The Key Problem of Diabetes Treatment: Results are Out-of-Target NHANES 1999-2000, GOAL Survey % of Subjects n = 404 37.2% >8% 63% 7% 7.8% 25.8% 37.0% 17.0% A1c 12.4% Saydah SH et al. JAMA 2004; 291: 335-342.

DCCT Experience: Tight Blood Glucose Control Allows Reduction of Retinopathy but is Associated With an Increase of Severe Hypoglycemia 20 40 60 80 100 120 2 4 6 8 10 progression of retinopathy (per 100 patient-years) (per 100 patient-years) severe hypoglycemia 11 10 9 8 7 6 5 HbA1c (%)

To Reach Normoglycemia Using Open-loop Insulin Delivery May However Be a Nightmare For some Type 1 Diabetic Patients… And Their Doctors

Discrepancies Between SMBG Data and HbA1c Raise Questions About Treatment Adaptation 350 300 4 daily insulin shots HbA1c = 8.5% Starting complications 250 200 BLOOD GLUCOSE (mg/dl) 150 100 50 MEAL MEAL MEAL SNACK 6:00 12:00 18:00 24:00 TIME PREMEAL BG DATA

It is hard being good all the time! 350 300 250 200 BLOOD GLUCOSE (mg/dl) 150 100 50 MEAL MEAL MEAL SNACK 6:00 12:00 18:00 24:00 TIME PREMEAL BG DATA GLUCOSE SENSOR

Continuous Glucose Monitoring in the Clinical Setting: How helpful might it be? CBGM can identify hyperglycemic deviations in poorly controlled diabetic patients CBGM can detect hypoglycemic deviations in diabetic patients aiming at tight control CBGM can identify hyperglycemia in non diabetic patients in critical situations

Continuous Glucose Monitoring in the Clinical Setting: How to perform it?

Needle-type Subcutaneous Glucose Sensor Guardian RT®, Medtronic Glucose Oxidase 2e- Glucose Interstitial Fluid Gluconic Acid Semi-permeable Membrane Pt Electrode 0.5 volts To Monitor CGMS®, Medtronic Guardian RT®, Medtronic STS®, DexCom

Les instruments de mesure continue du glucose actuels CGMS Gold® GlucoDay®, A. Menarini Diagnostics GlucoWatch Biographer®, Cygnus Glucose oxydase dans aiguille SC Etalonnage 2/j Durée: 63h 99% corrélation BG 4min délai réponse  Holter glycémique Microdialyse: mesure extracorporelle Etalonnage 1/j Durée: 24h 97% corrélation BG <3min délai réponse Iontophorèse inverse Etalonnage 1/j Durée: 12h 97% corrélation BG 20 min délai réponse

Les nouveaux dispositifs de mesure en temps réel Guardian RT® Freestyle Navigator® DEXCOM STS system® Mesures sur 5 jours consécutifs avec mise à jour toutes les minutes Affichage des tendances Calibration 1/j Mesures sur 3 jours consécutifs avec mise à jour toutes les 5 minutes Calibration 2/j Mesures accessibles en direct sur 3 jours Affichage des tendances pour les 3, 6 et 9 dernières heures Calibration 2/j

Continuous Glucose Monitoring in the Clinical Setting: How to perform it? Monitoring of SC interstitial glucose is the current way to approach blood glucose. Enzymatic sensors using Glucose Oxidase are the currently used sensing systems. All are at least minimally-invasive. They allow retrospective (‘Holter-style’) or ‘On-line’ monitoring. Obtained data are blood glucose estimations according to sensor signal calibration.

Continuous Glucose Monitoring in the Clinical Setting: How accurate and reliable is it?

Key Conditions for Effective Glucose Sensing in the Clinical Setting Accuracy +++ According to Aimed Use: On-line use: Reactivity (short response time) Continuous use: Durability (days, weeks, months, years)

Stability of Glucose Measurement by CGMS® Using 4 Times-daily Calibration

Drift of Needle-type SC Sensor Signal (CGMS®) After Day 3

Metzger et al, Diabetes Care 2002 Assessment of Reproducibility Between Two Needle-type Sensors (CGMS®) in the Same Patients Metzger et al, Diabetes Care 2002

Delay of Sensor Glucose vs Blood Glucose with GlucoWatch Biographer® Kulcu et al, Diabetes Care 2003

Respective Characteristics of Glucose Sensing According to Available Devices GlucoWatch CGMS ® GlucoDay® STS® Biographer ® ACCURACY - Mean Absolute Deviation (%) 14,5 12,8-15,7 -2,0/6,9/11,2 21,2 - % paired points in A & B zones of Clarke Point Error Grid 96,6 98,9 97,0 95,4 Correlation Factor (r) 0,90 0,87-0,92** 0,90 0,88 AVERAGE SENSING TIME (hours) 12 63 48 72 CALIBRATION (number of points) 1 4 /day 1/day 2/day RESPONSE TIME (min) 20 4 < 3 < 5 REFERENCE Potts et al Guerci et al Maran et al Garg et al

