The Future of Pumping Henry Anhalt, DO, CDE Director, Pediatric Endocrinology and Diabetes Saint Barnabas Medical Center Livingston, NJ
`In the past we had a light that flickered, in the present, a light that flames, and in the future we will have a light that shines over all the land and the sea’ Winston Churchill
DCCTRelationship of HbA1c to Risk of Microvascular Complications 15 Retinopathy Nephropathy 13 Neuropathy 11 Microalbuminuria 9 Relative Risk 7 5 3 1 6 7 8 9 10 11 12 HbA1c(%) Skyler. Endocrinol Metab Clin. 1996;25:243-254, with permission.
Limitations/Challenges to Better Glycemic Control • A1c’centric • Hypoglycemic Risk • Glucose excursions above and below what the HbA1c average represents may be more important than HbA1c • Inadequate Postprandial Glucose Control • Weight Gain
Obstacles in Glycemic Control • Invasive glucose monitoring devices-owie!!!!! • Limited availability of reliable continuous glucose monitoring • Lack of alternate routes of insulin delivery.
Alternate Site Glucose Testing(Forearm, Thighs, Abdomen vs. Fingers) • Rubbing/exercising/suction does not uniformly increase the blood flow but glucose values may be better correlated to fingers. • At extremes of glucose values fingerstick testing is mandatory for confirmation. • Rapid changes in glucose values, fingers are the best
Alternate Site Glucose Measurements Over-reads Under-reads
MAJOR RESEARCH CHALLENGES? • CLINICALLY Development of new methods for achieving tight control without hypoglycemia • RESEARCH Development of methods for replacing beta cell function (islet cell transplantation, artificial pancreas) Enhanced understanding of immunopathogenesis(interaction of genes, environment and immune system) allowing for more effective preventative therapies
APPROACHES TO CURING TYPE 1 DIABETES in vivo Differentiation of Pancreatic Progenitors Immune Interventions/ Tolerance Induction Manipulation Of non-islet tissue (Transdifferentiation Transplantation Stem Cells Growth Factors Islets Adult Whole pancreas Gene Therapy Modulate Autoimmunity Islet neogenesis Fetal Embryonic
Implanted Closed-Loop External Closed-Loop TOWARDS CLOSED LOOP DELIVERY
Glucose Contributions to HbA1c HbA1c = Postprandial Glucose Influenced by: • Preprandial glucose • Insulin dose • Glucose load from meal • Insulin sensitivity in peripheral tissues Fasting Glucose influenced by: • Liver glucose production • Liver sensitivity to insulin + Humalog, Novalog Lantus, Basal rates,
HbA1c = 8% HbA1c = 8% Are All HbA1c Values Created Equal? Blood Glucose Time
Lesser Known Outcomes from the DCCT The DCCT Research Group stated HbA1c is not the entire answer to glycemic control. “The Average HbA1c is not the most complete expression of the degree of glycemia and the risk of complications may be more highly dependent on the excursions or influenced by counterregulatory hormonal responses to hypoglycemia.” Diabetes 44:968-983, 1995
Actual writing on Hospital charts:Top Ten • She has no rigors or shaking chills, but her husband states she was very hot in bed last night. • Patient has chest pain if she lies on her left side for over a year. • On the second day the knee was better, and on the third day it disappeared. • The patient is tearful and crying constantly. She also appears to be depressed. • The patient has been depressed since she began seeing me in 1993.
Model derived from animal studies *Inferred satiety effect GLP-1 central effect on glucose homeostasis isinferred from animal studies Model of Multihormonal Regulationof Glucose Homeostasis Brain Food Intake* — Gastric Emptying — Liver Stomach PostprandialGlucagon Rate ofglucoseappearance Plasma Glucose Gut Rate ofglucosedisappearance Glucose Disposal Insulin Amylin Pancreas Tissues GLP-1
N = 9, CSII treated (insulin lispro); A1C average 6.7% (range 5.8%-7.1%) ; 24-hour CGMS glucose sensor data Desired glycemic range in non-diabetic subjects: 80-140 mg/dL Excessive 24-Hour Glucose Fluctuations in Type 1 Patients with Mean A1C of 6.7% 400 300 Glucose Concentration (mg/dL) 200 100 12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM Levetan C, et al. Diabetes Care 2003; 26:1-8
Intensively-treated T1DM: Diurnal Glucose Fluctuation and Nocturnal Hypoglycemia Mean A1C = 7.7% Postprandial Hyperglycemia Nocturnal Hypoglycemia 100 90 > 300 mg/dL 241–300 mg/dL 181–240 mg/dL 41–60 mg/dL 40 mg/dL 80 80 70 70 60 60 % Peak Postmeal Glucose Levels Over Target 50 50 % Patients 40 40 30 30 20 20 10 10 0 0 1 Night 2 Nights 3 Nights Breakfast Lunch Supper 90% of Postprandial Readings Exceeded ADA Guidelines Nearly 70% of Patients Had 1 Night With PG < 60 mg/dL Continuous Glucose Monitoring System (CGMS) data, 56 adolescents, T1DM on CSII or MDI CSII = Continuous subcutaneous insulin infusion; PG = Plasma glucose Boland E, et al. Diabetes Care. 2001;24:1858-1864.
