Type 1 Diabetes in Adults Francine Ratner Kaufman

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

Prevalence of Diabetes in the United States US Population: 275 Million in 2000 Undiagnosed diabetes 5. 2 million Diagnosed type 2 diabetes 12 million Diagnosed type 1 diabetes ~1. 0 million Type 1 diabetes misdiagnosed as type 2 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. 2 nd ed. Bethesda, Md: NIDDK; 1995: 15 -36; U. S. Census Bureau Statistical Abstract of the U. S. ; 2001

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

Making the Diagnosis of Type 1 Diabetes Symptoms of diabetes Polyuria, polydipsia, polyphagia, diabetic plus ketoacidosis (DKA) Random plasma glucose 200 mg/d. L* Fasting plasma glucose (FPG) 126 mg/d. L* Oral glucose tolerance test (OGTT) with 2 -hour value 200 mg/d. L* Loss of c-peptide<0. 8 ng/d. L Presence of islet autoantibodies GADA, ICA, IA-2 A, IAA *Requires confirmation by repeat testing American Diabetes Association. Diabetes Care. 2004; 27(suppl 1): S 5 -S 10

Natural History of “Pre”–Type 1 Diabetes -Cell mass 100% Putative trigger Cellular autoimmunity Circulating autoantibodies (ICA, GAD 65, ICA 512 A, IAA) Loss of first-phase insulin response (IVGTT) Abnormal glucose tolerance (OGTT) Genetic predisposition Insulitis -Cell injury Time Eisenbarth GS. N Engl J Med. 1986; 314: 1360 -1368 -Cell insufficienc y Diabetes Clinical onset

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

Cumulative Incidence of Nephropathy DCCT Cumulative percentage 40% Combined Primary Prevention and Secondary Intervention Cohorts Intensive Conventional 30% Microalbuminuria P<0. 001 20% 10% Albuminuria P=0. 006 0% 0 1 2 3 4 5 Years DCCT Research Group. N Engl J Med. 1993; 329: 977 -986 6 7 8 9

Risk of Progression of Microvascular Complications vs A 1 C DCCT Relative 20 risk Retinopathy Neuropathy Microalbuminuria 15 10 5 0 1 5 6 7 8 9 A 1 C (%) A 1 C=hemoglobin A 1 c Skyler JS. Endocrinol Metab Clin North Am. 1996; 25: 243 -254 10 11 12

Intensive Therapy for Diabetes: Reduction in Incidence of Complications T 1 DM DCCT T 2 DM Kumamoto T 2 DM UKPDS 9% 7% 8% 7% Retinopathy 63% 69% 17%– 21% Nephropathy 54% 70% 24%– 33% Neuropathy 60% 58% – Cardiovascular disease 41%* 52* 16%* A 1 C T 1 DM = type 1 diabetes mellitus; T 2 DM = type 2 diabetes mellitus. *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.

Long-term Microvascular Risk Reduction in Type 1 Diabetes Combined DCCT-EDIC Intensive A 1 C 12 % Conventional Retinopathy progression (incidence) 10 % 8% 6% P<0. 00 P=0. 61 1 1 DCCT EDIC End of Year 1 Year 7 randomized treatment No. Evaluated Conventional Intensive DCCT/EDIC Research Group. JAMA. 2002; 287: 2563 -2569 191 203 222 220 197 581 596 158 170 192 218 200 180

Cost-Effectiveness of Intensive Therapy in Type 1 Diabetes DCCT Modeling Study Proliferative retinopathy Years Free From Complication (Projected Average) Conventional Intensive treatment 39. 1 53. 9 Blindness 49. 1 56. 8 Microalbuminuria 34. 5 43. 7 End-stage renal disease (ESRD) Neuropathy 55. 6 61. 3 42. 3 53. 2 Amputation 39. 1 53. 9 DCCT Research Group. JAMA. 1996; 276: 1409 -1415

Principles of Intensive Therapy of Type 1 Diabetes Targets

Current Targets for Glycemic Control ADA A 1 C (%) ACE LA IDF <7. 0 6. 5 90 -130 <110 <100 <180* <140 <135 <6. 5 Normal: 4%– 6% Fasting/Preprandial (mg/d. L) (plasma equivalent) Postprandial (mg/d. L) (2 -hour) *Peak American Diabetes Association. Diabetes Care. 2004, 27: S 15 -S 35. 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.

