Lipoproteins in Diabetes Mellitus (Contemporary Diabetes) [2 ed.] 3031266803, 9783031266805

Diabetes mellitus has become epidemic on a global scale, and millions of new cases are diagnosed every year. With an est

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Table of contents :
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
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Lipoproteins in Diabetes Mellitus (Contemporary Diabetes) [2 ed.]
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Contemporary Diabetes Series Editor: Aristidis Veves

Alicia J. Jenkins Peter P. Toth Editors

Lipoproteins in Diabetes Mellitus Second Edition

Contemporary Diabetes Series Editor Aristidis Veves, Beth Israel Deaconess Medical Center Boston, MA, USA

The Contemporary Diabetes series focuses on the clinical aspects of obesity and diabetes and provides the practicing health provider with all the latest information regarding their management. The series also targets both basic and clinical researchers. The audience includes endocrinologists, internists, cardiologists, neurologists, nephrologists, podiatrists, ophthalmologists, family physicians, nurse practitioners, nurse educators, and physician assistants.

Alicia J. Jenkins  •  Peter P. Toth Editors

Lipoproteins in Diabetes Mellitus Second Edition

Editors Alicia J. Jenkins NHMRC Clinical Trials Centre University of Sydney Sydney, NSW, Australia

Peter P. Toth Department of Medicine, Division of Cardiology Johns Hopkins University School of Medicine Baltimore, MD, USA

ISSN 2197-7836     ISSN 2197-7844 (electronic) Contemporary Diabetes ISBN 978-3-031-26680-5    ISBN 978-3-031-26681-2 (eBook) https://doi.org/10.1007/978-3-031-26681-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014, 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Humana imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This book is dedicated to Professor Richard Louis Klein, Ph.D. (1951–2020). For most of his professional career, Richard (Rick) was an academic and Research Scientist in the Veterans Affairs Department and at the Medical University of South Carolina in Charleston, South Carolina, USA. He was a valued and dear colleague, mentor, and friend to many authors of the book chapters herein. Rick updated his three chapters in this second edition, also involving Andrea Semler, who researched with him in the laboratory for over two decades and whom he supervised for her master’s degree. Rick was a highly intelligent man, a skilled basic scientist with excellent knowledge of both the laboratory and clinical aspects of lipoproteins. He was a quiet achiever, whose research and mentoring significantly advanced knowledge in lipoproteins, diabetes, and vascular medicine. Rick’s legacy also includes his family, many colleagues, and friends from around the world, and many treasured memories of his and his wife Karen’s hospitality, kindness, and capacity for friendship and fun.

Preface

There is an ongoing pandemic of diabetes mellitus. Globally an estimated 537 million adults (1 in 10 adults) and over 1.2 million children live with diabetes, with approximately 80% of affected people being in disadvantaged regions. Almost 1 in 2 (240 million) adults with diabetes are undiagnosed (International Diabetes Federation Atlas, 10th edition, 2021). All people with Type 1 or Type 2 diabetes are at risk of acute and chronic complications, with the latter including micro- and macro-vascular damage. Globally diabetes is the commonest cause of adult-onset vision loss, a common cause of kidney failure, peripheral and autonomic neuropathy, lower limb amputations, and of accelerated atherosclerosis. Both quantitative and qualitative changes in lipoproteins are contributory to these devastating complications. As Elliott P. Joslin (1869–1962), the first doctor in the USA to specialize in diabetes, said in 1928, “People with diabetes die of too much fat: Too much fat in the diet, in the blood, in the body and in the blood vessels.” Just over a century after the discovery of insulin, enabling life for people with Type 1 diabetes and improving health outcomes for many people with Type 2 diabetes and women with gestational diabetes, this statement is still relevant. Fortunately, we now have much more knowledge regarding lipoproteins in people with diabetes, more clinical and research laboratory-related tests, many more effective treatments to reduce the adverse effects of lipoproteins, and greater capacity to detect and treat the chronic complications of diabetes. The field continues to advance. Over 8 years has passed since the first (2014) edition of this book, Lipoproteins in Diabetes Mellitus. Further knowledge, new tests, new treatment strategies and therapies, including lifestyle and lipid-related therapies to reduce the burden of diabetes complications are now available. This even more comprehensive second edition includes chapters for clinicians, clinician researchers, and basic scientists. There are chapters on lipoprotein metabolism, relevant cell biology, the pathobiology of lipid-related neurovascular damage, clinical and research tests of lipoproteins, clinical trials, treatment strategies, and existent and emerging lipid-related therapies. An expert group of senior authors from many different countries and fields have voluntarily shared their knowledge and time, often co-authoring with emerging leaders in this important field. Chapters have been updated and many new vii

