1. Updates in Type 1 Diabetes Rodica Busui MD, PhD Professor of Internal Medicine, Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI

2. No Disclosures

3. The Diabetes Control and Complications Trial pt-yrs Rate/100 pt-yrs. N Engl J Med, 1993 Diabetologia, 1995 CAN Intensive Glucose Control Reduces Risk of all complications AT THE COST OF: Severe Hypoglycemia 62 vs. 19 incidents per 100py 16 vs. 5 coma/seizure per 100py Overweight >120% IBW 13 vs. 9 incidents per 100py (mean excess 4.6kg)

4. Long-Term Adherence to Glycemic Control in the DCCT/EDIC DCCT/EDIC Research Group. N Engl J Med. 2000;342:381-9.

5. CURRENT STATE OF AFFAIRS IN THE U.S.: A1c and Age Distribution in the T1D Exchange Cohort ~25% of youth/young adults with T1DM achieve A1c targets. Wood et al. T1D Exchange Clinic Network. Diabetes Care 36:2035–2037, 2013 How do we reconcile the problem of long-term adherence to glycemic control? Miller et al, Diabetes Care 2015,38: 971-978

6. Putative Strategies for Targeting Glycemic Control in T1D *Aschner P et al. Global Partnership for Effective Diabetes Management. Int J Clin Pract 2001c 1.Develop new means to implement and intensify the basal-bolus insulin regimen– pumps, CGM. 1.Reconcile psychosocial barriers* 2.Advance and complete the journey towards the artificial pancreas technologies

7. Putative Strategies for Targeting Glycemic Control in T1D *Aschner P et al. Global Partnership for Effective Diabetes Management. Int J Clin Pract 2001c 1.Develop new means to implement and intensify the basal-bolus insulin regimen– pumps, CGM. 1.Reconcile psychosocial barriers* 2.Advance and complete the journey towards the artificial pancreas technologies

8. Insulin Pumps

9. Progress with Insulin Pumps More adjustable –Finer dose adjustments (as low as 0.025 units) –Improved boluses (extended, dual wave etc.) –Multiple doses for a meal if extra food is eaten –Multiple basal rates (dawn phenomenon, active day, etc.) and patterns (Sat-Sun vs M-F) –Temporary changes in basal rates Lower after exercise, alcohol Higher with stress, illness, inactivity, pre-menstrual

10. Bolus calculators –Programmed with insulin to carbohydrate ratio (ICR) and correction factor (CF)- minimized mistakes in dose calculation –Insulin on Board Feature: eliminate insulin dose stacking –Lower temporary basal rates with exercise Lower rates of hypoglycemia Progress with Insulin Pumps Less weight gain Decrease insulin with exercise (vs. extra food)

11. Insulin dosing in a pump (setting basal) Adults: 50% basal, 50% bolus Children: 35-40% basal, 60-65% bolus If on NPH, calculate previous total daily dose (TDD), subtract 20% to generate a starting pump TDD –Or use a dose per kg/d: 0.5-1.0 u/kg/d Lean or athletic, start near the lower end As much as 1 u/kg/d in growing teenagers If on MDI, you can take the Lantus dose and subtract 0-20%, divide by 24

12. Insulin dosing in a pump (setting boluses) Carb Ratio (ICR): –Start with the predicted the total daily dose (TDD) –Use the “450 rule” (450/TDD=ICR) –Young children (<8) need more insulin for food coverage, use the 300 rule –These are starting doses if the patient did not have a previous ICR with multiple daily injections Correction Factor (CF-also called sensitivity factor or ISF) –Start with the predicted the total daily dose (TDD) –Use the “1800 rule” (1800/TDD=CF) –May need less in the youngest children (2200 rule)

13. Pump Therapy vs. MDI Trials in T1D: Outcome A1c Misso ML et al, Cochrane Database Syst Rev. 2010 Jan

14. Insulin Pumps- not enough! DKA risk Always attached Privacy Skin irritation Must carry supplies if the site gets pulled out Cost !

