Diabetes Update And Insulin Delivery Systems - Adaendo

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Diabetes Update New Insulins and Insulin Delivery Systems Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

Prevalence of Diabetes in the US Diagnosed Type 2 Diabetes 10.3 Million Diagnosed Type 1 Diabetes 0.5 – 1.0 Million Undiagnosed Diabetes 5.4 Million American Diabetes Association. Facts and Figures. Available at: http://www.diabetes.org/ada/facts.asp. Accessed January 18, 2000. 3

Causes of Death in People With Diabetes 50 40 %of Deaths 30 20 10 0 Ischemic Other Heart Disease Heart Disease Diabetes Cancer Stroke Infection Other Geiss LS, et al. In: Diabetes in America, 2nd ed. 1995. Bethesda, MD: National Institutes of Health; 1995:chap 11. 4

Goals of Intensive Diabetes Management Near-normal glycemia – HbA1c less than 6.5 to 7.0% Avoid short-term crisis – Hypoglycemia – Hyperglycemia – DKA Minimize long-term complications Improve QOL ADA: Clinical Practice Recommendations. 2001.

Relative Risk of Progression of Diabetic Complications by Mean HbA1C Based on DCCT Data 15 13 11 Retinop RELATIVE RISK 9 Neph 7 5 Neurop 3 1 Microalb 6 Skyler, Endo Met Cl N Am 1996 7 8 9 HbA1c 10 11 12

HbA1c and Plasma Glucose 26,056 data points (A1c and 7-point glucose profiles) from the DCCT Mean plasma glucose (A1c x 35.6) – 77.3 Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002

Emerging Concepts The Importance of Controlling Postprandial Glucose

ACE / AACE Targets for Glycemic Control HbA1c 6.5 % Fasting/preprandial glucose 110 mg/dL Postprandial glucose 140 mg/dL ACE / AACE Consensus Conference, Washington DC August 2001

Natural History of Type 2 Diabetes Glucose mg/dL Post-prandial glucose 350 300 250 200 150 100 Fasting glucose Relative to normal (%) 250 200 150 100 50 0 Insulin resistance At risk for diabetes -10 -5 Insulin level Beta-cell dysfunction 0 5 10 15 20 25 30 Years R.M. Bergenstal, International Diabetes Center

Major Metabolic Defects in Type 2 Diabetes Peripheralinsulin resistance in m uscle and fat D ecreased pancreatic insulin secretion Increased hepatic glucose output Haffner SM, et al. Diabetes Care, 1999

Insulin Resistance: An Underlying Cause of Type 2 Diabetes Aging Obesity and inactivity Genetic abnormalities INSULIN RESISTANCE Type 2 diabetes Medications Rare disorders PCOS Hypertension Reaven GM. Physiol Rev. 1995;75:473-486 Clauser, et al. Horm Res. 1992;38:5-12. Dyslipidemia Atherosclerosis

Type 2 Diabetes: Two Principal Defects Genes Genes Insulin resistance β-cell dysfunction/ failure Environment Environment IGT Glucose Toxicity IGT Type 2 diabetes Reaven GM. Physiol Rev. 1995;75:473-486 Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S; Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127. Glucose Toxicity

HbA1c in the UKPDS 9 HbA1c (%) Conventional 8 Intensive 7 6.2% upper limit of normal range 6 0 0 3 6 9 Years from randomisation 12 15

UKPDS: β-Cell Function for the Patients Remaining on Diet for 6 Years β-Cell Function (% β) 100 80 60 40 20 N 376 0 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 Years After Diagnosis Adapted from UKPDS Group. Diabetes. 1995; 44:1249-1258. 2 3 4 5 6

UKPDS: Benefits of Glycemic Control in Type 2 Diabetes Risk reduction over 10 years Any diabetes-related endpoint Microvascular endpoints Myocardial infarction Cataract extraction Retinopathy at 12 years Microalbuminuria at 12 years UKPDS 33. Lancet. 1998;352:837-853. 12% 25% 16% 24% 21% 33% P 0.029 P 0.0099 P 0.052 P 0.046 P 0.015 P 0.001

Metformin Prevents Heart Attacks and Reduces Deaths in Type 2 Diabetes Heart Attacks Coronary Deaths P 0.01 P 0.02 10 Incidence (per 1,000 patient years) 20 8 15 39% Reduction 6 50% Reduction 10 4 5 2 0 0 Conventional Metformin Therapy Conventioal Metformin Therapy

