Presentation on theme: "The Future of Pumping Henry Anhalt, DO, CDE"— Presentation transcript:
1 The Future of Pumping Henry Anhalt, DO, CDE Director, Pediatric Endocrinology and DiabetesSaint Barnabas Medical CenterLivingston, 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 RiskRetinopathyNephropathyNeuropathyMicroalbuminuriaHbA1c (%)15131197531681012Skyler. Endocrinol Metab Clin. 1996;25: , with permission.
5 Limitations/Challenges to Better Glycemic Control A1c’centricHypoglycemic RiskGlucose excursions above and below what the HbA1c average represents may be more important than HbA1cInadequate Postprandial Glucose ControlWeight Gain
6 Obstacles in Glycemic Control Invasive glucose monitoring devices-owie!!!!!Limited availability of reliable continuous glucose monitoringLack 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-readsUnder-reads
9 MAJOR RESEARCH CHALLENGES? CLINICALLYDevelopment of new methods for achieving tight control without hypoglycemiaRESEARCHDevelopment 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
10 APPROACHES TO CURING TYPE 1 DIABETES in vivo Differentiation of Pancreatic ProgenitorsImmune Interventions/Tolerance InductionManipulationOf non-islet tissue(TransdifferentiationTransplantationStem CellsGrowth FactorsIsletsAdultWhole pancreasGene TherapyModulate AutoimmunityIslet neogenesisFetalEmbryonic
11 TOWARDS CLOSED LOOP DELIVERY External Closed-LoopImplanted Closed-LoopBrad – describe implantable sensor and entire slide…Gary: ________
12 Glucose Contributions to HbA1c Postprandial GlucoseInfluenced by:Preprandial glucoseInsulin doseGlucose load from mealInsulin sensitivity in peripheral tissuesFasting Glucose influenced by:Liver glucose productionLiver sensitivity to insulin+Lantus, Basal rates,Humalog, Novalog
13 Are All HbA1c Values Created Equal? Blood GlucoseTimeHbA1c = 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.
17 Model of Multihormonal Regulation of Glucose Homeostasis BrainFoodIntake*—LiverGastricEmptying—Slide Index PH0016DISCUSSION POINTS:This diagram shows the key organ systems and hormones known to be involved in glucose regulationInsulin 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 emptyingAmylin 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 elevatedSuppressing inappropriately high glucagon secretion (which leads to inhibition of hepatic glucose output)Regulating gastric emptyingLong-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:StomachPostprandial GlucagonRate of glucose appearancePlasma GlucoseRate of glucose disappearanceGutGlucoseDisposalAmylinInsulinPancreasTissuesGLP-1Model derived from animal studies*Inferred satiety effectGLP-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%400300Glucose Concentration (mg/dL)20010012:00 AM4:00 AM8:00 AM12:00 PM4:00 PM8:00 PM12:00 AMN = 9, CSII treated (insulin lispro); A1C average 6.7% (range 5.8%-7.1%) ; 24-hour CGMS glucose sensor dataDesired glycemic range in non-diabetic subjects: mg/dLLevetan C, et al. Diabetes Care 2003; 26:1-8
19 % Peak Postmeal Glucose Levels Over Target Intensively-treated T1DM: Diurnal Glucose Fluctuation and Nocturnal HypoglycemiaMean A1C = 7.7%Postprandial HyperglycemiaNocturnal Hypoglycemia100CH: 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=56All patients were <18 years; mean age= 11 years, 9 monthsMost 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 hypoglycemiaPre-meal glucose concentrations were in or near target rangeAuthors 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 infusionsMDI: multiple daily injections90> 300 mg/dL241–300 mg/dL181–240 mg/dL41–60 mg/dL 40 mg/dL808070706060% Peak Postmeal Glucose Levels Over Target505040% Patients40303020201010BreakfastLunchSupper1 Night2 Nights3 Nights90% of Postprandial Readings Exceeded ADA GuidelinesNearly 70% of Patients Had 1 Night With PG < 60 mg/dLContinuous Glucose Monitoring System (CGMS) data, 56 adolescents, T1DM on CSII or MDICSII = Continuous subcutaneous insulin infusion; PG = Plasma glucoseBoland E, et al. Diabetes Care. 2001;24:
20 Blood Glucose Values (SMBG) Needed to Attain Different HbA1C Values ATR33%ATR41%ATR46%WTR45%WTR49%WTR42%BTR18%BTR12%BTR14%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 DirectionMagnitudeDurationFrequencyCause of fluctuationAlerts/AlarmsImprove therapeutics decisions
23 DexCom Implantable Sensors Glucose SensorsDexCom Implantable SensorsPendra®GlucoWatchFreeStyle NavigatorSensys Medical NIRCH: 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 1999Tamada & Garg SK, et al. JAMA, 1999Pendra Caduff et al. ADA, IDF, 03DexCom Garg SK, et al. Diabetes Care. 2004MiniMed Tamborlane, Saudek and and Bode Diabetes CareFreestyle Feldman et al. ADA and DT&T, 2003Sensys Monfre and Garg SK, et al. Diabetes, 2000MiniMed
24 MiniMed® Continuous Glucose Monitoring System (CGMS)
26 Schematics of the Autosensor & Biographer MaskHydrogel PadsIontoSensorElectrodeAssemblyAAA BatteryElectronicComponentsGarg et al. Diabetes Care 1999;22:
27 Device Evaluation Advantages Disadvantages Real-time measurement Non-invasive (no-biological fluids)Calibration stability71% of patients calibrateTrending capabilityDisadvantagesNot portableSkin temperature controlSampling site criticalFailure modes not all identifiedRequires daily finger stick
