Lipoproteins in Diabetes Mellitus (Contemporary Diabetes)

Diabetes mellitus has become epidemic on a global scale, and millions of new cases are diagnosed every year. With an estimated 80% of people with diabetes living in disadvantaged regions, and the key roles of lipoproteins in the pathogenesis of the chronic complications of diabetes, this volume will be relevant to many readers globally. It is our intention that the contents will advance knowledge of the readers who will use it to contribute to the reduction of the burden associated with altered lipoproteins in people with diabetes. The second edition of this book provides an updated and comprehensive review of the field. The book, which includes many tables and figures, is presented in three main sections: (i) Lipoprotein metabolism, qualitative changes and measurements; (ii) Lipoproteins and the complications of diabetes; and (iii) the treatment of lipoproteins in diabetes. Each chapter from the first edition has been updated, and new topics added. New topics include the links between glycemia and lipoproteins, the role of lipoproteins in ischemic stroke, the diagnosis and management of statin intolerance (which is thought to be more common in people with diabetes) and the use of PCSK9 inhibitors and fish oils in the management of lipoproteins in people with diabetes. This book is written by an international group of experts in the clinical, laboratory and research aspects of lipoproteins in diabetes. Lipoproteins in Diabetes Mellitus, 2nd Edition is a comprehensive reference on the clinical and scientific aspects of lipoproteins in diabetes. It is a must-have resource for primary care and specialist clinicians, clinical and basic science researchers and to trainees and students. Preface Acknowledgments Contents Contributors Part I: Lipoprotein Metabolism, Qualitative Changes and Measurements Chapter 1: Laboratory Assessment of Lipoproteins in Type 2 Diabetes Introduction Lipids, Lipoproteins, and Other Analytes in Diabetes Routine Lipoprotein Assessment LDL Composition and Particle Number Etiological Assessment Lipoprotein Overproduction Reduced Lipoprotein Catabolism Apolipoprotein Measurement Other Laboratory Markers Summary References Chapter 2: Tools for Assessing Lipoprotein Metabolism in Diabetes Mellitus Introduction Lipoprotein Kinetic Studies Apolipoprotein B Turnover Studies Radiation-Based Studies Stable Isotope-Based Studies Dual Radiolabel Studies HDL-Related Turnover Studies Lipoprotein Metabolism in Cultured Cells Lipoprotein Binding to Cells Lipoprotein Degradation by Cells Lipoprotein Accumulation by Cells Studies of Glycated LDL Metabolism by Human Macrophages Cellular Metabolism of Lipoprotein Cholesterol Lipidomics and Lipoprotein Subclass Analyses Conclusions and Future Directions References Chapter 3: Links Between Glucose and Lipoproteins Introduction Lipoprotein Functions Contributors to Lipoprotein Levels in Diabetes Effects of Glycemia on Lipoproteins and Lipids Effects of Lipoproteins on Glycemia and Insulin HDL Effects on Glucose Metabolism Hypertriglyceridemia Associations Between Lipid Levels and Diabetes Onset Type 2 Diabetes Type 1 Diabetes HDL and Glycemic Progression in Type 2 Diabetes Glucose and Lipid Variability and Diabetes Complications Aspects of Glycemia Lipids and Lipid Variability in Diabetes and Effects on Chronic Complications Lipid Drugs and Effects on Glycemia LDL-Lowering Drugs Triglyceride Lowering Drugs Marked HDL-C Elevating Drugs (Research Only) Future Directions Conclusions References Chapter 4: Apoproteins and Cell Surface Receptors Regulating Lipoprotein Metabolism in the Setting of Type 2 Diabetes Introduction Lipoprotein Structure and Nomenclature Measurement of Lipids and Lipoproteins Cellular Lipid Homeostasis The Apolipoprotein B Family of Lipoproteins The Apolipoprotein A-I Family of Lipoproteins Insulin Resistance and Type 2 