Slide 1:Type 1 Diabetes in Adults 

Francine Ratner Kaufman, M.D. Distinguished Professor of Pediatrics The Keck School of Medicine of USC Head, Center for Diabetes and Endocrinology Childrens Hospital Los Angele

Slide 2:Prevalence of Diabetesin the United States

Diagnosed type 2 diabetes 12 million Diagnosed type 1 diabetes ~1.0 million Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm;EURODIAB ACE Study Group. Lancet. 2000;355:873-876; Harris MI. In: NationalDiabetes 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 2000 Type 1 diabetes misdiagnosed as type 2 diabetes ~1.0 million

Slide 3:Incidence of Type 1 Diabetes

Incidence increasing by 3.4% per year 50% of patients diagnosed before age 20 years 50% of patients diagnosed after age 20 years Often mistaken for type 2 diabetes—may make up 10% to 30% of individuals diagnosed with type 2 diabetes Oral agents ineffective; insulin therapy required Autoimmune process slower and possibly different Can usually be confirmed by beta cell antibodies Loss of c-peptide EURODIAB ACE Study Group. Lancet. 2000;355:873-876; Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308-315

Slide 4:Making the Diagnosis of Type 1 Diabetes

Slide 5:Natural History of “Pre”–Type 1 Diabetes

Slide 6:Rationale for Intensive Therapyof Type 1 DiabetesGlucose Control Is Critical

Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254 Retinopathy Neuropathy Microalbuminuria 20 15 10 5 0 5 1 Relative risk A1C (%) 6 7 8 9 10 11 12

Slide 8:Risk of Progression of Microvascular Complications vs A1C DCCT

A1C=hemoglobin A1c

Slide 9:Intensive Therapy for Diabetes:Reduction in Incidence of Complications

T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus. Review DataReview Data

Slide 10:Long-term Microvascular Risk Reduction in Type 1 DiabetesCombined DCCT-EDIC

DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569 No. Evaluated Conventional 169 203 220 581 158 192 200 Intensive 191 222 197 596 170 218 180 DCCTEnd of randomized treatment EDICYear 1 EDICYear 7 6% 8% 10% 12% A1C Retinopathy progression (incidence) P<0.001 P<0.001 P=0.61

Slide 11:Cost-Effectiveness of IntensiveTherapy in Type 1 Diabetes DCCT Modeling Study

DCCT Research Group. JAMA. 1996;276:1409-1415

Slide 13:Current Targets for Glycemic Control

*Peak American Diabetes Association. Diabetes Care. 2004,27:S15-S35. The American Association of Clinical Endocrinologists. Endocr Pract. 2002; 8(suppl. 1):40-82. Chacra AR, et al. Diabetes Obes Metab. 2005;7:148-160. IDF (Europe) European Diabetes Policy Group. Diabet Med. 1999;16:716-730.

Slide 15:Action Profiles of Insulins

Plasma insulin levels Regular 6–8 hours NPH 12–16 hours Ultralente 18–20 hours Hours Glargine ~24 hours Aspart, glulisine, lispro 4–5 hours Detemir ~14 hours Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26:575-598; Barlocco D. Curr Opin Invest Drugs. 2003;4:1240-1244; Danne T et al. Diabetes Care. 2003;26:3087-3092

Slide 16:Normal Daily Plasma Insulin ProfileNondiabetic Obese Individuals

B=breakfast; L=lunch; D=dinner 0800 1800 1200 2400 ?U/mL

Slide 17:Basal/Bolus Treatment Program with Rapid-acting and Basal Analogs

Rapid Rapid Rapid

Slide 18:Basal insulin Controls glucose production between meals and overnight Near-constant levels Usually ~50% of daily needs Bolus insulin (mealtime or prandial) Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour postmeal 10% to 20% of total daily insulin requirement at each meal For ideal insulin replacement therapy, each component should come from a different insulin with a specific profile or via an insulin pump (with one insulin)

