Diabetes, Metabolic Syndrome and Cardiovascular Disease

There has been a dramatic increase in the incidence of diabetes worldwide, which has been exacerbated by the growing obesity problem across the globe. Once thought of as primarily a childhood disease--sometimes referred to as juvenile diabetes, now mostly Type 1 diabetes--the obesity crisis linked to the adoption of a high-fat, high-carbohydrate, high-calorie American diet has resulted in skyrocketing rates of diabetes among adults across the world. To compound the global diabetes epidemic, health professionals are witnessing an alarming increase in inflammatory diseases resulting from adult onset (i.e., Type 2) diabetes. This phenomenon is referred to as "metabolic syndrome" where a confluence of inflammatory conditions occur along with the diabetes. As a result, growing evidence appears to show that metabolic syndrome makes the diabetic patient susceptible to degenerative health conditions such as cardiovascular disease, stroke and, now believed, Alzheimer’s disease. As the diabetes epidemic escalates, a new sense of urgency has taken hold. Proactive strategies for prevention of the disease are being put in place by international health organizations such as the World Health Organization (WHO), as well as by the health departments of industrialized and developing countries, and even at the local level where food ingredients regulations are being passed. This TriMark Publications report charts the changing landscape of the global diabetic population and explores the added health concerns resulting from the metabolic syndrome phenomenon and one of its major risk factors: cardiovascular disease (CVD). Furthermore, this study evaluates widely-accepted therapeutic approaches to diabetes that are currently in use, while providing an in-depth analysis of emerging technologies that will be used to treat diabetes and other inflammatory diseases in the future.

1. Overview 8
1.1 Statement of Report 8
1.2 About this Report 8
1.3 Scope of the Report 9
1.4 Methodology 9
1.5 Executive Summary 11

2. Introduction 17
2.1 Demographics of Diabetes 17
2.1.1 Worldwide Diabetes 17
2.1.2 U.S. Diabetes 18
2.2 Economics of Diabetes 22

3. Understanding the Metabolic Conditions Underlying and Associated with Diabetes 28
3.1 Pre-Diabetes Syndrome 29
3.2 Metabolic Syndrome 29
3.3 Diabetes and Inflammation 32
3.4 Progression of Diabetes 32
3.5 Complications and Co-Morbidities in Type 2 Diabetes 33
3.6 Hypoglycemia and Treatment 38
3.7 Risk Factors and Diabetes 39
3.8 Cardiovascular Disease (CVD) Facts 40

4. Pharmaceutical Industry and the Anti-Diabetes Market 51
4.1 The Worldwide Pharmaceutical Industry 51
4.2 Total Diabetes Drug Market Size and Growth 58
4.2.1 Sales of Anti-Diabetic Drugs Continue to Rise 61
4.3 Epidemiology/Cost of Treatment 62
4.4 Diabetic Medications Overview 63
4.4.1 Recent Trends in Diabetic Drug Usage 63
4.4.2 Market Influence Factors 67

5. Non-Insulin Anti-Diabetes Products 69
5.1 Anti-Diabetic Drug Therapy Overview 69
5.1.1 Sulfonylureas 72
5.1.2 Meglitinides 73
5.1.3 Biguanides 73
5.1.4 Thiazolidinediones (TZDs) 74
5.1.5 a-Glucosidase Inhibitors 77
5.1.6 Incretin Mimetics/Glucagon-like Peptide (GLP-1) Analog 77
5.1.7 Amylin Analog 79
5.1.8 DPP-IV Inhibitors 79
5.1.9 Other Classes 81
5.1.10 Combination Therapy 81
5.2 Drivers and Trends 82
5.2.1 Market Share of Anti-Diabetic Drugs 82
5.2.2 Forecasts for Anti-Diabetic Drugs 82
5.2.3 Sales Forecast for the Global Diabetes Market 83
5.3 The Future 84
5.3.1 Practice Patterns 84
5.3.2 New Products in Pipeline 85
5.4 Anti-Diabetic Drug Patent Expiry 91
5.5 Regulatory Issues 91