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Preface

chapters added. New topics include: the epidemiology of diabetes and of lipid disorders in diabetes, the roles of lipoproteins and lipid therapies in diabetic peripheral neuropathy, stroke and peripheral vascular disease, the bidirectional links between lipoprotein and glucose metabolism, lipoprotein dysfunction in diabetes, lipid treatment in people with Type 1 diabetes, and detailed chapters on novel therapeutics including PCSK9 inhibitors. Each chapter includes an abstract, summary, key tables and/or figures, suggested research directions, and relevant references. We hope this book will serve the readership well, helping clinicians provide the best possible care for their patients living with diabetes and helping basic scientists and clinical trialists develop and test the next generation of effective lipoprotein-­ related therapies. Each of these approaches is key to improving health outcomes for people with diabetes and reducing the great personal and socioeconomic burden of diabetes. We encourage readers to also advocate for equitable access to proven treatments for all people with diabetes who may benefit. Sydney, NSW, Australia Baltimore, MD 

Alicia J. Jenkins Peter P. Toth

Acknowledgments

Alicia Jenkins gratefully acknowledges the assistance of Marina Zadonskaia and Peter Bennett.

ix

Contents

Part I Lipoprotein Metabolism, Qualitative Changes and Measurements 1

 Laboratory Assessment of Lipoproteins in Type 2 Diabetes����������������    3 David R. Sullivan

2

 Tools for Assessing Lipoprotein Metabolism in Diabetes Mellitus������   17 Richard L. Klein, Andrea J. Semler, and Alicia J. Jenkins

3

 Links Between Glucose and Lipoproteins ��������������������������������������������   33 Alicia J. Jenkins

4

 Apoproteins and Cell Surface Receptors Regulating Lipoprotein Metabolism in the Setting of Type 2 Diabetes ��������������������������������������   55 Thomas D. Dayspring and Peter P. Toth

5

Lipoprotein Metabolism and Alterations Induced by Insulin Resistance and Diabetes ������������������������������������������������������������  111 Gerald H. Tomkin and Daphne Owens

6

 The PPAR System in Diabetes����������������������������������������������������������������  145 Jean Claude Ansquer

7

Production and Metabolism of Triglyceride-Rich Lipoproteins: Impact of Diabetes ����������������������������������������������������������  169 Angela Pirillo, Giuseppe D. Norata, and Alberico L. Catapano

8

Triglyceride- and Cholesterol-Rich Remnant Lipoproteins in Risk of Cardiovascular Disease in Diabetes Mellitus��������������������������������������������������������������������  195 Benjamin Nilsson Wadström, Anders Berg Wulff, Kasper Mønsted Pedersen, and Børge Grønne Nordestgaard

9

 HDL Function in Diabetes����������������������������������������������������������������������  223 Anna Gluba-Brzózka, Magdalena Rysz-Górzyńska, and Jacek Rysz