Management of Type 2 DM Step Therapy Diet Exercise Sulfonylurea or Metformin Add Alternate Agent Add hs NPH vs TZD Switch to Mixed Insulin bid Switch to Multiple Dose Insulin Utilitarian, Common Sense, Recommended Prone to Failure from Misscheduling and Mismanagement

Management of Type 2 DM Stumble Therapy WAG Diet Golf Cart Exercise Sample of the Week Medication – Interrupted – Not Combined Poor Understanding of Goals Poor Monitoring HbA1c 8% (If Seen)

Consider A New Treatment Paradigm Treatment designed to correct the dual impairments Vigorous effort to meet glycemic targets Simultaneous rather than sequential therapy Combination therapy from the outset Early step-wise titrations to meet glycemic targets

Goals in Management of Type 2 Diabetes Fasting BG 110 mg/dL Post-meal 140 mg/dL HbA1c 6.5% Blood Pressure 130/80 LDL 100 mg/dl HDL 45 mg/dl

Thiazolidinediones: Mode of Action Peroxisome Proliferator-Activated Receptors PPARγ – Affects glucose, lipid and protein metabolism PPARα – Affects lipoprotein metabolism (some TZDs) Saltiel & Olefsky. Diabetes 1996;45:1661–9

Thiazolidinediones: Rationale for Type 2 Diabetes Therapy Proven characteristics – – – – Target insulin resistance, a core defect Improve glycemic control Do not cause hypoglycemia Improve lipid profile (pioglitazone and troglitazone) Potential benefits – Preservation of pancreatic b-cell function – Prevention of progression from impaired glucose tolerance to type 2 diabetes – Improvement in cardiovascular outcomes Saltiel & Olefsky. Diabetes 1996;45:1661–9 Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

Change in Lipid Profile at Endpoint: ACTOS Added to Sulfonylurea from baseline at 16 weeks SU Placebo (n 187) SU ACTOS 30 mg (n 189) 20 * 12.00 10.15 10 7.02 4.07 (%) 6.57 2.33 0 -0.95 -10 -15.89 -20 * Triglycerides Baseline (mg/dL) 258.6 259.5 LOCF * p 0.05 vs. placebo Total cholesterol 211.5 214.4 HDL cholesterol 42.9 41.8 LDL cholesterol 123.7 126.5 Takeda Pharmaceuticals America, Data on file Study 010

Incidence of Edema 100 U.S. Placebo-controlled Studies Placebo ACTOS 80 60 (%) 40 20 15.3 1.2 4.8 7.5 2.1 2.5 6.0 7.0 0 3/259 29/606 4/187 28/373 4/160 10/168 13/187 58/379 Monotherapy Combination with sulfonylurea Combination with metformin Combination with insulin 2 patients from combination therapy trials and 0 from the monotherapy trials discontinued due to edema Pioglitazone HCl Package Insert July, 1999

Approach to Combination Oral Therapy Intensifying of Oral Therapies metformin &/or glitazone sulfonylurea/repaglinide &/or glucosidase inh FPG 120 mg/dl Continue HbA1c 7.0% sulfonylurea/repaglinide &/or glucosidase inh metformin &/or glitazone FPG 120 mg/dl Add Insulin HbA1c 7.0%

Insulin The most powerful agent we have to control glucose

Comparison of Human Insulins / Analogues Insulin preparations Onset of action Peak Duration of action Regular 30–60 min 2–4 h 6–10 h NPH/Lente 1–2 h 4–8 h 10–20 h Ultralente 2–4 h Lispro/aspart 5–15 min 1–2 h 4–6 h Glargine 1–2 h Flat 24 h Unpredictable 16–20 h

Short-Acting Insulin Analogs 400 Regular Lispro 350 300 250 200 150 100 50 0 0 30 60 90 120 150 180 210 240 Plasma insulin (pmol/L) Plasma insulin (pmol/L) Lispro and Aspart Plasma Insulin Profiles 500 450 400 350 300 250 200 150 100 50 0 Regular Aspart 0 50 Time (min) Meal SC injection 100 150 200 Time (min) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care. 1999;22:1501–1506. 250 300

