1. Type 1 Diabetes in Adults 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

2. Undiagnosed diabetes 5.2 million Prevalence of Diabetes in 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: 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 2000 Type 1 diabetes misdiagnosed as type 2 diabetes ~1.0 million

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 diabetesmay 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

4. American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10 *Requires confirmation by repeat testing Making the Diagnosis of Type 1 Diabetes Symptoms of diabetesPolyuria, polydipsia, polyphagia, diabetic plusketoacidosis (DKA) Random plasma glucose 200 mg/dL* Fasting plasma glucose (FPG) 126 mg/dL* Oral glucose tolerance test (OGTT) with 2-hour value 200 mg/dL* Loss of c-peptidec-peptide<0.8 ng/dL Presence of islet autoantibodiesGADA, ICA, IA-2A, IAA

5. Putative trigger Circulating autoantibodies (ICA, GAD65, ICA512A, IAA) Cellular autoimmunity Loss of first-phase insulin response (IVGTT) Abnormal glucose tolerance (OGTT) Clinical onset Time -Cell mass 100% -Cell insufficienc y Genetic predisposition Insulitis -Cell injury Eisenbarth GS. N Engl J Med. 1986;314:1360-1368 Diabetes Natural History of Pre–Type 1 Diabetes

6. Rationale for Intensive Therapy of Type 1 Diabetes Glucose Control Is Critical

7. Cumulative Incidence of Nephropathy DCCT Years 10% 20% 30% 40% Microalbuminuria Albuminuria 0% 0123456789 Cumulative percentage Intensive Conventional Combined Primary Prevention and Secondary Intervention Cohorts P<0.001 P=0.006 DCCT Research Group. N Engl J Med. 1993;329:977-986

8. Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254 Retinopathy Neuropathy Microalbuminuria 20 15 10 5 0 5 1 Relative risk A1C (%) 678910 1112 Risk of Progression of Microvascular Complications vs A1C DCCT A1C=hemoglobin A 1c

9. *Not statistically significant due to small number of events. Showed statistical significance in subsequent epidemiologic analysis. DCCT Research Group. N Engl J Med. 1993;329:977-986; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J. 2000;321:405-412. Intensive Therapy for Diabetes: Reduction in Incidence of Complications T1DM DCCT T2DM Kumamoto T2DM UKPDS A1C 9% 7% 8% 7% Retinopathy63%69%17%–21% Nephropathy54%70%24%–33% Neuropathy60%58%– Cardiovascular disease 41%*52*16%* T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

10. Long-term Microvascular Risk Reduction in Type 1 Diabetes Combined DCCT-EDIC DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569 No. Evaluated Conventional169203220581158192200 Intensive191222197596170218180 DCCT End of randomized treatment EDIC Year 1 EDIC Year 7 6% 8% 10 % 12 % A1C Retinopathy progression (incidence) Intensive Conventional P<0.00 1 P=0.61

11. Cost-Effectiveness of Intensive Therapy in Type 1 Diabetes DCCT Modeling Study Years Free From Complication (Projected Average) Conventional treatment Intensive treatment Proliferative retinopathy39.153.9 Blindness49.156.8 Microalbuminuria34.543.7 End-stage renal disease (ESRD) 55.661.3 Neuropathy42.353.2 Amputation39.153.9 DCCT Research Group. JAMA. 1996;276:1409-1415

12. Principles of Intensive Therapy of Type 1 Diabetes Targets

13. Current Targets for Glycemic Control ADAACELAIDF A1C (%) Normal: 4%–6% <7.0 6.5 <6.5 6.5 Fasting/Preprandial (mg/dL) (plasma equivalent) 90-130<110110<100 Postprandial (mg/dL) (2-hour) <180*<140140<135 *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.

14. Principles of Intensive Therapy of Type 1 Diabetes Insulin Options

15. Action Profiles of Insulins 01 25346789 1011 12131415161718192021222324 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

16. Polonsky KS et al. N Engl J Med. 1988;318:1231-1239 0600 Time of day 20 40 60 80 100 BLD Normal Daily Plasma Insulin Profile Nondiabetic Obese Individuals B=breakfast; L=lunch; D=dinner 0800 1800 12002400 U/mL

17. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal Plasma insulin Basal/Bolus Treatment Program with Rapid- acting and Basal Analogs Rapid

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 Regimens The Basal-Bolus Insulin Concept

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)

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

21. 0.1110 Mealtime Insulin and Severe Hypoglycemia Aspart vs Regular Insulin All severe hypoglycemia Nocturnal event Nocturnal, glucagon required 4–6 hours postmeal Favors Aspart Favors Regular Insulin Relative risk Home PD et al. Diabet Med. 2000;17:762-770 P Values NS 0.076 <0.050 <0.005

22. Variable Basal Rate Continuous Subcutaneous Insulin Infusion (CSII) 4:00 25 50 75 16:0020:0024:004:00 BreakfastLunchDinner Plasma Insulin U/ml) Plasma Insulin µ U/ml) 8:00 12:008:00 Time Basal Infusion Bolus

