Expanding The Indications For CSII and Sensing Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

Undiagnosed diabetes ~5.2 million Prevalence of Glycemic Abnormalities in the United States Additional million with IGT Diagnosed type 2 diabetes ~12 million Diagnosed type 1 diabetes ~1.0 million Centers for Disease Control. Available at: Harris MI. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK; 1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001 US Population: 275 Million in

Relative Risk of Progression of Diabetic Complications DCCT Research Group, N Engl J Med 1993, 329: RELATIVE RISK Mean A1C

Gain of 15.3 years of complication free living compared to conventional therapy Gain of 5.1 years of life compared to conventional therapy Lifetime Benefits of Intensive Therapy (DCCT) DCCT Study Group, JAMA 1996, 276:

1-905 Stratton IM et al. BMJ 2000;321:405 Effect of A1C on Myocardial Infarction and Microvascular Complications in the UKPDS Study A1C

Lessons from the DCCT and UKPDS: Sustained Intensification of Therapy is Difficult DCCT EDIC (Type 1) UKPDS (Type 2), Insulin Group DCCT/EDIC Research Group. New Engl J Med 2000; 342: Steffes M et al. Diabetes 2001; 50 (suppl 2):A63 UK Prospective Diabetes Study Group (UKPDS) 33 Lancet 1998; 352: yrs DCCT EDIC yrs A1C (%) Normal Baseline A1C (%)

Specific Goals in Management of Diabetes Fasting < 110 mg/dL Post-meal < 140 mg/dL A1C < 6.5% Blood Pressure < 130/80 LDL 45 mg/dL Triglycerides < 150 mg/dL

Primary Objectives of Effective Management A1C % SBP mm Hg LDL mg/dL Diagnosis Patient Age Reduction of both micro- and macro- vascular event rates …by 75%! lGæde P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:

Insulin The most powerful agent we have to control glucose

Patient J.L., December 15, 1922 February 15, 1923 The Miracle of Insulin

Progression of Type 1 Diabetes Adapted from: Atkinson. Lancet. 2002;358: Age (y) Precipitating Event Beta-cell mass Genetic predisposition Normal insulin release Glucose normal Overt diabetes No C-peptide present Progressive loss of insulin release C-peptide present Antibody

Options in Insulin Therapy for Type 1 Diabetes Current —Multiple injections —Insulin pump (CSII) Future —Implant (artificial pancreas) —Transplant (pancreas; islet cells)

Type 2 Diabetes … A Progressive Disease Over time, most patients will need insulin to control glucose

Multiple factors may drive progressive decline of  -cell function  -cell (genetic background) Hyperglycaemia (glucose toxicity) Protein glycation Amyloid deposition Insulin resistance “lipotoxicity” elevated FFA,TG

Goals of Targeted Insulin Therapy (Intensive/Physiologic/Flexible) Maintain near-normal glycemia Avoid short-term crisis Minimize long-term complications Improve the quality of life Hours

4: :0012:0016:0020:0024:004:00 BreakfastLunchDinner Plasma insulin (U/ml) Plasma insulin ( µ U/ml) Time 8:00 Physiological Serum Insulin Secretion Profile

4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs LisproLisproLispro AspartAspartAspart or

4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal infusion Bolus Plasma insulin Variable Basal Rate: CSII Program

Insulin aspart (CSII) vs insulin aspart / glargine (MDI) Run-in (1 week)Period 1 (5 weeks)Period 2 (5 weeks) IAsp CSII IAsp + Gar MDI CSII vs MDI with Glargine in Adults Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract patients with type 1 on CSII at entry A1C <9% Efficacy: A1C, fructosamine, 8-point BG profile, glucose exposure (CGMS) Safety: frequency of hypoglycemia, AEs

Pumps vs MDI: Characteristics of Enrolled Population Data of file, Novo Nordisk. ANA-2155 Treatment Sequence a CSII to MDIMDI to CSIIAll Subjects Subjects Treated Age (years) 41.7    11.1 BMI (kg/m 2 ) 27.1    4.0 A1C at screening (%) 7.5    0.8 Duration of diabetes (years) 19.7    11.9 Daily insulin dose 42.3  17.9 (n = 45) 41.6  16.1 (n = 50) 41.9  16.9 (n = 95) Basal 21.1    9.2 Bolus 22.7    11.4

CSII vs MDI: Better BG Control Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438. Mean ± 2 SEM Self- monitored BG (mg/dL) BBAB BL ALBDADMidnight 3 AM CSII (n=93) MDI (n=91)

n=63 in each treatment CSII MDI P= *Measurement of AUC (glu) ≥80 mg/dL during the 48-hour continuous glucose monitoring period. AUC glu (mgh/dL) Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438. CSII vs MDI: Less Glucose Exposure

CSII vs MDI: Rate of Hypoglycemia Episodes/subject/5 weeks TotalDaytimeNocturnal P= P< P= CSII MDI Bode, et al. Diabetes 52,(Suppl 1), 2003 Abstract 438.