Diabetes The TG/HDL Axis: The HDL, ApoA-I Containing Lipoproteins The TG/HDL Axis: Relating ApoB and ApoA-I Containing Lipoproteins Conclusions References Chapter 5: Lipoprotein Metabolism and Alterations Induced by Insulin Resistance and Diabetes Lipoprotein Metabolism Overview Apolipoproteins and Triglyceride-Rich Lipoprotein Metabolism Low Density Lipoprotein High Density Lipoprotein The Chylomicron Intestinal Niemann-Pick C1-Like 1 Protein Intestinal ATP Binding Cassette Proteins G5/G8 Microsomal Triglyceride Transport Protein Apolipoprotein B48 and B100 Cholesterol Synthesis and HMGCoA Reductase Very Low Density Lipoprotein Cholesterol Synthesis and Transport in the Liver Hepatic NPC1L1 Hepatic ABCG5 and G8 MTP in the Liver Triglyceride-Rich Lipoproteins in Diabetes LDL in Diabetes High Density Lipoprotein in Diabetes Conclusions References Chapter 6: The PPAR System in Diabetes Introduction PPAR Gene and Gene Variants, Proteins and Natural Ligands Synthetic Ligands: From PPAR Activators to PPAR Agonists The PPAR Machinery PPAR Coactivators and Corepressors Phosphorylation Ubiquitination Sumoylation Acetylation Methylation Partial Agonists or SPPARMs Effects of PPAR Agonists in Diabetes Effects of PPAR Agonists in Type 1 Diabetes Effects of PPAR Agonists in Type 2 Diabetes and Dyslipidemia Conclusion and Perspectives References Chapter 7: Production and Metabolism of Triglyceride-Rich Lipoproteins: Impact of Diabetes Introduction TG-Rich Lipoproteins Secretion by Liver and Intestine VLDL Assembly and Secretion Chylomicron Assembly and Secretion Lipoprotein Lipase-Mediated Lipolysis Hepatic Clearance of Remnants The Role of Insulin in TGRLs Metabolism Insulin Resistance The Role of Insulin Resistance in TGRL Metabolism Hepatic TG in Insulin Resistance Diabetes and Hepatic Uptake of Remnant Lipoproteins Triglyceride-Rich Lipoproteins and Vascular Dysfunction The Role of ApoC-III in the Metabolism of TGRLs The Role of ANGPTL3 in the Metabolism of TGRLs TGRLs and Their Remnants: Novel Targets for Anti-atherosclerotic Therapy? Conclusions References Chapter 8: Triglyceride- and Cholesterol-Rich Remnant Lipoproteins in Risk of Cardiovascular Disease in Diabetes Mellitus Introduction Clinical Signs Blood Sample Characteristics Physical Examination Lipids and Lipoproteins Composition of Lipoproteins Standard Lipid Profile Remnant Cholesterol and Non-HDL Cholesterol Lipoprotein Composition in Diabetes Mellitus Metabolomic Profiling of Lipoproteins Low High-Density Lipoprotein as a Marker of Elevated Remnant Lipoproteins Atherosclerotic Cardiovascular Disease Triglycerides Remnant Cholesterol Lipoprotein Subclasses Evidence in Diabetes Mellitus Clinical Interventions Mechanisms Translational Perspective Acute Pancreatitis Guidelines Future Perspectives References Chapter 9: HDL Function in Diabetes Introduction Type I Diabetes Mellitus and Its Impact on Lipoproteins Levels Type II Diabetes Mellitus and Its Impact on Lipoproteins Levels HDL Particle Structure and Function The Impact of Type 1 Diabetes on HDL Particle Composition and Function The Impact of Type 2 Diabetes on HDL Particle Composition and Function Cholesterol Efflux Capacity Antioxidant Properties Anti-inflammatory Properties Vasodilatory Properties References Chapter 10: Lipoprotein(a): Metabolism, Pathophysiology, and Impact on Diabetes Mellitus Introduction The Structures and Composition of Lp(a) and Apo(a) Lp(a) Metabolism The Assembly of Lp(a) In Vivo Metabolism of Lp(a) The Transcription of Apo(a) Genetics of Lp(a) Factors Affecting Plasma Lp(a) Concentrations The Role of the Kidney in Lp(a) Metabolism Lp(a) and the Risk for Atherosclerotic Diseases Impact of Lp(a) on Hemostasis Lp(a) and Diabetes Mellitus Lp(a) in Type-1 Diabetes Mellitus (T1DM) Patients Lp(a) in Type-2 Diabetes Mellitus (T2DM) Patients T2DM Paradox of Lp(a) Lp(a) as a Risk Factor for CAD in Patients with Diabetes