xi

xii

Contents

10 L  ipoprotein(a): Metabolism, Pathophysiology, and Impact on Diabetes Mellitus������������������������������������������������������������  247 Karam Kostner and Gerhard M. Kostner 11 Lipoprotein  Glycation in Diabetes Mellitus������������������������������������������  275 Alicia J. Jenkins, Richard L. Klein, Andrea J. Semler, and Andrzej S. Januszewski 12 Lipid:  Extracellular Matrix Interactions as Therapeutic Targets in the Atherosclerosis of Diabetes������������������������  319 Danielle Kamato and Peter J. Little Part II Lipoproteins and the Complications of Diabetes 13 The  Role of Modified Forms of LDL and Corresponding Autoantibodies in the Development of Complications in Diabetes ������������������������������������������  339 Maria F. Lopes-Virella and Gabriel Virella 14 Endothelial  Dysfunction in Type 2 Diabetes with an Update on New Interventions����������������������������������������������������  357 Natalie C. Ward, Wann Jia Loh, and Gerald F. Watts 15 Lipoproteins  and Diabetic Kidney Disease��������������������������������������������  407 Fanny Jansson Sigfrids, Nina Elonen, and Per-Henrik Groop 16 Lipids  and Diabetic Retinopathy������������������������������������������������������������  439 Alicia J. Jenkins 17 Roles  of Extravasated and Modified Plasma Lipoproteins in Diabetic Retinopathy����������������������������������������������������  465 Timothy J. Lyons 18 The  Role of Lipids and Lipoproteins in Peripheral Neuropathy��������  485 Juan D. Collazos-Alemán, María P. Salazar-Ocampo, and Carlos O. Mendivil 19 Lipoproteins  and Ischemic Stroke in Diabetes��������������������������������������  503 Renato Quispe, Michael Goestch, Brigitte Kazzi, Fawzi Zghyer, Arielle Abovich, Steven Zeiler, Seth S. Martin, Peter P. Toth, and Steven R. Jones Part III Lipoprotein Treatment in Diabetes 20 About  Randomized Clinical Trials Related to Lipoproteins in Diabetes Mellitus����������������������������������������������������������  525 Anthony Keech, Alicia J. Jenkins, Val Gebski, and Ian Marschner 21 Effects  of Lifestyle (Diet, Plant Sterols, Exercise, and Smoking) and Glycemic Control on Lipoproteins in Diabetes������������  555 Peter Clifton

Contents

xiii

22 Statin  Therapy: Impact on Dyslipidemia and Cardiovascular Events in Patients with Diabetes ��������������������������������  579 Brent M. Gudenkauf, Steven R. Jones, and Seth S. Martin 23 Statin  Intolerance: An Overview for Clinicians������������������������������������  597 Stanisław Surma, Joanna Lewek, Peter E. Penson, and Maciej Banach 24 Fibrate  Therapy: Impact on Dyslipidemia and Cardiovascular Events in Patients with Diabetes Mellitus Type 2������  637 Eliot A. Brinton and Vishnu Priya Pulipati 25 EPA and Mixed Omega-3 Fatty Acids: Impact on Dyslipidemia and Cardiovascular Events in Patients with Diabetes ������������������������  681 Om P. Ganda, Robert Busch, J. R. Nelson, and Sephy Philip 26 Cholesterol  Absorption Inhibitors (Ezetimibe) and Bile Acid-Binding Resins (Colesevelam HCl) as Therapy for Dyslipidemia in Patients with Diabetes Mellitus ������������  705 Harold Edward Bays 27 Clinical  Efficacy of Proprotein Convertase Synthase Kexin Type 9 Inhibition in Persons with Diabetes Mellitus����������������������������������������  735 Peter P. Toth, Manfredi Rizzo, and Maciej Banach 28 Clinical  Care of Lipids in People with Type 1 Diabetes ����������������������  755 Nick S. R. Lan, Alicia J. Jenkins, and P. Gerry Fegan 29 Adjunct  Drug Treatment to Reduce Vascular Disease in People with Diabetes����������������������������������������������������������������������������������������������������  779 Alicia J. Jenkins 30 Emerging  Lipoprotein-Related Therapeutics for Patients with Diabetes����������������������������������������������������������������������������������������������������  821 Alex Bobik, Neale Cohen, Alicia J. Jenkins, Tin Kyaw, David Sullivan, Xiaoqian Wu, Xi-Yong Yu, and Peter J. Little Part IV Epidemiology of Diabetes and Diabetic Dyslipidemia 31 Diabetes  Epidemiology and Its Implications ����������������������������������������  881 Zachary Bloomgarden and Yehuda Handelsman 32 Epidemiology,  Control, and Cardiovascular Outcomes of Dyslipidemia in Diabetes ������������������������������������������������������������������������  891 Wenjun Fan and Nathan D. Wong Index�������������������������������������������������������������������������������������������������������������������� 915

