Diabetes Management: Current High Tech Innovations How Far We ve Come in the Last 40 Years William V. Tamborlane, MD Department of Pediatrics Yale School of Medicine
Disclosures I am a consultant for: AstraZeneca Boehringer Ingelheim Insuline Medical Janssen Medtronic Novo Nordisk Sanofi Takeda
Bad Old Days of Diabetes (Before 1980) Aggressive therapy unsafe and of unknown benefits HbA1c 11-12% Eye & kidney complications
Era of Intensive Treatment (1980 s)
First Successful Study of Pumps in T1DM Reduction to normal of plasma glucose in juvenile diabetes by subcutaneous administration of insulin with a portable infusion pump WV Tamborlane, RS Sherwin, M Genel, and P Felig NEJM 1979; 300:573-8
DCCT (1983-93)/EDIC (Ongoing) Most children and adults with T1D should be treated with intensive therapy to lower glucose and A1c levels as close to normal as possible and as early in the course of the disease as possible ISPAD Pediatric Target A1c <7.5%
Treatment Advances during 24 years post- DCCT Insulin Analogs Smart Insulin Pumps Improved Blood Glucose Meters Continuous Glucose Monitoring Systems
In the USA: The Inconvenient Truth Too many children and adolescents with T1D fail to achieve target A1c goals Rates of severe hypoglycemia and DKA remain too high Too few pediatric patients take full advantage of advances in diabetes technologies
T1D Exchange Clinic Network & Clinic Registry 73 Adult and Pediatric Clinics with >150,000 patients with T1D > 26,000 T1D Patients (age 2-95 yrs) Enrolled in Registry
HbA1c Levels by Age in T1DX Registry (2015)
Percent of Patients Meeting A1c Targets 100% Mean HbA1c (%) 80% 60% 40% 20% 0% A1c Goal = <7.0% A1c Goal = <7.5% 21% 21% 17% 13% 32% 29% <6 6-<13 13-<18 Age (years) 18-<26 26-<50 50
Frequency of Severe Hypoglycemia* by Age (% with 1 or more events in 12m) * Seizure or Coma
Frequency of Diabetic Ketoacidosis by Age 20% 1 or more events in 12 months 10% 8% 6% 10% 10% 5% 5% 4% 4% 0% Age (years)
50% 40% 30% Continuous Glucose Monitoring Use 20% 20% 22% 22% 13% 10% 5% 5% 5% 7% 0% Age (years)
No treatment of T1D will eliminate the risk of hypoglycemia unless there is feedback control of insulin delivery especially in the overnight period.
Lights at the End of the Tunnel Mechanical Solutions Sensor-augmented pump systems with automatic suspend capabilities to reduce risk of hypoglycemia Closed-loop systems Adjunctive therapies New T2D drugs for T1D Biologic: Pancreas/Islet transplants Encapsulated embryonic stem cells
Spectrum of Mechanical Solutions Auto-Suspend - Threshold - Predictive Hybrid CL - Manual Bolus Full CL - Insulin only - Insulin+glucagon Automation System Complexity
Spectrum of closed-loop systems Auto-Suspend Turning off insulin automatically for 2hr is safe - Threshold Turning on insulin automatically is potentially dangerous - Predictive Automation System Complexity
Example of Threshold Suspend Cycle Insulin Suspends for 2 hours / Resumes for 4 hours Insulin infusion stops Suspend time maximum = 2 hrs Basal insulin infusion will resume even if glucose is below Thresh Suspend limit Basal Insulin Basal Insulin 19
ASPIRE In-Clinic Study: Results 150 Mean ± SE of YSI Glucose Conc. (mg/dl) 140 130 120 110 100 90 80 70 LGS On Sessions LGS Off Sessions 60-200 -150-100 -50 0 50 100 150 200 Time (min) from crossing 70 mg/dl Garg S, Brazg RL, Bailey TS, et al. Diabetes Technol Ther. 2012;14:205-209.
Problems with Threshold Suspend Does not prevent hypoglycemia Too many alarms Garg S, Brazg RL, Bailey TS, et al. Diabetes Technol Ther. 2012;14:205-209.
Predictive Low Glucose Suspend The basal insulin infusion is suspended for up to two hours (or less) based on the rate of fall of sensor glucose levels to prevent hypoglycemia without setting off alarms. Garg S, Brazg RL, Bailey TS, et al. Diabetes Technol Ther. 2012;14:205-209.
