Type 1 Diabetes in Adults Andrej Janež, MD PhD Dept. of Endocrinology Diabetes and Metabolic Diseases University Medical Center Ljubljana

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. 2nd 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/dL* Fasting plasma glucose (FPG) 126 mg/dL* Oral glucose tolerance test (OGTT) with 2-hour value 200 mg/dL* Loss of c-peptide c-peptide<0.8 ng/dL Presence of islet autoantibodies GADA, ICA, IA-2A, IAA *Requires confirmation by repeat testing American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10

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

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

Risk of Progression of Microvascular Complications vs A1C DCCT Relative risk 20 Retinopathy Neuropathy 15 Microalbuminuria 10 5 1 5 6 7 8 9 10 11 12 A1C (%) A1C=hemoglobin A1c Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254

T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus. Intensive Therapy for Diabetes: Reduction in Incidence of Complications T1DM DCCT T2DM Kumamoto UKPDS A1C 9%  7% 8%  7% Retinopathy 63% 69% 17%–21% Nephropathy 54% 70% 24%–33% Neuropathy 60% 58% – Cardiovascular disease 41%* 52* 16%* Review Data T1DM = type 1 diabetes mellitus; T2DM = 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.

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

Cost-Effectiveness of Intensive Therapy in Type 1 Diabetes DCCT Modeling Study Years Free From Complication (Projected Average) Conventional treatment Intensive treatment Proliferative retinopathy 39.1 53.9 Blindness 49.1 56.8 Microalbuminuria 34.5 43.7 End-stage renal disease (ESRD) 55.6 61.3 Neuropathy 42.3 53.2 Amputation DCCT Research Group. JAMA. 1996;276:1409-1415

Principles of Intensive Therapy of Type 1 Diabetes Targets

Current Targets for Glycemic Control ADA ACE LA IDF A1C (%) Normal: 4%–6% <7.0 6.5 <6.5 Fasting/Preprandial (mg/dL) (plasma equivalent) 90-130 <110 110 <100 Postprandial (mg/dL) (2-hour) <180* <140 140 <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.

Principles of Intensive Therapy of Type 1 Diabetes Insulin Options

Action Profiles of Insulins Aspart, glulisine, lispro 4–5 hours Regular 6–8 hours Plasma insulin levels NPH 12–16 hours Detemir ~14 hours Ultralente 18–20 hours Glargine ~24 hours 1 2 5 3 4 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/mL 100 B L D 80 60 40 20 0600 0800 1200 1800 2400 0600 Time of day B=breakfast; L=lunch; D=dinner Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

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

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 Favors Regular Insulin Favors Aspart P Values NS 0.076 <0.050 <0.005 All severe hypoglycemia Nocturnal event Nocturnal, glucagon required 4–6 hours postmeal 0.1 1 10 Relative risk Home PD et al. Diabet Med. 2000;17:762-770

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

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 A1C Insulin dose -2 -1 0 1 2 Mean difference Pickup et al. 12 RCTs Weissberg-Benchell et al. 11 RCTs RCT=randomized controlled trial Pickup J et al. BMJ. 2002;324:1-6; Weissberg-Benchell J et al. Diabetes Care. 2003;26:1079-1087

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

Hypoglycemia Risk 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

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

Future Glucose Monitors Guardian™ CGMS External Closed-Loop Minimally invasive continuous glucose monitors Implanted glucose sensors Implanted insulin pumps “Closed-loop” systems Freestyle Navigator™ 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 A1C (%) Mean C-peptide (ng/mL) * 5.7 8.4% * * 2.5 5.7% 0.48 Baseline 6 months after transplant Baseline Fasting 90 min postmeal 6 months after transplant *P<0.001 vs baseline Shapiro AMJ et al. N Engl J Med. 2000;343:230-238

Opportunities for Intervention in Type 1 Diabetes TrialNet Multiple antibody positive Genetically at risk Loss of first-phase insulin response -Cell mass Newly diagnosed diabetes Genetic predisposition Insulitis -Cell injury -Cell insufficiency Diabetes Time