Pharmacokinetic Comparison NovoLog vs Humalog 350 NovoLog Free Insulin (pmol/L) 300 Humalog 250 200 150 100 50 0 7 8 Hedman, Diabetes Care 2001; 24(6):1120-21 9 10 Time (hours) 11 12 13

Lispro Mix 75/25 Pharmacodynamics Glucose infusion rate mg/kg/min 12 Lispro 10 Lispro Mix 75/25 8 NPL 6 4 2 0 0 4 Heise T, et al. Diabetes Care. 1998;21:800–803. 8 12 Hours 16 20 24

Limitations of NPH, Lente, and Ultralente Do not mimic basal insulin profile – Variable absorption – Pronounced peaks – Less than 24-hour duration of action Cause unpredictable hypoglycemia – Major factor limiting insulin adjustments – More weight gain

Insulin Glargine A New Long-Acting Insulin Analog Modifications to human insulin chain – Substitution of glycine at position A21 – Addition of 2 arginines at position B30 Gradual release from injection site Peakless, long-lasting insulin profile Gly 1 5 10 15 20 Asp 1 5 10 15 20 Substitution 25 30 Extension Arg Arg

Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp Glucose utilization rate (mg/kg/h) 6 NPH Glargine 5 4 3 2 1 0 0 10 20 30 Time (h) after SC injection End of observation period Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

Glucose Infusion Rate SC insulin n 20 T1DM Mean SEM 4.0 24 3.0 16 Ultralente 12 2.0 CSII 1.0 4 Glargine 0 0 NPH 0 4 8 12 16 Time (hours) Lepore M, et al. Diabetes. 2000;49:2142–2148. 8 20 24 µmol/kg/min mg/kg/min 20

Plasma Glucose SC insulin n 20 T1DM Mean SEM 11 200 mg/dL 12 180 10 NPH Ultralente 9 160 Glargine 140 CSII 120 0 4 8 12 Time (hours) Lepore M, et al. Diabetes. 2000;49:2142–2148. 16 20 24 8 7 mmol/L 220

Overall Summary: Glargine Insulin glargine has the following clinical benefits – Once-daily dosing because of its prolonged duration of action and smooth, peakless timeaction profile (23.5 hours on repeat injections) – Comparable or better glycemic control (FBG) – Lower risk of nocturnal hypoglycemic events – Safety profile similar to that of human insulin

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

Insulin Therapy in Type 2 Diabetes Indications Significant hyperglycemia at presentation Hyperglycemia on maximal doses of oral agents Decompensation – – – – Acute injury, stress, infection, myocardial ischemia Severe hyperglycemia with ketonemia and/or ketonuria Uncontrolled weight loss Use of diabetogenic medications (eg, corticosteroids) Surgery Pregnancy Renal or hepatic disease

Mimicking Nature The Basal/Bolus Insulin Concept 6-16

The Basal/Bolus Insulin Concept Basal insulin – Suppresses glucose production between meals and overnight – 40% to 50% of daily needs Bolus insulin (mealtime) – Limits hyperglycemia after meals – Immediate rise and sharp peak at 1 hour – 10% to 20% of total daily insulin requirement at each meal

Basal vs Mealtime Hyperglycemia in Diabetes Basal hyperglycemia Plasma Glucose (mg/dL) 250 Mealtime hyperglycemia 200 Type 2 Diabetes 150 100 50 Normal 0 0600 1200 1800 Time of Day 2400 0600 AUC from normal basal 1875 mgm/dL.hr; Est HbA1c 8.7% Riddle. Diabetes Care. 1990;13:676-686. 6-18

Basal vs Mealtime Hyperglycemia in Diabetes When Basal Corrected Basal hyperglycemia Plasma Glucose (mg/dL) 250 Mealtime hyperglycemia 200 150 100 50 Normal 0 0600 1200 1800 Time of Day 2400 0600 AUC from normal basal 900 mgm/dL.hr; Est HbA1c 7.2% 6-18

Basal vs Mealtime Hyperglycemia in Diabetes When Mealtime Hyperglycemia Corrected Basal hyperglycemia Plasma Glucose (mg/dL) 250 Mealtime hyperglycemia 200 150 100 50 Normal 0 0600 1200 1800 Time of Day 2400 0600 AUC from normal basal 1425 mgm/dL.hr; Est HbA1c 7.9 6-18