6. Insulin 92
6.1 Insulin Markets 92
6.1.1 Major Players and Market Share 93
6.2 Insulin and Analogs 95
6.2.1 Rapid-Acting Insulin 95
6.2.2 Intermediate-Acting Insulin 97
6.2.3 Long-Acting Insulin/Ultra Long-Acting Insulin 97
6.2.4 Insulin Mixtures 99
6.3 Insulin Analogs 100
6.4 Non-Insulins in Development 100
6.5 Pipeline Insulin 101
6.6 Non-Invasive Insulin Delivery 101
6.6.1 Inhaled Insulin 101
6.6.1.1 Inhaled Insulin Overview 102
6.6.2 Oral Insulin 104
6.6.3 Transdermal Insulin 106
6.6.4 Oral Spray Insulin 108
6.7 Barriers for Non-Injected Insulin 109
6.8 Patient Potential for Non-Injected Insulin 109
6.9 Insulin Delivery Devices 109
6.9.1 Lancets and Lancing Devices 110
6.9.2 Insulin Pens 113
6.9.3 Injections Aids 117
6.9.3.1 Automatic Injectors 117
6.9.3.2 Syringe Magnifiers 118
6.9.3.3 Insulin Infusers 118
6.9.4 Insulin Jet Injectors 118
6.9.5 Insulin Pumps 119
6.9.5.1 External Insulin Pumps 119
6.9.5.2 Implantable Insulin Pumps 122
6.9.5.3 Insulin Pump Market Share 123
6.9.5.4 Drivers of Demand for Pumps 128
6.10 Market Forecasts for Insulin Administration Technologies 129

7. Emerging Anti-Diabetes Products 130
7.1 Projections for the Anti-Diabetes Drug Market 130
7.2 Artificial Pancreas 134
7.3 Insulin-Producing Cells 135
7.3.1 Cell Therapy Companies for Diabetes 135
7.4 Transplantation Procedures 137
7.4.1 Pancreatic Transplantation 138
7.4.1.1 Pancreatic Organ Transplantation 138
7.4.1.2 Allo-Islet Transplantation 138
7.4.1.3 Transplantation of Encapsulated Pancreatic Cells 139
7.4.1.4 Implantation of Genetically Engineered-Cells or Embryonic Stem Cells 139
7.4.2 Current Status 140
7.5 Gastric Bypass Surgery to Treat Type 2 Diabetes 140
7.6 Immune Modulators 141
7.7 Anti-Obesity Drug Xenical to Prevent or Delay Development of Type 2 Diabetes 141
7.8 Other Anti-Diabetic Therapy Drug Candidates 141
7.8.1 Lipid Abnormalities 142
7.8.2 High Blood Pressure 143
7.8.3 Anticoagulants 144
7.9 Drugs Used "Off-Label" 145
7.9.1 Niacin Derivatives 145
7.9.2 Benfluorex 145
7.9.3 D-Chiro-Inositol 145
7.9.4 Warfarin Sodium 145
7.10 Pipeline Diabetic Drug Candidates 146
7.11 Drug Research Overview 149
7.12 Future Anti-Diabetic Drugs in Late-Stage Development 151

8. Diagnosing Diabetes Using In Vitro Laboratory Tests 154
8.1 New Diagnostic Guidelines 154
8.2 Diabetes Tests 155
8.2.1 Fasting Plasma Glucose (FPG) Test 155
8.2.2 Glucose Tolerance Test 155
8.2.3 Test for Glycosylated Hemoglobin 156
8.2.4 Fructosamine 157
8.3 Glucose Monitoring 157
8.3.1 Overview of Market Segment 160
8.3.2 Competitive Strategies 160
8.3.3 Analyses of the Current Market Conditions, Competition and Product Mix 162
8.3.3.1 First-Generation Monitors 162
8.3.3.2 Second-Generation Monitors 162
8.3.3.3 Third-Generation SMBG Technologies 164
8.3.3.4 Product Overview 165
8.3.3.4.1 LifeScan 165
8.3.3.4.2 Roche Diagnostics 168
8.3.3.4.3 Bayer Diagnostics 169
8.3.3.4.4 Abbott Diagnostics 172
8.3.3.4.5 Other Players 174
8.3.4 What Are the Advantages of Using a Continuous Glucose-Monitoring Device? 177
8.3.5 Other Monitoring Device Advancements 178
8.3.6 Future of Non-Invasive Glucose Technology 179