Physiologic Multiple Injection RegimensThe Basal-Bolus Insulin Concept

Slide 19:Basal-bolus Therapy:

More frequent decision making, testing, and insulin dosing Allows for variable food consumption based on hunger level Ability to skip meal or snack if desired (bedtime) Reduced variability of insulin absorption Easy to adapt to acute changes in schedule (exercise, sleeping in on weekends)

Slide 20:Insulin Injection Devices

Insulin pens Faster and easier than syringes Improve patient attitude and adherence Have accurate dosing mechanisms, but inadequate resuspension of NPH may be a problem

Slide 21:Mealtime Insulin and Severe HypoglycemiaAspart vs Regular Insulin

All severe hypoglycemia Nocturnal event Nocturnal, glucagon required 4–6 hours postmeal Favors Aspart Favors RegularInsulin Relative risk Home PD et al. Diabet Med. 2000;17:762-770 P Values NS 0.076 <0.050 <0.005

Slide 23:Insulin PumpsContinuous Subcutaneous Insulin Infusion (CSII)

For motivated patients Expensive External, programmable pump connected to an indwelling subcutaneous catheter Only rapid-acting insulin Programmable basal rates Bolus dose without extra injection New pumps with dose calculator function Bolus history Requires support system of qualified providers

Slide 24:CSII vs Multiple Injections of InsulinMeta-analyses

Blood glucose concentration Glycated hemoglobin A1C Insulin dose InjectionTherapyBetter PumpTherapyBetter Mean difference Pickup J et al. BMJ. 2002;324:1-6; Weissberg-Benchell J et al. Diabetes Care. 2003;26:1079-1087 RCT=randomized controlled trial

Slide 25:Balancing Risk of Severe Hypoglycemia Against the Risk of ComplicationsDCCT

DCCT Research Group. N Engl J Med. 1993;329:977-986 2 0 A1C (%) 4 6 8 10 12 14 16 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 100 patient-years 0 100 patient-years 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 20 40 60 80 100 120 A1C (%) Severe Hypoglycemia Retinopathy Progression

Slide 26:HypoglycemiaRisk Factors

Patient Factors Hypoglycemia unawareness History of previous hypoglycemia Defective glucose counterregulation Long duration of diabetes Erratic insulin absorption Age less than 5 to 7 years Behavioral Factors Dietary inconsistency Prolonged fasting Missed meal or snack Strenuous exercise Medical Factors Drug side effects (?-blockers) Dosing errors Unpredictable insulin kinetics Inappropriate insulin distribution

Slide 27:Weight Gain

Insulin therapy reverses catabolic effects of diabetes Glycosuria reduced Normal fuel-storage mechanisms restored Risk of hypoglycemia often causes patients to increase caloric intake and avoid exercise Risk of weight gain decreases with more physiologic insulin administration Flexible insulin dosing to meet dietary and exercise needs

Slide 28:Elderly Treatment Considerations

Slide 29:Special Considerations in the ElderlyWith Type 1 Diabetes

Intensive therapy/tight control for otherwise healthy elderly patients Less strict glycemic goals for elderly patients with severe complications or comorbidities or with cognitive impairment FPG <140 mg/dL PPG <220 mg/dL Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

Slide 30:Risk of Hypoglycemia in the Elderly

Erratic eating (quantities) Erratic timing of meals Renal impairment 40 50 60 70 80 Risk of Hypoglycemia Food Intake Renal Function Age (years)

Slide 31:Treatment Challenges in the ElderlyWith Type 1 Diabetes

Lack of thirst perception predisposes to hyperosmolar state Confusion of polyuria with urinary incontinence or bladder dysfunction Increased risk of and from hypoglycemia Altered perception of hypoglycemic symptoms Susceptibility to serious injury from falls or accidents Compounding of diabetic complications by effects of aging Frequent concurrent illnesses and/or medications More frequent and severe foot problems Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

