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

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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

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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

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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].

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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