糖尿病と合併症：治療の進歩と研究開発の最適化に向けた戦略

Abstract

A worldwide epidemic of type 2 diabetes has been in progress since the mid-1980s, according to the World Health Organization. The worldwide number of diabetics was 30 million in 1985 and is projected to increase to at least 366 million by 2030.

In the United States, an estimated 33% of people with type 2 diabetes have a serious co-morbidity associated with the disease, and almost 8% of diabetics have 4 or more of these complications, according to a report from the American Association of Clinical Endocrinologists (AACE).

In Diabetes and Its Complications: Strategies to Advance Therapy and Optimize R&D, a new report from Insight Pharma Reports (formerly Advances Reports), author Allan B. Haberman, PhD, provides a strategic perspective on the field of drugs for diabetes and its complications, with an emphasis on novel and emerging drugs and therapeutic strategies.

In the United States, almost 21 million people, or 7% of the population, have diabetes, and an estimated 54 million people are in a state of prediabetes, according to the American Diabetes Association. The AACE report estimates the direct medical costs related to diabetes complications in 2006 alone amounted to $22.9 billion in the United States. Typical complications from diabetes include heart attack, chronic kidney disease, congestive heart failure, stroke, coronary heart disease, foot problems, and eye damage.

Diabetes and Its Complications: Strategies to Advance Therapy and Optimize R&D gives individuals involved in the research, development, licensing, and portfolio management of current and potential diabetes therapies a complete picture of today' s therapeutic landscape, including:

• Background for understanding the nature, epidemiology, pathobiology, and cost of diabetes
• Experimental therapeutic strategies for prevention of type 1 diabetes in susceptible individuals.
• The pathogenesis of type 2 diabetes and its relationship to obesity
• Current diagnosis and treatment modalities for diabetes, types 1 and 2
• An evaluation of competitors in the diabetes market-their pipelines and specific products, alliances, therapeutic focus, and more
• Assessment of novel classes of antidiabetics that include drugs introduced into the market in 2005 and 2006, as well as drugs in still newer classes now in corporate pipelines
• Assessment of leading research and preclinical-stage drugs, and novel therapeutic strategies for type 2 diabetes
• Assessment of agents in development for diabetic complications, including a novel unifying model for induction of microvascular complications, and a novel model for induction of macrovascular complications
• The market outlook for new antidiabetic drugs

The report also includes a survey conducted by CHI in January 2007 of the views and plans of individuals at the forefront of R&D for diabetes and its complications.

The worldwide epidemic in diabetes, overwhelmingly type 2 diabetes, is driven by increased rates of obesity, especially in industrialized countries and in emerging industrial countries such as India and China, coupled with the aging of the populations in both sets of countries. A key factor in the discovery and development of successful new antidiabetic drugs is addressing the major unmet needs in type 2 diabetes, especially the need for drugs that both lower blood glucose and enable patients to lose weight, and the need to slow or reverse the decline in pancreatic beta-cell function, which is the major cause of the progression of the disease. Other unmet needs include:

• Treatments for diabetic complications
• Methods to prevent the development of type 1 diabetes in susceptible individuals
• Better strategies to prevent type 2 diabetes in prediabetic individuals

Diabetes and Its Complications: Strategies to Advance Therapy and Optimize R&D, with thorough analyses of the therapeutic sectors, combined with detailed tables and figures, puts this complex disease and its sequelae in perspective.

Table of Contents

Chapter 1

• Introduction
• 1.1. Risk Factors for Type 2 Diabetes
  • Preventing Development of Diabetes in Prediabetic Individuals
• 1.2. Growth in Prevalence of Diabetes
  • Worldwide Increase in Obesity
• 1.3. Economic Burden of Diabetes
• 1.4. Market Size for Current Diabetes Drugs
• 1.5. Unmet Medical Needs in Diabetes
  • Type 2 Diabetes
  • Type 1 Diabetes

Chapter 2

• Type 1 Diabetes as an Autoimmune Disease
• 2.1. Genetic and Environmental Determination of Type 1 Diabetes
  • Genetic Determinants
  • Environmental Determinants
• 2.2. Pathogenesis of Type 1 Diabetes
  • Trials of Agents to Prevent or Ameliorate Type 1 Diabetes in Patients with Prediabetes or New-Onset Diabetes
  • ENDIT and DPT-1
  • Anti-CD3 Agents
  • New Approaches to Treatment of Established Type 1 Diabetes

Chapter 3

• Type 2 Diabetes as a Metabolic Disease
• 3.1. Obesity as a Cause of Insulin Resistance and Beta-Cell Dysfunction
  • Adipokines, Obesity, and Insulin Resistance
  • Free Fatty Acids as a Critical Factor in Both Insulin Resistance and Beta-Cell Dysfunction
  • Obesity, Inflammation, and Insulin Resistance
  • Salicylates as Therapeutic Drugs
  • Chemical Chaperones as Therapeutic Agents: PBA and TUDCA
• 3.2. Genetic Factors in Development of Beta-Cell Dysfunction
  • Activating Mutations in the KCNJ11 Gene
  • TCF7L2: A Major Risk Factor for Late-Onset Type 2 Diabetes
  • Type 2 Diabetes Is Caused by a Combination of Genetic Risk Factors