Slide 32:Monitoring Outcomes andManaging Risk Factors

Slide 33:Follow-up VisitsMonitoring of Target Values:Cardiovascular Risk Factors

Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

Slide 34:Follow-up VisitsQuarterly Evaluations

Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

Slide 35:Follow-up VisitsAnnual Evaluations

Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

Slide 36:Diabetes as a Risk Equivalent of CAD

DM=diabetes mellitus; MI=myocardial infarction. Haffner SM, et al. N Engl J Med. 1998;339:229-234. 7-Year Incidence ofMyocardial Infarction (%) Nondiabetic, n=1373 Diabetic, n=1059 3.5% 18.8% 20.2% 45.0%

Slide 37:ABCs of CVD Risk Management

CVD=cardiovascular disease; ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker; BP=blood pressure; EF=ejection fraction; MI=myocardial infarction. Braunstein JB et al. Cardiol Rev. 2001;9:96-105.

Slide 38:ABCs of CVD Risk Management (cont.)

Braunstein JB et al. Cardiol Rev. 2001;9:96-105.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Slide 39:ABCs of CVD Risk Management (cont.)

BMI=body mass index; HbA1c=glycosylated hemoglobin;CAD=coronary artery disease. Braunstein JB et al. Cardiol Rev. 2001;9:96-105.

Slide 40:Management of Cardiovascular Risk in DiabetesBlood Pressure Control

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S65-S67; Arauz-Pacheco C et al. Diabetes Care. 2002;25:134-147

Slide 41:Management of Cardiovascular Risk in DiabetesLDL Control

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S68-S71; Grundy SM et al. Circulation. 2004;110:227-239; Haffner SM. Diabetes Care. 1998;21:160-178; Lindgärde F. J Intern Med. 2000;248:245-254 HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A

Slide 42:The Future of Type 1 Diabetes Care

Slide 43:Emerging Type 1 Diabetes Therapies

Slide 44:Inhaled Insulin in Type 1 Diabetes

Skyler JS et al. Lancet. 2001;357:331-335 10 Weeks A1C (%) 0 4 8 12 73 Patients Taking Inhaled Insulin TID in Addition to Injected Long-Acting Insulin 9 8 7 6

Slide 45:New Class of Agents for Diabetes

Pramlintide

Slide 46:Glucose Flux in Healthy Subjects

DISCUSSION POINTS: Left figure: Plasma glucose rises after a meal and returns to pre-meal levels as postprandial glucoregulatory mechanisms take effect. Right figure: Tracer studies show derivation of plasma glucose over time after a meal. As glucose from the meal enters the circulation, endogenous glucose production falls. The increase in glucose disappearance (for energy storage) is mediated by insulin action. SLIDE BACKGROUND: N = 5 healthy volunteers (age: 36 y, weight: 69 kg), received a primed, continuous infusion of tritiated glucose for 2 h before the liquid meal (45% dextrose enriched with deuterated glucose, 35% fat, and 20% mixture of amino acids). The labeled glucose was utilized to determine total glucose production (tritiated glucose) and the contribution of meal-related glucose (deuterated glucose). DISCUSSION POINTS: Left figure: Plasma glucose rises after a meal and returns to pre-meal levels as postprandial glucoregulatory mechanisms take effect. Right figure: Tracer studies show derivation of plasma glucose over time after a meal. As glucose from the meal enters the circulation, endogenous glucose production falls. The increase in glucose disappearance (for energy storage) is mediated by insulin action. SLIDE BACKGROUND: N = 5 healthy volunteers (age: 36 y, weight: 69 kg), received a primed, continuous infusion of tritiated glucose for 2 h before the liquid meal (45% dextrose enriched with deuterated glucose, 35% fat, and 20% mixture of amino acids). The labeled glucose was utilized to determine total glucose production (tritiated glucose) and the contribution of meal-related glucose (deuterated glucose).