Principles of Intensive Therapy of Type 1 Diabetes Insulin Options

Action Profiles of Insulins Aspart, glulisine, lispro 4– 5 hours Plasma insulin levels Regular 6– 8 hours NPH 12– 16 hours Detemir ~14 hours Ultralente 18– 20 hours Glargine ~24 hours 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 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

Normal Daily Plasma Insulin Profile Nondiabetic Obese Individuals U/m. L 100 B L D 1200 1800 80 60 40 20 0600 0800 Time of day B=breakfast; L=lunch; D=dinner Polonsky KS et al. N Engl J Med. 1988; 318: 1231 -1239 2400 0600

Basal/Bolus Treatment Program with Rapidacting and Basal Analogs Plasma insulin Breakfast Lunch Rapid Dinner Rapid Basal 4: 00 8: 00 12: 00 16: 00 Time 20: 00 24: 00 8: 00

Physiologic Multiple Injection Regimens The Basal-Bolus Insulin Concept • 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)

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)

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

Mealtime Insulin and Severe Hypoglycemia Aspart vs Regular Insulin All severe hypoglycemia Favors Aspart Favors Regular Insulin P Values NS Nocturnal event 0. 076 Nocturnal, glucagon required <0. 050 4– 6 hours postmeal <0. 005 0. 1 Home PD et al. Diabet Med. 2000; 17: 762 -770 1 Relative risk 10

Variable Basal Rate Continuous Subcutaneous Insulin Infusion (CSII) Plasma Insulin µU/ml) 75 Breakfast Lunch Dinner 50 Bolus 25 Basal Infusion 4: 00 8: 00 12: 00 16: 00 Time 20: 00 24: 00 8: 00

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

CSII vs Multiple Injections of Insulin Meta-analyses Injection Therapy Better Pump Therapy Better Blood glucose concentration Glycated hemoglobin A 1 C Insulin dose -2 -1 0 Mean difference Pickup et al. 12 RCTs RCT=randomized controlled trial 1 2 Weissberg-Benchell et al. 11 RCTs Pickup J et al. BMJ. 2002; 324: 1 -6; Weissberg-Benchell J et al. Diabetes Care. 2003; 26: 1079 -1087

Balancing Risk of Severe Hypoglycemia Against the Risk of Complications DCCT Retinopathy Progression Severe Hypoglycemia 100 16 patient-14 years 120 100 patient 100 -years 12 80 10 60 8 6 40 4 20 2 0 5. 5 6. 0 6. 5 7. 0 7. 5 8. 0 8. 5 9. 0 9. 510. 010. 5 A 1 C (%) DCCT Research Group. N Engl J Med. 1993; 329: 977 -986 A 1 C (%)

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

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

Elderly Treatment Considerations

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/d. L — PPG <220 mg/d. L Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

Risk of Hypoglycemia in the Elderly • Erratic eating (quantities) Food Intake c Renal Function ly g po sk Ri 40 ia em 50 y H f • Erratic timing of meals o • Renal impairment 60 Age (years) 70 80

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

Monitoring Outcomes and Managing Risk Factors

Follow-up Visits Monitoring of Target Values: Cardiovascular Risk Factors Frequency Goal Blood pressure Quarterly <130/80 mm Hg HDL cholesterol Annually (more often >40 mg/d. L, males if control poor) >50 mg/d. L, females LDL cholesterol Annually (more often <100 mg/d. L if control poor) May be different in young children Triglycerides Annually (more often <150 mg/d. L if control poor) Creatinine Annually <1. 3 mg/d. L Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

Follow-up Visits Quarterly Evaluations Frequency Assessment General checkup (including weight/BMI, A 1 C) Quarterly General health Foot exam Quarterly (or every visit) Peripheral neuropathy and infection Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004

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

Diabetes as a Risk Equivalent of CAD 7 -Year Incidence of Myocardial Infarction (%) Nondiabetic, n=1373 Diabetic, n=1059 18. 8% 3. 5% DM=diabetes mellitus; MI=myocardial infarction. Haffner SM, et al. N Engl J Med. 1998; 339: 229 -234. 45. 0% 20. 2%

ABCs of CVD Risk Management Intervention A • A 1 c • Antiplatelets/anticoagulants • ACE inhibitors/ARBs • Antianginals B • BP control • -blockers Goals • 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 • Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes • Post MI or low EF 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.

ABCs of CVD Risk Management (cont. ) Intervention C • Cholesterol management Goals • LDL-C targets, ATP III guidelines — CHD, CHD risk equivalents: <100 mg/d. L — 2 RF: <130 mg/d. L — 0 -1 RF: <160 mg/d. L • Cigarette-smoking cessation • HDL-C: 40 mg/d. L (men) 50 mg/d. L (women) • TG: <150 mg/d. L • Long-term smoking cessation 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.

