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The Future of Pumping Henry Anhalt, DO, CDE

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1 The Future of Pumping Henry Anhalt, DO, CDE
Director, Pediatric Endocrinology and Diabetes Saint Barnabas Medical Center Livingston, NJ

2 `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

3 DCCT Relationship of HbA1c to Risk of Microvascular Complications
Relative Risk Retinopathy Nephropathy Neuropathy Microalbuminuria HbA1c (%) 15 13 11 9 7 5 3 1 6 8 10 12 Skyler. Endocrinol Metab Clin. 1996;25: , with permission.

4 Treatment Goals A1c (%) <7.0 <6.5 FBG (mg/dl) 80-120 <100
ADA IDF AACE A1c (%) <7.0 <6.5 FBG (mg/dl) 80-120 <100 <110 2 Hr.PP (mg/dl) <180 <135 <140

5 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

6 Obstacles in Glycemic Control
Invasive glucose monitoring devices-owie!!!!! Limited availability of reliable continuous glucose monitoring Lack of alternate routes of insulin delivery.

7 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

8 Alternate Site Glucose Measurements
Over-reads Under-reads

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

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

External Closed-Loop Implanted Closed-Loop Brad – describe implantable sensor and entire slide… Gary: ________

12 Glucose Contributions to 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 + Lantus, Basal rates, Humalog, Novalog

13 Are All HbA1c Values Created Equal?
Blood Glucose Time HbA1c = 8% HbA1c = 8%

14 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: , 1995

15 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.

16 Why do we need Glucose Sensors?

17 Model of Multihormonal Regulation of Glucose Homeostasis
Brain Food Intake* Liver Gastric Emptying Slide Index PH0016 DISCUSSION POINTS: This diagram shows the key organ systems and hormones known to be involved in glucose regulation Insulin is a major hormonal regulator of glucose production and disposal. Glucagon secretion is important to maintain glucose homeostasis under basal (fasting) conditions when endogenous glucose production, primarily by the liver, is necessary. An endogenous source of glucose is no longer needed during and immediately following mealtime. Glucagon is normally suppressed postprandially, leading to a near-total suppression of hepatic glucose output. Amylin is co-secreted with insulin at meal times. It is a neuroendocrine hormone and its action is mediated by the central nervous system via efferent signals from the brain. Amylin acts to reduce the rate of glucose inflow to a rate that better matches insulin’s effects on glucose disposal by: Reducing glucagon excess in the postprandial period. Regulating the rate of gastric emptying Amylin also appears to have an effect on satiety in animal studies. Short-term animal studies have shown a reduction in food intake, thereby reducing nutrient load. GLP-1 is also secreted postprandially from the L-cells in the jejunum and ileum. GLP-1 works to lower glucose by: Enhancing pancreatic insulin and amylin secretion when glucose concentrations are elevated Suppressing inappropriately high glucagon secretion (which leads to inhibition of hepatic glucose output) Regulating gastric emptying Long-term effects of GLP-1 demonstrated in animals include increased beta-cell mass and maintenance of beta-cell function, improved insulin sensitivity, and reduction of food intake. SLIDE BACKGROUND: Stomach Postprandial Glucagon Rate of glucose appearance Plasma Glucose Rate of glucose disappearance Gut Glucose Disposal Amylin Insulin Pancreas Tissues GLP-1 Model derived from animal studies *Inferred satiety effect GLP-1 central effect on glucose homeostasis is inferred from animal studies

18 Glucose Concentration (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 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: mg/dL Levetan C, et al. Diabetes Care 2003; 26:1-8

