Reduction in Hypoglycemia and No Increase in A1C with Threshold-Based Sensor-Augmented Pump (SAP) Insulin Suspension: ASPIRE In-Home

Reduction in Hypoglycemia and No Increase in A1C with Threshold-Based Sensor-Augmented Pump (SAP) Insulin Suspension: ASPIRE In-Home Richard M. Bergenstal 1, David C. Klonoff 2, Bruce W. Bode 3, Satish Garg 4, Andrew Ahmann 5, Robert Slover 4, Melissa Meredith 6, Francine R. Kaufman 7, ASPIRE In-Home Study Group Late Breaking Poster 48 Available Saturday June 22 at 10 AM Presented Sunday June 23 at Noon 2PM 1, International Diabetes Center at Park Nicollet, Minneapolis, MN; 2, Mills-Peninsula Health Services, San Mateo, CA; 3, Atlanta Diabetes Associates, Atlanta, GA; 4, Barbara Davis Center for Childhood Diabetes, Aurora, CO; 5, Oregon Health and Sciences University, Portland, OR; 6, University of Wisconsin, Madison, WI; 7, Medtronic, Inc., Northridge, CA

Published on June 22, 2013 at NEJM.org N Engl J Med 2013 DOI: 10.0156/NEJMoa1303576

Reducing the Risk of Complications Intensive Glycemic Control in Type 1 Diabetes Rate of Retinopathy (per 100 patient-years) 12 10 8 6 4 2 0 6 7 8 9 10 11 120 100 80 60 40 20 0 Severe Hypoglycemia (per 100 patient-years) A1C (%) The Diabetes Control and Complications Research Group N Engl J Med 329:977, 1993

Bergenstal RM, Tamborlane WV, Ahmann A et al. N Engl J Med. 2010;363:311-320. Highlights from the American Diabetes Association 70 th Scientific Sessions l October 2010 l 4

STAR 3 Two Therapy Groups Multiple Daily Injections (2 types of insulin) Sensor- Augmented Pump Presented at ADA 2010 and published NEJM 2010

STAR 3: A1C at 3, 6, 9, 12 months: All Patients 8.0% 7.3% 8.1% 8.1% 8.0% 7.5% 7.5% 7.5% Values are means ± SE. Asterisks denote P<0.001 for comparisons between SAP group and MDI group at each time point. Adapted from Bergenstal RM, Tamborlane WV, Ahmann A et al. N Engl J Med. 2010;363:311 320.

Severe Hypoglycemia and A1C DCCT (1993), JDRF (2008), STAR 3 (2010) & ASPIRE in Home (2013) Studies Severe Reaction Every: 1.6 yrs. DCCT (intensive therapy): 62 per 100 pt-yrs, A1C(6.5 yr): 9.0% 7.2% 5 yrs. 7.5 yrs. JDRF CGM (adults, 1 subject excluded): 20.0 per 100 pt-yrs; A1C (6 mo): 7.5% 7.1% STAR 3 MDI (all ages): 13.5 per 100 pt-yrs; A1C (1 yr): 8.3% 8.1% STAR 3 SAP (all ages): 13.3 per 100 pt-yrs; A1C (1 yr): 8.3% 7.5% None Ideal Adapted from Figure 5B of: DCCT. N Engl J Med. 1993;329:977-986. JDRF data from: JDRF CGM Study Group. N Engl J Med. 2008;359:1465-1476. Bergenstal RM, Tamborlane WV, Ahmann A, et al. [published online ahead of print June 29, 2010]. N Engl J Med. doi: [].

Sensor Augmented Pump (SAP) Sensor Augmented Pump + Threshold Suspend (SAP + TS)

Participants Baseline Enrollment (414) Screen failures or withdrawals (94) Run-in Phase (2 weeks) (320) Randomized (247) Threshold Suspend (121) Control (126) Withdrawals or did not meet randomization criteria (73) which included at least one episode of nocturnal hypoglycemia in 2 weeks Early withdrawals (5 Threshold Suspend, 2 Control) Threshold Suspend Control Age 41.6 ± 12.8 44.8 ± 13.8 % Male 38 39.7 Diabetes Duration 27.1 ± 12.5 26.7 ± 12.7 BMI, kg/m 2 27.6 ± 4.7 27.1 ± 4.3 Study Phase (3 months) A1C and Nocturnal Hypoglycemia AUC