CSII vs MDI with Glargine in Children – Preliminary Data Boland et al., Diabetes 2003, 52:S1, A45, 192-OR Subjects at baseline Age: 8-19 yr (mean 12.7 ± 2.7) Type 1 DM > 1 yr duration Standard insulin therapy (2-3 injections/day) CSII (aspart) n=12 MDI (aspart/glargine) n=14 16 Week treatment period Injection therapy Randomized, Parallel-group, 16 week study

Baseline4 weeks8 weeks12 weeks16 weeks Glargine (n=16) CSII (n=14) CSII vs. MDI with Glargine in Children (Preliminary Data) Boland, E. Diabetes 52,(Suppl 1), 2003 Abstract 192. A1c

CSII vs MDI in Children – Preliminary Data Safety and Preference Safety Severe hypoglycemic episodes MDI: 4 CSII: 2 No cases of DKA Preference (at 16 weeks) All 12 CSII subjects remained on CSII 12 of 14 MDI subjects switched to CSII Boland et al., Diabetes 2003, 52:S1, A45, 192-OR

CSII Reduced HbA1c in Type 2 Patients CSIIMDI Baseline End of study (24 weeks) Raskin et al. Diabetes. 2001;50(suppl 2):A128. A1C (%) N=127

Change in scores (raw units) from baseline to endpoint Convenience Less burden Less hassle Advocacy Preference General satisfaction Flexibility Less life interference Less pain Fewer social limitations MDICSII Patient Satisfaction in Type 2 DM Testa et al. Diabetes. 2001;50(suppl 2):1781

Metabolic Advantages with CSII Improved glycemic control Better pharmacokinetic delivery of insulin —Less hypoglycemia —Less insulin required Improved quality of life

N=165. Average duration=3.6 years. Average discontinuation <1%/y. Continued 97% Discontinued 3% Current Continuation Rate: Continuous Subcutaneous Insulin Infusion (CSII) Bode BW, et al. Diabetes. 1998;47(suppl 1):392.

US Pump Usage: Total Patients Using Insulin Pumps Industry estimates

Photograph reproduced with permission of manufacturer.

Pump Infusion Sets

Current Pump Therapy Indications Diagnosed with diabetes (even new-onset type 1 diabetes) Need to normalize blood glucose —A1C > 6.5% —Glycemic excursions —Hypoglycemia Need for flexible insulin program

Monitoring —A1C = (0.21 x BG per day) Recording 7.4 vs 7.8 Diet practiced —CHO: 7.2 —Fixed: 7.5 —WAG: 8.0 Insulin type (Aspart) CSII Factors Affecting A1C Bode et al. Diabetes 1999;48 Suppl 1:264 Bode et al. Diabetes Care 2002;25 439

Initial Adult Dosage: Calculations Starting doses Based on pre-pump total daily dose (TDD)  reduce TDD by 25% to 30% for pump TDD Calculated based on weight  0.24 x weight in lb (0.53 x weight in kg) Bode BW, et al. Diabetes. 1999;48(suppl 1):84. Bell D, Ovalle F. Endocr Pract. 2000;6: Crawford LM. Endocr Pract. 2000;6:

Normal —Preprandial: mg/dl —1 hr postprandial:<160 mg/dl Hypoglycemic unawareness —Preprandial: mg/dl Pregnant —Preprandial: mg/dl —1 hr postprandial:<120 mg/dl Individually set for each patient Target BG Ranges for CSII Fanelli CG et al., Diabetologia 1994, 37: Jovanovich L, AMJObGynec 1991, 164:

Initial Adult Dosage: Calculations Basal rate 45% to 50% of pump TDD Divide total basal by 24 hours to decide on hourly basal Start with only 1 basal rate See how it goes before adding basals

Basal Dose Adjustment Overnight Rule of 30: Check BG Bedtime 12 AM 3 AM 6AM Adjust overnight basal if readings vary > 30 mg/dl

Adults often need an increase in basal rate in the “Dawn” hours (4 am to 9 am) Children often need an increase in basal rate earlier starting at 10 pm to 2 am Basal Dose Adjustment Overnight

4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal infusion Bolus Plasma insulin Variable Basal Rate: CSII Program