19 % Peak Postmeal Glucose Levels Over Target
Intensively-treated T1DM: Diurnal Glucose Fluctuation and Nocturnal Hypoglycemia Mean A1C = 7.7% Postprandial Hyperglycemia Nocturnal Hypoglycemia 100 CH: Still pretty crowded, although I have worked on rearranging text detail to emphasize main point of data. DISCUSSION POINTS: Even in intensively treated patients with “reasonable” A1C values (mean of 7.7% for this group), use of continuous glucose monitoring systems (CGMS) can now document excessive hyperglycemic excursions and unrecognized nocturnal hypoglycemia. The bars on the left illustrate the percentage of peak postprandial glucose concentrations that exceeded target of 180 mg/dL. Approximately 90% of these peaks exceeded target, even in these patients that were previously thought to be well controlled. Almost 50% of these peaks were above 300 mg/dL. The bars on the right illustrate the percentage of patients recording a low overnight sensor glucose concentration in the hypoglycemic range (less than 60 mg/dL). Nearly 70% of these patients recorded at least one episode of nocturnal hypoglycemia. Over 30% had glucose concentrations of 40 mg/dL or less recorded at least once. Over 20% (12 patients) recorded nocturnal hypoglycemia on all 3 nights. SLIDE BACKGROUND: Study was conducted at the Yale Children’s Diabetes Clinic. (Tamborlane was senior author for paper) N=56 All patients were <18 years; mean age= 11 years, 9 months Most patients used insulin pump (n=42). Others used 2 insulin injections/day (n=12) or 3-4 insulin injections/day (n=2) Patients were monitored for 3 days using the Medtronic MiniMed Continuous Glucose Monitoring System™ (CGMS) Nocturnal hypoglycemia Pre-meal glucose concentrations were in or near target range Authors describe the mean A1C of 7.7% and the patients’ pre-meal glucose values as “suggestive of good diabetes control” in this pediatric population. Target A1C for these patients was <8%. CSII: continuous subcutaneous insulin infusions MDI: multiple daily injections 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 40 % Patients 40 30 30 20 20 10 10 Breakfast Lunch Supper 1 Night 2 Nights 3 Nights 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:

20 Blood Glucose Values (SMBG) Needed to Attain Different HbA1C Values
ATR 33% ATR 41% ATR 46% WTR 45% WTR 49% WTR 42% BTR 18% BTR 12% BTR 14% HbA1c = 7.0% HbA1c = 8.0% HbA1c = 8.5% WTR = within target range ( mg/dl) BTR = below target range (<70 mg/dl) ATR = above target range (>150 mg/dl) Brewer KW, Chase PH, Owen S, Garg SK. Diabetes Care 1998;21(2):

21 Need for Continuous glucose monitoring
Direction Magnitude Duration Frequency Cause of fluctuation Alerts/Alarms Improve therapeutics decisions

22 Glucose Sensors Continuous Glucose Monitoring System (CGMS)
GlucoWatch Automatic Biographer Navigator Near-InfraRed (NIR) Implantable glucose sensors-Dexcom Optical sensors Ultrasonic sensors

23 DexCom Implantable Sensors
Glucose Sensors DexCom Implantable Sensors Pendra® GlucoWatch FreeStyle Navigator Sensys Medical NIR CH: Is this a problem to mention name brands for all these devices? Check with Maryland Academy of Family Physicians. Re-sized images for better fit. Deleted references to lessen “busyness” of slide. GlucoWatch Garg SK, et al. Diabetes Care 1999 Tamada & Garg SK, et al. JAMA, 1999 Pendra Caduff et al. ADA, IDF, 03 DexCom Garg SK, et al. Diabetes Care. 2004 MiniMed Tamborlane, Saudek and and Bode Diabetes Care Freestyle Feldman et al. ADA and DT&T, 2003 Sensys Monfre and Garg SK, et al. Diabetes, 2000 MiniMed

24 MiniMed® Continuous Glucose Monitoring System (CGMS)

25 GlucoWatch® Biographer

26 Schematics of the Autosensor & Biographer
Mask Hydrogel Pads Ionto Sensor Electrode Assembly AAA Battery Electronic Components Garg et al. Diabetes Care 1999;22:

27 Device Evaluation Advantages Disadvantages 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

28 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)

29 Sensors in Development
DexCom and Vascular Sensors NIR, Nostix, Therasense The Pendra, Pendragon Medica Sensys Glucose Tracking System, Sensys Glucon Solution, Glucon Sugartrac, Lifetrac Systems GlucoNIR, CME Telemetrix ReSense, MedOptix Pindi, Pindi Products Head-Mounted Goggles, NASA

30 Role of Frequent Glucose Monitoring

31 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):

