Type 1 Diabetes in Adults
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  • Review Data
  • 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: 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: 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: 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: 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.

Transcript

  • 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
  • 2. Prevalence of Diabetes in the United States Undiagnosed diabetes 5.2 million 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 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
  • 4. Making the Diagnosis of Type 1 Diabetes American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10 *Requires confirmation by repeat testing
    • 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
  • 5. Natural History of “Pre” – Type 1 Diabetes 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 insufficiency Genetic predisposition Insulitis  -Cell injury Eisenbarth GS. N Engl J Med . 1986;314:1360-1368 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% 0 1 2 3 4 5 6 7 8 9 Cumulative percentage 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 Intensive
  • 8. Risk of Progression of Microvascular Complications vs A1C D CCT 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 A1C=hemoglobin A 1c
  • 9. Intensive Therapy for Diabetes: Reduction in Incidence of Complications *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. T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus. 16%*  52* 41%* Cardiovascular disease – 58% 60% Neuropathy 24% – 33% 70% 54% Nephropathy 17% – 21% 69% 63% Retinopathy 8%  7% 9%  7% 9%  7% A1C T2DM UKPDS T2DM Kumamoto T1DM DCCT
  • 10. Long-term Microvascular Risk Reduction in Type 1 Diabetes Combined 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 DCCT End of randomized treatment EDIC Year 1 EDIC Year 7 6% 8% 10% 12% A1C Retinopathy progression (incidence) P <0.001 P <0.001 P =0.61 Intensive Conventional
  • 11. Cost-Effectiveness of Intensive Therapy in Type 1 Diabetes DCCT Modeling Study DCCT Research Group. JAMA . 1996;276:1409-1415 Years Free From Complication (Projected Average) Intensive treatment Conventional treatment 56.8 49.1 Blindness 53.9 39.1 Amputation 53.2 42.3 Neuropathy 61.3 55.6 End-stage renal disease (ESRD) 43.7 34.5 Microalbuminuria 53.9 39.1 Proliferative retinopathy
  • 12. Principles of Intensive Therapy of Type 1 Diabetes Targets
  • 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. <100 110 <110 90-130 Fasting/Preprandial (mg/dL) (plasma equivalent) IDF LA ACE ADA <135 140 <140 <180* Postprandial (mg/dL) (2-hour)  6.5 <6.5  6.5 <7.0 A1C (%) Normal: 4% – 6%
  • 14. Principles of Intensive Therapy of Type 1 Diabetes Insulin Options
  • 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 0 1 2 5 3 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
  • 16. Normal Daily Plasma Insulin Profile Nondiabetic Obese Individuals Polonsky KS et al. N Engl J Med. 1988;318:1231-1239 0600 0600 Time of day 20 40 60 80 100 B L D B=breakfast; L=lunch; D=dinner 0800 1800 1200 2400  U/mL
  • 17. Basal/Bolus Treatment Program with Rapid-acting and Basal Analogs 4:00 16:00 20:00 24:00 4:00 Breakfast Lunch Dinner 8:00 12:00 8:00 Time Basal Plasma insulin Rapid Rapid 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. Mealtime Insulin and Severe Hypoglycemia Aspart vs Regular Insulin 0.1 1 10 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 16:00 20:00 24:00 4:00 Breakfast Lunch Dinner Plasma Insulin µ U/ml) 8:00 12:00 8:00 Time Basal Infusion Bolus Bolus 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. CSII vs Multiple Injections of Insulin Meta-analyses -2 -1 0 1 2 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 RCT=randomized controlled trial Pickup et al. 12 RCTs Weissberg-Benchell et al. 11 RCTs
  • 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 5.5 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
  • 26. 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
  • 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