Basal vs Mealtime Hyperglycemia in Diabetes When Both Basal & Mealtime Hyperglycemia Corrected Basal hyperglycemia Plasma Glucose (mg/dL) 250 Mealtime hyperglycemia 200 150 100 50 Normal 0 0600 1200 1800 Time of Day 2400 0600 AUC from normal basal 225 mgm/dL.hr; Est HbA1c 6.4% 6-18

MIMICKING NATURE WITH INSULIN THERAPY Over time, most patients will need both basal and mealtime insulin to control glucose 6-19

Starting With Basal Insulin Advantages 1 injection with no mixing Insulin pens for increased acceptance Slow, safe, and simple titration Low dosage Effective improvement in glycemic control Limited weight gain 6-37

Starting With Basal Insulin Bedtime NPH Added to Diet Diet only Bedtime NPH Plasma Glucose (mg/dL) 400 300 200 100 0 0800 1200 1600 2000 2400 Time of Day 0400 0800 Cusi & Cunningham. Diabetes Care. 1995;18:843-851. 6-38

Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA Type 2 DM on 1 or 2 oral agents (SU, MET, TZD) Age 30 to 70 BMI 26 to 40 A1C 7.5 to 10% and FPG 140 mg/dL Anti GAD negative Willing to enter a 24 week randomized, open labeled study

Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA Add 10 units Basal insulin at bedtime (NPH or Glargine) Continue current oral agents Titrate insulin weekly to fasting BG 100 mg/dL - if 100-120 mg/dL, increase 2 units - if 120-140 mg/dL, increase 4 units - if 140-160 mg/dL, increase 6 units - if 160-180 mg/dL, increase 8 units

Treatment to Target Study; A1C Decrease M ean H b A 1c% 9 8.6 8.5 8 7.5 7.5 7.1 7 6.9 6.5 0 5 10 W eek s in S tu d y (N 691) 15 20

Patients in Target (A1c 7%) 70 66.2 60 48.8 50 P ercen tage of 40 P atien ts 30 32.3 20 10 2.5 0 W eek 0 W eek 8 W eek 12 W eek 18

Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA Nocturnal Hypoglycemia reduced by ?% in the Glargine group

Advancing Basal/Bolus Insulin Indicated when FBG acceptable but – HbA1c 7% or 6.5% and/or – SMBG before dinner 140 mg/dL Insulin options – To glargine or NPH, add mealtime aspart / lispro – To suppertime 70/30, add morning 70/30 – Consider insulin pump therapy Oral agent options – Usually stop sulfonylurea – Continue metformin for weight control – Continue glitazone for glycemic stability?

Starting With Bolus Insulin Combination Oral Agents Mealtime Insulin 6-46

Starting With Bolus Insulin Mealtime Lispro vs NPH or Metformin Added to Sulfonylurea 12 8 10.0% 10.2% 1.9% 2.3% 1.9% 10 8 6 6 4 4 2 0 3.4 kg Su LP (n 42) 2.3 kg Su NPH (n 50) Baseline HbA1c Weight Gain (kg) HbA1c (%) 10 12 10.4% Follow-up HbA1c Follow-up Weight 2 0.9 kg Su Metformin (n 40) 0 Browdos, et al. Diabetes. 1999;48(suppl 1):A104. 6-47

Case #1: DM 2 on SU with infection 49 year old white male DM 2 onset age 43, wt 173 lbs, Ht 70 inches On glimepiride (Amaryl) 4 mg/day , HbA1c 7.3% (intolerant to metformin) Infection in colostomy pouch (ulcerative colitis) glucose up to 300 mg/dL plus SBGM 3 times per day

Case #1: DM 2 on SU with infection Started on MDI; starting dose 0.2 x wgt. in lbs. Wgt. 180 lbs which 36 units Bolus dose (lispro/aspart) 20% of starting dose at each meal, which 7 to 8 units ac (tid) Basal dose (glargine) 40% of starting dose at HS, which 14 units at HS Correction bolus (BG - 100)/ SF, where SF 1500/total daily dose; SF 40

Correction Bolus Formula Current BG - Ideal BG Glucose Correction factor Example: –Current BG: –Ideal BG: 220 mg/dl 100 mg/dl –Glucose Correction Factor: 40 mg/dl 220 -100 3.0u 40