Slide 47:Multihormonal Regulation of Glucose Appearance and Disappearance

Time (min) From Start of Mixed Meal Mixed Meal (with ~85 g Dextrose) 0 120 240 360 480 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 Grams of Glucose flux/min -30 Calculated from data in Pehling G, et al. J Clin Invest 1984; 74: 985-991 Insulin-mediated glucose uptake Balance of insulin suppression and glucagon stimulation Regulated by hormones: amylin, CCK, GLP-1, etc. Meal-Derived Glucose Hepatic Glucose Production Total Glucose Uptake DISCUSSION POINTS: Different hormones are responsible for mediating the different glucose fluxes that occur postprandially: Meal-derived glucose appearance is modulated by a number of hormones that regulate the rate of gastric emptying. Increase in glucose disappearance is insulin dependent. Suppression of hepatic glucose production is regulated by the opposing effects of insulin and glucagon. SLIDE BACKGROUND: Subjects received a 2-h primed, continuous infusion of tritiated glucose before the liquid meal (45% dextrose enriched with deuterated glucose, 35% fat, and 20% mixture of amino acids). The labeled glucose was utilized to determine total glucose production (tritiated glucose) and the contribution of meal-related glucose (deuterated glucose). DISCUSSION POINTS: Different hormones are responsible for mediating the different glucose fluxes that occur postprandially: Meal-derived glucose appearance is modulated by a number of hormones that regulate the rate of gastric emptying. Increase in glucose disappearance is insulin dependent. Suppression of hepatic glucose production is regulated by the opposing effects of insulin and glucagon. SLIDE BACKGROUND: Subjects received a 2-h primed, continuous infusion of tritiated glucose before the liquid meal (45% dextrose enriched with deuterated glucose, 35% fat, and 20% mixture of amino acids). The labeled glucose was utilized to determine total glucose production (tritiated glucose) and the contribution of meal-related glucose (deuterated glucose).

Slide 48:Pramlintide Improves Postprandial GlucoseTYPE 1 DIABETES

100 150 200 250 300 0 60 120 180 240 Time Relative to Meal and Pramlintide (min) Mean (SE) Plasma Glucose  (mg/dL) 100 150 200 250 300 0 60 120 180 240 Mean (SE) Plasma Glucose (mg/dL) Lispro Insulin Pramlintide 60 ?g + Lispro Insulin Regular Insulin Pramlintide 60 ?g + Regular Insulin Pramlintide Acetate Prescribing Information, 2005Data from Weyer C, et al. Diabetes Care 2003; 26:3074-3079 DISCUSSION POINTS: Pramlintide administered at 0 min relative to the mixed meal with regular insulin or insulin lispro Pramlintide prevented the initial postprandial increase in plasma glucose and reduced the overall glucose excursion in both the regular insulin and insulin lispro groups compared to placebo. The profile of the postprandial glucose excursion was influenced by, and in fact reflective of, the onset and duration of action of the concomitantly injected insulin. The optimal timing for pramlintide administration is at mealtime or just prior to the meal. SLIDE BACKGROUND: Regular insulin was administered according to package insert recommendations (t = -30 min), and pramlintide was injected immediately before the meal (t = 0 min). Insulin lispro was administered according to package insert recommendations (t = 0 min), and pramlintide was injected immediately before the meal (t = 0 min). In this study, pramlintide injections were also given at -15, +15, and +30 minutes with respect to the timing of the mixed meal (data not shown on this slide). Pramlintide injections at -15 min prevented the initial postprandial surge in plasma glucose, and the overall glucose excursion was reduced. Pramlintide injections at +15 and +30 min resulted in an initial postprandial surge in plasma glucose, and the overall glucose excursions were not reduced to the same extent as seen at -15 and 0 min pramlintide dose timings. Pramlintide was generally well tolerated. There were no reports of severe hypoglycemic events or serious adverse events. Mild to moderate hypoglycemia (majority in patients with fasting glucose <126 mg/dL) and mild nausea were the most frequent treatment-emergent adverse events. Data are for evaluable patients.DISCUSSION POINTS: Pramlintide administered at 0 min relative to the mixed meal with regular insulin or insulin lispro Pramlintide prevented the initial postprandial increase in plasma glucose and reduced the overall glucose excursion in both the regular insulin and insulin lispro groups compared to placebo. The profile of the postprandial glucose excursion was influenced by, and in fact reflective of, the onset and duration of action of the concomitantly injected insulin. The optimal timing for pramlintide administration is at mealtime or just prior to the meal. SLIDE BACKGROUND: Regular insulin was administered according to package insert recommendations (t = -30 min), and pramlintide was injected immediately before the meal (t = 0 min). Insulin lispro was administered according to package insert recommendations (t = 0 min), and pramlintide was injected immediately before the meal (t = 0 min). In this study, pramlintide injections were also given at -15, +15, and +30 minutes with respect to the timing of the mixed meal (data not shown on this slide). Pramlintide injections at -15 min prevented the initial postprandial surge in plasma glucose, and the overall glucose excursion was reduced. Pramlintide injections at +15 and +30 min resulted in an initial postprandial surge in plasma glucose, and the overall glucose excursions were not reduced to the same extent as seen at -15 and 0 min pramlintide dose timings. Pramlintide was generally well tolerated. There were no reports of severe hypoglycemic events or serious adverse events. Mild to moderate hypoglycemia (majority in patients with fasting glucose <126 mg/dL) and mild nausea were the most frequent treatment-emergent adverse events. Data are for evaluable patients.