15. CGM Systems Medtronic Dexcom(Freestyle Libre)

16. Effect of CGM Alone (patients with A1c 7-10%) Insignificant effect of CGM on younger subgroups (n=224) A separate report of 129 subjects with A1c <7.0% showed substantial benefit in a composite outcome including hypoglycemic events −0.53%, P<0.001 JDRF Continuous Glucose Monitoring Study Group. N Engl J Med. 2008 JDRF Continuous Glucose Monitoring Study Group. Diabetes Care 2009 6 month study, N=322.

17. Treat to target* RealTrend* Current Evidence Supports a Moderate Independent Effect of CGM on A1c Reduction Langendan M et al. CGM systems for T1DM (Systematic Review). Cochrane Database 2012. Battelino Diabetologia. 2012 -0.43% (-0.32 to -0.55; P<0.001)

18. Putative Strategies for Targeting Glycemic Control in T1D *Aschner P et al. Global Partnership for Effective Diabetes Management. Int J Clin Pract 2001c 1.Develop new means to implement and intensify the basal-bolus insulin regimen– pumps, CGM. 1.Reconcile psychosocial barriers* 2.Advance and complete the journey towards the artificial pancreas technologies

19. Artificial Pancreas: a long journey

20. “Closed-Loop” Concepts: Intravenous Sensor with Intraperitoneal Insulin Delivery

21. The Goal

22. 2) Sensor- Augmented Pump Two Therapy Groups: 1) Multiple Daily Injections (glargine, aspart) Sensor Augmented Pump Therapy STAR 3 Trial Bergenstal, et al. N Engl J Med. 2010 All Patients (N = 485)

23. = MDI= SAP n = 244n = 241 7.0% 7.5% 8.0% 8.5% 036912 A1C Primary Endpoint: A1C Reduction Comparisons between SAP group and MDI group are significant for each time period (P<0.001). Months 8.3% 7.3% 7.5% 8.0% 8.1% ∆ -0.2 ∆ -0.8 - 0.6 P<0.001 Bergenstal, et al. N Engl J Med. 2010 Maximal A1C reduction was correlated with sensor use in post-hoc analysis A1c reduction durable to 18 months in a non-randomized continuation phase Bergenstal, et al. Diabetes Care 2011

24. AUC for Hyper- and Hypoglycemia Hypoglycemia AUC (< 70 mg/dL or <4mM) p =0.54 Hyperglycemia AUC (>180 mg/dL or >10mM) = MDI= SAP n = 247n = 248 p<0.001 Extent & duration of hyperglycemia in SAP was a third lower compared to MDI – without excess hypoglycemia. Comparisons between SAP group and MDI group were significant for each time period (P<0.001). Bergenstal, et al. N Engl J Med. 2010;363:311-20.

25. Overall (n=153) Adult (n=81) Pediatric (n=72) *p<0.0001 * Battelino Diabetologia. 2012 Effect of CGM Alone vs. SAP - “SWITCH STUDY” N=153 in 4 European Centers, pump patients with inclusion criteria otherwise similar to STAR 3

26. The ASPIRE In-Home trial (Automation to Simulate Pancreatic Insulin Response) Design: 3-month (2w run-in) randomized, controlled, multi-center, open-label trial N= 247. Patients: 27years of T1DM, A1c 7.2%, no recent severe hypo/DKA, wore a sensor ≥80% Primary Endpoint (Efficacy): AUC 10p-8a HYPO INTERVENTION SAP with Low Glucose Suspend LGS set at < 3.9 mmol/L CONTROL Standard SAP No LGS Bergenstal RM et al for the ASPIRE In-Home Study Group. N Engl J Med 2013;369:224-32.

27. Extent & duration of hyperglycemia in LGS/TS was a third (38%) lower compared to Control Safety Efficacy Bergenstal RM et al for the ASPIRE In-Home Study Group. N Engl J Med 2013;369:224-32. Number of Discrete Events decreased by 30%: Nocturnal 1.5 vs. 2.2 events per patient∙week Combined 3.3 vs. 4.7 events per patient∙week Severe hypoglycemia: 0 vs. 4 total events in the control. The ASPIRE In-Home trial (Automation to Simulate Pancreatic Insulin Response)