Predictors of Nocturnal Hypoglycemia During the Run In Phase of the ASPIRE 2 Study Bruce W. Bode 1, Scott W. Lee 2, Francine R. Kaufman 2, ASPIRE In Home Study Group 1, Atlanta Diabetes Associates, Atlanta, GA; 2, Medtronic, Inc., Northridge, CA Background Results (updated after study completion) Summary In an attempt to mitigate hypoglycemia, particularly that which occurs at night, sensor augmented pump systems have been developed that allow for automatic insulin suspension at a preset sensor glucose threshold (Threshold Suspend, TS, previously referred to as Low Glucose Suspend). Previous studies have shown the benefit of the TS feature in mitigating hypoglycemia. The present study was conducted to examine the safety and efficacy of the TS feature in a randomized, controlled study in which the study patient population was enhanced for nocturnal hypoglycemia. Data from those who completed the run in period of this study were used to examine predictors of hypoglycemia. Methods Screened (414) Entered Run in Phase (2 weeks) (320) Completed Run In Phase (314) Randomized (247) Screen failures or withdrawals (94) Withdrawals and Randomization Failures (73) Patient Characteristics (N=314 patients who completed the Run-In Phase) Age, 43.6 ± 13.83 years (range, 16-70) Sex, 60.2% female Race, 96.5% white Height, 169.9 ± 9.76 cm (range, 137.2-195.6) Weight, 79.5 ± 16.01 kg (range, 48.7-137.3) BMI, 27.5 ± 4.82 kg/m 2 (range, 19.2-51.5) Diabetes duration, 26.9 ± 12.69 years (range, 2.4-61.8) The incidence of NH was higher in patients with lower baseline A1C values and higher glycemic variability (GV). The findings of higher rates of NH in younger patients, patients with shorter diabetes duration, and patients with lower BMI appears to result from greater GV in these patients. Gender and race had no effect on NH. Conclusion The rate of NH events was 0.3 per patient night. The tables show variables examined More than in 3 months association CGM: with 56.7% the mean (±SD) number of NH events per patient per 2 week interval. N, number of NH events in each patient category. The total number of NH events was 314. GV, glycemic variability. A1C at screening visit, 7.6 ± 0.9% (range, 5.8-10.0) Baseline A1C N NH Events 7% 92 5.05 ± 3.39 > 7% 222 3.80 ± 2.66 P value <0.001 P value (adjusted for GV) <0.001 Diabetes Duration N NH Events 15 years 63 5.10 ± 3.46 > 15 years 245 3.94 ± 2.77 P value < 0.001 P value (adjusted for GV) 0.82 In an attempt to identify patients potentially most at risk for NH, the use of glycemic variability coupled with A1C might be useful in clinical practice or to define a study cohort at risk. Study Visit Schedule Coefficient of Variation (a measure of glycemic N NH Events variability) 40% 154 2.90 ± 2.19 > 40% 160 5.39 ± 3.06 P value <0.001 Basal:Bolus Ratio N NH Events Basal Bolus 165 4.05 ± 2.95 Basal > Bolus 149 4.30 ± 2.95 P value 0.27 P value (adjusted for GV) 0.12 Age N NH Events 50 years 207 4.43 ± 2.95 > 50 years 107 3.67 ± 2.88 P value 0.002 P value (adjusted for GV) 0.86 BMI N NH Events < 25 kg/m 2 96 4.46 ± 2.85 25 kg/m 2 218 4.04 ± 2.98 P value 0.098 P value (adjusted for GV) 0.34 Continuous Variable P value P value (adjusted for GV) Baseline A1C <0.001 <0.001 Coefficient of Variation <0.001 N/A Basal:Bolus Ratio 0.76 0.20 Age <0.001 0.26 Diabetes Duration <0.001 0.92 BMI 0.026 0.39 There was no effect of gender (P=0.77) or race (P=0.13). See Poster LB 48 for study results. ASPIRE In Home Study Group AMCR Institute, Escondido, CA: T. Bailey; Atlanta Diabetes Associates, Atlanta, GA: B. Bode; Rainier Clinical Research Center, Renton, WA: R. Brazg; Texas Diabetes and Endocrinology, Austin, TX: L. Casaubon; University of Colorado Denver and the Barbara Davis Center, Aurora, CO: S. Garg, R. Slover; Palm Beach Diabetes and Endocrine Specialists, West Palm Beach, FL: B. Horowitz; Diabetes Research Institute Mills Peninsula Health Services, San Mateo, CA: D. Klonoff; Rocky Mountain Diabetes and Osteoporosis Center, Idaho Falls, ID: D. Liljenquist; Physicians Research Associates, LLC, Lawrenceville, GA: O. Odugbesan; Endocrine Research Solutions, Inc., Roswell, GA: J. Reed; Ohio University Diabetes Center, Athens, OH: F. Schwartz; Arkansas Diabetes Clinic and Research Center, Little Rock, AR: J. Thrasher; Oregon Health and Science University, Portland, OR: A. Ahmann; International Diabetes Center at Park Nicollet, Minneapolis, MN: R. Bergenstal; Iowa Diabetes and Endocrinology Center (IDEC), Des Moines, IA: A. Bhargava; The Naomi Berrie Diabetes Center, Columbia University, New York, NY: R. Goland; The Board of Regents of the University of Wisconsin Madison, Madison, WI: M. Meredith; Joslin Diabetes Center (Syracuse University), Syracuse, NY: R. Weinstock. Presentation Number 984-P Clinical Therapeutics/New Technology Insulin Delivery Systems Sunday, June 23, 2013 Noon 2:00 PM

Nocturnal Hypoglycemia (NH) SG < 65 mg/dl for > 20 min. From 10PM to 8AM No patient intervention Each pt > 2 events over 2 wks. Rates NH 0.3 events per pt night Approx 2.1 NH events per patient per wk