Basal Dose Adjustment Daytime Rule of 30: Check BG Before usual meal time Skip meal Every 2 hrs (for 6 hrs) Adjust daytime basal if readings vary > 30 mg/dl

Bolus Dose Calculations Meal (food) Bolus Method 1 Test BG before meal Give pre-determined insulin dose for pre-determined CHO content Test BG after meal Goal < 60 mg/dl rise post meal or < 160 mg/dl

Individually determined CIR = (2.8 x wgt in lbs) / TDD Anywhere from 5 to 25 g CHO is covered by 1 unit of insulin Estimating the Carbohydrate to Insulin Ratio (CIR) Davidson et al: Diabetes Tech & Therap. April 2003

What Type of Bolus to Use? 9 DM 1 patients on CSII ate pizza, tiramisu, and coke on four consecutive Saturdays Single bolus Double bolus at -10 and 90 min Square wave bolus over 2 hours Dual wave bolus (70% at meal, 30% as 2-h square) Chase HP et al: Diabetic Medicine 2002;19:

BG Change from Baseline in mg/dl 1 bolus 2 bolus Square Dual Comparison of Pump Boluses with High Carbohydrate & High Fat Meal Hours from Baseline Chase HP et al: Diabetic Medicine 2002;19:

Correction Bolus Must determine how much glucose is lowered by 1 U of rapid-acting insulin This number is known as the correction factor (CF) Use the 1700 rule to estimate the CF CF=1700 divided by TDD example: if TDD=36 U, then CF=1700/36=  50, meaning 1 U will lower the BG  50 mg/dL

Correction Bolus Formula Example: —Current BG:220 mg/dL —Ideal BG: 100 mg/dL —Glucose CF: 50 mg/dL Current BG - Ideal BG Glucose Correction Factor = 2.4 U

If A1C is Not to Goal SMBG frequency and recording Diet practiced —Do they know what they are eating? —Do they bolus for all food and snacks? Infusion site areas —Are they in areas of lipohypertrophy? Other factors: —Fear of low BG —Overtreatment of low BG Must look at:

If A1C Is Not at Goal and No Reason Identified Place on a continuous glucose monitoring system CGMS by Medtronic MiniMed or GlucoWatch by Cygnus to determine the cause

GlucoWatch ® Biographer

CGMS

CGMS Sensor

Monitor and Com-Station

Case Study # 1 GL, male, age 39 Type 1 X 8 years A1C= 7%; recent increase from 6% CSII basal rates: 12 am 1.0 u/h; 4:30 am 1.6 u/h; 11:30 am 1.0 u/h Insulin: carbohydrate ratio =1u : 10 grams Correction Factor: BG divided by 40 CGMS done to assist with improving overall glycemic control

Modal Day View

Cheese / Crackers 20 g; 3units 30 gm CHO; Heavy Exercise 80 CHO; 7u 2u; 57 g CHO Milk choc 15g; 8u Juice box; no insulin Ice Cream; 3 u 6u

Most common bolusing errors Under-estimation of carbohydrates consumed (CHO bolus) Over-correction of post-prandial elevations (CF bolus) — Remaining unused, active insulin — Stacking of boluses

Bolus: Source of Errors “Inability” to count carbs correctly — Lack of knowledge, skill — Lack of time — Too much work Incorrect use of SMBG number Incorrect math in calculation “WAG” estimations

The Major Problems ♦Up until now we have not taken the active insulin issue into consideration ♦The math involved with this has become too complicated, and it would be impossible to accurately calculate the active insulin without assistance

Dosing Tools: The FUTURE

Monitor sends BG value to pump via radio waves : No transcribing error Enter carbohydrate intake into pump “Bolus Wizard” calculates suggested dose Paradigm Link ™ Paradigm 512 ™ ) ) ) ) ) ) ) ) ) ) ) ) ) Bolus Wizard Calculator : meter-entered

The Bolus Wizard™ Calculator Can be customized with up to 8 different setting per day for: —Blood glucose targets —Carbohydrate ratios —Insulin-sensitivity factors Simplifies Diabetes Management —Reduces math errors —Decreases the number of correction boluses required * —Lowers the entry error rate when using the Paradigm Link TM Blood Glucose Monitor, powered by BD Logic TM Technology

Bolus Wizard TM Calculator Uses an Active Insulin Formula Based on insulin pharmacodynamic data Helps prevent insulin stacking

Insulin Activity Over Time Rapid Acting Regular Insulin Activity (GIR) Time (hrs) Insulin Pharmacodynamic Data Adapted from Henry R: Diabetes Care 1999