Contributors

Arielle  Abovich  Department Baltimore, MD, USA

of

Medicine,

Johns

Hopkins

Hospital,

Jean Claude Ansquer  Department of Nephrology, Centre Hospitalier Universitaire, Dijon, France Maciej Banach  Polish Lipid Association (PLA), Lodz, Poland Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland Department of Cardiology and Adult Congenital Heart Diseases, Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland Cardiovascular Research Centre, University of Zielona Góra, Zielona Góra, Poland Harold Edward Bays  Louisville Metabolic and Atherosclerosis Research Center, University of Louisville School of Medicine, Louisville, KY, USA Zachary Bloomgarden  Icahn School of Medicine, Mount Sinai Medical Center, New York, NY, USA Alex  Bobik  Vascular Biology and Arteriosclerosis Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia Eliot A. Brinton  Utah Lipid Center, Salt Lake City, UT, USA Robert  Busch  Department of Medicine, Community Endocrine Group, Albany Medical Center, Albany, NY, USA Alberico L. Catapano  IRCCS Multimedica, Milan, Italy Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy Peter Clifton  University of South Australia, Adelaide, SA, Australia Neale  Cohen  Diabetes Centre, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia xv

xvi

Contributors

Juan D. Collazos-Alemán  School of Medicine, Universidad de los Andes, Bogotá, DC, Colombia Thomas D. Dayspring  True Health Diagnostics, Glen Allen, VA, USA Nina  Elonen  Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland Wenjun  Fan  Heart Disease Prevention Program, C240 Medical Sciences, University of California, Irvine, CA, USA P.  Gerry  Fegan  Department of Endocrinology and Diabetes, Fiona Stanley and Fremantle Hospitals, Perth, WA, Australia Medical School, Curtin University, Perth, WA, Australia Om  P.  Ganda  Clinical Research and Adult Diabetes Sections, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA, USA Val Gebski  NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia Anna  Gluba-Brzózka  Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland Michael  Goestch  Department Baltimore, MD, USA

of

Medicine,

Johns

Hopkins

Hospital,

Per-Henrik Groop  Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia Brent  M.  Gudenkauf  Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, USA Yehuda Handelsman  Metabolic Institute of America, Tarzana, CA, USA Andrzej  S.  Januszewski  NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Melbourne, VIC, Australia

Contributors

xvii

Alicia  J.  Jenkins  NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia Department of Medicine, St. Vincent’s Hospital, The University of Melbourne, Melbourne, VIC, Australia Department of Endocrinology and Diabetes, St. Vincent’s Hospital, Fitzroy, VIC, Australia Diabetes and Vascular Medicine, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia Steven R. Jones  Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, USA Danielle  Kamato  School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia Griffith Institute for Drug Discovery and School of Environment and Science, Griffith University, Nathan, QLD, Australia Brigitte  Kazzi  Department Baltimore, MD, USA

of

Medicine,

Johns

Hopkins

Hospital,

Anthony  Keech  NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia Richard  L.  Klein  Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston, SC, USA Gerhard M. Kostner  Institute of Molecular Biology and Biochemistry, Gottfried Schatz Research Centre, Medical University of Graz, Graz, Austria Karam Kostner  Medicine, University of Queensland, Brisbane, QLD, Australia Cardiology, Mater Hospital, Brisbane, QLD, Australia Tin  Kyaw  Vascular Biology and Arteriosclerosis Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia Nick  S.  R.  Lan  Department of Cardiology, Fiona Stanley Hospital, Perth, WA, Australia Medical School, The University of Western Australia, Perth, WA, Australia Joanna Lewek  Polish Lipid Association (PLA), Lodz, Poland Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland Department of Cardiology and Adult Congenital Heart Diseases, Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland

xviii

Contributors

Peter J. Little  School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, QLD, Australia Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China Wann Jia Loh  School of Medicine, University of Western Australia, Perth, WA, Australia Cardiometabolic Service, Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, WA, Australia Department of Endocrinology, Changi General Hospital, Singapore, Singapore Duke-NUS Medical School, Singapore, Singapore Maria  F.  Lopes-Virella  Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA Timothy  J.  Lyons  Division of Endocrinology, Medical University of South Carolina, Charleston, SC, USA Ian  Marschner  NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia Seth  S.  Martin  Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, USA Carlos O. Mendivil  School of Medicine, Universidad de los Andes, Bogotá, DC, Colombia Endocrinology Section, Fundación Santa Fe de Bogotá, Bogotá, DC, Colombia J. R. Nelson  California Cardiovascular Institute, Fresno, CA, USA Giuseppe  D.  Norata  Center for the Study of Atherosclerosis-SISA Lombardia, Bassini Hospital, Cinisello Balsamo, Milan, Italy Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy Børge  Grønne  Nordestgaard  Department of Clinical Biochemistry, Herlev og Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Daphne Owens  Diabetes Institute of Ireland, and Trinity College, Dublin, Ireland Kasper  Mønsted  Pedersen  Department of Clinical Biochemistry, Herlev og Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

Contributors

xix

Peter E. Penson  School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK Liverpool Centre for Cardiovascular Science, Liverpool, UK Sephy Philip  Medical Affairs, Amarin Pharma, Inc., Bridgewater, NJ, USA Angela Pirillo  Center for the Study of Atherosclerosis-SISA Lombardia, Bassini Hospital, Cinisello Balsamo, Milan, Italy IRCCS Multimedica, Milan, Italy Vishnu Priya Pulipati  Warren Clinic Endocrinology, Tulsa, OK, USA Renato  Quispe  Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Manfredi Rizzo  University of Palermo, School of Medicine, Palermo, Italy Jacek  Rysz  Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland Magdalena  Rysz-Górzyńska  Department of Ophthalmology and Visual Rehabilitation, Medical University of Lodz, Lodz, Poland María P. Salazar-Ocampo  School of Medicine, Universidad de los Andes, Bogotá, DC, Colombia Andrea  J.  Semler  Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston, SC, USA Fanny  Jansson  Sigfrids  Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland David R. Sullivan  NSW Health Pathology and Department of Chemical Pathology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia Department of Chemical Pathology, Royal Prince Alfred Hospital, NSW Health Pathology, Camperdown, NSW, Australia Stanisław Surma  Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland Club of Young Hypertensiologists, Polish Society of Hypertension, Gdansk, Poland Polish Lipid Association (PLA), Lodz, Poland Gerald H. Tomkin  Diabetes Institute of Ireland, and Trinity College, Dublin, Ireland

xx

Contributors

Peter P. Toth  CGH Medical Center, Sterling, IL, USA Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA Gabriel Virella  Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA Benjamin  Nilsson  Wadström  Department of Clinical Biochemistry, Herlev og Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Natalie  C.  Ward  Dobney Hypertension Centre, Medical School, University of Western Australia, Perth, WA, Australia Gerald F. Watts  School of Medicine, University of Western Australia, Perth, WA, Australia Cardiometabolic Service, Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, WA, Australia Nathan  D.  Wong  Heart Disease Prevention Program, C240 Medical Sciences, University of California, Irvine, CA, USA Xiaoqian Wu  School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, People’s Republic of China Anders  Berg  Wulff  Department of Clinical Biochemistry, Herlev og Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Xi-Yong  Yu  Guangzhou Medical University, Guangzhou, People’s Republic of China Steven  Zeiler  Department Baltimore, MD, USA Fawzi  Zghyer  Department Baltimore, MD, USA

of of

Neurology,

Johns

Hopkins

Hospital,

Medicine,

Johns

Hopkins

Hospital,

Part I

Lipoprotein Metabolism, Qualitative Changes and Measurements

Chapter 1

Laboratory Assessment of Lipoproteins in Type 2 Diabetes David R. Sullivan

Abbreviations ApoB Apolipoprotein B CETP Cholesteryl ester transfer protein CVD Cardiovascular disease HDL-C High-density lipoprotein cholesterol LDL-C Low-density lipoprotein cholesterol Lp(a) Lipoprotein(a) NHDL-C Non-high-density lipoprotein cholesterol TC Total cholesterol TG Triglycerides TRL Triglyceride-rich lipoproteins

