Dyslipidemia: Opportunities in Cardiovascular Risk Reduction

Table of Contents

Executive Summary

Chapter 1 Introduction

• 1.0 Chapter summary
• 1.1 Dyslipidemia and atherosclerosis
• 1.2 Atherosclerotic vascular diseases
• 1.3 Background on lipids and lipoproteins
  • 1.3.1 Lipids
  • 1.3.2 Lipoproteins
    • 1.3.2.1 Apolipoproteins
  • 1.3.3 Association with atherosclerosis
  • 1.3.4 Lipid metabolism
• 1.4 Atherosclerosis
  • 1.4.1 Overview
  • 1.4.2 Plaque evolution
    • 1.4.2.1 Role of apoB-containing lipoproteins
  • 1.4.3 Vulnerable plaques
  • 1.4.4 Diagnosis and treatment
• 1.5 Hyperlipidemia
• 1.6 Atherogenic dyslipidemia
• 1.7 Lipids, CVD risk and treatment goals
  • 1.7.1 Targeting elevated LDL-C
  • 1.7.2 Targeting elevated triglycerides
  • 1.7.3 Targeting low HDL-C
  • 1.7.4 Targeting the metabolic syndrome

Chapter 2 Biomarkers and surrogates of atherosclerosis

• 2.0 Chapter summary
• 2.1 Introduction
• 2.2 Vascular imaging technologies
  • 2.2.1 Quantitative coronary angiography
    • 2.2.1.1 Brown-Dodge system
    • 2.2.1.2 Edge detection systems
    • 2.2.1.3 Videodensitometric methods
    • 2.2.1.4 Problems and disadvantages
    • 2.2.1.5 Predicting lesion progression
  • 2.2.2 B-Mode ultrasound
    • 2.2.2.1 Principle of B-mode imaging
    • 2.2.2.2 Carotid intimal-medial thickness (CIMT)
    • 2.2.2.3 Risk factors for CIMT and its progression
    • 2.2.2.4 Lipid lowering and CIMT trials
    • 2.2.2.5 Effect of other interventions on CIMT
  • 2.2.3 Intravascular ultrasound (IVUS)
    • 2.2.3.1 Overview of the technique
    • 2.2.3.2 Advantages and disadvantages
    • 2.2.3.3 IVUS trials
    • 2.2.3.4 Intravascular ultrasound elastography
    • 2.2.3.5 Integrated backscatter IVUS
  • 2.2.4 Coronary angioscopy
  • 2.2.5 Optical coherence tomography
  • 2.2.6 Intravascular thermography
  • 2.2.7 Regulatory status of vascular imaging
• 2.3 Plasma biomarkers
  • 2.3.1 Diagnosis of dyslipidemia
    • 2.3.1.1 Fasting lipid panel tests
    • 2.3.1.2 apoB and apoAI
    • 2.3.1.3 Lp(a)
    • 2.3.1.4 Small dense LDL particles
  • 2.3.2 Emerging biomarkers of risk
    • 2.3.2.1 OxLDL
    • 2.3.2.2 Lp-PLA2
    • 2.3.2.3 CRP
    • 2.3.2.4 Myeloperoxidase
    • 2.3.2.5 Homocysteine
    • 2.3.2.6 PAPP-A
    • 2.3.2.7 CD40L
    • 2.3.2.8 IL-18
    • 2.3.2.9 Other biomarkers

Chapter 3 Improving mainstay therapies

• 3.0 Chapter summary
• 3.1 Introduction
• 3.2 Dietary manipulations
  • 3.2.1 Plant sterols and stanols
  • 3.2.2 Soy-derived isoflavones
  • 3.2.3 Red yeast rice
  • 3.2.4 Essential fatty acids
  • 3.2.5 Omega-3 products
    • 3.2.5.1 Dietary supplements
    • 3.2.5.2 Prescription products on the market
    • 3.2.5.3 Prescription drugs in development
• 3.3 Statins
  • 3.3.1 Overview
  • 3.3.2 Mode of action
  • 3.3.3 Statins on the market
    • 3.3.3.1 Lovastatin and simvastatin
    • 3.3.3.2 Pravastatin
    • 3.3.3.3 Atorvastatin
    • 3.3.3.4 Fluvastatin
    • 3.3.3.5 Rosuvastatin
    • 3.3.3.6 Other agents and indications
  • 3.3.4 Pharmacogenomics of statin efficacy
• 3.4 Cholesterol absorption inhibitors
  • 3.4.1 Ezetimibe
  • 3.4.2 Drugs in development
• 3.5 Niacin
• 3.6 Fibrates
• 3.7 Bile acid sequestrants
• 3.8 Combination therapies
  • 3.8.1 Statin + ezetimibe
  • 3.8.2 Statin + niacin
  • 3.8.3 Statin + fibrate
  • 3.8.4 Other combination products
  • 3.8.5 Statin-containing "polypills"