Case #1: DM 2 on SU with infection Started on MDI Did well, average BG 138 mg/dL at 1 month and 117 mg/dL at 2 months post episode with HbA1c 6.1%

Strategies to Improve Glycemic Control: Type 2 Diabetes Monitor glycemic targets – Fasting and postprandial glucose, HbA1c Self-monitoring of blood glucose is essential Nutrition and activity are cornerstones of therapy Combinations of pharmacologic agents are often necessary to achieve glycemic targets

Intensive Therapy for Type 1 Diabetes Careful balance of food, activity, and insulin Daily self-monitoring BG Patient trained to vary insulin and food Define target BG levels (individualized) Frequent contact of patient and diabetes team Monitoring HbA1c Basal / Bolus insulin regimen

Options in Insulin Therapy Current – Multiple injections – Insulin pump (CSII) Future – Implant (artificial pancreas) – Transplant (pancreas; islet cells)

Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal 1.0 0.8 Insulin 0.6 0 Time

Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal 1.0 Injections 0.8 Insulin 0.6 0 Time

Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal 1.0 Injections 0.8 Insulin 0.6 0 Time

Multiple Injection Therapy Glargine & Short-Acting Insulin Pre-Meal 1.0 Injections 0.8 Insulin 0.6 0 Time

Case #2: DM 1 on MDI 46 year old white male power line supervisor DM 1 age 40 On MDI: 10 u lispro pre-meal, 20 u NPH HS HbA1c 7.4% SMBG avg 124 mg/dL based on 1.9 tests/day (fasting 171 mg/dL, noon 105 mg/dL, pm 125 mg/dL, HS 75 mg/dL)

Case #2: DM 1 on MDI Lantus (glargine) 20 u HS added in place of NPH No change in behavior (diet, SMBG frequency) Seen three months later (8-16-01) HbA1c 6.3% SMBG average 104 mg/dL (fasting BG 91 mg/dL, noon 126 mg/dL, pm 116 mg/dL, HS 126 mg/dL NO HYPOGLYCEMIA HAPPY

Insulin Pens

Introducing InDuo The world’s first combined insulin doser and blood glucose monitoring system A major break- through in Diabetes Care

InDuo - Integration Feature Combined insulin doser and blood glucose monitor

InDuo - Compact Size Feature Compact, discreet design Benefit Allows discreet testing and injecting anywhere, anytime

InDuo - Doser Remembers Feature Remembers amount of insulin delivered and time since last dose Benefit Helps people inject the right amount of insulin at the right time

Variability of Insulin Absorption CSII 2.8% Fraction at inj. site Subcutaneous Injectable 10% to 52% 1.00 Fast (n 12) Semilente (n 9) Intermediate (n 36) 0.75 0.50 0.25 0 Lauritzen. Diabetologia. 1983;24:326–329. 6 12 18 24 30 36 42 Hours after single SC injections Femoral region 48

Pump Therapy Basal & Bolus Short-Acting Insulin

Pump Therapy Basal & Bolus Short-Acting Insulin

Pump Therapy Basal & Bolus Short-Acting Insulin Combined with SMBG, physiologic insulin requirements can be achieved more closely Flexibility in lifestyle

History of Pumps

PARADIGM PUMP Paradigm. Simple. Easy.

Paradigm Pump: Advantages 29% smaller, water resistant Menu driven: bolus, suspend, basal, prime, utilities Reservoir based (easier to fill) Silent motor AAA batteries

Paradigm Pump: Advantages Various bolus options normal, square, dual, and “easy bolus” Enhanced memory Enhanced safety features (low reservoir alarm, auto off, etc.)

Pump Infusion Sets Softset QR Silhouette

Pharmacokinetic Advantages CSII vs MDI Uses only regular or very rapid insulin – More predictable absorption than modified insulins (variation 3% vs 19 to 52%) Uses 1 injection site – Reduces variations in absorption due to site rotation Eliminates most of the subcutaneous insulin depot Programmable delivery simulates normal pancreatic function Lauritzen. Diabetologia. 1983;24:326–329.