Benefits & Limits of Interstitial Glucose Sensing With Current Devices New data from estimated blood glucose by sensor Identification of BG deviations undetected by SMBG (post-meal and night-time) Limits Limited accuracy related to SC glucose measurement = trends more than absolute BG values Limited biocompatibility = short-term use Most valuable data are retrospective (‘Holter-style’) On-line data need confirmation by SMBG before decisions

Continuous Glucose Monitoring in the Clinical Setting: Success and Pitfalls

CGMS® Recordings May Improve Effectiveness of Insulin Delivery Poor modulation of insulin infusion Improved control following CGMS-based adjustments of infusion

Assessment of the Benefits of Permanent vs Iterative CBGM vs SMBG for 3 Months: GuardControl Study Significant benefit only b/w permanent CBGM and SMBG Deiss et al, Diabetes Care, 2006; 29: 2730-2

Résultats d’une mesure continue instantanée: STS Dexcom Le disposituf dexcom offre les mêmes atouts que le navigator mais un temps de mesure limité à 3 jour /capteur: capteur avec transmission sans fil, affichage en direct des glycémies , bonne précision par rapport à une technique de référence. Dans une étude randomisée incluant 91 patients, le fait de démasquer les données fournies par le lecteur permet aux patients de réduire le temps passé dans des zones basses ou hautes et d’intégrer progressivement la technique avec une amélioration progressive au fil du temps. ↓ 21 % de glycémies < 0,55 g/L ↓ 23 % de glycémies > 2,40 g/L Garg S. et al., Diabetes Care, 2006

Résultats d’une mesure continue instantanée: FreeStyle Navigator Eude multicentrique, n = 137 (37 type 2) 20 jours en lecture « masquée » 20 jours suivants en lecture directe et alarmes * p<0,05 ↓ 42 % ↓ 18 %

Success and Pitfalls in Using Continuous Glucose Monitoring in the Clinical Setting Short-term improvements in poorly-controlled patients. No significant benefits to intensively treated patients performing multiple-daily SMBG. Sustained benefits (> 3 months) of CBGM use lack any evidence.

A Closed Loop Insulin Delivery System would Help in Restoring Stable Normoglycemia Blood Glucose INSULIN DELIVERY DEVICE GLUCOSE SENSOR ? 2 CONTROL SYSTEM 1 ? 3 ?

Les obstacles à la boucle fermée: délai mesure/action Délai de 30 min entre mesure et action de l’insuline Action de l’insuline (-30 min) Cellule β et voie IV-IV Délai de 70 min entre mesure et action de l’insuline Absorption de l’insuline IP (-40 min) Action de l’insuline (-30 min) Approche IV-IP Délai de 100 min entre mesure et action de l’insuline Absorption de l’insuline SC (-50 min) Action de l’insuline (-30 min) Délai GI et GP (~10min) Transport* (~15min) Approche SC-SC

Les résultats SC-SC: Boucle fermée Hyperglycémies post prandiales Hypoglycémies à distance Boucle semi fermée: bolus lors des repas By courtesy of W. Tamborlane

Fully Implantable Glucose Sensor (LTSS): an Option for IV Sensing

(LTSS-02 study, Lapeyronie Hospital, Montpellier) ? CONTINUOUS BLOOD GLUCOSE MONITORING BY IV LONG-TERM GLUCOSE SENSOR IMPLANTED SINCE 13 MONTHS IN A TYPE 1 DIABETIC PATIENT (AXM 01-04) (LTSS-02 study, Lapeyronie Hospital, Montpellier)

CLARKE ERROR GRID ANALYSIS OF SENSOR DATA 2 ? CLARKE ERROR GRID ANALYSIS OF SENSOR DATA FROM PATIENT AXM OVER 11 MONTHS (vs. HemoCue) D E C B A r = 0.9191 50 100 150 200 250 300 350 400 450 Sensor # 7037- 11 Month Clarke Plot Points = 3014 ; A= 2322 (77.1%); B= 597 (19.8%); C= 0 (0.%); D= 93 (3.1%); E= 0 (0.%) Sensor Glucose ClarkeShifted Reference Glucose Reference Glucose

IMPLANTABLE PUMP USING IP ROUTE A Closed Loop Insulin Delivery System would Help in Restoring Stable Normoglycemia Blood Glucose INSULIN DELIVERY DEVICE GLUCOSE SENSOR ? 2 CONTROL SYSTEM IMPLANTABLE PUMP USING IP ROUTE 1 3 ?

CLOSED-LOOP GLUCOSE CONTROL USING LTSS AT NIGHT-TIME (12 AM - 6 AM) BASAL TIGHT GLUCOSE CONTROL

FIRST TRIAL OF CLOSED-LOOP INSULIN DELIVERY USING LTSS (April 2001, Lapeyronie Hospital, Montpellier) Feasibility and safety in a diabetic human Basal normoglycemia Post-meal hyperglycemic excursions