28. Sensor Glucose Values Before, During and After the 2-Hour Nocturnal Suspends Bergenstal RM, Klonoff DC, Garg SK, et al for the ASPIRE In-Home Study Group. Threshold-based insulin-pump interruption for reduction of hypogylycemia. N Engl J Med 2013;369:224-32. 3.9 mmol/L 5.1 mmol/L 9.4 mmol/L There were no DKA events A separate study of 95 T1D subjets with NEAR-TOTAL LOSS OF HYPOGLYCEMIA AWARENESS demonstrated 70% reduction (9.5 vs 34 incidents per patient-months)* Bergenstal RM et al for the ASPIRE In-Home Study Group. N Engl J Med 2013;369:224-32. *Ly et al. JAMA Sept 26, 2013 Low risk of severe rebound hyperglycemia with LGS

29. Ly et al, Diabetes Care 2014, 37: 2310 Glucose Control During Overnight Closed Loop Closed loop SAP

30. Medtronic Closed-Loop Camp Study Ly et al, Diabetes Care, 2015, 38: 1205-11

31. Medtronic Closed-Loop Camp Study Ly et al, Diabetes Care, 2015, 38: 1205-11

32. The MD-Logic Closed Loop System- at Camp N Engl J Med 2013; 368:824-833

33. 12-Week Outpatient Single Hormone Artificial Pancreas Thabit/Hovorka (University of Cambridge group) and the AP@Home Consortium NEJM 2015 N=58 33 adults 25 children/adol. 2 separate trials vs. SAP Run-in period Carb count SMBG 24h Support Hotline

34. 12-Week Outpatient Single Hormone Artificial Pancreas Thabit/Hovorka and the AP@Home Consortium NEJM 2015 Also: Hood T et al., Lancet Diabetes Endocrinol. 2014; Leelarathna L et al., Diabetes Care. 2014 Hovorka R et al., Diabetes Care. 2014;37:1204–1211 ADULTS 10% greater time-in-target Mean glucose 0.6mM lower (8.7 vs. 9.3) % time in hypo 2.9 vs. 3.0 % A1c 0.3% lower CHILDREN/ADOL. 10% greater time-in-target Mean glucose 0.6mM lower (9.5 vs. 10.1) % time in hypo 3.1 vs. 3.8 % A1c 0.3% lower Closed-loop Control Difference Single Hormone AP - Summary Automated outpatient trials  Night and 24h trials  Adults & pediatrics  Compared to sensor augmented pump therapy  Glucose time in target:+10–15%  Mean blood glucose:-0.8 mmol/L  Hypoglycemia:possible reduction  A1c reduction:Yes

35. Bionic Pancreas Russel SJ et al. NEJM. 2014;371(4):313–325. Also: Haider A et al. CMAJ. 2013

36. Mean Glucose Levels in Adults Russel SJ et al. NEJM. 2014;371(4):313–325. Also: Haider A et al. CMAJ. 2013 Mean Glucose 7.4 vs. 8.8 mmol/l, P<0.001 Time in Target 4-10 80% vs 59%, p<0.001 Time in Hypoglycemia 4.1% vs. 7.3%, P = 0.01 Similar findings in the adolescents 5d “outpatient” intervention in 20 adults and 32 adolescents

37. Single-hormone AP Insulin only Dual-hormone AP Insulin & Glucagon FUNDAMENTAL RESEARCH GAP: DIRECT COMPARISON BETWEEN SINGLE- and DUAL-HORMONE AP Control Algorithm Infusion Pump Glucose Sensor Artificial Pancreas: still unanswered questions? If ultra-rapid insulin is available, glucagon may not be needed

38. Artificial Pancreas: still unanswered questions? Increased CGM Accuracy (replacement of finger sticks) REPLACE BG trial Critical Question: When will the CGM be accurate enough to control insulin/glucagon for patients not in research studies?

39. The Artificial Pancreas is Close but Not Quite Ready for Prime Time… Rapidly progressing field Extremely promising short-term results especially for overnight Daytime/Postprandial AP strategies require urgent research attention Interest in adjunctive-to-insulin therapy, faster-acting insulin If dual, then stable glucagon and dual-chamber pump Will need step-by-step market introduction (first version will likely require meal & exercise announcements) KEY RESEARCH NEEDS: Longer-term comparative trials with standard outcomes and reporting.

40. Thank You !