23. Insulin Pumps Continuous 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

24. -2-1012 CSII vs Multiple Injections of Insulin Meta-analyses Blood glucose concentration Glycated hemoglobin A1C Insulin dose Injection Therapy Better Pump Therapy Better Mean difference Pickup J et al. BMJ. 2002;324:1-6; Weissberg-Benchell J et al. Diabetes Care. 2003;26:1079-1087 Pickup et al. 12 RCTs Weissberg-Benchell et al. 11 RCTs RCT=randomized controlled trial

25. Balancing Risk of Severe Hypoglycemia Against the Risk of Complications DCCT DCCT Research Group. N Engl J Med. 1993;329:977-986 2 0 A1C (%) 4 6 8 10 12 14 16 5.0 5.56.06.57.07.58.08.59.09.510.010.5 100 patient- years 0 5.05.56.06.57.07.5 8.0 8.59.09.510.0 10.5 20 40 60 80 100 120 A1C (%) Severe Hypoglycemia Retinopathy Progression

26. Hypoglycemia Risk Factors Patient Factors Hypoglycemia unawarenessHypoglycemia unawareness History of previous hypoglycemiaHistory of previous hypoglycemia Defective glucose counterregulationDefective glucose counterregulation Long duration of diabetesLong duration of diabetes Erratic insulin absorptionErratic insulin absorption Age less than 5 to 7 yearsAge less than 5 to 7 years Behavioral Factors Dietary inconsistencyDietary inconsistency –Prolonged fasting –Missed meal or snack Strenuous exerciseStrenuous exercise Medical Factors Drug side effects ( -blockers)Drug side effects ( -blockers) Dosing errorsDosing errors Unpredictable insulin kineticsUnpredictable insulin kinetics Inappropriate insulin distributionInappropriate insulin distribution

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

28. Elderly Treatment Considerations

29. Special Considerations in the Elderly With 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

30. Risk of Hypoglycemia in the Elderly Erratic eating (quantities) Erratic timing of meals Renal impairment 4050607080 Risk of Hypoglycemia Food Intake Renal Function Age (years)

31. Treatment Challenges in the Elderly With 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

32. Monitoring Outcomes and Managing Risk Factors

33. Follow-up Visits Monitoring of Target Values: Cardiovascular Risk Factors FrequencyGoal Blood pressureQuarterly<130/80 mm Hg HDL cholesterolAnnually (more often if control poor) >40 mg/dL, males >50 mg/dL, females LDL cholesterolAnnually (more often if control poor) <100 mg/dL May be different in young children TriglyceridesAnnually (more often if control poor) <150 mg/dL CreatinineAnnually<1.3 mg/dL Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

34. FrequencyAssessment General checkup (including weight/BMI, A1C) QuarterlyGeneral health Foot examQuarterly (or every visit) Peripheral neuropathy and infection Follow-up Visits Quarterly Evaluations Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

35. FrequencyAssessment Skin examinationAnnuallyPeripheral neuropathy Neurologic examinationAnnuallyAutonomic and peripheral neuropathy Dilated eye examination Annually (in adolescents and >3 years after type 1 diagnosis) Retinopathy MicroalbuminuriaAnnually (in adolescents and >3 years after type 1 diagnosis) Target <30 mg/g creatinine Cardiac examinationAnnually (more often if CVD present) Development/ progression of CVD Screening for other autoimmune conditions AnnuallyThyroid disease, celiac disease, etc Follow-up Visits Annual Evaluations Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

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 of Myocardial Infarction (%) Nondiabetic, n=1373 Diabetic, n=1059 3.5% 18.8% 20.2% 45.0%

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. Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes Post MI or low EF BP control -blockers B Treat all high-risk patients with one of these Optimize BP especially if CVD, type 2 diabetes, or low EF present Relieve anginal symptoms, allow patient to exercise A1c Antiplatelets/anticoagulants ACE inhibitors/ARBs Antianginals A GoalsIntervention

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. HDL-C: 40 mg/dL (men) 50 mg/dL (women) TG: <150 mg/dL Long-term smoking cessationCigarette-smoking cessation LDL-C targets, ATP III guidelines CHD, CHD risk equivalents: <100 mg/dL 2 RF: <130 mg/dL 0-1 RF: <160 mg/dL Cholesterol management C GoalsIntervention

39. ABCs of CVD Risk Management (cont.) BMI=body mass index; HbA 1c =glycosylated hemoglobin; CAD=coronary artery disease. Braunstein JB et al. Cardiol Rev. 2001;9:96-105. Improve physical fitness (aim for 30 min/d on most days per week) Optimize awareness of CAD risk factors Exercise Education of patients and families E Achieve optimal BMI saturated fats; fruits, vegetables, fiber Achieve HbA 1c <7% Dietary/weight counseling Diabetes management D GoalsIntervention