28 Near Infrared Ray (NIR) Large desk-like apparatusSkin temperature and hydrationCalibration is too cumbersomePatient intervention requiredReal 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 SensorsNIR, Nostix, TherasenseThe 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
31 More Frequent Testing Improves HbA1c in Type 1 Patients 11< 2< 210HbA1c (%)98> 4> 4> 476InitialNo ContactCross-OverIntensifySchiffrin A, Belmonte M. Diabetes Care 1982;(5):
32 Current Medical Practice Repeated finger-sticks are required to obtain glucose readings periodicallyTesting is generally performed before mealsOccasional measurements provide limited information about glucose levels801214012016020024028032036040011:00AM1:00PM3:005:007:009:00Glucose (mg/dL)Pre LunchPre DinnerThis 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 automaticallyFrequent readings provide more information about glucose levelsTrend information helps to identify opportunities for improved glucose control400360BiographerBlood Glucose320Calibration Point280240Glucose (mg/dL)20016012080Pre DinnerHe 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.40Pre Lunch11:001:003:005:007:009:0011:001:00AMPMPMPMPMPMPMAMGarg SK et al Diabetes Care ; 22; , 1999
34 Measurement of Blood Glucose Conventional Blood Glucose Meters 400360BiographerBlood GlucoseCalibration PointBased 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.320280240Glucose (mg/dL)2001211608012080Pre Dinner40Pre Lunch11:001:003:005:007:009:0011:001:00AMPMPMPMPMPMPMAMGarg et al Diabetes Care ; 22; , 1999
35 Continuous Subcutaneous Glucose Monitoring in a Subject with Type 1 Diabetes Meter ValueSensor ValueInsulinMeal450400350300250Glucose Concentration (mg/dL)2001501005012 MN12 MN1:30 AM3:00 AM4:30 AM6:00 AM7:30 AM9:00 AM1:30 PM3:00 PM4:30 PM6:00 PM10:30 AM12 NOON7:30 PM9:00 PM10:30 PMTimeChase and Garg , Pediatrics:107; , 2001
36 Technical Aspects of Continuous Glucose Monitoring Interstitial vs. Blood glucose –reported Lag of few seconds to 15 minutesHigh frequency of measurementsSignal Stability –Quick and over timeCalibration IssuesDuration of Sensor application
37 Limitations with Current Technologies SMBGSolitary Data points with no trend informationCGMSNo real time feedback, 4T/day calibrationUnreliable data, size of the needleGlucoWatch- Prospective data but too many skips,12 hr.sensor- Skin irritation, Sweating,Temperature changes* HbA1c and Fructosamine AssayPurely retrospectiveNo immediate Feedback
38 Device Description: Sensor DexCom G1 SensorSubcutaneous implant in theabdominal wallMulti-layer membrane systemMeasures glucose every 30 secondsWireless transmission to receiverGarg 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 alertsGarg et al., Diabetes Care, 27:734-38, 2004
40 Profile With Continuous Glucose Sensor in Patients With Insulin-requiring Diabetes Blinded periodUnblinded period1037%* increaseMean A1C = 7.2%4%* decrease31%* decrease8641%* increaseTime Spent (hours/day)38%* decrease42CH: 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.2.461.532.133.006.378.746.466.166.584.5740–5556–7980–140141–239240–400Glucose Range (mg/dL)*P < 0.05, Student’s t testGarg 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 phaseBlinded phaseWTR37%WTR51%ATR41%ATR51%BTR12%BTR8%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)*BlindedUnblindedChangeHyperglycemic (200 mg/dl)307 62215 29-30%**352 12332 14-13%**Hypoglycemic(80 mg/dl)181 15138 10-24%**50 351 4+3%* Expressed as Mean SEM** Two-sided paired t-Test, p 0.05Scott and Garg. ADA (LB5), o4 and EASD 2004
43 Hyperglycemia Exposure (mg/dl*hrs)* Results (G2)Hyperglycemia Exposure (mg/dl*hrs)*BlindedUnblindedChange573 123340 64-40%*** Expressed as Mean SEM** Two-sided paired t-Test, p 0.05Scott and Garg. ADA (LB5)and EASD 2004
44 Closing the Loop: The Artificial Pancreas Accurate, reliable continuous glucose monitoring systems, in progressAlgorithms to incorporate glucose trend data into proper dose adjustmentsExternal or internal insulin pump systems
45 Family of Insulin Pumps Pardigm Link & Bolus Wizard Paradigm 512 ONLY Medtronic MiniMed’sFamily of Insulin PumpsRemote ControlParadigm 511MiniMed 508Paradigm 512Paradigm Link MeterB102 mg/dLPardigm 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 numbersMinimize the moodiness associated with wide glucose excursionsUnderstand glucose profiles over extended timeImprove implementation of new regimensKnowledge and acceptance of inaccuracies and data interpretation
48 ConclusionsContinuous glucose monitoring promises the goal of normalization of blood sugars while minimizing risk of hypoglycemiaThe result of full implementation will be normal HbA1c with further reduction in complications of diabetesA closed loop, artificial pancreas either externally or internally based is now on the horizon
49 Implantable pumpImplanted 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 RUBEven 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 StengelAdapted from Niels Bohr - Nobel Prize (Physics) 1922