Principles and Treatment of Lipoprotein Disorders · Blood Lipid Regulation 13 E. Lipoprotein Metabolism 15 I. Transport of Exogenous Lipids 15 II. Transport of Endogenous Lipids

Principles andTreatment ofLipoprotein DisordersContributors

D.H. Blankenhorn, H.B. Brewer, G.A. Coetzee, S.L. ConnorW.E. Connor, J. Davignon, A. Gaw, A.J.R. HabenichtE. von Hodenberg, H.N. Hodis, D.R. IllingworthU. JanBen-Timmen, D. Kritchevsky, K.J. Lackner, H.J. MenzelG. Olivecrona, T. Olivecrona, A.G. Olsson, C.J. PackardJ.R. Patsch, W.O. Richter, P.B. Salbach, E.B. SchmidtP. Schwandt, D. Seidel, J. Shepherd, G. UtermannW.J.S. de Villiers, D.R. van der Westhuyzen

Editors

Gotthard Schettler and Andreas J.R. Habenicht

Springer-VerlagBerlin Heidelberg New York London ParisTokyo Hong Kong Barcelona Budapest

_ r

Contents

Section A: Physiology and Pathophysiology of Lipid Metabolism

CHAPTER 1

An Introduction to the Biochemistry and Biology of Blood Lipids andLipoproteinsJ.R. PATSCH. With 1 Figure 3

A. Introduction 3B. Blood Lipid Transport: Historical Aspects 4C. Blood Lipids, Apolipoproteins, and Lipoproteins 6

I. Lipids 6II. Apolipoproteins 9

III. Lipoproteins 12D. Enzymes and Transfer Factors Involved in the Biochemistry of

Blood Lipid Regulation 13E. Lipoprotein Metabolism 15

I. Transport of Exogenous Lipids 15II. Transport of Endogenous Lipids 17

F. Cholesterol and Atherosclerosis 18G. High-Density Lipoprotein Cholesterol and Reverse Cholesterol

Transport 19H. Triglycerides, High-Density Lipoprotein Cholesterol, and

Coronary Artery Disease 20I. Conclusion 22References 22

CHAPTER 2

Lipoprotein MetabolismH.B. BREWER. With 9 Figures 29

A. Introduction 29B. Plasma Apolipoproteins 30

XII Contents

C. Cellular Receptors 33I. Low-Density Lipoprotein Receptor 33

II. Scavenger Receptor(s) 34III. Chylomicron Remnant Receptor 34IV. High-Density Lipoprotein Receptor 36

D. Lipoprotein Metabolism 36I. ApoB Metabolic Cascade 36

II. High-Density Lipoprotein Metabolism 38III. Lp(a) 42

E. Major Plasma Atherogenic and Antiatherogenic Lipoproteins . . . 43I. Low-Density Lipoproteins 44

II. p Very Low Density Lipoproteins 45III. Lp(a) 45IV. High-Density Lipoproteins 46

F. Summary 46References 46

CHAPTER 3

Lipoprotein ReceptorsW.J.S. DE VILLIERS, G.A. COETZEE, and D.R. VAN DER WESTHUYZEN.With 6 Figures 53

A. Introduction 53B. The Low-Density Lipoprotein Receptor 53

I. Functions of the Low-Density Lipoprotein Receptor in theBody ". 54

II. Structure of the Low-Density Lipoprotein Receptor 551. Domains 552. Evolution 573. Low-Density Lipoprotein Receptor Polymorphisms 58

III. Low-Density Lipoprotein Receptor Endocytosis, Recyclingand Turnover 58

IV. Low-Density Lipoprotein Receptor Mutations and FamilialHypercholesterolaemia 601. Classes of Low-Density Lipoprotein Receptor Mutations 60

a) Class I Mutations (Null Alleles) 61b) Class II Mutations (Transport-Defective Alleles) 62c) Class HI Mutations (Binding-Defective Alleles) 62d) Class IV Mutations (Internalization-Defective

Alleles) 62e) Class V Mutations (Recycling-Defective Alleles) 62

2. Clinical Variability in Familial Hypercholesterolaemia . . . 63V. Low-Density Lipoprotein Receptor Regulation 63

1. Low-Density Lipoprotein Receptor Promoter 63

Contents XIII

2. Control in the Liver 64VI. Low-Density Lipoprotein Receptor and Therapy 65

1. Drug Therapy 652. Liver Transplantation 663. Gene Therapy 66

C. Chylomicron Remnant Receptor 66I. Receptor-Mediated Clearance of Chylomicron Remnants . . . 67

II. Low-Density Lipoprotein Receptor Related Protein:Candidate Chylomicron Remnant Receptor 67

III. Structure of Low-Density Lipoprotein Receptor RelatedProtein 67

IV. Properties of Low-Density Lipoprotein Receptor RelatedProtein 691. Binding of Ligands 692. Regulation of Ligand Binding 70