NH Something We Need to Fix Now Buckingham data published in Kowalski review: DTT 2009 15

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Participants Baseline Enrollment (414) Screen failures or withdrawals (94) Run-in Phase (2 weeks) (320) Randomized (247) Threshold Suspend (121) Control (126) Withdrawals or did not meet randomization criteria (73) which included at least one episode of nocturnal hypoglycemia in 2 weeks Early withdrawals (5 Threshold Suspend, 2 Control) Threshold Suspend Control Age 41.6 ± 12.8 44.8 ± 13.8 % Male 38 39.7 Diabetes Duration 27.1 ± 12.5 26.7 ± 12.7 BMI, kg/m 2 27.6 ± 4.7 27.1 ± 4.3 Study Phase (3 months) A1C and Nocturnal Hypoglycemia AUC

Sensor Augmented Pump (SAP) Sensor Augmented Pump + Threshold Suspend (SAP + TS)

Results Reduction in hypoglycemia (duration and severity) in the Threshold Suspend Group AUC (mg/dl min) 1800 1600 1400 1200 1000 800 600 400 200 0 Mean AUC of Nocturnal Hypoglycemia Events 1547 (2035) 980 (1200) Threshold Suspend 38% reduction p<0.001 1406 (1950) Control 1568 (1995) Run-In Phase Study Phase The mean AUC of NH events was 38% lower in the Threshold Suspend Group. SD values are shown in parentheses.

Results Reduction in hypoglycemia events in the Threshold Suspend Group Hypoglycemia Events per Patient-Week Events per Patient-Week 6 5 4 3 2 1 2.4 (1.2) 1.5 (1.0) 32% reduction p<0.001 2.5 (1.5) 2.2 (1.3) 5.0 (2.8) 3.3 (2.0) 30% reduction p<0.001 5.1 (3.0) 4.7 (2.7) Run-In Study 0 Threshold Suspend Nocturnal Control Threshold Suspend Control Combined Day and Night Hypoglycemia events were less frequent in the Threshold Suspend Group. SD values are shown in parentheses.

Results Characterization of Threshold Suspend events lasting 2 Hours 300 250 n=1438 Sensor Glucose (mg/dl) 200 150 100 50 Insulin Suspended 0-180 -150-120 -90-60 -30 0 30 60 90 120 150 180 210 240 270 300 330 360 Time from TS Event Start (min) Mean ± SD of sensor glucose values surrounding 2-hour TS events. The dotted line is at 70 mg/dl.

Results No significant between-group difference in A1C 10 A1C 9.5 9 A1C (%) 8.5 8 7.5 = 0.00±0.44 = -0.04±0.42 Randomization 3-month 7 6.5 7.26 (0.71) 7.24 (0.67) 7.21 (0.77) 7.14 (0.77) 6 Threshold Suspend Control 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%.

Summary The TS feature improves upon SAP therapy by significantly reducing NH. Reduction in mean event AUC. Reduced percentage of time spent with SG values in the hypoglycemic range. Decreased number of NH events per week No deterioration in A1C with TS use. Low risk of severe rebound hyperglycemia following 2-hour TS events. No severe hypoglycemia in TS feature group

Conclusion Automating insulin delivery appears to be an effective and safe strategy to reduce hypoglycemia.

Severe Hypoglycemia and A1C DCCT (1993), JDRF (2008), STAR 3 (2010) & ASPIRE in Home (2013) Studies Severe Reaction Every: 1.6 yrs. DCCT (intensive therapy): 62 per 100 pt-yrs, A1C(6.5 yr): 9.0% 7.2% 5 yrs. 7.5yrs. 7.7yrs. JDRF CGM (adults, 1 subject excluded): 20.0 per 100 pt-yrs; A1C (6 mo): 7.5% 7.1% STAR 3 MDI (all ages): 13.5 per 100 pt-yrs; A1C (1 yr): 8.3% 8.1% STAR 3 SAP (all ages): 13.3 per 100 pt-yrs; A1C (1 yr): 8.3% 7.5% ASPIRE SAP 13.0 per 100 pt-yrs; A1C (3mo.): 7.2% 7.1% Never Adapted from Figure 5B of: DCCT. N Engl J Med. 1993;329:977-986. JDRF data from: JDRF CGM Study Group. N Engl J Med. 2008;359:1465-1476. Bergenstal RM, Tamborlane WV, Ahmann A, et al. [published online ahead of print June 29, 2010]. N Engl J Med. doi: []. ASPIRE SAP + TS 0.0 per 100 pt-yrs; A1C (3mo.): 7.3% 7.2% Future AP system

AP Strategy Iterative Increases in Automation Artificial Pancreas presentations at ADA Scientific Sessions 2013 addressing the various strategies of AP development Bergenstal LB 48 Trang, Jones Australia 228 OR Cameron 9 OR Danne 357 OR Buckingham 37 LB Zisser 11OR Nimir, Phillip, Battelino 13OR Finan 10OR Bode 984 P Russell, Nathan, Damiano OR 15 Castle, Ward 14OR Lee, Renard 16OR 26