Mellitus Treatment of Elevated Lp(a) Levels Diet Statins Ezetimibe Nicotinic Acid Fibrates Other Agents Apheresis Novel Lipid Lowering Compounds ApoB Antisense and MTP Inhibitors Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors Diabetes Therapies and Lp(a) References Chapter 11: Lipoprotein Glycation in Diabetes Mellitus Introduction Lipids and Lipoproteins in Diabetes The Chemistry of Lipoprotein Glycation Differences Between Glycation and Glycosylation Glycation of Apolipoproteins in Lipoproteins Extent of Lipoprotein Glycation The Measurement of Lipoprotein Glycation General Consequences of Lipoprotein Glycation Human Studies of Glycated Lipoproteins Glycation of Major Lipoprotein Classes VLDL Glycation Levels of Glycated VLDL Effects on VLDL Metabolism LDL Glycation Levels of Glycation LDL Size and Glycation Susceptibility to Oxidation Glycated LDL and Immune Complex Formation Matrix Binding by LDL Effects on Receptor Interactions and Cell Signaling Adverse Cellular Effects of Glycated LDL Glycated LDL Effects on Modulators of Fibrinolysis Glycated LDL Effects on Platelet Reactivity Glycated LDL Effects on Vasoreactivity HDL Glycation Levels of Glycated HDL Antioxidant Effects of HDL HDL Effects on Modulators of Fibrinolysis HDL Effects on Vasoreactivity Reverse Cholesterol Transport Anti-inflammatory Effects of HDL Lipoprotein(a) Glycation Levels of Glycated Lp(a) Susceptibility to Oxidation of Lp(a) Effects on Lp(a) Glycation on Modulators of Fibrinolysis Effects of Glycated Lp(a) on Vascular Reactivity Glycation of Lipoprotein Related Enzymes Platelet Activating Factor Acetylhydrolase (PAFAH) Paraoxonase (PON) Lecithin: Cholesterol Acyl Transferase (LCAT) Cholesteryl Ester Transfer Protein (CETP) Treatment of Lipoprotein Glycation in Diabetes Glucose Control Agents Lipid Control LDL Apheresis Anti-glycation Agents, AGE Preventers, Decoys, and Breakers Deglycating Agents Compounds Altering Responses to Glycated Lipoproteins Conclusions and Future Directions References Chapter 12: Lipid: Extracellular Matrix Interactions as Therapeutic Targets in the Atherosclerosis of Diabetes Introduction Biochemical and Cellular Mechanisms of Atherosclerosis Therapeutic Advances for Treatment of Atherosclerosis Proteoglycans: Structure and Function in the Vessel Wall Role of Proteoglycans in Atherosclerosis Cellular Signalling Pathways That Drive Glycosaminoglycan Chain Elongation Proteoglycans as a Therapeutic Target in Atherosclerosis Glycosaminoglycan Targeting Monoclonal Antibodies ApoB100 Peptide Mimetics Small Chemical Entity Targeting Changes in the Vessel Wall Proteoglycans as Biomarkers of Atherosclerosis Conclusions References Part II: Lipoproteins and the Complications of Diabetes Chapter 13: The Role of Modified Forms of LDL and Corresponding Autoantibodies in the Development of Complications in Diabetes Introduction The Pathogenic Role of Modified Forms of LDL The Adaptive Immune Response Elicited by Modified LDL The Composition of Circulating Modified LDL Immune Complexes and Diabetes Complications Pathogenic Mechanisms of Modified LDL-IC References Chapter 14: Endothelial Dysfunction in Type 2 Diabetes with an Update on New Interventions Introduction Endothelial Function Normal Endothelial Function and Nitric Oxide In Vivo Measurement of Endothelial Function Endothelial Dysfunction Endothelial Dysfunction: Uncoupling of eNOS Predictive Value of Endothelial Dysfunction Pathogenesis of Endothelial Dysfunction in Type 2 Diabetes Mellitus Treating Endothelial Dysfunction in Type 2 Diabetes Lifestyle Interventions Lipid-Lowering Therapies Hydroxymethylglutaryl (HMG)-CoA Reductase Inhibitors (Statins) Fibric Acid Derivatives Nicotinic Acid (Niacin) Omega-3 Fatty Acids Combination Therapies Statins and Fibrates Statins and Niacins Statins and Antioxidants Statins and Antihypertensive Agents Fibrates and Antioxidants Other Combinations: Ezetimibe, Omega-3 Fatty Acids, CETP Inhibitors Antiglycemic Agents and Insulin Sensitizers Insulin Sulfonylureas and Insulin Secretagogues Metformin Thiazolidinediones Alpha-Glucosidase Inhibitors Incretins Amylin Agonists Sodium Glucose Co-transporter (SGLT2) Inhibitors Antihypertensive Agents Angiotensin-Converting Enzyme (ACE) Inhibitors Angiotensin Receptor Antagonists Aldosterone Antagonists Calcium Channel Blockers Antioxidants and Nutritional Supplements Miscellaneous Therapies Phosphodiesterase Inhibitors Estrogens Testosterone Anti-cytokine Agents Xanthine Oxidase Inhibitors Conclusion References Chapter 15: Lipoproteins and Diabetic Kidney Disease Introduction Conventional Lipoprotein Lipids, Albuminuria, and Kidney Function DCCT/EDIC EURODIAB FinnDiane Pittsburgh EDC Swedish National Diabetes Register Kidney Disease and Dyslipidemia in Type 2 Diabetes Interpretation of the Epidemiological Data Can Dyslipidemia Cause Kidney Disease? Lipoprotein Subclasses and Albuminuria in Type 1 Diabetes VLDL Subclasses IDL and LDL Subclasses Apolipoprotein B HDL Subclasses Apolipoproteins A-I and A-II Apolipoprotein C-III Lipoprotein Abnormalities in Impaired Kidney Function and Their Relevance to Diabetic Kidney Disease Lipid Medications and Diabetic Kidney Disease Statins Fenofibrate Ezetimibe Clinical Utility of Lipid Treatment in Diabetic Kidney Disease Concluding Remarks References Chapter 16: Lipids and Diabetic Retinopathy Introduction Epidemiology of Diabetic Retinopathy Diabetic Retinopathy in Pre-diabetes Development and Staging of Diabetic Retinopathy Types and Assessment of Diabetic Retinopathy Subclinical Retinal Changes and Diabetic Retinopathy Eye Screening Traditional and Novel Risk Factors for Diabetic Retinopathy Lipid Variability and Detailed Lipid Analysis Considerations in Evaluating Roles of Lipids and Lipid Drugs in Diabetic Retinopathy Retinal Lipid Metabolism Effects of Lipid Drugs on Diabetic Retinopathy Triglyceride Lowering Agents Fibrates The FIELD Trial The ACCORD-EYE Trial Omega-3 Fatty Acids HMG CoA Reductase Inhibitors Meta-analysis of Statin and/or Fibrate Trials for Diabetic Retinopathy Future Directions Conclusions References Chapter 17: Roles of Extravasated and Modified Plasma Lipoproteins in Diabetic Retinopathy Introduction: Diabetic Retinopathy (DR) The Initiation of DR Treatment Considerations for DR Challenges in Defining the Role of Plasma Lipoproteins in DR Studies of the Associations Between Plasma Lipoproteins and DR Fibrate Drugs May Be Effective Against DR: But Not Because They Lower Plasma Triglycerides Plasma Lipoproteins as “Secondary Mediators” of DR Extravasated, Modified LDL in the Pathogenesis of DR Effects of Modified LDL on Retinal Capillary Vascular Cells Modified LDL Mediates Apoptosis of Retinal Capillary Endothelial Cells and Pericytes Modified LDL Influences Gene Expression in Human Retinal Capillary Pericytes Aminoguanidine Mitigates Toxicity in Human Retinal Capillary Pericytes Exposed to HOG-LDL Effects of Pigment Epithelium-Derived Factor Effects of Modified Lipoproteins on Retinal Müller Cells and RPE Immunologic Consequences Evidence for the Presence of Modified Lipoproteins in the Diabetic Retina An Animal Model to Simulate Intraretinal Effects of Extravasated, Modified, Lipoproteins Summary Conclusion References Chapter 18: The Role of Lipids and Lipoproteins in Peripheral Neuropathy Overview of the Diabetic Neuropathies Epidemiology of Diabetic Neuropathy Pathophysiology of Diabetic Neuropathy Pathways in the Pathophysiology of Diabetic Neuropathy Association Between Glycemic Control and Prevention of Diabetic Neuropathy Role of Lipids and Lipoproteins on Diabetic Peripheral Neuropathy Free Fatty Acids Mediate Insulin Resistance and Malfunction in Peripheral Nerves Alterations of Lipid Metabolism Cause an Imbalance in Mitochondrial Bioenergetics That Promotes Neuropathy Oxidized