Slide 49:Pramlintide Clinical EffectsTYPE 1 DIABETES COMBINED PIVOTALS

-0.8 -0.6 -0.4 -0.2 0 -4 -2 0 2 4 6 8 -2 -1 0 1 *** *** *** ** * *** *** *** Week 4 Week 13 Week 26 Week 4 Week 13 Week 26 Week 4 Week 13 Week 26 ? Insulin Use (%) ? A1C (%) ? Weight (kg) Placebo + Insulin 30 or 60 ?g Pramlintide TID or QID + Insulin Placebo + insulin (N = 538), Baseline A1C = 9.0% Pramlintide + insulin (N = 716), Baseline A1C = 8.9% *P <0.05, **P <0.01, ***P <0.0001; ITT population; Mean (SE) change from baseline Pramlintide Acetate Prescribing Information, 2005; Data on file, Amylin Pharmaceuticals, Inc. Data from Whitehouse FW, et al. Diabetes Care 2002; 25:724-730 Data from Ratner R, et al. Diabetic Med 2004; 21:1204-1212 DISCUSSION POINTS: Summary of clinical data from type 1 diabetes Phase 3 studies. Pramlintide-treated subjects had an overall reduction in A1C, with less insulin used, which was accompanied by a reduction in weight compared with placebo. SLIDE BACKGROUND: Pooled data analysis includes patients in the 3 type 1 Pivotal Phase 3 Studies who received 30 or 60 ?g pramlintide TID or QID. Pivotal Studies were double-blind, placebo-controlled, with 30/60 ?g pramlintide TID or QID dose, and fixed insulin dose, and with patients who tended to reside in more generalist practices. DISCUSSION POINTS: Summary of clinical data from type 1 diabetes Phase 3 studies. Pramlintide-treated subjects had an overall reduction in A1C, with less insulin used, which was accompanied by a reduction in weight compared with placebo. SLIDE BACKGROUND: Pooled data analysis includes patients in the 3 type 1 Pivotal Phase 3 Studies who received 30 or 60 ?g pramlintide TID or QID. Pivotal Studies were double-blind, placebo-controlled, with 30/60 ?g pramlintide TID or QID dose, and fixed insulin dose, and with patients who tended to reside in more generalist practices.