32 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 80 121 40 120 160 200 240 280 320 360 400 11:00 AM 1:00 PM 3:00 5:00 7:00 9:00 Glucose (mg/dL) Pre Lunch Pre Dinner This slide has been previously shown to you by Dr. Pitzer. He shows you two time points where the blood sugars are incredibly normal. A pre-lunch and pre-dinner blood sugar that are in the normal range. Now a clinician would look at this glucose diary and tell the patient that the patient was doing excellently. Not to come back for several months and continue to do everything the patient was doing at that moment. Garg et al Diabetes Care ; 22; , 1999

33 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 80 Pre Dinner He then showed you what the GlucoWatch Biographer would have shown us had we had the opportunity to know the glucose patterns in between the pre-lunch and pre-dinner numbers. You can see the long periods of time the patient is sustained in the hyperglycemic levels. With this new information, we would not have concluded the patient was doing excellently, and could have counseled them on ways to improve their glucose control. 40 Pre Lunch 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; , 1999

34 Measurement of Blood Glucose Conventional Blood Glucose Meters
400 360 Biographer Blood Glucose Calibration Point 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 80 Pre Dinner 40 Pre Lunch 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; , 1999

35 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 12 MN 12 MN 1:30 AM 3:00 AM 4:30 AM 6:00 AM 7:30 AM 9:00 AM 1:30 PM 3:00 PM 4:30 PM 6:00 PM 10:30 AM 12 NOON 7:30 PM 9:00 PM 10:30 PM Time Chase and Garg , Pediatrics:107; , 2001

36 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

37 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

38 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

39 Device Description: DEXCOM Receiver Long Or Short Term Use
Receives and processes data from sensor Updates and displays glucose values every 5 minutes Displays 1, 3 and 9 hour trends High and low glucose alerts Garg et al., Diabetes Care, 27:734-38, 2004

40 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 CH: Shortened title and re-arranged some elements of figure to try to lessen “busyness.” Needs more work in graphic design to make he graph smaller. As you can see, this patient had a 74% drop in glucose levels under 55 mg/dL once the real-time values were displayed to him. In addition, this patient saw a 110% increase in values in the target range while he spent 4.4 hours less per day above 240 mg/dL. 2.46 1.53 2.13 3.00 6.37 8.74 6.46 6.16 6.58 4.57 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:

41 Slicing the Pie from DCGM Sensor Downloads Blinded vs
Slicing the Pie from DCGM Sensor Downloads Blinded vs. Unblinded phases (n=14) Unblinded phase Blinded phase WTR 37% WTR 51% ATR 41% ATR 51% BTR 12% BTR 8% WTR = within target range ( mg/dl) BTR = below target range (<60 mg/dl) ATR = above target range (>150 mg/dl)

42 Results (G2) 307  62 215  29 -30%** 352  12 332  14 -13%**
Excursion Duration (min)* Excursion Amplitude (mg/dl)* Blinded Unblinded Change Hyperglycemic (200 mg/dl) 307  62 215  29 -30%** 352  12 332  14 -13%** Hypoglycemic (80 mg/dl) 181  15 138  10 -24%** 50  3 51  4 +3% * Expressed as Mean  SEM ** Two-sided paired t-Test, p  0.05 Scott and Garg. ADA (LB5), o4 and EASD 2004

43 Hyperglycemia Exposure (mg/dl*hrs)*
Results (G2) Hyperglycemia Exposure (mg/dl*hrs)* Blinded Unblinded Change 573  123 340  64 -40%** * Expressed as Mean  SEM ** Two-sided paired t-Test, p  0.05 Scott and Garg. ADA (LB5)and EASD 2004

44 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

45 Family of Insulin Pumps Pardigm Link & Bolus Wizard Paradigm 512 ONLY
Medtronic MiniMed’s Family of Insulin Pumps Remote Control Paradigm 511 MiniMed 508 Paradigm 512 Paradigm Link Meter B 102 mg/dL Pardigm Link & Bolus Wizard Paradigm 512 ONLY

46 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.

47 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

48 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

49 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%.

50 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.”

51 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.

52 Predictions are difficult - particularly when you’re talking about the future!
Casey Stengel Adapted from Niels Bohr - Nobel Prize (Physics) 1922

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