WTR = within target range (70-150 mg/dl) BTR = below target range (<70 mg/dl) ATR = above target range (>150 mg/dl) Blood Glucose Values (SMBG) Needed to Attain DifferentHbA1CValues ATR 33% ATR 41% ATR 46% WTR 45% WTR 49% WTR 42% BTR 18% BTR 12% BTR 14% HbA1c = 7.0% HbA1c = 8.5% HbA1c = 8.0% Brewer KW, Chase PH, Owen S, Garg SK. Diabetes Care 1998;21(2):209-212.
Need for Continuous glucose monitoring • Direction • Magnitude • Duration • Frequency • Cause of fluctuation • Alerts/Alarms • Improve therapeutics decisions
Glucose Sensors • Continuous Glucose Monitoring System (CGMS) • GlucoWatch Automatic Biographer • Navigator • Near-InfraRed (NIR) • Implantable glucose sensors-Dexcom • Optical sensors • Ultrasonic sensors
Glucose Sensors DexCom Implantable Sensors Pendra® GlucoWatch FreeStyle Navigator Sensys Medical NIR MiniMed
Schematics of the Autosensor & Biographer Mask Hydrogel Pads Ionto Sensor Electrode Assembly AAA Battery Electronic Components Garg et al. Diabetes Care 1999;22:1708-1714
Device Evaluation Advantages • Real-time measurement • Non-invasive (no-biological fluids) • Calibration stability • 71% of patients calibrate • Trending capability Disadvantages • Not portable • Skin temperature control • Sampling site critical • Failure modes not all identified • Requires daily finger stick
Near Infrared Ray (NIR) • Large desk-like apparatus • Skin temperature and hydration • Calibration is too cumbersome • Patient intervention required Real Need! • Need a small wearable, patient-friendly continuous glucose monitor with alarms and remote displays and feed the information to insulin pumps (closed-loop system)
Sensors in Development DexCom and Vascular Sensors NIR, Nostix, Therasense The Pendra, Pendragon MedicaSensys Glucose Tracking System, SensysGlucon Solution, GluconSugartrac, Lifetrac SystemsGlucoNIR, CME TelemetrixReSense, MedOptixPindi, Pindi ProductsHead-Mounted Goggles, NASA
More Frequent Testing Improves HbA1c in Type 1 Patients 11 < 2 < 2 10 HbA1c (%) 9 8 > 4 > 4 > 4 7 6 Initial No Contact Cross-Over Intensify Schiffrin A, Belmonte M. Diabetes Care 1982;(5):479-84.
400 360 320 280 240 Glucose (mg/dL) 200 160 121 120 80 Pre Dinner 80 Pre Lunch 40 0 11:00 1:00 3:00 5:00 7:00 9:00 11:00 1:00 AM PM PM PM PM PM PM AM Current Medical Practice • Repeated finger-sticks are required to obtain glucose readings periodically • Testing is generally performed before meals • Occasional measurements provide limited information about glucose levels Garg et al Diabetes Care ; 22; 1708-1714, 1999
With the GlucoWatch® Biographer • After one fingerstick for calibration, glucose readings are available automatically • Frequent readings provide more information about glucose levels • Trend information helps to identify opportunities for improved glucose control 400 360 Biographer Blood Glucose 320 Calibration Point 280 240 Glucose (mg/dL) 200 160 120 Pre Dinner 80 Pre Lunch 40 0 11:00 1:00 3:00 5:00 7:00 9:00 11:00 1:00 AM PM PM PM PM PM PM AM Garg SK et al Diabetes Care ; 22; 1708-1714, 1999
Biographer Blood Glucose Calibration Point Measurement of Blood GlucoseConventional Blood Glucose Meters 400 360 • Based on significant postprandial hyperglycemia, the dose of pre-meal boluses on insulin lispro were adjusted and HbA1c values have remained consistently below 6.5% during the subsequent year. 320 280 240 Glucose (mg/dL) 200 121 160 80 120 Pre Dinner 80 Pre Lunch 40 0 11:00 1:00 3:00 5:00 7:00 9:00 11:00 1:00 AM PM PM PM PM PM PM AM Garg et al Diabetes Care ; 22; 1708-1714, 1999
Continuous Subcutaneous Glucose Monitoring in a Subject with Type 1 Diabetes Meter Value Sensor Value Insulin Meal 450 400 350 300 250 Glucose Concentration (mg/dL) 200 150 100 50 0 12 MN 12 MN 1:30 PM 3:00 PM 4:30 PM 6:00 PM 1:30 AM 3:00 AM 4:30 AM 6:00 AM 7:30 AM 9:00 AM 7:30 PM 9:00 PM 10:30 AM 12 NOON 10:30 PM Time Chase and Garg , Pediatrics:107; 222-226, 2001
Technical Aspects of Continuous Glucose Monitoring • Interstitial vs. Blood glucose –reported Lag of few seconds to 15 minutes • High frequency of measurements • Signal Stability –Quick and over time • Calibration Issues • Duration of Sensor application