D. High-Density Lipoprotein Receptor 70I. Cholesterol Efflux 71

II. High-Density Lipoprotein Endocytosis 72E. The Scavenger Receptor 72

I. The Modified Low-Density Lipoprotein Hypothesis 72II. Scavenger Receptor Structure 73

III. Scavenger Receptor Function 76IV. Human Scavenger Receptor Gene 77V. Expression and Regulation 77

VI. Scavenger Receptor and Atherogenesis 77F. Conclusion 79References 79

CHAPTER 4

Genetic Disorders of Lipoprotein MetabolismG. UTERMANN and H.J. MENZEL. With 7 Figures 89

A. Introduction 89B. Familial Hyperchylomicronemia 95

I. Lipoprotein Lipase Deficiency 97II. Apolipoprotein C-II Deficiency 99

C. Familial Hypercholesterolemia 100I. Heterozygous Familial Hypercholesterolemia 100

1. Low-Density Lipoprotein 1022. Pathophysiology and Clinics of Familial

Hypercholesterolemia 1063. Diagnosis of Familial Hypercholesterolemia 108

II. Homozygous Familial Hypercholesterolemia 109III. Familial Defective ApoB-100 110

XIV Contents

1. Population Genetics of Familial Defective ApoB-100 1112. Diagnosis of Familial Defective ApoB-100 I l l3. The Familial Defective ApoB-100 Phenotype I l l

D. Lp(a) Hyperlipoproteinemia 113I. Structure and Evolution 113

II. Genetics 114III. Genetics of Lp(a) and of Lp(a) Hyperlipoproteinemia 114IV. Lp(a) Hyperlipoproteinemia and Atherosclerotic Vascular

Disease 116E. Hyperlipoproteinemia Type III 117

I. ApoE Polymorphism....; 117II. Multifactorial Type III Hyperlipoproteinemia 119

III. Dominant Type III Hyperlipoproteinemia 121IV. Pathophysiology of Type III Hyperlipoproteinemia 123

F. Familial Combined Hyperlipoproteinemia 124G. Polygenic Hypercholesterolemia 126H. Familial Hypertriglyceridemia 127I. Familial Hyperalphalipoproteinemia and Familial

Hypoalphalipoproteinemia 128References 130

CHAPTER 5

Interactions Between Lipoproteins and the Arterial WallA.J.R. HABENICHT, P.B. SALBACH, and U. JANSSEN-TIMMEN.With 2 Figures 139

A. The Molecular Mechanisms of Atherogenesis Are Not Known . . . 139B. The Low-Density Lipoprotein Receptor Pathway and the

Pathogenesis of Atherosclerosis 141C. Is Low-Density Lipoprotein Atherogenic? 144D. The Low-Density Lipoprotein Receptor is a Member of a Family

of Lipoprotein Receptors: The Low-Density LipoproteinReceptor Related Proteins, a Very Low-Density LipoproteinReceptor, and Glycoprotein 330 145

E. The Low-Density Lipoprotein Receptor Dependent-ArachidonicAcid Pathway 148

F. The Oxidation and Scavenger Receptor Hypotheses 151G. High-Density Lipoproteins and the Reverse Cholesterol

Transport Hypothesis 156H. Arterial Wall Cells Form Biologically Active Mediators of

Inflammation in Response to Cholesterol Feeding 157I. Adhesion Molecules Are Involved in Leukocyte-Endothelial

Cell Interactions ; . . . . 160J. Proto-oncogenes Are Expressed in Atherosclerotic Lesions 162References 163

Contents XV

CHAPTER 6

Lipoprotein Lipase and Hepatic LipaseT. OLIVECRONA and G. OLIVECRONA.