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

Glycemic Control 10 HbA1c 9 Adolescent (37) Adult (166) 8.9 8.5 8.2 8 8.1 8 7.6 7 7 7 6.9 6.9 6 Baseline Atlanta Diabetes Associates 1 yr 2 yr 3 yr 4 yr

HbA1c CSII Reduces HbA1c 10.0 9.5 .09 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 Pre-pump Bell Rudolph n 58 n 107 Mean dur. 36 Mean dur. 36 Adults Post-pump Chanteleau Bode Boland n 116 Mean dur. 54 n 50 Mean dur. 42 n 25 Mean dur. 12 Adolescents Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327; Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Bell DSH, et al. Endocrine Practice. 2000;6:357–360; Chase HP, et al. Pediatrics. 2001;107:351–356. Chase n 56 Mean dur. 12

CSII Factors Affecting HbA1c Monitoring – HbA1c 8.3 - (0.21 x BG per day) Recording 7.4 vs 7.8 Diet practiced – CHO: 7.2 – Fixed: 7.5 – Other: 8.0 Insulin type – Lispro: 7.3 – R: 7.7

CSII Usage in Type 2 Patients Atlanta Diabetes Experience 10.00 9.2 9.00 8.00 7.57 7.19 7.00 6.00 5.00 Baseline N 11 6 months 18 months P 0.026 P 0.040 Mean HbA1c (%)

Glycemic Control in Type 2 DM: CSII vs MDI in 127 patients A1C Baseline End of Study (24 wks) 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 CSII MDI Raskin, Diabetes 2001; 50(S2):A106

DM 2 Study: CSII vs MDI Overall treatment satisfaction improved in the CSII group: 59% pre to 79% at 24 weeks 93% in the CSII group preferred the pump to their prior regiment (insulin /- OHA) CSII group had less hyperglycemic episodes (3 subjects, 6 episodes vs. 11 subjects, 26 episodes in the MDI group)

CSII Reduces Hypoglycemia 160 Pre-pump Events per hundred patient years 140 Post-pump 120 100 80 60 40 20 0 Bode Rudolph Chanteleau Boland Chase n 55 Mean age 42 n 107 Mean age 36 n 116 Mean age 29 n 25 Mean age 14 n 56 Mean age 17 Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327; Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Chase HP, et al. Pediatrics. 2001;107:351–356.

Insulin Reduction Following CSII 60 50 48.1 40 -28% 34.5 * -18% -16% -17% 39.3 * 40.1 * 39.8 * 30 20 10 0 * P 0.001 Baseline (MDI) 15 days 6 mos 18 mos 36 mos n 389 n 389 n 298 n 246 n 187

Normalization of Lifestyle Liberalization of diet — timing & amount Increased control with exercise Able to work shifts & through lunch Less hassle with travel — time zones Weight control Less anxiety in trying to keep on schedule

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

U.S. Pump Usage Total Patients Using Insulin Pumps 1 6 2 ,0 0 0 150,000 1 2 0 ,0 0 0 100,000 8 1 ,0 0 0 6 0 ,0 0 0 50,000 3 5 ,0 0 0 2 0 ,0 0 0 4 3 ,0 0 0 2 6 ,5 0 0 1 5 ,0 0 0 6 ,6 0 0 8 ,7 0 0 1 1 ,4 0 0 '90 '91 '92 0 '93 '94 '95 '96 '97 '98 '99 2000 2001

Pump Therapy Indications HbA1c 7.0% Hectic lifestyle Frequent hypoglycemia Shift work Dawn phenomenon Type 2 Exercise Pediatrics Pregnancy Gastroparesis Marcus. Postgrad Med. 1995.

Poor Candidates for CSII Unwilling to comply with medical follow-up Unwilling to perform self blood glucose monitoring 4 times daily Unwilling to quantitate food intake

Current Candidate Selection Patient Requirements –Willing to monitor and record BG –Motivated to take insulin –Willing to quantify food intake –Willing to follow-up –Interested in extending life

Pump Therapy Basal rate Continuous flow of insulin Takes the place of NPH or glargine insulin Units 6 5 4 3 2 1 12 am Meal boluses Insulin needed pre-meal – Pre-meal BG – Carbohydrates in meal – Activity level Correction bolus for high BG Meal bolus Basal rate 12 pm Time of day 12 am

