PREVENTION OF NOCTURNAL HYPOGLYCEMIA USING PREDICTIVE LOW GLUCOSE SUSPEND (PLGS)

Transcription

1 PREVENTION OF NOCTURNAL HYPOGLYCEMIA USING PREDICTIVE LOW GLUCOSE SUSPEND (PLGS) Pathways for Future Treatment and Management of Diabetes H. Peter Chase, MD Carousel of Hope Symposium Beverly Hilton, Beverly Hills, CA October 11, 2014 No Pertinent Disclosures 1

2 Severe Hypoglycemia 1. Nocturnal Severe Hypoglycemia i) DCCT = 55% (Diabetes Care, 18:1415, 1995) ii)davis, et al 75% (Diabetes Care, 20:22, 1997) 2. Incidence of Severe Hypoglycemia i) General peds diabetes clinic: 19/100 patient years (Rewers, Chase, et al: JAMA 287:2511, 2002) ii) JDRF-RCT (CSII or MDI): 17.9/100 patient years (N Engl J Med 359:1464, 2008) iii) Star 3 (CSII + CGM) 495 patients = 13.3/100 patient years (N Engl J Med, 363:311, 2010) 2

3 Incidence of Severe Hypoglycemia per 100 Patient Years- T1D Exchange (Helmsley) (26,000 patients with T1D from 70 diabetes clinics in US) Garg S, et al. Presented at 5 th International Conference on Advanced Technologies & Treatment for Diabetes, Barcelona,

4 Mean HbA 1c by Age Group Type 1 Diabetes Exchange Registry (Helmsley) Bergenstal R, et al. Presented at 5 th International Conference on Advanced Technologies & Treatment for Diabetes, Barcelona, 2012.

5 PREVENTION OF HYPOGLYCEMIA IS A KEY TO IMPROVED GLYCEMIC CONTROL Development of the Artificial Pancreas (AP) will be necessary for the prevention of hypoglycemia. I. Low Glucose Suspend (LGS) II. Predictive Low Glucose Suspend (PLGS) III. Overnight AP Glucose Control IV. Complete AP

6 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. 6

7 ASPIRE: In Clinic Study I. Randomized Trial of LGS after Exercise in Clinic (Garg S, Brazg RL, Bailey TS, et al. Diabetes Technol Ther. 2012;14: )

8 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: )

9 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:

10 Threshold Suspend Control ASPIRE- Home Study 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:

11 ASPIRE In-Home Study: Reduction in Nocturnal Hypoglycemia (Bergenstal RM, Klonoff DC, Garg SK et al. N Engl J Med 2013; 369: ) Mean AUC of Nocturnal Hypoglycemia Events AUC (mg/dl min) (2035) 980 (1200) 38% reduction TS compared to Control p< (1950) 1568 (1995) Run-In Phase Study Phase Threshold Suspend Control 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 11

12 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

13 II. Predictive Low Glucose Suspend (PLGS) Studies: Initial CRC Studies Diabetes Care 2010, 33: Two day admissions to CRC Use of Navigator CGM Increase basal rate up to 180% RESULTS: SG <60 mg/dl (<2.2 mmol/l): PLGS System ON: 28% PLGS System OFF: 85% 13

14 Example Plot: Predictive Low Glucose Suspend (PLGS) 14

15 Algorithm Description 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. 15

16 Initial outpatient (in-home) safety study 19 pts, ages 18 to 56 yrs with T1D 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 16% of PLGS nights versus 30% of control nights

17 System Description Overall System 17

18 PLGS: Outpatient Study Randomization Flowchart of patients and randomized nights 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 <4 hrs of CGM data 32 nights Control 1,002 nights Intervention 1,005 nights <4 hrs of CGM data 63 nights Analyzed 970 nights Analyzed 942 nights Study Results 18

19 Demographics (N=45; yo) PLGS: Outpatient Study Characteristic Value Age (yr) median (IQR) 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) 19

20 Example Plot PLGS: Outpatient Study Figure 1. Sample overnight data profile for intervention night System Description 20

21 Overall Results: 1,912 nights PLGS Study: Outpatient Study Control 970 Nights Intervention 942 Nights P- value Overnight Mean Glucose median 125 (98, 163) 132 (110, 163) <0.001 (IQR) Percentage of glucose between % (46%, 82% (54%, <0.001 mg/dl median (IQR) 93%) 99%) Morning BG mg/dlmedian (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%

22 Duration of Hypo and Hyperglycemia PLGS: Outpatient Study Control 970 Nights Intervention 942 Nights P-value Participants 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%

23 Duration of Pump Suspension PLGS: Outpatient Study # 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) * median (IQR) 71 (29, 115) *Restricted to 719 nights with at least one pump suspension. 23

24 Overall Results PLGS: Outpatient Study Control 970 Nights Intervention 942 Nights P-value Participants 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 50 mg/dl 19% 10% <0.001 % nights with >1 value 60 mg/dl 33% 21% <0.001 % nights with >1 value 70 mg/dl 45% 32% <0.001 % nights with >1 value >180 mg/dl 57% 59% 0.17 % nights with >1 value >250 mg/dl 20% 20% 0.93 % nights with >1 value >300 mg/dl 5% 6%