Chapter 4 Focus on HDL

• 4.0 Chapter summary
• 4.1 HDL-C levels and cardiovascular risk
  • 4.1.1 Prevalence of low HDL-C
• 4.2 Background on HDL
  • 4.2.1 Structure
  • 4.2.2 Metabolism
  • 4.2.3 Lab measurements
  • 4.2.4 Antiatherogenic activities
    • 4.2.4.1 Cellular cholesterol efflux
    • 4.2.4.2 Antioxidative action
    • 4.2.4.3 Anti-inflammatory activity
  • 4.2.5 HDL in dyslipidemic and inflammatory states
• 4.3 Current treatments which increase HDL
  • 4.3.1 Niacin
  • 4.3.2 Fibrates
  • 4.3.3 Statins
  • 4.3.4 Combination therapies
• 4.4 Novel therapies in commercial development
  • 4.4.1 HDL mimetics
  • 4.4.2 ApoAI mimetics
  • 4.4.3 ApoAI-boosting therapies
  • 4.4.4 ABCA1-boosting therapies
  • 4.4.5 CETP-suppressing therapies
  • 4.4.6 Niacin receptor agonists

Chapter 5 Other lipid modulators in development

• 5.0 Chapter summary
• 5.1 Introduction
• 5.2 PPAR agonists
  • 5.2.1 PPAR alpha agonists
    • 5.2.1.1 Agents in development
  • 5.2.2 PPAR gamma agonists
    • 5.2.2.1 TZDs
    • 5.2.2.2 Agents in development
  • 5.2.3 Dual PPAR alpha/gamma agonists
  • 5.2.4 PPAR delta agonists
  • 5.2.5 PPAR pan agonists
  • 5.2.6 Other insulin sensitizers
• 5.3 Anti-obesity therapies
  • 5.3.1 Obesity and dyslipidemia
  • 5.3.2 Approved therapies
  • 5.3.3 Drugs in development
• 5.4 Thyroid hormone function agonists
• 5.5 MTP inhibitors
• 5.6 Leukotriene antagonists
  • 5.6.1 Targeting Lp-PLA2
  • 5.6.2 Targeting 5-LO and LTA4H
• 5.7 Succinobucol
• 5.8 ApoB inhibitors
• 5.9 Kinase modulators
  • 5.9.1 Targeting MAPK14
  • 5.9.2 Targeting other kinases
• 5.10 Miscellaneous drugs targeting lipid metabolism
• 5.11 Miscellaneous drugs targeting inflammation

Chapter 6 Market outlook

• 6.0 Chapter summary
• 6.1 Introduction
• 6.2 The broad spectrum of dyslipidemia
• 6.3 The dyslipidemia market by therapy
  • 6.3.1 Statins
    • 6.3.1.1 Overview
    • 6.3.1.2 Lipitor
    • 6.3.1.3 Crestor
    • 6.3.1.4 Lescol
    • 6.3.1.5 Livalo
    • 6.3.1.6 Generic statins: lovastatin,
    • 6.3.1.7 Statin-containing "polypills"
  • 6.3.2 Ezetimibe
  • 6.3.3 CETP Inhibitors
  • 6.3.4 Niacin-based Combination Therapy
  • 6.3.5 Fibrates
  • 6.3.6 Bile acid sequestrants
  • 6.3.7 Omega-3 fatty acid derivatives
  • 6.3.8 Other agents
• 6.4 Forecasts

