Contents:

DIABETES: OPINION LEADER FORUM EXPERT’S VIEWS AND PERSPECTIVE ON DIAGNOSIS, TREATMENT, PRODUCT PERFORMANCE…AND CLOSING THE NEED GAP TABLE OF CONTENTS EXECUTIVE SUMMARY......................................................................................................................................... i SECTION 1 INTRODUCTION................................................................................................................................ 1 1.1 SCOPE AND OBJECTIVES OF RESEARCH INVESTIGATION........................................................... 1 1.2 METHODOLOGY OF INVESTIGATION................................................................................................ 2 1.3 LIMITATIONS OF INVESTIGATION ..................................................................................................... 5 SECTION 2 GENERAL ISSUES IN THE MANAGEMENT OF DIABETES..................................................... 7 2.1 THE FUNDAMENTALS OF DIABETES................................................................................................. 7 2.2 TYPE I DIABETES................................................................................................................................... 7 2.2.1 Epidemiology .................................................................................................................................. 8 2.2.2 Etiology ........................................................................................................................................... 8 2.2.3 Genetic Predisposition..................................................................................................................... 9 2.2.4 Pathophysiology ............................................................................................................................... 9 2.2.5 Environmental Viruses ................................................................................................................... 10 2.2.6 Adhesion Molecules ....................................................................................................................... 11 2.2.7 Glutamic Acid Decarboxylase (GAD) ........................................................................................... 11 2.2.8 Diagnosis of Type I Diabetes ......................................................................................................... 12 2.2.9 The Hyperglycemic Condition ....................................................................................................... 12 2.2.10 Biochemical Markers ..................................................................................................................... 13 2.2.11 Tests for Predicting Evolving (Early Stage) Diabetes Before Symptoms Appear.......................... 14 2.3 TYPE II DIABETES................................................................................................................................ 15 2.3.1 Risk Factors for Type II diabetes ................................................................................................... 15 2.3.2 Insulin Resistance.......................................................................................................................... 16 2.3.3 Role of Insulin Resistance in Diabetes ........................................................................................... 17 2.3.4 Pregnancy/Gestational Diabetes ..................................................................................................... 17 2.3.5 HNKS-Hyperosmoler Nonketotic Syndrome ................................................................................. 17 2.3.6 Epidemiology ................................................................................................................................ 18 2.3.7 Prevalence ..................................................................................................................................... 18 2.3.8 Etiology ......................................................................................................................................... 19 2.3.9 Insulin Secretion............................................................................................................................ 19 2.3.10 Insulin Action/Resistance............................................................................................................... 21 2.3.11 Genetics......................................................................................................................................... 21 2.3.12 Obesity .......................................................................................................................................... 22 2.3.13 Pathophysiology ............................................................................................................................. 22 2.3.14 Sorbitol and the Polyol Pathway .................................................................................................... 22 2.3.15 Advanced Glycation End (AGE) Products ..................................................................................... 23 2.3.16 Vascular Hemodynamic Dysfunction............................................................................................. 23 2.3.17 Diagnosis of Type II Diabetes........................................................................................................ 24 2.3.18 Treatment Goals ............................................................................................................................. 24 2.3.19 Innovative Therapy for Diabetes .................................................................................................... 25 2.3.20 Complexity of Treatment ............................................................................................................... 26 2.3.21 Quality of Life ............................................................................................................................... 26 2.3.22 Mortality........................................................................................................................................ 26 2.3.23 Current Therapy: Value And Limitations....................................................................................... 27 2.3.24 Exercise ......................................................................................................................................... 28 2.3.25 Dietary Control.............................................................................................................................. 28 2.4 DIABETES DRUGS OF THE ‘90S.......................................................................................................... 29 2.5 DIABETIC RETINOPATHY................................................................................................................... 31 2.5.1 Angiogenesis ................................................................................................................................. 33 2.5.2 Neovascular Diseases of the Eye.................................................................................................... 34 2.5.3 Epidemiology ................................................................................................................................ 35 2.5.4 Nonproliferative Diabetic Retinopathy........................................................................................... 36 2.5.5 Proliferative Diabetic Retinopathy ................................................................................................. 