Introduction Lipids, Lipoproteins, and Other Analytes in Diabetes Type 1 and type 2 diabetes are often regarded as abnormalities of insulin and glucose metabolism, but it is more appropriate to recognize that they disrupt the pathophysiology of macronutrient metabolism as a whole. Accordingly, it is

D. R. Sullivan (*) NSW Health Pathology and Department of Chemical Pathology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. J. Jenkins, P. P. Toth (eds.), Lipoproteins in Diabetes Mellitus, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-26681-2_1

3

4

D. R. Sullivan

essential to recognize the effects of diabetes on the other major class of macronutrients, namely lipids. The fundamental differences in the pathophysiology and treatment of type 1 and type 2 diabetes are manifest in the changes in lipoprotein metabolism that accompany these two forms of diabetes. Consequently, the role of altered lipoprotein metabolism in the atherosclerotic process that underlies macrovascular complications may differ. Fully treated type 1 diabetes often causes minimal disturbance to the lipoprotein profile, in fact the level of triglycerides may be slightly decreased and that of HDL-C may be slightly increased in insulin-treated patients partly due to activation of lipoprotein lipase due to supraphysiologic levels of insulin [1, 2]. Nevertheless, non-enzymatic glycation of the apolipoprotein component of lipoproteins [3], as well as other modifications, may render lipoproteins dysfunctional in type 1 diabetes. Consequently, the atherogenicity of the diabetic state in type 1, combined with the early age of onset, results in an increased life-long risk of CVD that demands efforts to maintain lipoproteins at target levels or better [4]. This may be difficult to achieve in the face of complications of type 1 diabetes such as renal impairment, obesity, poor glucose control, or the need for immune-­ suppressive therapy subsequent to organ or islet transplantation. Hypercholesterolemia may occur in type 1 diabetes in association with severe chronic hyperglycaemia [5]. Furthermore, as insulin is required for the action of lipoprotein lipase, in the setting of newly diagnosed type 1 diabetes prior to insulin therapy or with insulin omission or diabetic ketoacidosis, massive hypertriglyceridemia can occur [6]. Type 2 diabetes, on the other hand, is associated with a well characterized disturbance of the lipoprotein profile which features mild to moderate increase in triglyceride-­rich lipoproteins (TRL), reduced HDL-C, and modification of LDL particle composition. Type 2 diabetes is becoming increasingly prevalent in the setting of increased dietary energy intakes and reduced physical activity levels in affluent and disadvantaged societies, so it will be the major focus of attention here. Lipid abnormalities manifest as disturbances of the levels of the lipoproteins that transport lipids in the bloodstream. These disturbances may contribute to the macrovascular complications of diabetes by influencing the processes that underlie atherosclerosis and thrombosis. Less frequently, they may lead to massive increase in TG that greatly increase the risk of acute pancreatitis with associated loss of beta cell function and pancreatic exocrine function. Evidence suggests that disturbances in lipoprotein metabolism may also contribute to the microvascular complications of diabetes such as renal impairment, retinopathy, and neuropathy, which is discussed in other chapters in this book, however the relevant mechanisms are not yet fully elucidated [7]. The laboratory assessment of lipoprotein status in diabetes relies on minimization of the effect of potential confounding factors. Sample collection procedures are designed to reduce pre-analytical sources of variability [8]. One of the most important sources of variability is the presence of intercurrent illness because the associated inflammatory response mediates modifications of the lipid and lipoprotein profile which share many of the features of those associated with type 2 diabetes, as will be described later. The magnitude of modifications associated with an inflammatory response is usually proportional to the severity of the underlying illness [9],