Lipids Promote DPN Atypical Sphingolipids Current Evidence on Lipid Modification and Diabetic Neuropathy α-Lipoic Acid (ALA) Statins Fibrates Other Ongoing and Future Trials of Lipid Modification for Diabetic Neuropathy References Chapter 19: Lipoproteins and Ischemic Stroke in Diabetes Introduction Pathophysiology of Atherosclerosis in Stroke Burden of Ischemic Stroke in Diabetes Mellitus Evidence for the Role of Lipoproteins in Ischemic Stroke in the General Population LDL-C HDL-C TG-Rich Lipoproteins Lipoprotein (a) Pathophysiology of Ischemic Stroke in DM Pathophysiologic Role of Lipids in Ischemic Stroke in DM Evidence of Lipid-Lowering Therapy and Ischemic Stroke in Diabetes Conclusions References Part III: Lipoprotein Treatment in Diabetes Chapter 20: About Randomized Clinical Trials Related to Lipoproteins in Diabetes Mellitus Introduction Definition Precursors to and Phases of an RCT Elements of a Good RCT Novel RCT Designs Challenges of Conducting an RCT Related to Lipoproteins in Diabetes Mellitus Different Types and Stages of Diabetes Multiple Risk Factors for Complications Including Genetic and Epigenetic Effects Slow Vascular Disease Development Metabolic Memory or the Legacy Effect Variability in Some RCT End Points Pleiotropic Effects Reporting and Interpreting RCT Results Adverse Events Generalizability of RCT Results to Clinical Practice Landmark Trials of Lipoprotein Treatments in Diabetes Combining Results from RCTs Other Resources Conclusions and the Future of RCTs of Treatments Related to Lipoproteins in Diabetes References Chapter 21: Effects of Lifestyle (Diet, Plant Sterols, Exercise, and Smoking) and Glycemic Control on Lipoproteins in Diabetes Lipid Conversion Units General Considerations Dietary Fat and Lipoproteins Saturated, n6 Polyunsaturated, and Monounsaturated Fat Dietary Fat vs. Carbohydrate Lipids Glycemic Control Relationship Between Diet and Coronary Events in People with Type 2 Diabetes Fish Oil Dietary Cholesterol Cholesterol Synthesis and Absorption Plant Sterols Epidemiology of Cholesterol Intake and CVD Fiber Low-Glycemic-Index Carbohydrate Fructose Weight Loss Nondiabetic Subjects Diabetic Subjects Glycemic Control Interventions to Improve Glycemic Control Alcohol Intake Exercise Smoking New Research Areas Conclusions References Chapter 22: Statin Therapy: Impact on Dyslipidemia and Cardiovascular Events in Patients with Diabetes Introduction Impact of Statin Therapy on Dyslipidemia Impact of Statin Therapy on Cardiovascular Events in Patients with Diabetes Evidence from Key Randomized Clinical Trials Heart Protection Study Anglo-Scandinavian Cardiac Outcomes Trial Collaborative Atorvastatin Diabetes Study Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Meta-Analysis Potential Risks of Statin Therapy Putting the Evidence in Perspective Implementing the Evidence in Practice Residual Risk of Cardiovascular Events in Patients with Diabetes on Statin Therapy Residual Risk Data Lipoprotein Epidemiology and the Ideal Therapeutic Target Guidelines Combination Therapy Conclusions References Chapter 23: Statin Intolerance: An Overview for Clinicians Introduction Statins: A Brief Clinical Overview Statins: Safety of Use SAMS Kidney Dysfunction Liver Dysfunction NOD Efficacy and Safety of Statin Use Among Older People Efficacy and Safety of Statin Use Among Children Safety of Statin Use Among Pregnant Women Statin Intolerance: Definition and Real Global Prevalence Nonadherence/Discontinuation of Statin Therapy: Prevalence, Causes, and Consequences Prevalence Causes Complications Statin Intolerance: Diagnosis and Therapeutic Management SAMS: Management Tips NOD: Management Tips ALT Elevated Level: Management Tips Conclusions References Chapter 24: Fibrate Therapy: Impact on Dyslipidemia and Cardiovascular Events in Patients with Diabetes Mellitus Type 2 Introduction Pathophysiology of “Atherogenic” and Other