36 2.5.6 Etiology and Pathophysiology........................................................................................................ 37 2.5.7 Diagnosis....................................................................................................................................... 39 2.5.8 Treatment ...................................................................................................................................... 39 2.6 DIABETIC NEUROPATHY.................................................................................................................... 40 2.6.1 Definition ...................................................................................................................................... 40 2.6.2 Types of Neuropathy ...................................................................................................................... 41 2.6.3 Epidemiology ................................................................................................................................ 42 2.6.4 Etiology ......................................................................................................................................... 43 2.6.5 Pathophysiology ............................................................................................................................. 43 2.6.6 Diagnosis....................................................................................................................................... 44 2.6.7 Conventional Treatment ................................................................................................................. 44 2.7 DIABETIC NEPHROPATHY.................................................................................................................. 46 2.7.1 Definition ...................................................................................................................................... 46 2.7.2 Genetics of Nephropathy................................................................................................................ 47 2.7.3 Epidemiology ................................................................................................................................ 48 2.7.4 Etiology ......................................................................................................................................... 48 2.7.5 Pathophysiology ............................................................................................................................. 49 2.7.6 Modification of Cardiovascular Risk ............................................................................................. 51 2.7.7 Diagnosis....................................................................................................................................... 51 2.7.8 Conventional Treatment ................................................................................................................. 51 2.8 THE PUBLIC HEALTH BURDEN OF DIABETES MELLITUS IN THE UNITED STATES ............. 53 SECTION 3 CLINICAL MANAGEMENT OF DIABETES ................................................................................ 63 3.1 PHARMACEUTICAL STRATEGIES FOR MANAGING DIABETES ................................................. 63 3.2 PATIENT CARE STRATEGIES.............................................................................................................. 68 3.2.1 Patient and Physician Responsibilities for Effective Diabetes Care............................................... 68 3.2.2 Challenges in the Management of Diabetes ................................................................................... 70 3.2.3 Intensive Treatment Of Comorbid Conditions ............................................................................... 73 3.2.4 Young People with Type II diabetes .............................................................................................. 79 3.2.5 Diabetic Wound Care ..................................................................................................................... 81 SECTION 4 ISSUES IN CURRENT PHARMACEUTICAL APPROACHES TO THE MANAGEMENT OF DIABETES................................................................................................................................... 85 4.1 CURRENT PRODUCT TECHNOLOGY FOR DIABETES TYPE I ...................................................... 85 4.2 CURRENT PRODUCT TECHNOLOGY FOR DIABETES TYPE II..................................................... 88 4.3 GLUCOVANCE ...................................................................................................................................... 89 4.4 OTHER ORAL HYPOGLYCEMIC DRUGS .......................................................................................... 90 4.5 COMBINATION THERAPY................................................................................................................... 91 SECTION 5 PHARMACEUTICAL TECHNOLOGIES IN DEVELOPMENT FOR THE MANAGEMENT OF DIABETES ............................................................................................................................. 95 5.1 PRODUCT TECHNOLOGY FOR TYPE I DIABETES.......................................................................... 95 5.2 PRODUCT TECHNOLOGY FOR TYPE II DIABETES ........................................................................ 96 5.3 EXPERT COMMENTARY ON PHARMACEUTICAL TECHNOLOGIES UNDER DEVELOPMENT FOR THE MANAGEMENT OF DIABETES .......................................................................................... 97 5.3.1 Inhaled Insulin............................................................................................................................... 99 5.3.2 Alternative Delivery Systems for Insulin ..................................................................................... 102 5.3.3 Insulin Pump Therapy .................................................................................................................. 105 5.3.4 Experts Comments on Insulin Pump Therapy .............................................................................. 107 5.3.5 The Role of Genetics in Managing Diabetes................................................................................ 111 5.3.6 Diabetic Retinopathy and Macular Edema ................................................................................... 114 SECTION 6 RECENT AND ONGOING DIAGNOSTIC DEVELOPMENTS IN THE MANAGEMENT OF DIABETES AND ITS COMPLICATIONS ............................................................................. 117 6.1 AUTONOMIC DYSFUNCTION/HEART RATE VARIABILITY....................................................... 117 6.2 GLUCOWATCH ................................................................................................................................... 119 6.3 LASER GLUCOSE MONITOR............................................................................................................. 125 6.4 NEAR-INFRA (NIR) GLUCOSE MONITORING................................................................................ 127 6.5 MINIMALLY INVASIVE CONTINUOUS SUBCUTANEOUS GLUCOSE MONITOR ................... 129 SECTION 7 THE DIABETES MARKET: DELIVERY SYSTEM ISSUES..................................................... 133 7.1 AMERICA’S ASSAULT ON DIABETES AND CARDIOVASCULAR DISEASE LAUNCHED...... 133 7.2 DISEASE MANAGEMENT GUIDELINES FOR MANAGING DIABETES...................................... 