Chapter 4

• Current Diagnosis and Treatment of Diabetes
• 4.1. Diagnosis of Diabetes
• 4.2. Treatment of Diabetes
  • Diet and Exercise
  • Concurrent Treatment of Other Aspects of the Metabolic Syndrome
• 4.3. Insulin Products
  • Insulin Formulations with Different Durations of Action
  • Long-Acting Insulin Glargine
  • Inhaled Insulin
• 4.4. Established Oral Antidiabetics
  • Sulfonylureas
  • Biguanides: Metformin
  • Meglitinides
  • Alpha-glucosidase Inhibitors
  • Thiazolidinediones
• 4.5. Type 2 Diabetes Management Using the Established Oral Antidiabetics and Insulin
  • ADA/EASD Consensus Statement
  • ADA/EASD Panel' s Recommendations versus Traditional Treatments
  • De-emphasis of Newer Drugs in the Panel' s Recommendations
  • Disagreement with the Panel' s Findings

Chapter 5

• Novel and emerging antidiabetic drugs
• 5.1. Approved and Pipeline Drugs Belonging to Drug Classes Introduced into the Market since 2005
  • Amylin Analogs: Pramlintide
  • Incretin Mimetics
  • Exenatide
  • GSK716155
  • Liraglutide
  • Dipeptidyl Peptidase-IV Inhibitors
  • Sitagliptin
  • Vildagliptin
  • Saxagliptin
  • PSN9301
  • Outlook for the Newly Introduced Antidiabetic Drugs
• 5.2. Novel Classes of Antidiabetics in Corporate Pipelines
  • PPARa/PPARg Dual Agonists (Glitazars)
  • PPARg Partial Agonists
  • MBX-102
  • FK614 and PA-082
  • PPARg ,b ,a
  • Cannabinoid-1 Receptor Antagonists
  • RIO-Diabetes Study
  • SERENADE
  • 11 Beta-hydroxysteroid Dehydrogenase Type 1
  • Sodium Glucose Cotransporter-2 Inhibitors
  • Glucokinase Activators

Chapter 6

• Early-Stage Drugs and Novel Therapeutic Strategies for Type 2 Diabetes
• 6.1. Does the Lack of Scientific Knowledge of Type 2 Diabetes Hamper Development of Effective Treatments?
• 6.2. The Inadequacy of Animal Models in Type 2 Diabetes
• 6.3. Strategies for Making Drug Discovery and Development More Effective
  • Dealing with Multiple Molecular "Causes" of Disease by Hitting More than 1 Target
  • Whole-Pathway Approaches
  • Biology-Driven Drug Discovery
  • Biomarkers and Translational Medicine
  • Animal Models and Complex Diseases
• 6.4. The Diabetes Survey and Issues Related to Strategies to Improve the Effectiveness of Drug Discovery and Development
• 6.5. Selected Research-Stage Agents and Novel Therapeutic Strategies for Type 2 Diabetes
  • Small-Molecule GLP-1 Receptor Agonists
  • Boc5
  • Ago-Allosteric Modulators
  • Protein Tyrosine Phosphatase 1B Inhibitors
  • Preclinical Development of Small-Molecule PTP1B Inhibitors
  • Development of Antisense Drugs: ISIS 113715
  • AMP-Activated Protein Kinase Activators
  • CytRx Corporation' s RNAi-Based Drug Discovery Programs in Type 2 Diabetes and Obesity
  • Receptor-Interacting Protein 140
  • MAP4K4
  • Sirtuin Modulators
  • Ghrelin Antagonists (Growth Hormone Secretagog Receptor Antagonists)
  • GPR119 Agonists
• 6.6. Conclusions: Development of Novel Antidiabetics and the CHI Diabetes Survey

Chapter 7

• Diabetic Complications
• 7.1. Microvascular Complications
  • Diabetic Retinopathy
  • Diabetic Neuropathy
  • Diabetic Nephropathy
• 7.2. Prevention of Diabetic Complications
• 7.3. Pathogenesis of Diabetic Complications
  • Four Pathogenic Pathways in Diabetic Complications
  • A Unifying Model for Induction of Microvascular Diabetic Complications
  • Induction of Macrovascular Complications in Insulin-Resistant and Diabetic Individuals
• 7.4. Novel Drugs and Therapeutic Strategies for Diabetic Complications
  • Drugs for Diabetic Complications in Clinical Trials
  • Ranirestat
  • Ranibizumab and Pegaptanib
  • Ruboxistaurin
  • Alagebrium
  • Pyridoxamine
  • Sulodexide
• 7.5. Novel Therapeutic Strategies for Diabetic Complications
  • Therapeutic Strategies Based on Brownlee' s Unified Diabetic Complications Model
  • Development of Transketolase Activators
  • Development of PARP Inhibitors
  • Development of Catalytic Antioxidants
  • A Novel Therapeutic Strategy for Diabetic Retinopathy Based on Targeting Extracellular Carbonic Anhydrase and Kallikrein

Chapter 8

• Outlook
• 8.1. A Disease of Progress
• 8.2. Where to Go from Here
• 8.3. Addressing Unmet Needs
• 8.4. Aiming for Multiple Targets

Appendix

References

Company Index with Web addresses