Dyslipidemias and of ASCVD in DM-2 Fibrate Effects on Lipoprotein Levels, Especially in Insulin Resistance and DM-2 Long-Term Fibrate Effects on Lipids and Lipoproteins Lipid and Lipid-Related Effects of Fibrates vs. Statins and in Combination with Them Fibrate Effects on Other Atherosclerosis-Related Mechanisms Fibrate Effects on Atherosclerosis Fibrate Effects on ASCVD Event Risk in the General Patient Fibrate Effects on ASCVD in Patients with Insulin Resistance or Prediabetes Fibrate Effects on ASCVD in Patients with Diabetes Mellitus-2 Prediction of Fibrate Effects on ASCVD by Baseline Lipids and On-Treatment Lipid Effects Fibrate Effects on ASCVD in Combination with Statins Fibrate Effects on Diabetic Microvascular Disease Guideline Recommendations for Fibrate Use Dosage of Fenofibrate, Differing by Formulation Pemafibrate, Present and Future Perspective Summary and Conclusions References Chapter 25: EPA and Mixed Omega-3 Fatty Acids: Impact on Dyslipidemia and Cardiovascular Events in Patients with Diabetes Introduction History of OM3FAs and Glucose Homeostasis OM3FAs and Effects on Lipid and Lipoprotein Levels Mechanism of Lipid-Lowering Effects Effect of OM3FAs on CV Events Mixed OM3FAs Purified EPA JELIS REDUCE-IT RESPECT-EPA Dietary Supplements Pleiotropic Mechanisms of Action in Reducing the Risk of CV Events Antioxidant Activity Effect on Albuminuria Effect on Plaque Reduction and Stabilization Effect of OM3FAS on Microbiome OM3FAs, Gut Microbiome, and Glycemic Control Guidelines Conclusions References Chapter 26: Cholesterol Absorption Inhibitors (Ezetimibe) and Bile Acid-Binding Resins (Colesevelam HCl) as Therapy for Dyslipidemia in Patients with Diabetes Mellitus Diabetes Mellitus and Risk for Cardiovascular Disease General Considerations Clinical Relevance of Intestinal Cholesterol Ezetimibe Ezetimibe Mechanism of Action Further Complementary Mechanism of Action and Potential Benefits of Ezetimibe and Statin “Dual Inhibition” Pharmacokinetics, Safety, and Drug Interactions Ezetimibe in Special Patient Populations Ezetimibe in Patients with Diabetes Mellitus Non-HDL Cholesterol Apolipoprotein B Triglycerides HDL Cholesterol (HDL-C) Remnant-Like Lipoproteins Lipoprotein Particle Size High-Sensitivity C-Reactive Protein Clinical Trials of Ezetimibe in Patients with Diabetes Mellitus Recent Clinical Research of Ezetimibe in Patients with Diabetes Mellitus Bile Acid Sequestrants General Considerations Colesevelam HCl Pharmacokinetics, Safety, and Drug Interactions Colesevelam HCl: Cholesterol Lowering of Bile Acid Sequestration Colesevelam HCl: Glucose Lowering of Bile Acid Sequestration Ezetimibe and Colesevelam HCl Updated Clinical Research of Bile Acid Resins in Patients with Diabetes Mellitus Conclusion References Chapter 27: Clinical Efficacy of Proprotein Convertase Synthase Kexin Type 9 Inhibition in Persons with Diabetes Mellitus Introduction Proprotein Convertase Subtilisin/Kexin Type 9 Therapeutic Approaches to Inhibiting PCSK9 Monoclonal Antibodies PCSK9 and Risk for Diabetes Mellitus Impact of PCSK9 mAbs on Serum Lipids in Persons with Diabetes Mellitus The PCSK9 mAbs Reduce the Risk for ASCVD Events in Patients with Diabetes Mellitus Gene Silencing and PCSK9 Conclusions References Chapter 28: Clinical Care of Lipids in People with Type 1 Diabetes Background Guideline Recommendations for Lipid Lowering ASCVD Risk Calculators Other Methods of ASCVD Risk Stratification Evidence for Non-statin Lipid-Lowering Therapies Barriers to Optimal Clinical Care Conclusions References Chapter 29: Adjunct Drug Treatment to Reduce Vascular Disease in People with Diabetes Introduction Multiple Risk Factors for Vascular Complications Treating Multiple Risk Factors Is Beneficial Mnemonics to Guide Diabetes Care GLOBES Glucose Glucose Targets Treating Glucose Levels Nondrug Measures Glucose Control Drugs Glucose Control in Type 1 Diabetes and