With 4 Figures 175

A. Introduction 175B. Gene Structures 176C. Molecular Structure 178D. Effects of Apolipoproteins on Lipase Action 181E. Lipoprotein Lipase and Hepatic Lipase - What Are the

Functional Differences? 182F. Actions of Lipoprotein Lipase 183G. Sites of Synthesis 185H. Maturation into Active Lipoprotein Lipase 186I. Transfer to the Endothelium 188J. Transport in Blood 189K. Lipases in Pre- and Postheparin Plasma 190L. Regulation 192M. Lipoprotein Lipase as Ligand for Binding of Lipoproteins to Cells

and Receptors 193N. Is Lipoprotein Lipase Rate-Limiting for Catabolism of

Triglyceride-Rich Lipoproteins? 194O. Impact on Lipoprotein levels 195References 197

CHAPTER 7

Animal Models of Lipoprotein MetabolismD. KRITCHEVSKY 207

A. Introduction 207B. Animal Models 208C. Lipoproteins 211

I. Rabbit 211II. Monkey 212

D. Conclusion 214References 215

Section B: Lipid Lowering Therapy

CHAPTER 8

Rationale to TreatD.H. BLANKENHORN and H.N. HODIS 221

A. Introduction 221B. Mortality- and Morbidity-Based Drug Trials 221

XVI Contents

C. Mortality- and Morbidity-Based Diet Trials 224D. Atherosderotic Regression Trials - Uncontrolled Case Series and

Case Reports 224I. Femoral Artery 224

II. Popliteal Artery 228III. Renal Artery 228IV. Carotid Artery 228V. Coronary Artery and Aorta 228

E. Controlled Coronary Angiographic Studies of Drug Therapy . . . . 230F. Coronary Angiographic Studies of Diet Therapy 237G. Femoral Angiographic Drug Studies 238H. Atherosclerosis Regression in Experimental Animal Models 239I. Summary 241References 242

CHAPTER 9

The Dietary Therapy of Hyperlipidemia: Its Important Role in thePrevention of Coronary Heart DiseaseW.E. CONNOR and S.L. CONNOR. With 6 Figures 247

A. Introduction 247B. Dietary Cholesterol 249C. Effects of Dietary Fats Upon the Plasma Lipids

and Lipoproteins 251D. The Cholesterol-Saturated Fat Index of Foods 254E. Polyunsaturated Fatty Acids 258F. Carbohydrate 260G. Fiber, Saponins, and Antioxidants 261H. Protein 262I. Calories 263J. Alcohol 263K. Coffee and Tea 264L. The Dietary Design to Achieve Optimal Plasma

Lipid-Lipoprotein Levels 265M. A Phased Approach to the Dietary Treatment of

Hyperlipidemia 266N. Predicted Plasma Cholesterol Lowering from Three Phases of the

Low-Fat, High Complex Carbohydrate Diet 268O. The Applicability of the Low-Cholesterol, Low-Fat, High-

Carbohydrate Diet in the Treatment of the Various Phenotypesand Genotypes of Hyperlipidemia 269

P. The Use of the Low-Fat, High Complex Carbohydrate Diet inDiabetic Patients, Pregnant Patients, Children, and HypertensivePatients 271

Q. Interrelationship Between Dietary and Pharmaceutical Therapyof Hyperlipidemic States 273

Contents XVII

R. Summary 274References 275

CHAPTER 10

Lipid ApheresisD. SEIDEL. With 4 Figures 279

A. Introduction 279B. Low-Density Lipoprotein Apheresis Procedures 281C. The Heparin-Induced Extracorporeal Low-Density Lipoprotein

Plasmapheresis System 281D. Clinical Experience with the Heparin-Induced Extracorporeal

Low-Density Lipoprotein Plasmapheresis System 283E. Experience with Combined Heparin-Induced Extracorporeal

Low-Density Lipoprotein Plasmapheresis and3-Hydroxy-3-methylglutaryl Coenzyme A Reductase InhibitorTherapy 287

F. Treatment Tolerance and Safety of Heparin-InducedExtracorporeal Low-Density Lipoprotein Plasmapheresis 288

G. Typical Case Reports 290I. Case 1 290

II. Case 2 291H. The Heparin-Induced Extracorporeal Low-Density Lipoprotein

Plasmapheresis Treatment in Heart-Transplant Patients withSevere Hypercholesterolemia: Report of an Ongoing Study 292

I. The Heparin-Induced Extracorporeal Low-Density LipoproteinPlasmapheresis U System for a Simultaneous Hemodialysis:Low-Density Lipoprotein Apheresis 293

I. Case Report 294J. Comparison of Techniques to Lower Low-Density Lipoprotein

Levels by Apheresis 295K. Indication for Heparin-Induced Extracorporeal

Low-Density Lipoprotein Apheresis 296L. Conclusion 297References 297

Section C: Lipid Lowering Drugs

CHAPTER 11

3-Hydroxy-3-methylglutaryl Coenzyme A Reductase InhibitorsD.R. ILLINGWORTH and E.B. SCHMIDT. With 3 Figures 303

A. Introduction 303B. Structure and Mechanism of Action of 3-Hydroxy-3-

methylglutaryl Coenzyme A Reductase Inhibitors 304

XVIII Contents

I. Structure 304II. Pharmacokinetic Properties of Lovastatin, Pravastatin, and

Simvastatin 306III. Mechanism of Action 307IV. Effects on Lipoprotein Metabolism 308V. Other Potential Effects of 3-Hydroxy-3-methylglutaryl