What Type of Bolus Should You Give? 9 DM 1 patients on CSII ate pizza and coke on four consecutive Saturdays Dual wave bolus (70% at meal, 30% as 2-h square): 9 mg/dl glucose rise Single bolus: 33 mg/dl rise Double bolus at -10 and 90 min: 66 mg/dl rise Square wave bolus over 2 hours: 80 mg/dl rise Chase et al, Diabetes June 2001 #365

If HbA1c is Not to Goal Must look at: 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

Future of Diabetes Management

Improvements in Insulin & Delivery Insulin analogs and inhaled insulin External pumps Internal pumps Continuous glucose sensors Closed-loop systems

Pulmonary Insulin

Oral Agents Mealtime Inhaled Insulin Effect on HbA1c Oral Agents Alone 10 Oral Agents Inhaled Insulin HbA1c (%) 9 * 2.3% 8 7 6 5 *P .001 Baseline (0) Follow-up (12) Weeks Baseline (0) Follow-up (12) Weiss, et al. Diabetes. 1999;48(suppl 1):A12. 6-55

GLUCOSE MONITORING SYSTEMS Telemetry Consumer Product “Real time” glucose readings Wireless communication from sensor to monitor High and low glucose alarms FDA panel pending

Closed-loop control using an external insulin pump and a subcutaneous glucose sensor subcutaneous glucose sensor Insulin infusion pump (currently MiniMed 508)

Closed-Loop Setup for Canine Studies ESC F1 F2 1 F3 2 F4 3 F5 4 F6 5 F7 6 F8 7 F9 8 F10 F11 9 F12 Q Tab A Shift 1 2 Z Alt W E S D X C R T F V Y G B U H N I J , M Alt ; / ? Delete [ : ' " Shift Scroll { P L . - O K Insert 0 } ] \ Enter Print

24-h Closed-Loop Control (diabetic canine) GLUCOSE (mg/dl) 500 400 YSI GLC Sensor meals start control adjust control parameters 300 200 100 noon 6 pm midnight 6 am noon 12 10 100 (U/h) µU/ml 75 8 6 50 4 25 2 0 6 am noon 6 pm midnight Time (h) 6 am 0 noon Insulin (µU/ml) Closed Loop Resonse (U/h) 0 6 am

Implantable Pump Average HbA1c 7.1% Hypoglycemic events reduce to 4 episodes per 100 pt-years

MiniMed 2007 System Implantable Insulin Pump Placement

Implantable Insulin Pumps Indications for Use ! Diabetes out of control (frequent, rapid ρBG) ! Frequent hypoglycemic episodes ! Subcutaneous insulin absorption resistance ! Injection or infusion site reaction

Long-Term Glucose Sensor

LONG TERM IMPLANTABLE SYSTEM Human Clinical Trial 350 300 Glucose (mg/dL) 250 200 150 100 50 0 26 Thu 27 Fri 28 Sat 29 Sun 30 Mon Source: Medical Research Group, Inc. 31 Tue 1 Nov 2 Thu 3 Fri 4 Sat 5 Sun 6 Mon 7 Tue

Combine Pump and Sensor Technology LTSS Long Term Sensor System (“Open Loop Control”) Using an RF Telemetry Link .

Medtronic MiniMed’s Implantable Biomechanical Beta Cell

Today’s Reality Open-Loop Glucose Control Sensor # - 6347

LONG TERM IMPLANTABLE SYSTEM Automatic Glucose Regulation in a Fully Pancreatectomized Canine Manual Control Automatic Control Begins Control Terminated Manual Control 400 Glucose (mg/dL) 350 CLOSED LOOP CONTROL 300 250 200 150 100 50 16 Wed 17 Thu August 2000 18 Fri 19 Sat 20 Sun 21 Mon Source: Medical Research Group, Inc. 22 Tue 23 Wed

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

Conclusion Intensive therapy is the best way to treat patients with diabetes

QUESTIONS For a copy or viewing of these slides, contact WWW.adaendo.com

Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia American Diabetes Association. Facts and Figures. Available at: http://www.diabetes.org/ada/facts.asp. Accessed January 18, 2000. Diagnosed Type 1 Diabetes 0.5 - 1.0 Million Diagnosed Type 2 Diabetes 10.3 Million Undiagnosed Diabetes 5.4 Million Prevalence of Diabetes in the US 3

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