    40 50 60 70 80 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 Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004 <1.3 mg/dL Annually Creatinine <130/80 mm Hg Quarterly Blood pressure <150 mg/dL Annually (more often if control poor) Triglycerides <100 mg/dL May be different in young children Annually (more often if control poor) LDL cholesterol >40 mg/dL, males >50 mg/dL, females Annually (more often if control poor) HDL cholesterol Goal Frequency
  • 34. Follow-up Visits Quarterly Evaluations Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004 Peripheral neuropathy and infection Quarterly (or every visit) Foot exam General health Quarterly General checkup (including weight/BMI, A1C) Assessment Frequency
  • 35. Follow-up Visits Annual Evaluations Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004 Target <30 mg/g creatinine Annually (in adolescents and >3 years after type 1 diagnosis) Microalbuminuria Peripheral neuropathy Annually Skin examination Development/ progression of CVD Annually (more often if CVD present) Cardiac examination Autonomic and peripheral neuropathy Annually Neurologic examination Retinopathy Annually (in adolescents and >3 years after type 1 diagnosis) Dilated eye examination Thyroid disease, celiac disease, etc Annually Screening for other autoimmune conditions Assessment Frequency
  • 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 Goals Intervention
  • 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 cessation
    • Cigarette-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 Goals Intervention
  • 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 Goals Intervention
  • 40. 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
    •  -Adrenergic blocker or central adrenergic agent
    • Long-acting calcium channel blocker (CCB)
    • Loop diuretic
    Individualized options
    • Angiotensin-converting enzyme (ACE) inhibitor
    • Angiotensin-receptor blocker (ARB)
    • Thiazide
    •  -Blocker
    Standard methods (1, 2, or 3 agents may be needed) Treatment target: Blood pressure <130/80 mm Hg
  • 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
    • Intestinal cholesterol absorption inhibitors
    • Bile acid–binding resins
    • Nicotinic acid
    Individualized options
    • HMG-CoA reductase inhibitors (statins)
    Standard method Treatment target: LDL <100 mg/dL, no CVD LDL <70 mg/dL, with CVD
  • 42. The Future of Type 1 Diabetes Care
  • 43. Emerging Type 1 Diabetes Therapies Inhaled dry powder insulin; portable device delivery
      • Technosphere ® insulin
    Buccally absorbed, liquid aerosol insulin; portable device delivery
      • Oralin ®
    Transplantation of donor pancreatic  -cells; restores endogenous insulin secretion Islet cell transplant Insulins Injectable amylin analogue; slows gastric emptying, suppresses glucagon, and increases satiety Pramlintide (Symlin ® ) Inhaled liquid aerosol insulin; portable device delivery
      • AERx ®
    Particulate cloud inhaled insulin; portable device delivery
      • Exubera ®
    Inhaled liquid aerosol insulin; portable device delivery
      • Aerodose ®
  • 44. Inhaled Insulin in Type 1 Diabetes Subcutaneous insulin: 16 U regular + 31 U long-acting Inhaled insulin: 12 mg inhaled + 25 U ultralente 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
  • 45. New Class of Agents for Diabetes Pramlintide
  • 46. Glucose Flux in Healthy Subjects Time (min) Adapted and calculated from Pehling G., et al. J. Clin. Invest. 1984; 74: 985-991 Plasma Glucose (mg/dL) 0 120 0 40 80 120 160 200 -30 60 180 Mixed Meal (with ~85 g Dextrose) 0 120 -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 60 180 Hepatic Glucose Production Time (min) Appearance Disappearance
  • 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
  • 48. Pramlintide Improves Postprandial Glucose TYPE 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, 2005 Data from Weyer C, et al. Diabetes Care 2003; 26:3074-3079 Evaluable population; Mean (SE) Pramlintide + Lispro insulin (n = 20) Pramlintide + Regular insulin (n = 18)
  • 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 -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
  • 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 Studie s (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 *Excluding hypoglycemia, i ndicated dose (ITT) AE profile for Dose-Titration Study similar to Pivotals
  • 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 insufficiency Genetic predisposition Insulitis  -Cell injury Diabetes Time  -Cell mass