Coenzyme A Reductase Inhibitors 309C. Clinical Efficacy of 3-Hydroxy-3-methylglutaryl Coenzyme A

Reductase Inhibitors in the Treatment of Hyperlipidemia 310I. Effects in Primary Hypercholesterolemia 310

II. Effects in Combined Hyperlipidemia 314HI. Effects in Hypertriglyceridemia and

Hypoalphalipoproteinemia 315IV. Potential Utility of 3-Hydroxy-3-methylglutaryl Coenzyme A

Reductase Inhibitors in Patients with Secondary Causes ofHyperlipidemia 316

D. Safety and Side-Effect Profile of 3-Hydroxy-3-methylglutarylCoenzyme A Reductase Inhibitors 317

E. Contraindications and Inappropriate Uses of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors 319

F. Use of 3-Hydroxy-3-methylglutaryl Coenzyme A ReductaseInhibitors in Combination Drug Therapy 320

G. Conclusions 320References 321

CHAPTER 12

FibratesA. GAW, C.J. PACKARD, and J. SHEPHERD. With 2 Figures 325

A. Introduction 325I. Clinical Use 325

II. History and Development 325III. Helsinki Heart Study 327

B. Comparative Pharmacology of the Fibrates 327I. Clofibrate 327

II. Bezafibrate 328III. Ciprofibrate 328IV. Fenofibrate 329V. Gemfibrozil 329

C. Mechanism of Action 329I. Effects on Very Low-Density Lipoprotein Metabolism 336

II. Effects on Chylomicron Metabolism 336III. Effects on Low-Density Lipoprotein Metabolism 336IV. Effects on Low-Density Lipoprotein Composition and

Subfraction Profile 337

Contents XIX

V. Effects on Cholesterol Synthesis 338VI. Effects on High-Density Lipoprotein Metabolism 339

D. Toxicology 340I. Hepatomegaly and Carcinogenicity 340

II. Bile Lithogenicity 340E. Adverse Clinical Effects 341

I. Side Effects 341II. Drug Interactions 342

F. Special Uses 342I. Combination Therapy 342

II. Paediatric Use of the Fibrates 343G. Conclusions 343References 344

CHAPTER 13

Nicotinic Acid and DerivativesA.G. OLSSON. With 18 Figures 349

A. Introduction 349B. The Vitamin 350

I. Biochemistry and Requirements 350II. Mechanism of Action 351

III. Deficiency 352C. The Drug 352

I. Pharmacology 352II. Effects in Lipid Metabolism 353

1. Free Fatty Acid Metabolism 353a) Extracellular Metabolism 353b) Intracellular Metabolism 354

2. Plasma Lipoprotein Metabolism 356a) Very Low-Density Lipoproteins and their

Subtractions 356b) Low-Density Lipoprotein Concentrations and

Subfractions 357c) Apolipoprotein B, C, and E 358d) Kinetic Studies of Apolipoprotein B-Containing

Lipoproteins 359e) High-Density Lipoprotein Concentrations and

Subfractions 361f) Lipoprotein Lp(a) 365g) Postprandial Lipaemia 366

3. Enzyme Activities and Receptor Functions in LipidMetabolism 367a) Hormone-Sensitive Lipase 367b) Lipoprotein Lipase and Plasma Triglyceride Removal 367

XX Contents

c) Hepatic Lipase 367d) Other Enzymes and Receptors in Lipid Metabolism... 368

4. Biliary Lipid Metabolism and Cholesterol Balance 3685. Summary of the Mechanism of Hypolipidaemic Action of

Nicotinic Acid 3706. Prostanoid Metabolism 372

III. Effects on Glucose Metabolism . 3721. Basal Mechanisms 3722. Non-Insulin-Dependent Diabetes in Man 374

a) Short-Term Studies 374b) Long-Term Studies 375

3. Differences Between Nicotinic Acid Derivatives 3764. Conclusions About Effects on Glucose Metabolism 377

D. Clinical Approach 377I. Side Effects 377

1. Flushing 378a) Symptoms 378b) Preventing Flushing 378

2. Gastrointestinal Side Effects 3783. Hepatic Side Effects 3794. Cutaneous Side Effects 3795. Lactacidosis 3796. Gout 3807. Retinal Edema 3808. Time-Release Nicotinic Acid 380