9. Market Trends, Challenges and Strategic Options 182
9.1 Overview 182
9.2 Diabetes Drug Market Trends 182
9.2.1 Overview 182
9.2.2 Emergence of Therapeutics with Improved Administration Characteristics 182
9.2.3 Increasing Prevalence of Obesity 183
9.3 Diabetes Mellitus Market Challenges 185
9.3.1 Overview 185
9.3.2 Diabetic Pain Therapeutics 185
9.3.3 Market Prospects of Inhalable Drugs and Their Ability to Establish Safety Levels 186
9.3.4 Changing Consumer Preference Drives Product Development in Invasive Technology Segment 186
9.3.5 Non-Invasive Technology for Revenue Potential 186
9.3.6 Developing Countries Emerging as Key Markets for Diabetes Monitoring Devices 187
9.3.7 Consumer-Driven Marketing CampaignsEssential, though Expensive 189
9.3.8 Escalating Expenditure for R&D and Marketing Triggers Consolidation 189
9.3.9 Market Size Predictions 191
9.3.10 Major Competitors 191
9.4 Strategic Options 192
9.4.1 Overview 192
9.4.2 Combined Self-Testing Glucose Monitor with Insulin Delivery 193
9.4.3 Diabetes Drugs in Pipeline 194
9.5 FDA Therapeutic Targets 196
9.5.1 FDA Targets Cardiotoxicity 197
9.5.2 Avandia FDA Warning 197
9.6 Outlook to Anti-Diabetes Drugs 197
9.7 Outlook for Cardiovascular Drugs 201

10. Company Profiles 203
10.1 A. Menarini 203
10.2 Abbott Laboratories 203
10.3 Amgen 204
10.4 AstraZeneca 205
10.5 Bayer 206
10.6 BodyMedia 208
10.7 Cybermedical 208
10.8 Debiotech 208
10.9 DexCom 209
10.10 Echo Therapeutics 210
10.11 Elixir Pharmaceuticals 211
10.12 Eksigent 211
10.13 Flamel Technologies 211
10.14 GlaxoSmithKline 212
10.15 GlucoLight 212
10.16 Insulet 212
10.17 iSense Corporation 213
10.18 Isis Pharmaceuticals, Inc. 213
10.19 Johnson & Johnson 214
10.20 KYORIN 215
10.21 M-Biotech 215
10.22 Medtronic 215
10.23 Merck & Co. 217
10.24 Merck KGaA 218
10.25 MicroIslet 218
10.26 Mitsubishi Tanabe Pharma Corporation 219
10.27 Nipro Diabetes Systems 219
10.28 Novartis 219
10.29 Novo Nordisk 220
10.30 Novocell 221
10.31 ONO Pharmaceutical 221
10.32 Orexigen Therapeutics 222
10.33 Pfizer 223
10.34 ReNeuron 223
10.35 Roche Diagnostics 224
10.36 Sanofi-Aventis 225
10.37 Sensors for Medicine and Science 226
10.38 Siemens 227
10.39 Smiths Medical 227
10.40 Servier 228
10.41 SOOIL Development 228
10.42 Takeda 228
10.43 TheraFuse 229
10.44 Teco Diagnostics 229
10.45 Transition Therapeutics 229
10.46 U.S. Diagnostics 229
10.47 VeraLight 230
10.48 Vivus 230
10.49 Ypsomed Holding 231

Appendix 1: Contact Information for Companies Profiled 232
Appendix 2: Prescribing Patterns for Anti-Hyperglycemic Drugs 238
Appendix 3: Detailed List of Insulins Available 239
Appendix 4: The History of Insulin 240
Appendix 5: Diabetes and Obesity Drugs in Development 245
Appendix 6: Pharmaceutical Sampling Practices 253