1  Laboratory Assessment of Lipoproteins in Type 2 Diabetes

5

but proportionately smaller responses should also be anticipated in association with minor intercurrent episodes [10]. Routine Lipoprotein Assessment Clinical evaluation of lipoprotein metabolism in diabetes usually involves the measurement of total cholesterol, HDL-C and TG following a 12-h fast. LDL-C is derived from the fasting results by application of the Friedewald equation [11], but this calculation becomes less reliable in the setting of diabetes [12] and as TG levels increase beyond approximately 4 mmol/L (350 mg/dL). Modified calculations have been developed, but these are complex, relying on computation rather than mental arithmetic [13]. Sustained attention to standardization and quality assurance have established a high level of reliability [8] for routine lipid measurements [14]. Satisfactory analytical performance by clinical laboratories is sustained by well-established systems of internal and external quality assurance [15, 16]. These processes have been extended to include apolipoproteins, most importantly apoB [14] and Lp(a) [17]. Non-fasting plasma or serum has been shown to be a more sensitive marker for the detection of individuals with increased risk of CVD [18], but the un-­standardized nature of non-fasting samples makes them unsuitable for the characterization or serial monitoring of lipid status in diabetes. Indeed, even fasting TG levels show considerable within-individual variability [19]. This has implications for the serial measurement of LDL-C which is calculated from the fasting TG. The considerable biological variability of fasting TG increases the proportion by which a serial measurement of fasting TG (and hence LDL-C) must differ in order to indicate a clinically significant alteration [19]. Automated “direct” HDL-C measurements may suffer interference from the cholesterol content of VLDL and remnants, resulting in a positive bias [20]. Method comparison studies prior to 2000 suggested good agreement between “separation” HDL-C methods and the reference method [21], even in the presence of Intralipid [22] or TRL [23]. Where positive bias occurred, it was attributed to incomplete precipitation with the comparator method [24, 25] or the presence of apolipoprotein E-containing HDL [26], but the sources of TG used in these studies had a relatively low cholesterol content. “Direct” HDL methods initially involved the use of α-cyclodextrin, and positive interference from TRL was described in some [27], but not all [24] studies. Since methods involving α-cyclodextrin have been superseded, several recent studies of “direct” HDL methods have reported positive biases which were attributed to TRL [20] or the presence of diabetes [28]. This is an important issue because any overestimation of HDL-C risks underdiagnosis of the metabolic syndrome and insulin resistance, as well as underestimation of LDL-C and NHDL-C. These combined effects could result in a substantial underestimation of absolute risk of CVD, leading to loss of opportunity to effectively identify and treat patients on the basis of their metabolic risk factors. It is possible that TRL may also interfere with “direct” LDL-C assays that utilize a similar strategy based on selective effect of detergents [29].