Chapter 7 Market potential

• 7.0 Chapter summary
• 7.1 Introduction
• 7.2 New therapies
  • 7.2.1 Investing in biopharmaceuticals
• 7.3 Reaching more patients
  • 7.3.1 Introduction
  • 7.3.2 Maximising statin treatment
  • 7.3.3 Focusing on undertreated populations
    • 7.3.3.1 Targeting hypertensives
    • 7.3.3.2 Targeting women
    • 7.3.3.3 Targeting the elderly
    • 7.3.3.4 Targeting the obese
    • 7.3.3.5 Targeting diabetics
    • 7.3.3.6 Targeting rheumatoid arthritis patients
    • 7.3.3.7 Targeting HIV patients
    • 7.3.3.8 Targeting renal insufficiency patients
    • 7.3.3.9 Targeting schizophrenia patients
• 7.4 Increasing patient compliance
• 7.5 Promoting combination therapies

Appendices

• Appendix 1 Cholesterol Value Reporting
• Appendix 2 Abbreviations and Acronyms
  • A2.1 Scientific/medical terms
  • A2.2 Institutions
  • A2.3 Clinical trials
• Appendix 3 Research Methodology

List of Tables and Figures

• Figure 1.1 LDL-C and relative risk of CHD
• Table 1.1 Findings of the INTERHEART Study
• Table 1.2 First presentation of CHD in the UK
• Table 1.3 European Society of Cardiology Lipid Guidelines (2003)
• Table 1.4 European Society of Cardiology Lipid Guidelines (2007)
• Table 1.5 NCEP ATP III Lipid Goals and Cut-Points (2001)
• Table 1.6 Revised NCEP ATP III Lipid Goals and Cut-Points (2004)
• Table 1.7 Classification of fasting triglyceride levels in adults
• Table 1.8 Therapeutic goals for LDL-C and potential goals for non-HDL-C and total apo B
• Table 1.9 Metabolic Syndrome Criteria
• Table 2.1 Ongoing Clinical Trials Using an IVUS Endpoint
• Table 2.2 Changes in Percent Atheroma Volume and LDL-C in several IVUS trials
• Table 2.3 Ongoing Clinical Trials Using a CIMT Endpoint
• Table 2.4 Ongoing Clinical Trials Using Lp(a) as an Endpoint
• Table 2.5 Ongoing Clinical Trials Using Oxidized LDL as an Endpoint
• Table 2.6 Ongoing Clinical Trials Using CRP as an Endpoint
• Figure 3.1 Relative LDL Lowering Potencies of Five Marketed Statins
• Table 3.1 Some Landmark Trials in Dyslipidemia
• Table 3.2 Patent Data for Launched Statin Products
• Table 3.3 Suppliers of Off-Patent and Near Off-Patent Statins
• Table 3.4 Crestor Trial Programme (GALAXY)
• Table 3.5 Fixed Dose Combination Products On The Market Or In Development
• Table 3.6 Ongoing Clinical Trials in Dyslipidemia Using Statin/Ezetimibe Combinations
• Table 3.7 Ongoing Clinical Trials in Dyslipidemia Using Niacin Combinations
• Table 3.8 Ongoing Clinical Trials in Dyslipidemia Using Statin/Fibrate and Other Statin Combinations
• Table 3.9 Other Ongoing Clinical Trials in Dyslipidemia Using Combined Agents
• Table 5.1 Guide to 178 experimental therapies targeting lipid metabolism and/or inflammation
• Table 5.2 Ongoing Clinical Trials in Hypertriglyceridemia
• Figure 6.1 US Dyslipidemia Market (2002-2012)
• Figure 6.2 Non-US Dyslipidemia Market (2002-2012)
• Figure 6.3 World Dyslipidemia Market (2002-2012)
• Table 6.1 Worldwide Sales of Branded Statins in 2007
• Table 6.2 Worldwide Sales of Branded Non-Statin Antidyslipidemics in 2007
• Table 6.3 Statin Sales Analysis and Forecasts, 2007-2012
• Table 6.4 Statin Prescription Analysis and Forecasts, 2007-2012
• Table 6.5 Dyslipidemia Market by Drug Class, 2007-2012
• Table 6.6 Dyslipidemia Market by Prescriptions, 2007-2012
• Table 6.7 Dyslipidemia Market by Country, 2007-2012
• Figure 7.1 Dyslipidemia Target Landscape
• Table 7.1 Cancer and Cardiovascular Pipelines by Type of Agent
• Table 7.2 Dyslipidemia Market by Patient Numbers, 2007-2012
• Table 7.3 Ongoing Clinical Trials of Cardiovascular Drug Interventions in the Metabolic Syndrome