INDEX OF FIGURES

Figure 2.1: Worldwide Rates of Diabetes Cases, 2000-2025 17
Figure 2.2: Prevalence of Diabetes by Age in the U.S, 2007 18
Figure 2.3: New Adult Cases of Diabetes Diagnosed in the U.S., 2007 19
Figure 2.4: Distribution of Duration of Diabetes among Adults Aged 18 to 79 Years in the U.S., 2005 20
Figure 2.5: Number of Persons with Diagnosed Diabetes in the U.S., 1980-2007 20
Figure 2.6: Treatment with Insulin or Oral Medication among Adults Diagnosed with Diabetes, 2007 21
Figure 2.7: Rate of New Diabetes Cases among Children in the U.S., 2007 22
Figure 2.8: Expenditure Associated with Diabetes Complications in the U.S., 2007 25
Figure 2.9: Diabetes Death Rate by Race and Sex in the U.S., 1979-2006 27
Figure 3.1: Prevalence of Complications in Diabetics vs. People with Normal Blood Sugar Levels, 2007 34
Figure 3.2: Per Capita Costs for Diabetes-related Complications per Year, 2007 35
Figure 3.3: Total Spending on Healthcare in the U.S., 1960-2008 36
Figure 3.4: Percentage Breakdown of U.S. Healthcare Spending, 2008 36
Figure 3.5: Percentage of U.S. Population that Smokes, 1965-2005 42
Figure 3.6: Heart Disease Death Rate by Race and Sex in the U.S., 1979-2006 42
Figure 3.7: Hypertension Drugs Newly Prescribed or Continued in the U.S., 1994-2007 43
Figure 3.8: Annual Death Rate of U.S. Population from Strokes, 1950-2008 43
Figure 3.9: U.S. Male and Female Population Death Rates from Strokes, 2008 45
Figure 3.10: Annual Death Rate of U.S. Population from Heart Disease, 1950-2008 48
Figure 3.11: Percentage of U.S. Population that is Overweight, 1976-2004 50
Figure 4.1: Medical Research in the U.S. Outpaces the Rest of the World 52
Figure 4.2: Cost of Diabetes in the U.S., 2007 62
Figure 4.3: Top Therapeutic Classes Contributing to Drug Trend, 2007 65
Figure 4.4: U.S. Non-Insulin Anti-Diabetic Drug Prescriptions, 2006 65
Figure 5.1: Comparison of the Effects of the Pioglitazone and Rosiglitazone on Lipids 76
Figure 5.2: U.S. Non-Insulin Anti-Diabetes Sales, 2006 83
Figure 5.3: Sales Forecast for the Global Diabetes Market, 1992-2012 84
Figure 6.1: Insulin Pump Market Share, 2007 123
Figure 6.2: Relative Risk of Diabetes Complications by Mean HbA1c 123
Figure 9.1: Relationship between Diabetes Therapy and the Proposed Timeline 195
Figure A3.1: Novo Nordisk’s Rising Market Share in the U.S. Insulin Market, 1982-2008 244