136 7.3 LIFESTYLE ISSUES............................................................................................................................. 138 7.4 OBESITY............................................................................................................................................... 139 7.5 SELECTED EXPERT COMMENTS ON DISEASE MANAGEMENT................................................ 142 SECTION 8 NEEDS/GAPS ANALYSIS OF THE MANAGEMENT OF DIABETES.................................... 149 8.1 OVERVIEW .......................................................................................................................................... 149 8.2 EXPERTS’ VIEWS ON THE NEED/GAPS IN THE MANAGEMENT OF DIABETES .................... 149 8.3 POSTPRANDIAL GLUCOSE LEVELS................................................................................................ 152 ADDENDUM A THE PUBLIC HEALTH BURDEN OF DIABETES MELLITUS IN THE UNITED STATES ..................................................................................................................................................... 157 ADDENDUM B ECONOMIC IMPACT OF DIABETES JONATHAN C. JAVITT, MD, MPH, AND YENPIN CHIANG, PHD ................................................................................................................... 167 B.1 SUMMARY........................................................................................................................................... 167 B.2 INTRODUCTION ................................................................................................................................. 167 B.3 METHODOLOGICAL ISSUES IN ESTIMATING THE COSTS OF AN ILLNESS........................... 168 B.4 METHODS FOR ATTRIBUTING COSTS TO THE UNDERLYING CONDITION........................... 168 B.5 METHODS FOR VALUING HUMAN LIFE AND HEALTH.............................................................. 169 B.6 METHODS FOR ESTIMATING VOLUME OF MEDICAL SERVICES............................................. 170 B.7 DIRECT AND INDIRECT COSTS OF DIABETES ............................................................................. 171 B.8 DIRECT COSTS.................................................................................................................................... 173 B.9 INDIRECT COSTS................................................................................................................................ 174 B.10 THE COSTS OF SYSTEMIC MORBIDITY AND MORTALITY ATTRIBUTABLE TO DIABETES 175 B.11 ECONOMIC IMPACT OF DIABETES ON AFFECTED INDIVIDUALS........................................... 176 B.12 INTERNATIONAL COMPARISONS OF DIABETES COSTS ........................................................... 179 B.13 CONLUSIONS ...................................................................................................................................... 180 B.14 REFERENCES....................................................................................................................................... 181 ADDENDUM C DIABETES QUALITY IMPROVEMENT PROJECT: INITIAL MEASURE SET (FINAL VERSION) AUGUST 14, 1998.................................................................................................. 183 ADDENDUM D SUMMARY OF VHA/DOD CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT OF DIABETES MELLITUS IN THE PRIMARY CARE SETTING .... 197 ADDENDUM E AMERICAN ASSOCIATION OF ENDOCRINOLOGISTS GUIDELINES DIABETES MANAGEMENT STANLEY FELD, MD, FACP, MACE CHAIRMAN, DIABETES MEDICAL GUIDELINES TASK FORCE AACE DIABETES GUIDELINE..................... 209 ADDENDUM F CONQUERING DIABETES: A STRATEGIC PLAN FOR THE 21ST CENTURY........... 251 ADDENDUM G PRODUCT TECHNOLOGIES IMPACTING DIABETES THERAPEUTICS................... 269 ADDENDUM H PROFILES OF LEADING FIRMS DEVELOPING AND/OR MARKETING DIABETES MEDICINES.............................................................................................................................. 301 ADDENDUM I SELECTED RECENT EVENTS IN THE MANAGEMENT OF DIABETES ...................... 341 Table 1 Estimates of the Economic Costs of Diabetes in the United States Dollars in Billions............... 172 Table 2 Estimates of the Direct Costs of Diabetes in the United States Dollars in Billions..................... 172 Table 3 Total Economic Cost of Diabetes in the United States (1992) ..................................................... 176 Table 4 Total and Out-Of-Pocket Medical Expenses: Diabetic Patients Versus the General Population . 177 Table 5 Direct Medical Care Expenditures for Persons with Confirmed Diabetes and for Persons with Diabetes or High Blood Sugar...................................................................................................... 179 Table 6 Evidence Grading System ............................................................................................................ 200 Table 7 Comparison of VHA/DoD Diabetes Clinical Guidelines to Existing National Guidelines Relevant to Diabetes..................................................................................................................... 201 Table 8 VHA’s External Peer Review Specific Measures for Diabetes Mellitus...................................... 203 Table 9 General Preventive Measures Pertinent for Persons with Diabetes Preventive Measures........... 204 Table 10 Classification of Blood Pressure in DM(a) .................................................................................... 205 Table 11 Target Value for Hemoglobin A1c (HbA1c)................................................................................ 205 Table 12 Recommended Treatment Options for Type II Diabetes.............................................................. 206 Table 13 Oral Hypoglycemic Agents .......................................................................................................... 207 Table 14 Commonly Used Sulfonylureas: Dosage Data ............................................................................ 221 Table 15 Metformin: Dosage Data ............................................................................................................. 221 Table 16 a-Glucosidase Inhibitors: Dosage Data ....................................................................................... 221 Table 17 Thiazolidinediones: Dosage Data................................................................................................ 222 Table 18 Meglitinides: Dosage Data .......................................................................................................... 223 Table 19 Insulins: Available Types, Strengths and Duration of Action* ................................................... 224 Table 20 Fasting and Postprandial Blood Glucose and Glycosylated Hemoglobin Responses to Pharmacologic Treatment in Patients with Type 2 Diabetes* ...................................................... 224 Table 21 Effect of Pharmacologic Treatment of Type 2 Diabetes on Insulin Secretion and Glucose Production and Uptake ................................................................................................................. 224 Table 22 Summary of Patient and Physician Responsibilities in Intensive Diabetes Self-Management System......................................................................................................................................... 232 Table 23 Diabetes Drug Development Programs ........................................................................................ 334