Example of Predictive Suspend Cycle Insulin suspends for up to two hours but resumes automatically Insulin infusion stops Basal insulin infusion resumes to prevent excessive rebound Suspend time variable Basal Insulin Basal Insulin 23
Predictive Suspend Reduces Hypoglycemia 15% N=45 42 nights N=36 42 nights BG Levels < 70 mg/dl 10% 5% 0% 10% 5% 6% 3% 11-14 4-10 Control Intervention
Pros and Cons of PLGS Systems Pros Prevents hypos with fewer alarms Simplicity may be well suited and sufficient for well controlled T1D patients who bolus well BUT Cons Does not automatically increase basal insulin to help to gradually correct post-prandial and overnight hyperglycemia
Spectrum of closed-loop systems Hybrid CL - Manual Bolus - CL Control of Basal Rates Automation
Evolution of HCL Concept Original HCL Concept: Manual administration of small, pre-meal priming doses of insulin by paients to mitigate exaggerated post-prandial hyperglycemia due to delays in absorption of insulin delivered automatically during the meal. Current Concept: Manual administration of large pre-meal bolus doses to fully cover the carbohydrate content of the meal to mitigate the risk of over delivery of insulin by severely restricting that amount of insulin that can be delivered automatically Net result: the large doses of insulin required for meals are given manually and the system cleans up the back end by automatically adjusting the basal insulin infusion rates after meals and during the night
Yale Subject in HCL Study Glucose (mg/dl) 400 360 320 280 240 200 160 120 80 40 Date: 1-Oct-2014 0 00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 Infusion Rate (U/h) 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 Clock (HH:MM)
29 Medtronic 670G HCL System
Medtronic 670G System Algorithm
Medtronic Pivotal Closed-Loop Study 3 month study 124 subjects, 10 centers Hybrid: Bolus for meals
32 Baseline Characteristics
670 Outcomes: Run-in vs Study Phase Parameter All subjects Adults Adolescents Run-in Study p Run-in Study p Run-in Study p Median SG 150 151 0.64 146 148 0.11 163 159 0.07 SG > 300 mg/dl 2.3 1.7 0.01 1.8 1.3 0.08 3.8 2.8 0.08 SG > 180 mg/dl 27.4 24.5 <0.001 24.9 22.8 0.01 35.3 30.0 <0.001 71 to 180 mg/dl 66.7 72.2 <0.001 68.8 73.8 <0.001 60.4 67.2 <0.001 SG 70 mg/dl 5.9 3.3 <0.001 6.4 3.4 <0.001 4.3 2.8 <0.01 SG 50 mgldl 1.0 0.6 <0.001 1.1 0.6 <0.001 0.7 0.5 0.15 A1C (%) 7.4 ± 0.9 6.9 ± 0.6 <0.001 7.3 ± 0.9 6.8 ± 0.6 <0.001 7.7 ± 0.8 7.1 ± 0.6 <0.001 Bergenstal, JAMA 2016
Changes in A1c levels HbA1c range (%) <7.0 7.0 to 7.5 >7.5 N, (%) (start of runin period) 41 (33.1%) 31 (25.0%) 52 (41.9%) N, (%) (end of study period) 68 (55.3%) 39 (31.7%) 16 (13.0%) HbA1c (percentage points) -0.1-0.3-1.0
Adverse Events There were 17 device-related adverse events related to severe hyperglycemia: 5 during 2-week run-in and 12 during HCL treatment; 12 events were attributed to infusion set issues and none required emergency department care.
Still Room for Improvement Being switched off CL less often Being able to: adjust target glucose levels that are currently fixed at 120 mg/dl manually set temporary basal rates for periods of stress manually give correction doses that correct to glucose levels to values <150 mg/dl track glucose and insulin delivery remotely on smart phone aps Having automatic uploads of system data to the cloud
System Effectiveness Even in Teens in a Real-life Clinical Setting Claire B. s Model Day
Claire vs Teens in Pivotal Trial Sensor Glucose Ranges Adolescents Study Teens Claire > 180 mg/dl 30% 27% 71 to 180 mg/dl 67% 72% 70 mg/dl 2.8% 1%
What About FCL? Full CL - Insulin only - Insulin+glucagon Automation System Complexity
What About FCL? Wait Until Next Year
It Takes a Team..