Slide 50:Adverse Events* ?5%PRAMLINTIDE TYPE 1 DIABETES STUDIES

2 7 5 Arthralgia 5 7 4 Fatigue 7 11 7 Vomiting 8 14 10 Inflicted Injury 0 17 2 Anorexia 37 48 17 Nausea Clinical Practice Study Pivotal Studies (N=265) (N=716) (N=538) Adverse Event Pramlintide (%) Pramlintide (%) Placebo (%) 2 5 4 Dizziness <1 6 5 Allergic Reaction Pramlintide Acetate Prescribing Information, 2005 DISCUSSION POINTS: Most frequent adverse events in the Pivotal pramlintide studies in type 1 diabetes and the open-label Clinical-Practice Study Most frequently observed adverse events, excluding hypoglycemia, were gastrointestinal in nature (nausea, anorexia and vomiting) Anorexia may also have included loss of appetite based upon WHOART 2001 coding conventions. A variety of adverse events were coded to the WHOART 2001 term, “Inflicted Injuries,” including pain, headache, bruises, etc. reported as a result of accidental injuries. Inflicted injuries did not appear to be related to hypoglycemic events. Indicated dose (pramlintide 30/60 ?g) for Pivotal Studies, and ALL doses for Clinical-Practice Study. SLIDE BACKGROUND: Pivotal Studies were double-blind, placebo-controlled, with 30/60 ?g pramlintide TID or QID dose, and fixed insulin dose, and with patients who tended to reside in more generalist practices. Clinical-Practice Study was open-label, with insulin-dose reduction during pramlintide initiation, frequent self-monitoring of blood glucose and appropriate insulin dose adjustments, diabetes education, and investigators who were skilled in the use of insulin and who selected patients from their practices. DISCUSSION POINTS: Most frequent adverse events in the Pivotal pramlintide studies in type 1 diabetes and the open-label Clinical-Practice Study Most frequently observed adverse events, excluding hypoglycemia, were gastrointestinal in nature (nausea, anorexia and vomiting) Anorexia may also have included loss of appetite based upon WHOART 2001 coding conventions. A variety of adverse events were coded to the WHOART 2001 term, “Inflicted Injuries,” including pain, headache, bruises, etc. reported as a result of accidental injuries. Inflicted injuries did not appear to be related to hypoglycemic events. Indicated dose (pramlintide 30/60 ?g) for Pivotal Studies, and ALL doses for Clinical-Practice Study. SLIDE BACKGROUND: Pivotal Studies were double-blind, placebo-controlled, with 30/60 ?g pramlintide TID or QID dose, and fixed insulin dose, and with patients who tended to reside in more generalist practices. Clinical-Practice Study was open-label, with insulin-dose reduction during pramlintide initiation, frequent self-monitoring of blood glucose and appropriate insulin dose adjustments, diabetes education, and investigators who were skilled in the use of insulin and who selected patients from their practices.

Slide 51:Benefits of continuous glucose monitoring More complete glucose profile than with traditional SMBG Tracking of meal-related glycemic trends Detection of nocturnal hypoglycemia Facilitation of changes in insulin regimens Alarm for highs and lows (GlucoWatch) Remaining challenges Daily SMBG still required Not suited to many patients Limited accuracy, especially for hypoglycemia Glycemic pattern results confusing, subject to interpretation

Continuous Glucose Monitoring

Slide 52:Future Glucose Monitors

Minimally invasive continuous glucose monitors Implanted glucose sensors Implanted insulin pumps “Closed-loop” systems External Closed-Loop Implanted Closed-Loop Guardian™ CGMS Freestyle Navigator™

Slide 53:Can Type 1 Diabetes Be “Cured?”Islet Cell Transplantation

7 Type 1 Patients, Aged 29 to 54 Years, With History of Severe Hypoglycemia and Metabolic Instability Shapiro AMJ et al. N Engl J Med. 2000;343:230-238 Baseline 6 monthsafter transplant Mean A1C (%) Baseline 6 monthsafter transplant MeanC-peptide(ng/mL) Fasting 90 min postmeal 8.4% 5.7% 0.48 2.5 5.7 * * *P<0.001 vs baseline *