INDEX OF TABLES

Table 1.1: Criteria for the Diagnosis of Diabetes 11
Table 2.1: Top Ten Countries in Number of Diabetics (20 to 79 Age Group) in the World, 2007 and 2025 17
Table 2.2: Annual Estimated Cost of Diabetes Care in the U.S., 2007 23
Table 2.3: Impact of Diabetes on Americans 24
Table 2.4: How Diabetes Dollars are Spent in the U.S., 2007 24
Table 3.1: Percentage of GDP Healthcare Spending by Country, 2008 37
Table 3.2: Life Expectancy Rate by Country, 2008 37
Table 3.3: Normal Glucose ValuesFasting State 39
Table 3.4: Percentage of Adults Smokers by Country, 2008 44
Table 3.5: Worldwide Market for Cardiac Care Therapeutics, 2003-2010 45
Table 3.6: Death Rate from Cardiovascular Diseases by Country, 2008 49
Table 4.1: Leading Therapy Classes for R&D, 2008 51
Table 4.2: Pharmaceutical R&D Expenditures by World Region, 1990-2007 52
Table 4.3: Pharmaceutical Companies Ranked by Total R&D Expenditures, 2007 53
Table 4.4: Global Pharmaceutical Sales, 2007 53
Table 4.5: World Pharmaceutical Sales Share by Region, 2007 54
Table 4.6: The World’s Top-Selling Drugs (Audited Market), 2007 55
Table 4.7: Pharmaceutical Product Sales by Country Market, 2007 55
Table 4.8: Top Ten Global Pharmaceutical Companies by Global Sales, 2007 56
Table 4.9: Leading Therapy Classes by Global Pharmaceutical Sales (Audited Market), 2007 56
Table 4.10: Leading Ten Therapeutic Classes by U.S. Sales, 2003-2007 56
Table 4.11: Top Ten Therapeutic Classes by U.S. Dispensed Prescriptions, 2006 and 2007 57
Table 4.12: Top Ten Brand Drugs by U.S. Retail, 2007 57
Table 4.13: Worldwide Anti-Diabetes Drug Market, 2006-2012 58
Table 4.14: Oral Anti-Diabetic Therapy Major World Markets, 2006 59
Table 4.15: The Leading Ten Anti-Diabetics by Sales, 2007 61
Table 4.16: Non-Insulin Hypoglycemic Drugs Used to Treat Type 2 Diabetes, 2008 61
Table 4.17: Summary of Glucose-Lowering Interventions as Monotherapy 67
Table 5.1: Classes of Non-Insulin Hypoglycemic Agents 70
Table 5.2: Average Dose and Cost Comparison of Hypoglycemic Agents 71
Table 5.3: Relative Efficacy of Diabetes Drugs 72
Table 5.4: Thiazolidinediones Available for Type 2 Diabetes Mellitus 75
Table 5.5: Fixed Drug Combinations 81
Table 5.6: GLP-1 Pipeline: Selected Drugs in Development that Target GLP-1 88
Table 5.7: DPP-IV Inhibitor Pipeline 89
Table 6.1: Available Therapeutic Insulin Alternatives 92
Table 6.2: Worldwide Insulin Sales, 2005-2012 93
Table 6.3: Worldwide Insulin Sales and Market Share by World Region, 2007 93
Table 6.4: Worldwide Insulin Sales and Market Share by Company, 2007 94
Table 6.5: U.S. Insulin Sales and Market Share by Company, 2007 94
Table 6.6: U.S. Retail Insulin Sales, 2006-2009 95
Table 6.7: Comparison of Rapid-Acting Insulins 96
Table 6.8: Comparison of Long-Acting Insulins 98
Table 6.9: Pharmacokinetics of Available Insulins 98
Table 6.10: Status of Inhaled Insulin Products, 2009 103
Table 6.11: Key Drivers of the Type 2 Diabetes Insulin Market, 2012 109
Table 6.12: A Comparison of Existing Insulin Delivery Devices 110
Table 6.13: Lancet Characteristics 112
Table 6.14: Lancing Device Characteristics 113
Table 6.15: Insulin Pens 114
Table 6.16: Worldwide Demand for Insulin Injector Pens by Volume, 2006-2010 115
Table 6.17: Injection Aids 118
Table 6.18: Jet Injectors 118
Table 6.19: Leading Insulin Pump Manufacturers 119
Table 6.20: External Insulin Pumps 120
Table 6.21: Comparison of Current Insulin Pumps on the Market 120
Table 6.22: Control Averages by Treatment 122
Table 6.23: Reduced Risk for Various Diseases When Blood Glucose is Near Normal 122
Table 6.24: Worldwide Diabetes Market, 2008 124
Table 6.25: Types of Insulin Pumps on the Market 124
Table 7.1: Advantages and Disadvantages of Newer Type 2 Diabetes Therapies 134
Table 7.2: Cells of the Pancreas 140
Table 7.3: Lipoprotein Risk Levels and Treatment Goals in Adult Patients with Diabetes 142
Table 7.4: Agents for Lowering Lipid Levels in Patients with Dyslipidemia 143
Table 7.5: Suggested Pharmacological Treatment Agents for Hypertension in Patients with Diabetes 144
Table 7.6: Selected Mid-2008 Press Releases on Emerging Anti-Diabetes Agents 146
Table 7.7: Diabetes Agents in the Pipeline 147
Table 7.8: Future Anti-Diabetic Drugs in Late-Stage Development 151
Table 8.1: Laboratory Assessment of Diabetic Vascular Disease 158
Table 8.2: Worldwide Market for Diabetes Self-Testing (Meters, Strips and Lancets), 2004-2012 158
Table 8.3: Market for Glucose Self-Testing in the U.S., 2004-2012 159
Table 8.4: U.S. Sales for OTC Blood Glucose Meters and Strips, 2007 160
Table 9.1: BRIC countries, Percentage of GDP Spent on Healthcare, 2008 188
Table 9.2: Selected Licensing Deals in the Diabetes Arena, 2003-2008 190
Table 9.3: Top Therapeutic Categories in U.S. Development, 2008 194
Table 9.4: Pharmaceutical Companies by Number of Products in R&D Pipeline, 2007 194
Table 9.5: Pharmaceutical Companies by Number of Diabetes Products in Development 195
Table 9.6: Selected New Diabetes Drugs in Pipeline, 2007 196
Table 9.7: Comparison of New Molecular Entity Outcomes for FDA and EMEA (Jan 2006 to October 2008) 197
Table 9.8: Upcoming Milestones for Selected Diabetes Drugs 200
Table 9.9: Overview of Blockbuster Drugs Coming Off-Patent, 2008 to 2012 201
Table A1.1: Company Headquarters Contact Information 232
Table A3.1: Current Insulins 239
Table A4.1: Select Archived Press Release Excerpts 243
Table A5.1: The Diabetes/Obesity Pipeline by Developmental Stage, 2009 245