40. Treatment target: Blood pressure <130/80 mm Hg Standard methods (1, 2, or 3 agents may be needed) Angiotensin-converting enzyme (ACE) inhibitor Angiotensin-receptor blocker (ARB) Thiazide -Blocker Individualized options -Adrenergic blocker or central adrenergic agent Long-acting calcium channel blocker (CCB) Loop diuretic Management of Cardiovascular Risk in Diabetes Blood Pressure Control American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S65-S67; Arauz-Pacheco C et al. Diabetes Care. 2002;25:134-147

41. Management of Cardiovascular Risk in Diabetes LDL 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 Treatment target:LDL <100 mg/dL, no CVD LDL <70 mg/dL, with CVD Standard method HMG-CoA reductase inhibitors (statins) Individualized options Intestinal cholesterol absorption inhibitors Bile acid–binding resins Nicotinic acid

42. The Future of Type 1 Diabetes Care

43. Emerging Type 1 Diabetes Therapies Insulins Aerodose ® Inhaled liquid aerosol insulin; portable device delivery AERx ® Inhaled liquid aerosol insulin; portable device delivery Exubera ® Particulate cloud inhaled insulin; portable device delivery Oralin ® Buccally absorbed, liquid aerosol insulin; portable device delivery Technosphere ® insulin Inhaled dry powder insulin; portable device delivery Pramlintide (Symlin ® ) Injectable amylin analogue; slows gastric emptying, suppresses glucagon, and increases satiety Islet cell transplant Transplantation of donor pancreatic -cells; restores endogenous insulin secretion

44. Subcutaneous insulin: 16 U regular + 31 U long-acting Inhaled insulin: 12 mg inhaled + 25 U ultralente Inhaled Insulin in Type 1 Diabetes Skyler JS et al. Lancet. 2001;357:331-335 10 Weeks A1C (%) 0 4812 73 Patients Taking Inhaled Insulin TID in Addition to Injected Long-Acting Insulin 9 8 7 6

45. New Class of Agents for Diabetes Pramlintide

46. Time (min) Adapted and calculated from Pehling G., et al. J. Clin. Invest. 1984; 74: 985-991 Plasma Glucose (mg/dL) 0120 0 40 80 120 160 200 -3060180 Mixed Meal (with ~85 g Dextrose) 0120 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 Grams of Glucose flux/min -30 Mixed Meal (with ~85 g Dextrose) Meal Derived Glucose Total Glucose Uptake 60180 Hepatic Glucose Production Time (min) Appearance Disappearance Glucose Flux in Healthy Subjects

47. Multihormonal Regulation of Glucose Appearance and Disappearance Time (min) From Start of Mixed Meal Mixed Meal (with ~85 g Dextrose) 0120240360480 -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

48. Pramlintide Improves Postprandial Glucose TYPE 1 DIABETES 100 150 200 250 300 060120180240 Time Relative to Meal and Pramlintide (min) Mean (SE) Plasma Glucose (mg/dL) 100 150 200 250 300 060120180240 Mean (SE) Plasma Glucose (mg/dL) Lispro Insulin Pramlintide 60 g + Lispro Insulin Regular Insulin Pramlintide 60 g + Regular Insulin Evaluable population; Mean (SE) Pramlintide + Lispro insulin (n = 20) Pramlintide + Regular insulin (n = 18) Pramlintide Acetate Prescribing Information, 2005 Data from Weyer C, et al. Diabetes Care 2003; 26:3074-3079

49. Pramlintide Clinical Effects TYPE 1 DIABETES COMBINED PIVOTALS -0.8 -0.6 -0.4 -0.2 0 -4 -2 0 2 4 6 8 0 1 *** ** * *** Week 4Week 13Week 26Week 4Week 13Week 26 Week 4Week 13Week 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

50. Adverse Events* 5% PRAMLINTIDE TYPE 1 DIABETES STUDIES 27 5 Arthralgia 57 4 Fatigue 711 7 Vomiting 814 10 Inflicted Injury 017 2 Anorexia 3748 17 Nausea Clinical Practice StudyPivotal Studies (N=265)(N=716) (N=538) Adverse Event Pramlintide (%) Placebo (%) *Excluding hypoglycemia, indicated dose (ITT) AE profile for Dose-Titration Study similar to Pivotals 254Dizziness <16 5 Allergic Reaction Pramlintide Acetate Prescribing Information, 2005

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

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

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 months after transplant Mean A1C (%) Baseline 6 months after transplant Mean C-peptide (ng/mL) Fasting 90 min postmeal 8.4 % 5.7 % 0.48 2.5 5.7 * * *P<0.001 vs baseline *

54. Loss of first-phase insulin response Newly diagnosed diabetes Genetically at risk Multiple antibody positive Opportunities for Intervention in Type 1 Diabetes TrialNet -Cell insufficienc y Genetic predisposition Insulitis -Cell injury Diabete s Time -Cell mass