25 Morning Blood Ketones vs. Insulin Pump Suspension/ Control Nights PLGS: Outpatient Study Morning Blood Ketones (Precision Meter) System Active All Nights (N=977) System Active 1 Suspension (N=744) (99%) 733 (99%) 966 (99%) (<1%) 4 (<1%) 5 (<1%) (<1%) 2 (<1%) 2 (<1%) (<1%) 1 (<1%) 1 (<1%) (<1%) 1 (<1%) 1 (<1%) (<1%) 2 (<1%) 1 (<1%) (<1%) 1 (<1%) 1 (<1%) System Not Active All Nights (N=977)

26 Morning Urine Ketones vs. Insulin Pump Suspension/Control Nights PLGS: Outpatient Study Morning Urine Ketones System Active All Nights (N=977) System Active 1 Suspension (N=744) Negative 875 (90%) 656 (88%) 901 (92%) System Not Active All Nights (N=977) Trace 75 (8%) 64 (9%) 57 (6%) Small 25 (3%) 22 (3%) 12 (1%) Moderate 2 (<1%) 2 (<1%) 6 (<1%) Large 0 (0%) 0 (0%) 1 (<1%)

27 Summary Artificial Pancreas (AP) PLGS: Outpatient Study 1. Hypoglycemia (<60 mg/dl) lasting >2 hrs was decreased by 74% 2. The AUC <60 mg/dl was 81% lower with PLGS nights compared to control nights 3. Overnight mean glucose was higher with PLGS nights (median=132 mg/dl [7.3 mmol/l]) versus control nights (125 mg/dl [6.9 mmol/l]) 4. Median AM BG was 144 mg/dl (7.9 mmol/l) with PLGS and 129 mg/dl (7.2 mmol/l) for control nights 5. The likelihood of developing ketones with 120 to 180 minutes of pump should not be required in future similar suspension studies.

28 Future Studies 1) PLGS in yo age group 2) PLGS in 7-13 yo age group 3) PLGS in 3-6 yo age group 4) PLGS Pump Suspension with Hyperglycemia Minimization (PHM-1) Studies Thank You 28

29 Incidence of Biochemical Nocturnal Hypoglycemia JDRF Randomized Clinical Trial: 180 subjects with T1D Use of Navigator or Paradigm RT Systems: 36,000 nights, 2.4 million CGM readings. Frequency of Nocturnal Hypoglycemia 70 mg/dl 60 mg/dl 50 mg/dl ( 3.9 mmol/l) ( 3.3 mmol/l) ( 2.8 mmol/l) % of nights Single value hypoglycemic 25% 15% 7.6% 2 consecutive values hypoglycemic 23% 13% 6.7% 20 consecutive minutes hypoglycemic 18% 9.6% 4.5% 60 consecutive minutes hypoglycemic 9.7% 4.6% 2.0% Two predictors: Lower HbA1c and hypoglycemia on blinded baseline CGM JDRF-RCT: Diabetes Care, 33:1004,

30 PLGS: Outpatient Study Outpatient Glucose Levels Figure 4. % of nights with a CGM 60 mg/dl at a given time (dashed lines) 30

31 Nocturnal Severe Hypoglycemia (SH) Incidence: 55% of SH in DCCT (Diabetes Care 18,1415,1995) 75% of SH in children (Davis, Diabetes Care 20:22,1997) Causes: 1) Strenuous daytime exercise 2) Attenuated glucagon and epinephrine responses a. Particularly at night b. Particularly with antecedent hypoglycemia or prior exercise c. Reduced cognition: 71% of youth failing to respond to nocturnal alarms (Buckingham, Chase et al. DT&T, 7,440,2005) 3) Lower HbA1C 4) Wrong insulin dose 31

32 Mean HbA 1c by Age Group Type 1 Diabetes Exchange Registry (Helmsley) Bergenstal R, et al. Presented at 5 th International Conference on Advanced Technologies & Treatment for Diabetes, Barcelona,

33 Effect of Exercise Mean Glucose Level on Two Study Days (Same 50 Subjects) Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. DirecNet: J Pediatr, 2005 Oct; 147(4):

34 Decreased Epinephrine Responses in Children with T1D Subjects: 14 children 4-7 yo; duration 3.3 years 14 adolescents yo; duration 6.6 years No epinephrine response (>3SD above baseline) to insulininduced hypoglycemia (<60 mg/dl [<3.3 mmol/l]) 9 of 14 young children (average pg/ml) 8 of 14 adolescents (average pg/ml) 14 nondiabetic adolescents increased from 77 to 582 pg/ml in response to hypoglycemia Glucagon levels did not increase with hypoglycemia in young children or adolescent subjects with T1D (DirecNet, Diabetes Care, 32:1954, 2009) 34

35 ASPIRE: I. Randomized Trial of LGS after Exercise in Clinic

36 PLGS to prevent BG <60mg/dL (<2.2mmol/L) 22 subjects with 2 daytime admissions to CRC Navigator CGM Algorithm development: 80mg/dL threshold 30 minute projection: 60% prevention 45 minute projection: 80% prevention 36

37 37

38 Kalman Filter Look at all times after rule is active Activated times affecting 218 days ID# Morning BG Mean CGM % time < 70 % time > 180 mg/dl Risk With without Effect of Rule Simulated Effect of Algorithm Rules 38

39 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 39