6

D. R. Sullivan

The accuracy of standard lipid measurements is extremely important because this quantitative information is applied directly to patient management. The atherogenic effects of LDL-C and other apoB-containing lipoproteins such as Lp(a) represent independent risk factors for CVD. Whereas LDL-C (or TC) originally provided thresholds for initiation of treatment and targets for intervention, management decisions are now seen in a wider context that encompasses the overall (absolute) CVD risk of the individual patient. This incorporates the classic modifiable and non-modifiable risk factors to varying extents. The predominance of age is one of several inevitable limitations affecting the performance of the absolute risk calculation algorithms. Diabetes is no longer regarded as a “coronary risk equivalent,” but rather the presence or absence of diabetes is treated as a categorical variable, usually without adjustment for severity. The presence of pre-diabetes or impaired glucose tolerance is associated with increased CVD risk relative to the non-diabetic population, but is not associated with microvascular complications. Clinical uncertainty associated with intermediate levels of CVD risk has led to efforts to “re-­classify” patients in this category by a variety of methods. Some algorithms allow adjustment for factors such as ethnicity, duration of diabetes, HbAIc level, and the presence or absence of kidney damage such as microalbuminuria or eGFR loss, but most do not consider more than the presence or absence of diabetes, nor do they usually consider pre-diabetes which is associated with high risk of CVD [30]. While the additional CVD risk posed by the presence of diabetes or pre-diabetes often justifies active management of the lipid profile, clinicians need to remember that the presence of massive hypertriglyceridemia (>10 mmol/L, 880 mg/dL) poses a more immediate risk of acute pancreatitis. LDL Composition and Particle Number A clinical approach based purely on quantitative assessment of LDL-C and/or TC:HDL-C ratio is inappropriate, particularly in the presence of elevated TG, which often applies in the case in type 2 diabetes. Increased levels of TRL promote the action of cholesteryl ester transfer protein (CETP) which leads to a reduction in HDL-C and a depletion in the amount of cholesterol carried per LDL particle. These changes in LDL composition are proportional to the degree of postprandial lipemia [31, 32] which usually correlates with fasting triglyceride levels. The relationship between LDL-C and CVD risk [33] can be confounded because the formation of “small dense LDL” may result in an LDL-C level that is low relative to the number of LDL particles. This is illustrated by the superiority of other risk markers such as NHDL-C (calculated as the difference between TC and HDL-­ C) which reflects the full range of potentially atherogenic lipoproteins [34]. This superiority is thought to reflect the greater atherogenicity of the “small dense LDL” and hence the pre-eminence of particle number as the main determinant of the pro-­atherogenic associations of non-HDL lipoproteins. Direct measurement of LDL-C traditionally relied on quantitative ultracentrifuge studies which are too tedious to perform for clinical purposes [35]. Electrophoresis based on sizing gel techniques has attempted to circumvent this problem, leading to designation of

1  Laboratory Assessment of Lipoproteins in Type 2 Diabetes

7

so-called pattern A and pattern B profiles or estimations of LDL diameter. These methods are non-quantitative with respect to the number of atherogenic lipoprotein particles, so their clinical value is only marginal. Vertical ultracentrifugation has introduced another option for quantitative assessment of the spectrum of atherogenic lipoproteins, though this is not widely available as a clinical tool [36]. Detailed analysis from the CARE trial demonstrated that the apoC3 levels in VLDL and LDL were superior to TG for the prediction of CVD risk [37]. Subsequent Mendelian randomization studies have supported the development of anti-apoC3 small interfering RNA therapy as a treatment for elevated TG and the risk of CVD. An alternative approach to NHDL-C is based on the measurement of serum apoB level [38]. All particles that are capable of transporting cholesterol in a pro-­ atherogenic manner, such as LDL, Lp(a), and VLDL remnants contain one apoB molecule. As such, apoB provides a direct measurement of the number of atherogenic lipoprotein particles. Human apoB derived from the intestine is the product of post-transcriptional modification (m-RNA editing) that yields a product that consists of the first 48% of the non-intestinal apoB. The two gene products are designated apoB48 and apoB100, respectively. ApoB levels do not change markedly after a meal because the transport of dietary fat is largely accommodated by an increase in TG content per ApoB48 particle, rather than an increase in total apoB. This also reflects the fact that the number of apoB100 particles is large relative to the number of apoB48 particles. Hence apoB measurement need not depend on fasting or the ability to differentiate the apoB100 isoform. Evidence suggests that apoB measurement is superior to LDL-C or NHDL-C for CVD risk assessment [39]. When combined with LDL-C measurement, the LDL-C:ApoB ratio can reflect the degree to which cholesterol depletion of LDL has led to the formation of “small, dense LDL” [40]. Tables 1.1, 1.2, and 1.3 are provided as a means of including apoB measurement as a guide to diagnosis. Table 1.1  An algorithm for the prediction of the likely class of lipoproteins responsible for dyslipidemia in approximate order of prevalence in type 2 diabetes TG:ApoB ≥10 in mmol/L or >y in mg/dL (Y/N) N N N/A

TC:ApoB ≥6.2 in mmol/L or ≥ in mg/dL (Y/N) N N N/A

ApoB ≥1.2 N ApoB ≥0.75–1.2 Y

N/A Y

N/A N

ApoB