Rapid Acting Regular Time (hrs) Percent Remaining Adjusting for Active Insulin: How smart pumps do it

Wizard: On Carb Units: grams Carb Ratios: 10 BG Units: mg/dl Sensitivity: 50 BG Target: 100 Bolus Wizard Set Up Screen

Breakfast - Step 1. Check BG Use the Paradigm Link™, powered by BD Logic™ Technology or their currrent meter

Robin accepts the transferred blood glucose value —Requires confirmation —Can change glucose value if necessary Breakfast - Step 2. Accept BG Enters CHO grams —53 grams of carbohydrate

The Paradigm ® presents the dose —5.3 U for 53 grams carb (CIR = 10) —No correction dose —Shows total 5.3 U Accept suggested dose Pump delivers dose Breakfast - Step 3. Accept Dose

Robin has a late lunch at 2:10 PM — Blood glucose 160 — Accepts the transferred BG value Late Lunch - Step 1,2 Enters CHO grams — 50 grams of carbohydrate 50

The Paradigm ® presents the dose —5.0 U for 50 grams carb (CIR = 10) —Correction dose = 1.2 U ( ) / 50 = 60/50 = 1.2 —Shows total 6.2 U Accept suggested dose Pump delivers dose Late Lunch - Step 3. Accept Dose

Enters CHO grams —50 grams of carbohydrate 50 Robin plans to have appetizers at 5:30 PM — This is only 3.5 hours after lunch. — There is still an active insulin depot — Blood glucose is 157 — Accepts the transferred BG value Early Supper - Step 1,2

The Paradigm ® presents the dose — 5.0 U for 50 grams carb (CIR = 10) — Correction dose = 1.1 U ( )/50 — Remaining active insulin = 2.6 U — Remaining active insulin > correction dose — No correction dose is recommended — Total shows 5.0 U Early Supper - Step 3. Accept Dose Accept dose Pump delivers dose

For This System To Work ♦It is critical the target, basal doses, the correction doses, and the carbohydrate ratios are accurate ♦Understanding how to match carbohydrate amounts with insulin is critical ♦Even though the active insulin and complicated math is calculated by the system, the patient needs to understand the basic principles of how the insulin doses are calculated.

Do Smart Pumps Enable Others To Go To CSII? YES All patients with diabetes not at goal are candidates for Insulin Pump Therapy - Type 1 any age - Type 2 - Diabetes in Pregnancy

Paradigm ® Pathway to Future Diabetes Management As technology advances, so does the Paradigm pump New tools and applications will be available —Wireless communication —More memory and brain power

GLUCOSE MONITORING SYSTEMS - Telemetry Wireless communication from sensor to monitor High and low glucose alarms (Guardian 1 or 715) “Real time” glucose readings (Guardian 2 or 722) Not FDA approved Consumer Product

FreeStyle Navigator TheraSense Continuous Glucose Monitor Patient Inserted Sensor “On demand” glucose and trend arrow User-configurable Low Glucose and High Glucose Alarms Projected alarms give advance warning of glucose excursions Integrated FreeStyle blood glucose meter (3) BG calibrations for each 3-day sensor Wireless sensor-to-Meter path (10 foot operating range)

FreeStyle Navigator TheraSense Continuous Glucose Monitor –Designed to monitor interstitial fluid and provide continuous glucose readings –Patient-attached adhesive section includes sensor, and wireless transmitter –Designed to be self-inserted every three days and provide patients with glucose for use in managing therapy

The DexCom Continuous Glucose Sensor System Sensor —7 x 1 cm —Cylindrical —7 cc —Battery —Microprocessor —Antenna Receiver —Pager-Like Receiver with Graphical Display

The DexCom Continuous Glucose Sensor System Technology Description Sensor —Multi-layer membrane Modifies foreign body response Promotes local vascularization Glucose oxidase —Measures glucose every 30 seconds —Wireless transmission to receiver Receiver – Receives and processes data from sensor – Updates value every 5 minutes – Displays glucose value – Displays 1, 3, and 9 hour graphic trends – High and low Alerts

Implanted Closed-Loop External Closed-Loop Vision towards the Artificial Pancreas * This product concept not yet submitted to the FDA for commercialization.

Predicted Times Glucose Sensors - Alarm sensor (72 hr) early Replace fingersticks mid late 2005 Semi-Closed loop 2006 – 2007 Implantable

Summary Insulin remains the most powerful agent we have to control diabetes When used appropriately in a basal/bolus format, near-normal glycemia can be achieved Newer insulins and insulin delivery devices along with glucose sensors will revolutionize our care of diabetes

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