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.
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 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
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
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
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
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
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
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%
Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes
Post MI or low EF
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
A Goals Intervention
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
LDL-C targets, ATP III guidelines
CHD, CHD risk equivalents: <100 mg/dL
2 RF: <130 mg/dL
0-1 RF: <160 mg/dL
C Goals Intervention
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
Education of patients and families
Achieve optimal BMI
saturated fats; fruits, vegetables, fiber
Achieve HbA 1c <7%
D Goals Intervention
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)
Angiotensin-converting enzyme (ACE) inhibitor
Angiotensin-receptor blocker (ARB)
Standard methods (1, 2, or 3 agents may be needed) Treatment target: Blood pressure <130/80 mm Hg
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
HMG-CoA reductase inhibitors (statins)
Standard method Treatment target: LDL <100 mg/dL, no CVD LDL <70 mg/dL, with CVD
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
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
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)
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
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
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 *
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