Complications Lipids and Lipid Drugs Obesity Blood Pressure and Blood Pressure Drugs Individualizing BP Targets Emotions Smoking CAD Clotting Advocacy Devices STRIVE Screening TReating to Target Inflammation/Infections Vaccinations Education Other Mnemonics for Cardiovascular Disease Coronary Artery Disease Heart Failure Summary Conclusions References Chapter 30: Emerging Lipoprotein-Related Therapeutics for Patients with Diabetes Introduction Recent Developments in the Understanding of the Etiology of Atherosclerosis and Its Thrombotic Consequences Lipids, Lipoproteins, and the Development of Atherosclerosis Medical Management of Dyslipidemia for Reducing Atherosclerosis Specific Approaches to the Modification of Lipid Profiles to Reduce Cardiovascular Disease PCSK9 Inhibitors and CRISPR Drugs Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors PCSK9 Biology Current and Future Directions in PCSK9 Therapy Monoclonal Antibodies PCSK9 Vaccines PCSK9-Related Small Interfering RNA (siRNA) In Vivo CRISPR Base Editing to Reduce PCSK9 Small-Molecule Inhibitors of PCSK9 PCSK9 Therapy and Type 2 Diabetes Combined Lipid Lowering and Anti-inflammatory Strategies Interleukin-2 Muteins CAR-Tregs Conclusions Regarding Inhibitors of PCSK9 and of Inflammation ATP Citrate Lyase (ACLY) Inhibitors Mechanism of Action of Bempedoic Acid Pharmacokinetics of Bempedoic Acid Clinical Trials of Bempedoic Acid Bempedoic Acid Trials in Type 2 Diabetes Pleiotropic Effects of Bempedoic Acid Side Effects of Bempedoic Acid Summary and Conclusions Regarding ACLY Inhibitors Long-Chain Fatty Acids and Their Esters: Impact on Dyslipidemia and CVD Introduction Chemistry and Biosynthesis of PUFAs The Paradigm Changing REDUCE-IT Trial of Icosapent Ethyl The Positive Outcome JELIS Trial Other Relevant PUFA Clinical Trials Pleiotropic Actions Contributing to the Effects of PUFAs Impact of Recent Clinical Trials on the Management of Hypertriglyceridemia Summary and Conclusion Regarding Fatty Acids Emerging Molecular Therapies for Dyslipidemias ApoCIII-Targeting Therapies Basic Biochemical Action/Mechanism of Action of ApoCIII Gene Silencing Therapies ApoC3 Roles in Lipoprotein Metabolism ApoC3 Actions in Cells and Animal Models Overview Actions in Animals Actions in Cells Pleiotropic Actions of ApoC3 ApoC3 Therapies in Human Clinical Trials Volanesorsen Overview Phase II Clinical Trial Phase III Clinical Trial AKCEA-APOCIII-LRx ARO-APOC3 Other ApoC3-Based Therapies Adverse Effects of Some ApoC3-Targeting Therapies Thrombocytopenia Injection-Site Reactions Summary and Conclusion Regarding ApoC-Targeting Molecular Therapies Angiopoietin-Related Protein 3 (ANGPTL3): Antibodies, ASOs, and siRNAs Basic Biochemical Action/Mechanism of Action ANGPTL3 Actions on Lipid Metabolism in Cells and in Animal Models ANGPTL3 Actions in Humans, Including Clinical Trials Pleiotropic Actions and Adverse Drug Effects of ANGPTL3 Inhibitors Summary and Conclusions Regarding ANGPTL3 Inhibition Other Relatively New and Emerging Lipid Drugs Overall Summary and Conclusion References Part IV: Epidemiology of Diabetes and Diabetic Dyslipidemia Chapter 31: Diabetes Epidemiology and Its Implications Introduction Diabetes Definitions and Prevalence Estimates Relationships Between Diabetes and Obesity Relationships Between Diabetes and Aging Relationships Between Diabetes and Ethnicity Relationships Between Diabetes and Physical Activity, with Interactive Effect of Environmental Toxins Summary References Chapter 32: Epidemiology, Control, and Cardiovascular Outcomes of Dyslipidemia in Diabetes Prevalence and Risk Factors for Dyslipidemia in Diabetes Dyslipidemia in Diabetes: LDL-C Dyslipidemia in Diabetes: Triglycerides Dyslipidemia in Diabetes: HDL-C Other Lipid Measures: Lipoprotein(a) Control of Dyslipidemia in Diabetes Dyslipidemia Control and Cardiovascular Risk Reduction in Diabetes Conclusions References Index