Limitations with Current Technologies • SMBG • Solitary Data points with no trend information • CGMS • No real time feedback, 4T/day calibration • Unreliable data, size of the needle • GlucoWatch - Prospective data but too many skips,12 hr.sensor - Skin irritation, Sweating,Temperature changes * HbA1c and Fructosamine Assay • Purely retrospective • No immediate Feedback
Device Description: Sensor DexCom G1 Sensor • Subcutaneous implant in the abdominal wall • Multi-layer membrane system • Measures glucose every 30 seconds • Wireless transmission to receiver Garg et al., Diabetes Care, 27:734-38, 2004
Device Description: DEXCOM ReceiverLong Or Short Term Use Receives and processes data from sensorUpdates and displays glucose values every 5 minutesDisplays 1, 3 and 9 hour trendsHigh and low glucose alerts Garg et al., Diabetes Care, 27:734-38, 2004
Profile With Continuous Glucose Sensor in Patients With Insulin-requiring Diabetes Blinded period Unblinded period 10 37%*increase Mean A1C = 7.2% 4%*decrease 31%*decrease 8 6 41%*increase Time Spent (hours/day) 38%*decrease 4 2 8.74 6.46 6.16 4.57 2.46 1.53 2.13 3.00 6.37 6.58 0 40–55 56–79 80–140 141–239 240–400 Glucose Range (mg/dL) *P < 0.05, Student’s t test Garg SK, et al. Diabetes Care. 2004;27:734-738.
WTR = within target range (60-150 mg/dl) BTR = below target range(<60 mg/dl) ATR = above target range (>150 mg/dl) Slicing the Pie from DCGM Sensor Downloads Blinded vs. Unblinded phases (n=14) Unblinded phase Blinded phase WTR 51% ATR 41% WTR 37% ATR 51% BTR 12% BTR 8%
Results (G2) * Expressed as Mean SEM ** Two-sided paired t-Test, p 0.05 Scott and Garg. ADA (LB5), o4 and EASD 2004
Results (G2) * Expressed as Mean SEM ** Two-sided paired t-Test, p 0.05 Scott and Garg. ADA (LB5)and EASD 2004
Closing the Loop: The Artificial Pancreas • Accurate, reliable continuous glucose monitoring systems, in progress • Algorithms to incorporate glucose trend data into proper dose adjustments • External or internal insulin pump systems
B Medtronic MiniMed’s Family of Insulin Pumps Remote Control Paradigm 511 MiniMed 508 Paradigm 512 Paradigm Link Meter 102 mg/dL Pardigm Link & Bolus Wizard Paradigm 512 ONLY
Actual writing on Hospital charts:Top Ten (cont.) • Discharge status: Alive but without my permission. • Healthy appearing decrepit 69 year old male, mentally alert but forgetful. • Patient has left white blood cells at another hospital. • The patient has no previous history of suicides. • The patient refused autopsy.
Until the Cure-The Realities: • Learn to manage glucose TRENDS rather than isolated numbers • Minimize the moodiness associated with wide glucose excursions • Understand glucose profiles over extended time • Improve implementation of new regimens • Knowledge and acceptance of inaccuracies and data interpretation
Conclusions • Continuous glucose monitoring promises the goal of normalization of blood sugars while minimizing risk of hypoglycemia • The result of full implementation will be normal HbA1c with further reduction in complications of diabetes • A closed loop, artificial pancreas either externally or internally based is now on the horizon
Implantable pump • Implanted under the skin of the abdomen through a minor surgical procedure. • Controlled today by hand-held radio frequency telemetry. • Delivers short, frequent pulses of insulin into the peritoneal cavity. • Designed to be refilled in a physician’s office every 3 months. • Projected 10 year battery life. • Hypoglycemic events reduced 400%.
Out-takes from a Web Blog Of RT User “Now, I never look at a single reading. I check my NOW number and then quickly scroll back in time using the down arrow button. Five minutes per click. I usually glance at half an hour…I think about what I’m looking at. Direction? Is the BG going up or down? Or is it fairly stable? Speed? Speed I’m not always so good at, because that takes mental mathematics, which is my weak spot. That said I can get a rough idea of how fast things are moving.”
THE RUB Even if the continuous sensors are refined, reimbursement for the devices as well as for providers’ time to help analyze data remains a problem. As things now stand, relatively few doctors and nurses have the time or expertise to assess the log records of individual glucose readings.