II. Laboratory Safety Tests 381III. Start of Treatment 381

1. Fast Dosage Increase 3822. Slow Dosage Increase 382

IV. Treatment Compliance 382V. Combinations with Other Plasma Lipid-Lowering Drugs . . . . 382

1. Nicotinic Acid and Bile Acid Sequestrants 383a) Nicotinic Acid and Colestipol 383b) Acipimox and Cholestyramine 383c) Nicotinic Acid and Lovastatin 384

VI. Recommendations for Drug Treatment 3851. Policy Statement of the European Atherosclerosis

Society 3852. The National Cholesterol Education Program 385

E. Clinical Effects 385I. Coronary and Femoral Artery Disease 385

1. Mortality and Morbidity 385a) The Coronary Drug Project (CDP) 385b) The Stockholm Ischaemic Heart Disease Study 387

2. Regression of Atherosclerosis 388

Contents XXI

a) Coronary Atherosclerosis 388b) Femoral Atherosclerosis 392

3. Conclusion on the Effect of Nicotinic Acid onAtherosclerosis 393

II. Dementia 393F. General Conclusions 394References 394

CHAPTER 14

Ion Exchange ResinsP. SCHWANDT and W.O. RICHTER. With 5 Figures 401

A. Introduction 401B. Chemistry and Pharmacology 401C. Mode of Action 403D. Clinical Experience 405E. Pharmacodynamic and Pharmacokinetic Parameters 407F. Drug Interactions 409G. Adverse Effects of Resins 411H. Other Indications 412I. Children and Adolescents 413J. Combined Drug Treatment with Resins 413

I. Bile Acid Sequestrants and Cholesterol Synthesis EnzymeInhibitors 413

II. Bile Acid Sequestrants and Nicotinic Acid or Analog 414HI. Bile Acid Sequestrants plus Fibrates 416IV. Bile Acid Sequestrants plus Probucol 417V. Triple Drug Therapy 418

References 418

CHAPTER 15

ProbucolJ. DAVIGNON. With 7 Figures 429

A. Introduction 429B. Chemistry, Physical Properties, and Dosage 429C. Absorption, Metabolism, and Excretion 431D. Effects on Plasma Lipids, Lipoproteins, and Apolipoproteins 432

I. Cholesterol and Low-Density Lipoproteins 432II. High-Density Lipoproteins and Reverse Cholesterol

Transport , . . . 432III. Apolipoproteins, Lipoprotein Composition, and Enzymes . . . 435IV. Effect of Combination Therapy with Probucol 437

E. Antioxidant Properties and Antiatherogenic Effects 439

XXII Contents

I. Effect on Low-Density Lipoprotein 4391. In Vitro Studies 4392. In Vivo Studies 443

a) The Watanabe Heritable Hyperlipidemic Rabbit 443b) Other Animal Models 445

3. Studies in Man 446II. Studies with Lipoprotein (a) 446

F. Mechanisms of Action 447I. Mechanism of Low-Density Lipoprotein-Lowering Effect . . . 447

II. Mechanism of High-Density Lipoprotein-Lowering Effect... 449III. Antioxidant Effect 451

G. Side Effects, Safety, Tolerance, and Drug Interactions 452H. Other Properties and Use of Probucol in Specific Diseases 453

I. Anti-inflammatory Effect 453II. Probucol and Diabetes 454

III. Probucol and Renal Disease 456IV. Probucol and the Heart 457

I. Conclusions 458References 459

CHAPTER 16

Miscellaneous Lipid-Lowering DrugsK.J. LACKNER and E. VON HODENBERG. With 1 Figure 471

A. Introduction 471B. /?-Sitosterol ~. 473

I. Chemistry, Physical Properties, and Dosage Form 473II. Absorption, Metabolism, and Excretion 474

III. Effects on Plasma Lipids and Lipoproteins 4751. Treatment with /?-Sisterol Alone 4752. Combined Drug Treatment 476

IV. Mechanisms of Action 477V. Side Effects, Safety, Tolerance, and Drug Interactions 477

VI. Conclusions 478C. Neomycin 479

I. Chemistry, Physical Properties, and Dosage Form 479II. Absorption, Metabolism, and Excretion 480

HI. Effects on Plasma Lipids and Lipoproteins 4801. Treatment with Neomycin Alone 4802. Combined Drug Treatment 481

a) Neomycin and Niacin 481b) Neomycin and Cholestyramine 481c) Neomycin and Clofibrate 481d) Neomycin and Lovastatin 482

Contents XXIII

IV. Mechanisms of Action 482V. Side Effects, Safety, Tolerance, and Drug Interactions 483

VI. Conclusions 484D. Ketoconazole 484E. D-Thyroxine 487References 487

Subject Index 493