hypoglycemia Prevention With Use of Predictive Low Glucose Suspend (PLGS) A) Two day admissions to CRC 1) Use of Navigator CGM 2) Increase basal rate up to 180% 3) No PLGS=85% low (BG <60mg/dL; <2.2mmol/L) 4) With PLGS=28% low Diabetes Care 2010, 33:

13 II. Predictive Low Glucose Suspend (PLGS) 37 B. Initial outpatient (in-home) PLGS studies Use of MiniMed and Paradigm Real-time Revel System 21 night randomized trial with PLGS on or off (2:1) PLGS occurred on 53% of 77 intervention nights Hypoglycemia (<70mg/dL; [<3.9mmol/L]) occurred in 16% of PLGS nights versus 30% of control nights 38 System Description 39 13

14 C) Home Study: 2000 nights Demographics Value Age (yr) median (15-45 years) 30 (22, 39) Male / Female 21 / 24 Race White non-hispanic 42 (93%) Hispanic 2 (4%) Black 1 (2%) Weight (kg) median (IQR) 70 (62, 85) Height (cm) median (IQR) 172 (163, 178) Body-mass index (BMI) median (IQR) 24 (22, 27) Glycated hemoglobin (%) median (IQR) 6.8 (6.4, 7.6) Diabetes duration (yr) median (IQR) 15 (12, 26) Daily insulin dose (U/day) median (IQR) 45 (32, 60) 40 Predictive Low Glucose Suspend (PLGS) Home Study Randomization Did not meet hypoglycemia criteria N=4 Enrolled N= 50 Randomized 45 participants 2,007 nights Did not meet complete system use criteria N=1 Control 1,002 nights Intervention 1,005 nights <4 hrs of CGM data 32 nights Analyzed 970 nights Analyzed 942 nights <4 hrs of CGM data 63 nights Study Results 41 Safety Rules 1. Suspend for no more than 120 out of every 150 minutes. 2. Suspend for no more than 180 min/night. 3. Do not suspend when the glucose is rising 4. Suspend if CGM<70 mg/dl 5. Do not suspend if the CGM is above 230 mg/dl. 6. Do not suspend if the CGM is dropping by more than -8 mg/dl/min. Algorithm Description 42 14

15 Example Plot Figure 1. Sample overnight data profile for intervention night System Description 43 Overall Results Control 45 Participants Intervention 45 Participants P-value 125 (98, 163) 132 (110, 163) <0.001 Overnight Mean Glucose median (IQR) Percentage of glucose between % (46%, 82% (54%, <0.001 mg/dl median (IQR) 93%) 99%) Morning BG mg/dl a median (IQR) 129 (96, 173) 144 (114, 186) <0.001 % mornings with BG 60 mg/dl 4% <1% < mg/dl 9% 2% < mg/dl 70% 70% 0.82 >180 mg/dl 21% 27% >250 mg/dl 6% 6% 0.83 mornings w/ blood ketone >1 mmol/l b 0.3% 0.1% 0.62 c mornings w/ urine ketones 15 mg/dl d 2% 3% 0.07 a 1 morning blood glucose measurement in the control arm was missing b 9 blood ketone measurements in the control arm and 10 blood ketone measurements in the intervention arm were missing c P value computed using Fisher s exact test, which does not account for the correlated data. Too few events (3 in control arm vs. 1 in intervention arm) to detect any significant difference. d 12 urine ketone measurements in the control arm and 12 urine ketone measurements in the intervention arm were missing 44 Overall Results Control Intervention 45 Participants 45 Participants P-value # Nights Bedtime BG mg/dl median (IQR) 152 (114, 197) 144 (115, 195) # measurements per night 96 (84, 110) 96 (85, 107) % nights with >1 value 60 mg/dl 33% 21% <0.001 % nights with >1 value 50 mg/dl 19% 10% <0.001 % nights with >1 value 70 mg/dl 45% 32% <0.001 Low blood glucose index median (IQR) 0.7 (0.0, 3.5) 0.4 (0.0, 1.8) <0.001 % nights with >1 value >250 mg/dl 20% 20% 0.93 % nights with >1 value >180 mg/dl 57% 59% 0.17 % nights with >1 value >300 mg/dl 5% 6% 0.37 High blood glucose index median (IQR) 1.9 (0.3, 6.2) 2.4 (0.5, 6.5) <

16 Hypo and Hyperglycemia Control N=45 Participants Intervention N=45 Participants P-value # Nights Hypoglycemia % nights with glucose 60 mg/dl for > 30 min 24% 12% <0.001 > 60 min 18% 8% <0.001 > 120 min 11% 3% <0.001 > 180 min 8% 1% <0.001 Hyperglycemia % nights with glucose >250 mg/dl for > 30 min 12% 13% 0.80 > 60 min 9% 8% 0.74 > 120 min 5% 6% Outpatient Glucose Levels Percent of nights with a CGM 60 mg/dl at a given time (dashed lines) 47 Pump Suspension Duration # Nights 942 Nights with Pump Suspension All durations 719 (76%) 1 30 min 185 (20%) min 114 (12%) min 262 (28%) >120 min 158 (17%) Shutoff Duration Per Night (minutes) a median (IQR) 71 (29, 115) a Restricted to 719 nights with at least one pump suspension

17 Morning Blood and Urine Ketones Control N=45 Participants Intervention N=45 Participants # Mornings Morning Measures % mornings with a blood ketone a 0 mmol/l 14% 14% 0.1 mmol/l 64% 63% mmol/l 19% 20% mmol/l 2% 2% 0.7 mmol/l 0.6% 0.6% % mornings with a urine ketone b 40 mg/dl 0.7% 0.2% 80 mg/dl 0.1% 0 a-9 blood ketone measurements in the control group and 10 blood ketone measurements in the intervention group were missing b-12 urine ketone measurements in the control arm and 12 urine ketone measurements in the intervention arm were missing 49 Summary Bionic or Artificial Pancreas (AP) I. Low Glucose (Threshold) Suspend (LGS) - a reality II. Predictive Low Glucose Suspend (PLGS) - Will still need Phase III clinical trials III. Overnight Glucose Control - Studies in progress throughout the world IV. Complete AP - Studies in progress/other advances needed THANK YOU 17