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

Management of Cardiovascular Risk in Diabetes Blood Pressure Control 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 American Diabetes Association. Diabetes Care. 2004; 27(suppl 1): S 65 -S 67; Arauz-Pacheco C et al. Diabetes Care. 2002; 25: 134 -147

Management of Cardiovascular Risk in Diabetes LDL Control Treatment target: LDL <100 mg/d. L, no CVD LDL <70 mg/d. L, with CVD Standard method • HMG-Co. A reductase inhibitors (statins) Individualized options • Intestinal cholesterol absorption inhibitors • Bile acid–binding resins • Nicotinic acid HMG-Co. A=3 -hydroxy-3 -methylglutaryl coenzyme A American Diabetes Association. Diabetes Care. 2004; 27(suppl 1): S 68 -S 71; 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

The Future of Type 1 Diabetes Care

Emerging Type 1 Diabetes Therapies Insulins Aerodose® AERx® Exubera® Oralin® Technosphere® insulin Inhaled liquid aerosol insulin; portable device delivery Particulate cloud inhaled insulin; portable device delivery Buccally absorbed, liquid aerosol insulin; portable device delivery 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

Inhaled Insulin in Type 1 Diabetes 73 Patients Taking Inhaled Insulin TID in Addition to Injected Long-Acting Insulin A 1 C (%) Subcutaneous insulin: 16 U regular + 31 U long-acting 10 9 Inhaled insulin: 12 mg inhaled + 25 U ultralente 8 7 6 0 4 8 Weeks Skyler JS et al. Lancet. 2001; 357: 331 -335 12

New Class of Agents for Diabetes Pramlintide

Glucose Flux in Healthy Subjects Mixed Meal (with ~85 g Dextrose) 200 0. 6 0. 4 Grams of Glucose flux/min Plasma Glucose (mg/d. L) 160 120 80 40 Appearance Meal Derived Glucose 0. 2 Hepatic Glucose Production 0 Total Glucose Uptake -0. 2 Disappearance -0. 4 -0. 6 0 -30 0 60 120 180 Time (min) Adapted and calculated from Pehling G. , et al. J. Clin. Invest. 1984; 74: 985 -991 -30 0 60 120 Time (min) 180

Multihormonal Regulation of Glucose Appearance and Disappearance 0. 6 Mixed Meal (with ~85 g Dextrose) Regulated by hormones: amylin, CCK, GLP-1, etc. Grams of Glucose flux/min 0. 4 0. 2 Meal-Derived Glucose Hepatic Glucose Production 0 Balance of insulin suppression and glucagon stimulation Total Glucose Uptake -0. 2 Insulin-mediated glucose uptake -0. 4 -0. 6 -30 0 120 240 360 480 Time (min) From Start of Mixed Meal Calculated from data in Pehling G, et al. J Clin Invest 1984; 74: 985 -991

Pramlintide Improves Postprandial Glucose TYPE 1 DIABETES Lispro Insulin Pramlintide 60 g + Lispro Insulin 300 Mean (SE) Plasma Glucose (mg/d. L) 250 200 150 100 0 60 120 240 Regular Insulin Pramlintide 60 g + Regular Insulin 300 Mean (SE) Plasma Glucose (mg/d. L) 180 250 200 150 100 0 60 120 180 240 Time Relative to Meal and Pramlintide (min) 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

Pramlintide Clinical Effects TYPE 1 DIABETES COMBINED PIVOTALS Placebo + Insulin 30 or 60 g Pramlintide TID or QID + Insulin Use (%) A 1 C (%) Week 4 Week 13 Week 26 0 Week 4 Week 13 Week 26 1 6 0 4 -0. 4 * 2 *** *** -0. 8 Week 4 Week 13 Week 26 8 -0. 2 -0. 6 Weight (kg) -1 0 -2 *** ** -4 Placebo + insulin (N = 538), Baseline A 1 C = 9. 0% Pramlintide + insulin (N = 716), Baseline A 1 C = 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 *** -2 ***

Adverse Events* 5% PRAMLINTIDE TYPE 1 DIABETES STUDIES Adverse Event Nausea Anorexia Inflicted Injury Vomiting Arthralgia Fatigue Allergic Reaction Dizziness Pivotal Studies Pramlintide Placebo (%) (N=538) (N=716) 17 48 2 17 10 14 7 11 5 7 7 4 5 6 4 5 *Excluding hypoglycemia, indicated dose (ITT) AE profile for Dose-Titration Study similar to Pivotals Pramlintide Acetate Prescribing Information, 2005 Clinical Practice Study Pramlintide (%) (N=265) 37 0 8 7 2 5 <1 2

Continuous Glucose Monitoring • 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 (Gluco. Watch) • Remaining challenges — — Daily SMBG still required Not suited to many patients Limited accuracy, especially for hypoglycemia Glycemic pattern results confusing, subject to interpretation

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

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 Mean A 1 C (%) Mean C-peptide (ng/m. L) 8. 4 % * 5. 7 * * 5. 7 % Baseline 6 months after transplant *P<0. 001 vs baseline Shapiro AMJ et al. N Engl J Med. 2000; 343: 230 -238 2. 5 0. 48 Baseline Fasting 90 min postmeal 6 months after transplant

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